JP2004538087A - Patient temperature control system and method using temperature planning algorithm - Google Patents

Abstract

The present invention relates to a temperature control system for a human body, and uses an indwelling catheter having a heat transfer element mounted at a distal end. The catheter is fluidly connected to the console, which supplies a heating / cooling working fluid to exchange heat with the heat transfer element to heat / cool the blood. The heated / cooled blood then heats / cools the patient's body or selected organs. In particular, the software-equipped device and method manages cooling, reheating, and control based on a target control temperature measured by a temperature sensor in the catheter.

Description

【０４６７】
ここでＰ_catherterは抽出パワーであり、Ｍは作動流体の流速であり、Ｃ_fは作動流体の熱容量であり、ΔＴはカテーテルに入る作動流体とカテーテルから出る作動流体の温度差である。したがってＰ_catherterは循環流体の重量とカテーテルに入る作動流体とカテーテルから出る作動流体の温度差を測定することにより容易に計算できる。カテーテルにより除かれるパワーは患者の身体により失われるパワーに近似する。
【０４６８】
一般に温度Ｔの身体をＴ₀に冷却（または加熱）するのに必要なパワーＰについての閉形解は知られていない。ひとつの近似は指数関係の仮定である。
【０４６９】
【数２】

【０４７０】
温度について各側の導関数をとると、
【０４７１】
【数３】

【０４７２】
各側の逆元をとると
【０４７３】
【数４】

【０４７４】
または
【０４７５】
【数５】

【０４７６】
ここでΔＴは名目温度からの温度差であり、ΔＰは測定パワーである。該関係が線型であると仮定することにより近似が得られる。同等にパワーシリーズ拡大がとられて、線型タームが保持される。いずれにしても積分、線型関係、再配列：
【０４７７】
【数６】

【０４７８】
ここで比例性の定数はワット／℃のユニットを有しており、治療中にＴとＰとが不定であり既知である２個の点を使って定数αを決定できる。ひとつはいつ治療が始められたか（いつ患者が温度Ｔを持ちカテーテルがパワーＰを抽出したか）である。他の点はＴ＝Ｔ₀、Ｐ＝Ｐ₀の時に得られる。するといずれのＰ、Ｔは次の式で得られる。
【０４７９】
【数７】

【０４８０】
この一例を図５６に流れ図で示す。病院などにいる患者が発熱する（ステップ４８０）。一般に患者は入院が必要な病気などの結果発熱するもので、例えばＩＣＵ内の患者はほとんどが発熱を呈する。
【０４８１】
伝熱要素を載せたカテーテルが挿入され（ステップ４８２）、初期パワーＰ_startが抽出されて体温Ｔ_startが測定され（ステップ４８４）、治療が開始される（ステップ４８６）。治療は続き（ステップ４８８）、ＰとＴとが周期的、連続的に測定される（ステップ４９０）。測定されたＴが通常約３７℃である正常体温Ｔ＝Ｔ₀と比較される（ステップ４９２）。ＴがＴ₀より大なら治療が続けられ（ステップ４８８）、ＴがＴ₀より小さいとＴ＝Ｔ₀においてパワーＰ₀が測定される（ステップ４９４）。
【０４８２】
上記したような等式によりＴ_start、Ｐ_start、Ｐ₀、Ｔ₀から比例性定数αが決定され（ステップ４９６）、αからＴ_start、Ｐ_start、Ｐ₀、Ｔ_{0 、}Ｔ_{absence of cooling}を決定できる（ステップ４９８）。ついでＴ_{absence of cooling}がＴ₀と比較される（ステップ５００）。Ｔ_{absence of cooling}＞Ｔ₀なら患者は治療が中断されたら発熱を呈する新陳代謝によりまだ充分なパワーを発生しており、治療が続けられる（ステップ５０２）。Ｔ_{absence of cooling}＜＝Ｔ₀ならば患者は治療が中断されたら発熱を呈す新陳代謝により最早充分なパワーを発生せず、治療が中断される（ステップ５０４）。以上では種々の変更が可能である。
【０４８３】
この発明のマニフォルドを図５７中に５０６で示す。マニフォルド５０６は末端５０８において種々の目的で流体を循環させる３個の管腔カテーテル１０４に連結されている。この発明に関しては患者を冷却または加熱するために流体が循環される熱伝導カテーテルについて記載する。歪み開放スリーブ５１４がマニフォルド５０６の末端５０８近くにカテーテル５１２が捩じれるのを防止する。
【０４８４】
図５８に示す３個のカテーテル５１２は外管５３０、中間管５３８、内管５３４を有しており、カテーテルは管５３４の内面により画定されるガイドワイヤー空間または管腔５４０を有している。外環状管腔５４２は外管５３０の内面と中間管腔５３８の外面との間に画定される。内環状管腔５３６は中間管５３８の内面と内管５３４の外面との間に画定される。
【０４８５】
作用中、カテーテル５１２が一旦位置決めされると、サリンなどの水性溶液がカテーテルを通って循環して、内環状管腔５３６に流れ、カテーテルの末端において該管腔を出て外環状管腔５４２に入る。カテーテルが熱伝導のために用いられている場合には高伝導性材料から形成して、外面の温度が作動流体の温度に近づくようにする。管腔５３６中の作動流体からの熱エネルギーのロスを回避すべく、カテーテル５１２中に断熱層を入れる。ある場合には接触により熱が直接身体に与えられる部分は別として、管腔５４２に断熱処理する。
【０４８６】
図５７においてマニフォルド５０６は第１のマニフォルド５１８を有しており、これがポート５２４を経て管腔５３６へのアクセスを与える。またマニフォルド５０６の第２のマニフォルド５１６はポート５２２を経て管腔５４２へのアクセスを与える。第１のマニフォルド５１８はまたガイドワイヤー入口ポート５２６を有しており、これがガイドワイヤーのために管腔５４０へのアクセスを与える（図示せず）。装填されるとガイドワイヤーはマニフォルドを通って中央軸５２１を流れる。ポート５２６は傾斜付きとして障害を招くことなく挿入できるようにする。第１マニフォルド５１８の基端にはルアーフィッティング５２０がある。
【０４８７】
コンソール。図５９の熱伝導カテーテルシステム５４４は熱伝導カテーテル５４６、制御システム５４８、制御システムに収容された循環セット５５０を有している。制御システムには出力ディスプレー５５２と入力キー５５４とを装備して使用者と制御システムとの相互作用を容易にする。制御ユニットケース５５８にフード５５６を軸承して循環セットをカバーする。
【０４８８】
図６０、６１のカテーテル５６８は患者の身体または器官の温度の血管内調節をできる低体温法カテーテルであってもよい。該カテーテルの伝熱要素５６２は末端に位置しており、供給管腔５６４と復流管腔５６６とを有し、両管腔の末端は伝熱要素の末端部で終わり、基端は供給管腔ポート５７０で終わり、復流管腔はカテーテルハンドル５７３中で終わる。
【０４８９】
伝熱要素５６２は患者の血管中に配置されて伝熱要素に沿って流れる周りの血液と熱の授受を行い、患者の身体または器官の温度調節を行う。同様にして伝熱要素は組織中で使われて組織との間で熱の授受を行うこともできる。後者の場合、熱を配るのは主として伝導による。
【０４９０】
熱伝導カテーテル５６８を脳の冷却に使うこともあり、器官または全身の冷却・加熱により温度調節を行う。頚動脈は頭部と脳とに血液を供給する。内頚動脈は頚動脈から分枝して前脳に血液を供給する。伝熱要素５６２は大腿動脈または他の血管経路を経て頚動脈または頚動脈と内頚動脈の両方に配置される。循環セット５５０により供給、冷却、循環された熱伝導流体は伝熱要素をして頚動脈または内頚動脈から熱を引き出させる。これにより脳を冷却して身体障害の脳への影響を低減する。
【０４９１】
カテーテル５６８が伝熱要素５６２を有していると述べたが、上記以外のタイプの伝熱要素でも使える。循環セットが熱伝導カテーテルに関連して説明されたが、低体温法または熱伝導カテーテル以外のカテーテルと関連して使える。循環セットはカテーテル内に流体を供給および／または循環するカテーテルとも一緒に使える。
【０４９２】
循環セット。図５９、６２に示す循環セット５５０は流体貯留器５７４、ポンプ５７６、フィルター５７８、熱交換器５８０、温度圧力センサーユニット５８４、供給ライン５８６、復流ライン５８８の１以上を有している。供給管腔ポート５７０と復流管腔部分は循環セット５５０の供給・復流ラインに接続されている。供給・復流ラインは１片以上の管、コネクターなどを有して、セット５５０の構成要素をポート５７０、５７２に接続するようにするのが望ましい。循環セットは供給し、濾過し、循環し、さらにカテーテル５４６のために熱伝導流体の温度・圧力をモニターする。以下にこれを詳記する。
【０４９３】
流体貯留器。流体貯留器６０は改良２５０ｍｌＰＶＣＩＶバッグである。流体貯留器５７４はサリン、フレオン、パーフルオロカーボンなどの作動流体を充填できる。作動流体が手術室内の他の電子機器とＥＭＩ干渉を起こすのを防止すべく、作動流体は非イオン性流体であるのが望ましい、つまりＤ５Ｗ、１．５％グリセリンを含んだＤ５Ｗ、ソルビトール−マニトール、リンゲル溶液などである。
【０４９４】
流体貯留器５７４はシステム５４４のライン５８６、５８８、管腔５６４、５６６を優先するのに使われ、供給または入口管５９０を有し、該管は入口５９２において復流管腔５８８と反対側の端部または出口５９４において貯留器の入口５９６と連通する。また貯留器は復流または出口管５９８を有し、該管は一端で供給ライン５８６と他端または入口６０２において貯留器の内側５９６と連通する。
【０４９５】
貯留器５７４はシステム５４４から空気を追放、排気または除去するメカニズム６０４を有しており、該メカニズムはライン５８６、５８８、管腔５６４、５６６から空気を除去するのに用いられ、ポリカーボネート抜きスパイク６０８を具えた無針ポリカーボネート弁６０６を有している。システム５４４からの空気の除去はシステム５４４内の圧力の最大化と伝熱要素５６２の熱伝導の最大化とカテーテルの破損による血液への空気の侵入予防に重要である。
【０４９６】
供給管５９０の出口５９４は復流管５９８の入口６０２よりメカニズム６０４の近く、またはメカニズム６０４近くに位置して、管５９８により供給される気泡が、メカニズム６０４により除去されずに、復流管５９８に直接入るのを抑制する。抜気サイクルについて以下に詳記する。
【０４９７】
流体貯留器は作動流体を再循環なしにシステム５４４に供給し、ここでは供給管５９０とメカニズム６０４とは有してない。メカニズム６０４は循環セット５５０内において貯留器５７４外側に配置されている。ポンプ５７６は使捨て式でもよく、プラスチックマイクロポンプは使用後他の使捨て部品と一緒に捨てられる。ポンプ５７６は熱伝導流体を貯留器から引き抜き流体をライン５８６、５８８、管腔５６４、５６６に循環させるのに用いられる。ポンプは使捨て式でなくともよい。
【０４９８】
フィルター。フィルター５７８は雄雌容器に収容された５μフィルターであるのが望ましく、循環熱伝導流体から不純物を除く。循環セット５５０、は１個以上のフィルターを有してもよくまたはフィルターはセットの部品の一部であってもよい。
【０４９９】
熱交換器。図５９、６２において熱交換器５８０はステンレス製管５８２であって、ガルデンまたはエチレングリコールなどのバイオ相容性の流体である第２熱伝導流体槽５６０中に配置され、この例では管５８２は熱伝導流体中に配置されている。第２熱交換器（図示せず）は制御ユニット容器５５８中に配置されて槽５６０中の温度を調節してシステム５４４中の熱伝導流体の温度を制御する。熱交換器は再生可能の非使捨て式湿式熱交換器である。
【０５００】
図６３〜６６において使捨て式熱交換器体６１２を有する乾式熱交換器６１０が循環セット５５０中に用いられ、熱交換器体６１２はモルド体６１４、６１６中に取外し可能に固定されており、熱交換器モルド体６１４、６１６は熱可塑性絶縁材料から形成されて蛇行溝６１８を有している。該溝の一端は入口溝６２０で終わり他端は出口溝６２２で終わっている。出入り口溝は熱交換器体６１２の出入口管６２６、６２８と供給ライン５８６への接続のための対応する管（図示せず）を収容する。
【０５０１】
熱交換器モルド体６１４、６１６は１個以上の出入口を有してもよい。各モルド体は溝６１８の代わりに１以上の凹部を有してもよく、該凹部は熱交換流体が流過する貯留器を構成している。第１、２熱交換面６２４、６３２がモルド体の内面に位置しており、該面は打抜きステンレス製片であって、モルド体の内面に結合されてその間に熱交換路６３４（図６４）を構成している。該面は蛇行溝６３６を有しているのが望ましく、各溝は他の形状であってもよい。該面は熱交換器体６１２を熱交換路を流れる熱交換流体から絶縁して熱交換器を「乾」式にし、エチルアルコールなどの流体が熱交換器体の外面に接触しないようにする。
【０５０２】
熱交換器体６１２はＩＶバッグから形成して、バッグ体６３０に溶接された出入口管６２８、６２６を有しているのが望ましい。
【０５０３】
使用に際しては、熱交換器６１０はモルド体６１４、６１６を分離することにより開かれ、熱交換器体６１２がその間に置かれ、両モルド体を一緒にすることにより熱交換器が閉じられる。熱交換器が閉じられると熱交換器体が溝６３６の形状に倣い、対応する蛇行流路６３８を熱交換器体中に形成する。作動流体が該流路を流れると熱伝導流体と熱交換器表面６２４、６３２との間の熱伝導により該面と流路中の流体との間で熱伝導が起きる。使用後熱交換器体はモルド体６１４、６１６を分離することにより開かれて、循環セット中の他の使捨て部品とともに廃棄される。
【０５０４】
液体に接触しないので熱交換器６１０は乾式であり、液槽中に配置されるコイル式熱交換器５８０ほど使い難いことはない。熱交換器体６１２は安価なので使用後は捨ててもよい。また２個の熱交換器を「二階建てバス」状に相互に重ねて共通の熱交換器モルド体を使うようにしてもよい。熱交換器６１０は蛇行状などの通路を内蔵したバッグを具えてもよく、蛇行状などのステンレス製管を具えてもよい。
【０５０５】
温度・圧力センサー。図６７〜７０の温度・圧力センサー５８４は供給ライン５８６中の熱伝導流体がカテーテル５６８に入る前にその温度と圧力を測定し、かつ復流ライン５８８中の熱伝導流体がカテーテルを離れた後にその流体の温度と圧力とを測定するのに使われる。カテーテルを通過する流体の圧力とカテーテルの伝熱要素５６２で起きる熱伝導を決定するためにこの測定は重要である。カテーテルを通過する作動流体の圧力または速度を最大にすることにより伝熱要素の加熱または冷却効率を最適化できる。
【０５０６】
温度・圧力センサー５８４は温度または圧力だけを測定するのにも使用でき、さらに作動流体の他の物理的特性値も測定できる。温度・圧力センサー５８４は２個の主要な要素として、多用、固定、非使捨て式温度・圧力センサー電子体６４０と単用、使捨て式温度・圧力センサーブロック体６４２とを有している。図６７〜６８において温度・圧力センサー電子体６４０は基体６４４、ピン６４８によりこれに軸承されたラッチ６４６を有しており、基体は上面６６４とスカート６６６とを有している。上面とスカートとはブロック体の収容領域６６８を画定している。基体は第１、２の圧力トランスジューサー６７４、６７６を収容する第１、２の圧力トランスジューサー孔６７０、６７２と第１、２の熱電対６８２、６８４を収容する第１、２の熱電対孔６７８、６８０を有している。
【０５０７】
圧力トランスジューサーと熱電対とは基体下面の電子回路に接続されており、該回路は制御システム５４８に接続されている。基体の傾斜面６５０は肩部６５２で終わっている。ラッチのキャッチ部６５４は外側に偏移されて、ラッチが基体に軸承されると、肩部に係合する。ラッチの解放体６５６は使用者が指で操作してキャッチ部６５４を肩部から外す。
【０５０８】
図６９、７０の温度・圧力センサーブロック体６４２のポリカーボネート基体６５８は第１、２管腔６６０、６６２を有しており、該管腔は第１、２圧力トランスジューサーウエル６９８、７００（図６９）および第１、２熱電対ウエル７０２、７０４と連通している。ウエル６９８、７００の中央孔７０６は管腔６６０、６６２、内環状隆起部７０８、外環状凹部７１０、環状壁７１２とを有している。ウエル７０２、７０４の中央孔７１４は管腔６６０、６６２、内環状凹部７１６、外環状隆起部７１８、環状壁７２０と連通している。
【０５０９】
圧力トランスジューサーウエル６９８、７００は外環状凹部７１０上に固定されたＯリングシール６８６、該シールに固定された圧力センサーダイアフラム６８８、内環状隆起部７０８、環状壁７１２に固定された圧力センサーブッシュ６９０をダイアフラムの上に有している。各熱電対ウエル７０２、７０４は凹部７１６に固定されたＯリングシール６９２、該シールに固定されて中央孔７１４中に延在しているセンサー接続管６９４、環状壁７２０に固定された温度センサーブッシュ６９６をセンサー接続管の上に有している。
【０５１０】
温度・圧力センサー５８４はブロック体６４２を電子体６４０に適合させることにより組み合わされ、トランスジューサー６７４、６７６と熱電対６８２、６８４が対応するトランスジューサーウエル６９８、７００と熱電対ウエル７０２、７９４と会合する。ラッチ６４６がついでロック部分に軸承され、キャッチ部分６５４が基体６４４の肩部６５２に係合する。これによりブロック体６４２が電子体６４０に錠止される。
【０５１１】
循環セット５５０またはそれを使った作業１回が終わると、ブロック体６４２が電子体から外され廃棄されるの望ましい。これには解放体６５６を引いてキャッチ部を肩部から外してやる。ブロック体は他の使捨て部品と一緒に廃棄されて、再使用可能な部品は電子体だけとなる。上記したブロック体の構造により製造は安価であり使捨てでき、電子体は他の部品の汚染なく再使用できる。
【０５１２】
空気追放メカニズム６０４はシステム５４４のライン５８６、５８８および管腔５６４、５６６から空気を抜く。この抜気はシステム中の圧力を最大にし、伝熱要素５６２における熱伝導を最大にし、患者の血流への空気の侵入を低減する。メカニズム６０４はシステム５４４の各使用前の追放段階で使用され、追放段階は使用されているカテーテルの識別とシステム問題の早期発見に重要である。
【０５１３】
図７１、７２に示す方法においては、循環セット中における圧力を読んで循環セット５５０に接続されたカテーテルの自動識別またはカテーテルの伝熱要素の自動識別を行うものである。図７１においてポンプモータ速度対追放、アイドルの関係およびカテーテルシステム５４４の作動サイクルを示すものであり、モーター速度はシステム５４４における流速を示す。追放作業において、流速ははっきりしたステップで徐々に増加する。
【０５１４】
図７２において各カテーテル（１０Ｆ、１４Ｆなど）またはカテーテルに接続されている伝熱要素は特有の流れ抵抗、すなわち圧力対流れ反応を有している。追放サイクルにおいてカテーテル５６８の入口圧力とポンプ速度が測定されると、測定データ点を通って斜線が引け傾斜が計算される。図７２には循環セット５５９に取り付けられた１０Ｆと１４Ｆカテーテルについての斜線を示している。循環セット５４８と一緒に使用されたカテーテルまたはカテーテルの伝熱要素は斜線を経験的に得られた同様な斜線のリストと比較することにより自動的に識別できる。
【０５１５】
カテーテルが使われていることを自動的に識別した後、カテーテル５６８の作業のために対応する適切なパラメータを制御システム２６が与える。計算された傾斜が基準カテーテルのそれに合致しない場合には、該傾斜を使ってシステム５４４中に流体漏洩などの問題が起きたか否かを決定する。
【０５１６】
システムにより行われる熱治療の閉回路制御は治療が施される患者の状態を示す温度信号をフィードバックする必要があり、この信号は治療の目標温度と一緒にＰＩＤタイプ制御アルゴリズムにエラー入力されて患者に供給・除去されるエネルギーを調節する。
【０５１７】
そのようなシステムにあっては、サーボ利得を設定してほぼ０．２Ｃサーボエラーで最大システムパワーを配る。集積・引出し期間についてゼロ係数を有するＰＩＤ制御器がで０％（サーボエラー＝０Ｃ）〜１００％（サーボエラー＝０．２Ｃ以上）パワーで比例線型駆動信号を与える。
【０５１８】
このフィードバック信号取得のための正しい生理学的な部位の選択は治療の成功に重要である。システムにより誘発される熱的変化は患者の芯に直接適用されるので、制御信号は中心成分の熱的状態（温度）を表わすのが望ましい。現在の治療上受容されている温度モニター作業では、芯温度は食道、鼻道、鼓膜、嚢、直腸プローブにより得られる。
【０５１９】
これらはいずれも環境と平衡状態にある（急激な温度変化に曝されてなければ）患者の温度を表わすものであるが、嚢や直腸温度などは急速な芯温度変化間隔中の芯の反応を遅らせる。加えて食道、鼻道、鼓膜プローブは重沈静患者に使用できるが、不快であるか軽沈静または意識のある患者には実務的ではない。ある場合には末端食道中での温度モニターが芯体温モニターに適切であり、低体温法の誘発・保持の制御のためのフィードバック信号を与える。しかし患者によっては鼓動およびＡＭＩ患者を含む、食道温度モニターは患者が意識があるので実務的ではない。
【０５２０】
鼓室や嚢などの他のモニター部位も使える。しかしそのようなモニター部位でも理想的ではない。例えば鼓室温度プローブは患者を不快にしてモニター中に引張り出される。これが起きると、室温で患者温度が既に低体温法であると測定されて、システムは止まってしまう。嚢温度プローブはリアルタイムで芯で起きている動的な温度変化を表わさない。顕著な時間遅れがあり（２０〜４０分の遅延）１〜２℃の影響で真の芯温度を表わさないのである。
【０５２１】
意識のある患者において低体温法を誘発・制御するには過度に侵害的でない信頼性がある正確なモニター部位が必要とされる。スワンガンツ肺動脈カテーテル中に配置される肺動脈（ＰＡ）温度センサーは信頼性のあるモニター部位であるが、これは鼓動患者には示されない他の侵害的なカテーテル処置を必要とする。これに代えて中枢神経カテーテルは右心房に入る血液の温度を測定できるが、あまりに侵害的である。
【０５２２】
カテーテル内部に取り付けられたセンサーは別個の侵害的温度プローブを必要とせずにこのような問題に対処できてカテーテルのＩＶＣ中での中心配置の故に正確な制御温度測定を確約する。手術中にカテーテル内および外部環境の温度は一般に１０〜４０℃異なるので、カテーテル中での加熱・冷却熱伝導流体の存在の故に、サーミスターなどのカテーテル搭載プローブからの正確な制御温度取得に際しては、熱伝導流体を止めて治療を一時的に中断することになる。
【０５２３】
流体が止められた後、カテーテルと環境との熱的平衡または緩和の前には不定の期間が経過する。制御温度取得のための治療の中断は制御器の精度を損ねる。予測的なアルゴリズムが開発されて有用な制御温度の計算を可能とし、完全な平衡と患者芯温度の測定を必要としないようになった。平衡温度の予測方法は緩和履歴の仮定関数に基づいたものである。コンソールに復流するカテーテル「冷却剤」の温度を測定することによりカテーテル熱交換器により分配・消費されたパワーを決定・推定できる。例えば
【０５２４】
【数８】

【０５２５】
このパワーは患者の温度により直接影響され、温芯温度の方が冷芯温度よりも少ないパワーが分配される。一般に分配されるパワーは患者の血液温度と熱交換器の温度との間の温度勾配に比例する。
【０５２６】
【数９】

【０５２７】
患者温度３７〜３３℃から行くことによりパワーはほぼ下記だけ低くなる。
【０５２８】
【数１０】

【０５２９】
カテーテルにより供給・吸収されたパワーの増減をモニターすることにより、有用な制御温度または少なくとも血液温度を間接に推定することができる。出発患者温度（例えばＩＲ耳温度計により医師は患者温度に相当する値を入力できる）を知り所望の患者温度においてプログラムすることにより、装置は患者を冷却・加熱することができる。復流温度変化をモニターすることにより、装置は所望の低体温法状態に制御できる。
【０５３０】
図７６のコンソール７５０は両方向のカテーテル「冷却剤」または作動流体の温度を測定できる、つまりカテーテルに供給される流体７５２の温度Ｔ_Sおよびカテーテルから復流する流体７５４の温度Ｔ_Rである。この温度は例えば使捨て式循環セットを仲介しているサーミスターピンなどによりコンソール７５０で測定できる。該温度（つまりカテーテル冷却剤復流温度）を測定する他の方法としては、温度センサー７５６を復流管腔７６０中の伝熱要素７５８中に配置する。これにより温度測定は一段と正確になる。
【０５３１】
ＨＴＥ７６２においてカテーテル中の冷却剤復流温度Ｔ_Rを測定することにより、血流に供給・吸収される瞬間パワーを測定できる。このパワーは実際の血液温度に比例する。冷却モードでは血液温度が減少するので、カテーテルに分配されるパワーは温度勾配が小さい故減少する。これは再温モードでも同じである。患者が加熱されると血流に分配されるパワーは少なくなり、この関係は下記のように近似される。
【０５３２】
【数１１】

【０５３３】
コンソール７５０はカテーテル７６２に分配・吸収される瞬間パワーを測定し、冷却・加熱が行われているときに分配されるパワーの変化をモニターすることにより、初期温度が既知ならば新たな制御温度を予想・推定することができる。したがって次の関係が存在する。
【０５３４】
【数１２】

【０５３５】
この関係から「カテーテルパワーの変化」が「血液温度の変化」関係に変わる。例えばこの期間中に血流が劇的に変わると、カテーテル熱交換器効率が変化する。高い心臓出力によりパワーの吸収・分配が多くなる。
【０５３６】
この効果を是正すべく、カテーテル冷却剤流れが止められＨＴＥが血液温度と平衡する。この平衡において、ＨＴＥ上の温度センサーが血液温度を測定している。この測定を使って未来血液温度予見についての推定を是正する。いかに頻繁にポンプを止めてリアルタイム血液温度予知を与えるアルゴリズムを再調整する必要があるかを決定する必要がある。ここでＴ_Sはカテーテルに入る冷却剤の温度であり、Ｔ_Rはカテーテルから復流する冷却剤の温度であり、Ｔ_Bはカテーテル中での冷却剤の流れを止めて間接に推定された血液温度である。
【０５３７】
この方法は「送り出し」状態と復流状態との間の血液温度を推定する。変数により推定レベルが決まってくる。第１にポンプを所定期間「止めて」ＨＴＥ周囲を流れる血液との平衡に達する。
【０５３８】
例えばＨＴＥ出口センサーが流れている血液と平衡温度に達するには６０〜１２０秒掛る。加えて推定アルゴリズムを使って安定状態温度を予見できる。例えば図７８において、カテーテル搭載サーミスターにより完全ポンプ動作時に測定された温度は時間ｔ＝０において例えば１０Ｃである。このときポンプが止められると、測定温度は曲線７６６に沿って平衡温度まで上がる。時間ｔ＝１でポンプが再駆動されると、温度は曲線７６８に沿って冷える。デューティサイクルは下記により定義される。
【０５３９】
【数１３】

【０５４０】
よいデューティサイクルは例えば９０％を超えるものであるが、これは予見アルゴリズムがポンプを止める時間を短縮できれば達成される。図７９に示す制御温度予見アルゴリズムによれば、温度測定を短時間ででき、ポンプの「停止」時間を短縮でき上記したようなサイクルを上げることができる。以下に患者温度を常にモニターする必要なしに患者温度を少なくとも所定時間に亙って変更する原理を示す。
【０５４１】
システムによる最大駆動期間の間患者芯温度は動くことができ、例えば平均冷却速度は５℃／ｈｒであり平均加熱速度は２℃／ｈｒである。これらの値を１０分保つと体温はつぎのように変化する。
【０５４２】
【数１４】

【０５４３】
この初期期間（１０分）の後、アルゴリズムは所望の目標値に近づくとより急速に試料採取をして、例えば患者の初期温度が３７℃、最終温度が３３℃で４℃の変化なら、装置は４℃芯温度変化を誘発するには最少で３０〜４５分が必要であると予見する。装置はかくして最大パワーで３０分冷却を開始し、ついで停止して温度をチェックする。
【０５４４】
設定点に近い温度では、試料採取はより頻繁となり、表Ｉに示す試料採取アルゴリズムにおいては、患者目標温度と目標制御または計画または測定血液温度の差が下がると、ポンプ停止頻度と測定温度とが変えられる。表ＩＩＩとＩＶに速度の詳細な分析を示す。
【０５４５】
ＨＴＥ内に配置された温度センサー。実験例１。図７７の「Ｔ」タイプなど熱電対７５６はカテーテルのＨＴＥ７６２（例えば１４ｆｒ．ＨＴＥ）の基端７６４に結合されており、システムを最大冷却段階にして、ＨＴＥ温度センサー７５６がほぼ１８℃の温度を測定している。循環ポンプを止めると、温度センサーの温度は３７．４℃まで指数曲線的に上がり、時間定数はほぼ１０〜２０秒である。時間の関数として読まれた実際の温度を表ＩＩに示す。ポンプを３０秒止めると、温度センサーは最終値の約０．３℃に近づき、ポンプを２０秒止めると、温度センサーは最終値を約０．７℃小さくする。
【０５４６】
予測アルゴリズム。時間定数の決定。反応の時間定数はＨＴＥ内の捕捉されたサリン量に比例し、２４ｃｍ１４ｆｒ．ＨＴＥはほぼ下記を含んでいる。
【０５４７】
【数１５】

【０５４８】
２４ｃｍ９ｆｒ．ＨＴＥはほぼ下記を含んでいる。
【０５４９】
【数１６】

【０５５０】
したがって９ｆｒ．二重要素ＨＴＥは下記となる。
【０５５１】
【数１７】

【０５５２】
かくして９ｆｒ．カテーテルについては、「ポンプ停止」時間はほぼ１０〜１５秒減少される。
【０５５３】
実験例。１．所望の「目標温度」、必要なら速度を入力する。２．ＨＴＥ温度センサーから温度＝Ｔ_p(o)を推定し、ポンプを例えば３０秒「停止」する。３．装置が「サーボエラー」を計算する。
【０５５４】
【数１８】

【０５５５】
４．Ｅ（Ｏ）のサイズ（表Ｖ）に応じて冷却・加熱の時間を決定する。５．加熱・冷却期間の終わりにポンプを停止する。６．ＨＴＥ温度センサーから例えば０．１秒採取速度で温度データを捕捉する。９ｆｒについてはデータの１５秒捕捉、１４ｆｒ．についてはデータの３０秒捕捉。７．制御温度と表示値を推定する。この値を温度制御サーボループに入力する。８．サーボエラー（表ＶＩ）に基づいてポンプを始動する。ここで下記のようになる。
【０５５６】
【数１９】

【０５５７】
これに代えてポンプパワーをサーボエラーに比例させてもよい。ポンプ停止前にシステムを駆動する時間の決定は下記のとおりであり、ここでＴ₀（ｔ）は初期患者温度、Ｔ_Tは目標温度であり、冷却・加熱の最大速度は下記による。
【０５５８】
【数２０】

【０５５９】
目標制御温度を決定するひとつのアプローチは下記の通りである。図８０に指数Ｔ（ｔ）を示す。領域Ａ１は最初の１０秒間はＴ（ｔ）であり、領域Ａ２は次の１０秒間はＴ（ｔ）である。仮定は下記のようになる。
【０５６０】
【数２１】

【０５６１】
Ａ１、Ａ２は数的に測定でき、これからＢを計算できる。参照を容易にすべく検索テーブルを作成できる（表ＶＩＩ）。図８１において各領域Ａ１、Ａ２は１２秒採取時間を含んでいる。検索テーブルからＢが決まったらＡは下記から計算できる。
【０５６２】
【数２２】

【０５６３】
訂正の大きさは下記により計算できる。
【０５６４】
【数２３】

【０５６５】
図８２においてＡ１、Ａ２は非等時間を含むが、下記のようになる。
【０５６６】
【数２４】

【０５６７】
Ａ１_{12 sec}＝Ａ２についてｘを得る。
【０５６８】
【数２５】

【０５６９】
あるＢについてｘを解いて検索テーブルを作成し、これが与えられたカテーテルについての可能な時間定数範囲を定める。上記の実施には図８３に示すような装置を用いる。温度センサー温度Ｔ（ｔ）はポンプが遮断（ステップ７６８）されたときにスイッチ７８０により測定される。０．１秒の採取間隔が示されているが、これは変更できる。
【０５７０】
Ａ１／Ａ２の計算が続き（ステップ７７０）さらに検索テーブルからＢが決定される（ステップ７７２）。Ａが次いで計算され（ステップ７７４）、これからΔＴつまり訂正ファクターが計算される（ステップ７７６）。目標温度Ｔ（ ）がついで決定される（ステップ７７８）。これらの量を図８４に示す。
【０５７１】
図８５に示す状態ダイアグラムのステップはシステムのパワーをオンとし（ステップ７３０）所望のデータ入力を行う。入力に際してはカテーテルサイズ、目標温度、冷却・加熱の時間または速度など入力される。カテーテルと付帯する循環セットが相互およびコンソールに接続される。
【０５７２】
ついでシステムが清掃されて（ステップ７３４）、「停止」モードにされ（ステップ７３６）、カテーテルが検査・挿入などされる。必要ならシステムは患者温度モードに入り、カテーテル搭載サーミスターが患者温度を決定する（ステップ７３８）。この場合数「Ｘ」秒の遅れが起き（ステップ７４０）、温度測定がされ、Ｙ秒に亙って平均化が行われる（ステップ７４４）。カテーテルサイズによってはＸは例えば０〜２４秒以上の範囲にある。Ｘに続いてＹの間種々の温度が測定されまたは決定される。Ｔ_HTE（ｔ）、Ｔ（ｔ）_CONTROL、Ｔ（ｔ）_MONITORなどがそれである。これらは例えば１０Ｈｚなどの周波数で取得されるのが望ましく、時間についての患者温度平均的傾向はＨＴＥの温度の平均的傾向により近似できる。
【０５７３】
【数２６】

【０５７４】
患者温度がついで例えば２秒間表示され（ステップ７４６）、ついで実行モードに入り（ステップ７４２）、患者は冷却・加熱される。サーボエラーが決定され（ステップ７４４）、一旦サーボエラーのサイズが決まったら、最大冷却・加熱モードで実行するのに安全な時間が決定される（ステップ７４８）。この時間の後システムポンプが停止されて、制御温度の突出モードに入る（ステップ７８２）。システムが停止され時間は例えば１５秒または３０秒などのような１０〜４５秒であり、突出温度は将来の計算の基となり、必要なら表示される。
【０５７５】
一例として低体温法の誘発時間の間ポンプはほぼ３〜５回に亙り各約１５〜３０秒停止されて新たな患者温度の推定が行われる。総冷却時間は平均冷却時間より数分長くなる。
【０５７６】
図８６は比較器スイッチを示すもので、スイッチ７８８を閉じると積分器７８４による領域Ａ１の積分が始まり、スイッチ７９０を閉じると積分器７８６による領域Ａ２の積分が始まる。
【０５７７】
異なる理論的なモードにあっては、内部流体流れが止まって直ぐのカテーテルの遷移挙動をモデル化すべく温度がＴ₀で安定な軸流体流れ（定常温度Ｔ_Cでシリンダーから離れた）中に浸漬された単純な（線対称の）円筒のシステムを考える。シリンダーの内部温度が時間とともに変化するが各長手方向部分で均一ならば、シリンダー中での温度の長手方向変化はシリンダーと周囲との間の温度差より小さいと仮定すると、シリンダーの各部における温度変化の時間速度は下記で与えられる。
【０５７８】
【数２７】

【０５７９】
ここでαはシリンダーと周囲流体の材料性質および外部流れ領域の運動力学に左右される定数である。この単純化された分析は、カテーテル搭載温度センサーからの遷移信号が形態の関数に相関することを示唆している。
【０５８０】
【数２８】

【０５８１】
ここでＴ_∞は平衡温度であり、Ｃは出発温度（無視できないノイズを有したデータの場合には必ず未知である）からのＴ_∞のオフセットであり、αはカテーテルと熱伝導流体の材料性質および外部周囲の運動力学により左右される。αの範囲が経験的に絞ることができるならば、一連の二元最少二乗法が関数に適合し、最新の制御信号がいつ要求されても、ｅｑ．２の形態はＴ_∞を決定するのに充分である。
【０５８２】
Ｔ_∞を決定すべく、カテーテル中の流体流れがまず止められ、小時間の後遷移運動が消滅し、埋設サーミスターからのｎ温度値Ｔ_iのシーケンスが速度１／Δｔで取得されるが、ここでΔｔは（定常な）隣接する試料間の時間間隔である。データＴ_iとｅｑ２の形態を有した関数への最少二乗法の直接な適用に起因する非線型システムを回避すべく、αが特定化されて、得られる２−Ｄ線型システムが解かれる。カテーテル挙動の生体内評価により特定のカテーテルサイズについて
【０５８３】
【数２９】

【０５８４】
とすることが可能だと仮定すると、温度データとｅｑ２形態関数との間のエラーは特定のαについて下記により定義される。
【０５８５】
【数３０】

【０５８６】
ここでα_min＜α_j＜α_maxである。実際ε（α）はα_jのシーケンスにおいてＴ_∞およびＣについて最少化され、ｅｑ３において特定された変域は下記のようになる。
【０５８７】
【数３１】

【０５８８】
得られた関数ε（α）の（εは特定のαについてのεの最小値を表わす）離散表現がｅｑ３において特定された変域中に独特な最小値を有している場合には、データＴ_iの仮定された関数形態との最善の適合を与える三つ組み（Ｔ_∞、Ｃ、α）はε（α）において最小値を伴うαの値により定義される。試料ｍの数は関数ε（α）の充分な解を与えるように選ぶ。各α_jについて最少エラーε（α_j）を与える対応するＴ_{∞ ,j}とＣ_jは２個の導関数を得ることにより求められる。
【０５８９】
【数３２】

【０５９０】
これは、ゼロにならなければならず、ｅｑ６を行列形態で示すと
【数３３】

【０５９１】
【数３４】

【０５９２】
【数３５】

【０５９３】
各Ｔ_∞とＣについて解を求めると下記になる。
【０５９４】
【数３６】

【０５９５】
一旦Ｔ_∞とＣが分かると、ε（α_j）はｅｑ４で計算され、最後にα（温度データとｅｑ２の形の関数との間の最少二乗エラーを生じる）と対応するＴ_∞とＣとが関数ε（α）の離散表現の最小値で定義される。
【０５９６】
関数ε（α）が特有の最小値を持たないならばまたはε（α）における最小値が特定の限界より大なら、上記したようなプロセスの結果は無視されて、埋設サーミスターの温度を外部の周囲と平衡させることにより平衡温度Ｔ_∞が得られる。システム識別アルゴリズムの失敗はカテーテルの配置が不適切であったことを示している（例えば最適αがα_minより小なら、カテーテルが適正な外部血流を持たず、これは配置がＩＶＣではなく分枝静脈であることを示している）。
【０５９７】
これに代えて、αが各治療期間に亙って定常であると仮定できないならば、制御信号の取得の各段階（「実行」コマンドに従った後の最初の段階を含む）をシステム識別として扱わなければならない（ここでαがＴ_∞とＣに加えて決定される）。ついで等式６におけるようにαが結合されたと仮定され、ついで特定された間隔Δα、Ｔ_∞、Ｃが計算されて、最少二乗法的に下記が最少化される。
【０５９８】
【数３７】

【０５９９】
等式ｅｑ６．ε（α）により定められる変域中の各α_jについて関数が定められ、ｅｑ６中の限界が正しく選ばれていれば該関数は等式６の変域中に最小値を得る。この最小値は時間定数αを定め、ついでＴ_∞とＣが少なくとも温度緩和データのｎを使った等式５に表わされる形の関数に最少二乗法的に最も適合する。関数εが比較的小さなΔαで計算されるならば、ε（α）の最小値は単純選別アルゴリズムにより求められる。これに代えて、二次形態が仮定されて最小値が分析的に求められる。この方法は、等式１５の追加的な評価に比べて、二次曲線の関係コストの故に速く実行され得る。
【０６００】
一次線型期間の追加。上記したような基本的指数モデルは埋設サーミスターが環境と平衡できる時間の間外部環境の温度（例えばＩＶＣ中の血液）が定常であるとの仮定に基づいている。一般に外部環境の温度はこの時間に亙っては定常ではない。
【０６０１】
カテーテルが作業している間（例えば冷却モードにある）、身体の種々の構成要素（体重当りの血流に基づいて識別される）または特定の血流は動的状態にあり、カテーテルにより除かれた熱はそれらの組織から優先的に来て、これについては特定の血流は最大である。カテーテル中の冷却剤流れが止まると、身体の構成要素は平衡しようとする。血流の高い組織は、身体の内部熱が再分布されるので、血流の低い組織より暖かい。熱の再分布は主として血液による対流移送により起きるので、カテーテル周囲の温度は構成要素が平衡に近づくと変わらなければならない。
【０６０２】
カテーテルが周囲と平衡する期間に亙ってカテーテル近くの血液温度は変化するが、該変化の関数形態は未知である。単純にするため体温変化中の時間スケールはカテーテル内の温度緩和に伴う時間スケールより大であると仮定される。体温変化はＴａｙｌｏｒシリーズで説明される。
【０６０３】
【数３８】

【０６０４】
ここでＴ_extは周囲の温度であり、ｔ＝０がカテーテルを通る熱流れが止まるときである。上記したような仮定により、埋設サーミスターから温度データが得られる時間Δｔは顕著な体温変化が起きる時間に比べて「小」である。外部温度の変化は簡単な線型関数により正確にモデル化される。外部環境の変化する温度をモデル化するためにｅｑ２の関数形に線型成分を付加するのは不合理的ではない。
【０６０５】
【数３９】

【０６０６】
ここでβはカテーテルによる熱伝導の停止後で身体中に起きる外部温度の変化の未知速度である。
【０６０７】
埋設サーミスターから得られる温度データへのｅｑ１２形態を使った最善適合関数の計算は単純三次元モデルについて説明したのと同じである。αには一連の値が仮定され、エラーについての得られる線型最少二乗問題は三つ組み（Ｔ_∞、Ｃ、β）について解かれる。解はαとそれに伴う最少二乗エラーが最少である（Ｔ_∞、Ｃ、β）の値として定義される。
【０６０８】
体温の高次変化。ｅｑ２、ｅｑ１２に与えられた仮定関数についての上記したような方法は基本指数モデルに加えた線型・非線型改良とともに種々の他の形態にも敷延できる。
【０６０９】
温度推定エラーと精度。所望のセット点または目標温度に制御するシステムの能力は冷却力、熱的撹乱の度合（下記する）、カテーテル内の温度測定精度、ポンプが止まったときの試料採取中の患者温度駆動力、推定アルゴリズムの精度により制約される。
【０６１０】
神経外科的な治療経験からすると、低体温法維持期間中に対流加熱毛布が使用された時でさえも、低体温法を３３℃に保つのに必要な冷却パワーはシステムの最大パワーの約２０％未満である。１００％パワーについての０．２Ｃのサーボゲインだと、２０％の負荷は２０％Ｘ０．２Ｃ＝０．０４Ｃエラーのサーボタイプ１オフセットを与える。１４ｆｒ能力約６５％を有する９ｆｒカテーテルについては、ほぼ３０％Ｘ０．２Ｃ＝０．０６Ｃの低体温法維持中にオフセットエラーを与える。鼓動と急性心筋梗塞の治療においては、維持中の安定状態負荷はほぼ同じ、つまり約０．０６Ｃオフセットであり、これは患者から熱を抽出して表面加熱による患者の維持された新陳代謝熱をバランスさせる必要があるからである。
【０６１１】
サーミスターの精度は３２〜４２℃の温度範囲で、１００％信頼度（４標準偏差）で例えば＋／−０．１Ｃの明細である。電子および信号プロセスは＋／−０．１Ｃ（９５％信頼度＝＋／−２Ｓ．Ｄ．）の明細で、初期調節、動的温度範囲、ドリフト、劣化考察をカバーする。ハードウエア温度チャンネルの調節がチェックされて必要なら例えば年毎に再調節する。サーミスターとハードウエア信号条件付けとプロセスの精度は患者温度のモニターのために病院手術室や集中治療設定に使われる市販入手できる使捨て式センサーと装置に匹敵するものである。
【０６１２】
温度センサーデータの採取期間中（９ｆｒならほぼ３０秒で１４ｆｒ装置ならほぼ６０秒）、保持された新陳代謝熱と熱抽出の中断の故に患者は再温できる。観測された再温最大速度は約１．５Ｃ／時間未満かほぼ０．０２５Ｃ／６０秒であった。
【０６１３】
最後のエラーの原因は温度推定アルゴリズムの１ステップ入力に対するセンサーの温度反応の最終値を予見できる能力である。採取時間を変化させて推定温度を実際温度に比較することにより、エラー感度分析が行われた。２０秒の採取点（「停止」モードにあるポンプの２４秒の合計）については、エラーの標準偏差は０．１Ｃであった。採取点を１５（ポンプ停止の１９秒の合計）に減らすとエラーの標準偏差は０．１８Ｃに増加した。採取点を２５（２９秒の合計）に増加すると標準偏差は０．７Ｃに減少した。時間対推定の精度の最適妥協のために２０採取点アルゴリズムが選ばれた。
【０６１４】
温度測定と推定精度は統計的に独立なエラーの原因である考えられる（表ＶＩＩＩ参照）種々の成分を含んでおり、これらのエラー原因を総合すると例えば約０．５１Ｃの最大予想エラーが得られる（９５％信頼度）。二乗平均エラー（つまりＲＭＳエラー）をとると、約０．２６Ｃである。
【０６１５】
潜在的熱的撹乱。閉回路サーボ制御器のひとつの目的は種々の負荷状態中に制御を維持できる充分な能力である。この能力は撹乱をなくする最大熱パワーとして表わされ、いかなる量のエネルギーが特定のサーボエラーの大きさに引き出されるか、サーボゲインとして定義され、制御安定性のためのフィートバック制御器中での意図的な遅延またはリード（ｌｅａｄ）を制御器の反応は有しても良い。
【０６１６】
熱的入力に対する患者の応答は数時間に亙って一般に遅いので、最適安定性のためには制御器中におけるさらなる量または相の補償は必要ない。ループ安定性の鍵となる成分はサーボゲインレベルであって、エラーの度Ｃ当り５００〜８００ワットの範囲に選択され、これに基づいてカテーテルが選ばれる。このサーボゲインレベルだと、最少安定状態サーボエラーとよい応答で、不安定の問題は少しか、ゼロになることを臨床実験は論証する。
【０６１７】
潜在熱撹乱は室温（冷）流体のＩＶ注入である。２０Ｃ流体の１．４ｍｌ／ｍｉｎ（２４時間当り２リットル）の定常注入速度についてこれは約２ワットの熱入力速度を表わす。この安定状態熱撹乱を修正するためにシステムはほぼ（２ワット）／（６００ワット／Ｃ）または０．００３Ｃのサーボエラーを発生する。２ワットはこの発明の範囲内にあるので、この撹乱はよく制御される。
【０６１８】
熱撹乱に対するさらなる挑戦は流体の急速塊薬注入である（例えば５分に２５０ｍｌ）。流体が体温に加熱されてないならば、５分間についての約７０ワットの等量エネルギー入力についてこれは２０Ｃで約１ｃｃ／ｓｅｃの注入速度を表わす。平均の患者（７０Ｋｇ）の体温を１℃下げるためには１時間について約７０〜８５ワット必要とする。５分塊薬は１℃の５／６０、０．０８３Ｃを下げる効果を有しており、この発明の制御する能力の範囲内である。
【０６１９】
実際の治療においては対流または電気加熱毛布が患者の快適さと震え抑制に使われ、毛布温度とどのくらい患者の身体を毛布と接触させるかが患者から室へのエネルギー伝導を決める。Ｓｅｓｓｌｅｒ他は毛布は２０〜５０ワットの環境への熱損失が毛布により防止されると推定した。５０ワット熱を保持するには現行のシステムではさらに５０ワットの冷却を抽出して熱的バランスを保持する必要がある。サーボエラーは５０ワット／６００ワット／Ｃ＝０．０８３Ｃに動きシステムの能力の範囲内にある。要約すると上記したような熱撹乱は目標温度を０．５Ｃ以内に保つ閉回路制御システムの能力の範囲内にある。
【０６２０】
制御アルゴリズムはカテーテルにより熱が身体から抽出される速度を制御するのに使われることもある。該アルゴリズムはハードウエア、ソフトウエアまたは組合せの形で実現される。該アルゴリズムにより使われるゲイン要因は冷却されている身体または器官の有効熱量により左右される。したがって有効熱量を定めるのが重要であって、これによりフィードバック制御アルゴリズムのために適切なゲイン要因が計算される。
【０６２１】
冷却されている身体の重量（全身または器官）はカテーテルにより除かれるパワーを身体により失われるパワーに関係付けることにより推定される。カテーテルにより除かれるパワーは下記により表わされる。
【０６２２】
【数４０】

【０６２３】
ここでＭはカテーテルを循環している流体の流量速度（ｃｃ／ｓ）であり、ｃ_fは流体の熱容量であり、ΔＴはカテーテルに出入りする作動流体の温度差である。該循環流体の流量と温度差を測定すればＰ_catheterは簡単に計算できる。等式（１）で決定されるカテーテルにより除かれるパワーは患者の身体により失われるパワーに等しい。
【０６２４】
【数４１】

【０６２５】
Ｐ_catheterは患者の身体により失われるパワーであって等式（１）により計算される値を有しており、ｍは冷却されている身体の有効熱量であり、Ｃ_bは身体の熱容量であり、∂Ｔ／∂ｔは冷却されている重量の時間当りの温度変化である。したがって冷却されている身体の有効熱量は下記のようになる。
【０６２６】
【数４２】

【０６２７】
等式（３）中の全ての変数は既知または測定可能であるので有効量を決定できる。かく計算された重量は有効熱量であって、パワーが除かれている身体の部分を表わし（つまり冷却されている部分）、等式（３）における温度変化は冷却されている身体部分の温度変化を表わす。例えば全身冷却ならば、芯体温の変化が測定されて等式（３）により重量が計算される。一般に全身冷却については、患者が血管収縮ならば有効量は全体重の約５０％を呈する。患者が血管拡張ならば有効量は全体重に近い。
【０６２８】
これに代えて脳などの選ばれた器官が冷却されるならば、等式（３）で使われる温度変化は器官の温度変化であり、該器官は身体の残りの部分から大きく熱的に絶縁されていると少なくともちょっとは仮定できる。この場合決定される有効量は器官の重量に匹敵する。選ばれた冷却されるべき器官が脳ならば、カテーテルは頚動脈中、内頚動脈または両方に配置される。等式（３）で使われた温度変化は温度センサーを脳に挿入するかまたは鼓膜センサーを介して測定される。いずれも市販入手可能である。
【０６２９】
実験例。動物において全身冷却を行うに際して、カテーテルを大腿静脈、下大静脈、右心房、上大静脈に挿入した。作動流体を流速５ｃｃ／ｓｅｃで循環させて冷却を開始し、カテーテルを出入りする流体の温度差は１７℃であった。カテーテルにより抽出されたパワーは３５４ワットであった。
【０６３０】
身体芯温度が食道を介して測定され、２０分後に冷却を開始し、芯温度の変化速度を約１０分間測定し、平均温度変化は約４℃／ｈｒであった。上記したような等式（３）から有効熱量はｍ＝３５４ワット／（．９６５ワット／ｋｇ・℃）（１０℃／ｈｒ）＝３７ｋｇであった。動物の全重量は５３ｋｇ、有効重量は全重量の６９％であった。
【０６３１】
プロセスによる再温法。低体温法の採用は特殊な必要性と優先性とを有しており、再温法も同様である。これを以下に説明する。
【０６３２】
神経外科。神経外科における一般的な目標は、患者を低体温法温度（例えば約３３℃）から若干正常より低い温度（例えば約３５．５℃、芯）へと短時間に再温することにある。再温速度が約２．５℃より大きいと１時間未満で達成できる。一般的な閉時間は約６０分なので、再温は手術室で抜管するときに起きる。ついで意識のある患者に神経審査が行われる。これには食道温度プローブを使うが、他のプローブやセンサーでもよい。
【０６３３】
神経外科方式。１．患者を１〜２層で覆う。２．熱交換のために作動流体が流れる浴温を約５０℃にする。これと血液温度との間に充分な温度降下が起きて、血液温度は４２℃を超えて上昇することはない。３．制御システムのための目標温度は約３５．５℃にプログラムされる。４．目標温度が達成された後、患者はＰＡＣＵ／ＩＣＵに移されて、対流空気毛布などで適宜再温される。
【０６３４】
鼓動。鼓動における一般的な目標は例えば約１２〜２４時間に亙って患者を低体温法温度（約３３℃）から「正常」温度（約３６．５℃、芯）に徐々に再温することにある。ＩＣＰはリバウンド（ｒｅｂｏｕｎｄ）を最少とするのが望ましく、患者は震えや悪寒なしに快適に保たれる。これには嚢温度プローブを用いるが他のプローブでもよい。
【０６３５】
鼓動方式。１．患者を積極表面再温により約４１℃に温めて震えを防止する。この加熱には電気または対流空気毛布を用いる。２．コンソールが制御再温を行って目標温度ランプ機能に適合する。換言すると看護人によりランプ値が入力され、このランプは患者が再温される速度である。コンソール内の制御器がそのプログラムされたランプで真の速度に適合する。ランプは医者が望む患者体温の上昇時間と正常体温または前正常体温（３６．５℃）に達するのに必要な上昇量により決定される。３．患者にはメペリジンなどの抗震剤が投与される。４．目標温度に達した後、患者はＰＡＣＵ／ＩＣＵに移されて対流空気毛布などの従来技術により再温される。
【０６３６】
心臓血管手術。心臓血管手術の目標は例えば手術後最初の２４時間まで心肺バイパスからの分離に続く初期の前手術期間において正常体温を維持することにある。これには再温して最後の３０〜４５分の閉鎖の間は手術室中では患者体温を少なくとも約３６℃に再温および維持するのが望ましい。これを複雑としているのは、ＣＰＢポンプから分離すると、通常再分布と周囲への熱損失の故に１〜２℃の後降下がある。閉鎖中またはＩＣＵ内では積極表面再温を使わないのが望ましい。これには下記の方式により、食道温度プローブまたはＰＡカテーテルを使うが、他のタイプのプローブやセンサーでもよい。
【０６３７】
心臓血管手術方式。１．伝熱要素とカテーテルとが最初に挿入される。２．ＣＶプロセスが行われる。３．患者がポンプから離れたら、システムが再温モードで開始され、患者目標温度が３６．５℃に設定される。４．必要ならまたは患者が目標温度に達した後、カテーテルをコンソールから外して患者をＩＣＵに移送する。５．患者をコンソールに再接続して再温を対流空気毛布などの従来方法で続行する。６．つぎの２４時間または医師が定めた時間、正常体温維持が続けられる。
【０６３８】
伝熱要素の製造方法。伝熱要素の外面は複雑な形状として周囲の血流の混合を誘発しかつ伝熱要素内での作動流体の混合を誘発する。そのような形状を「混合誘発形状」と呼び、その例としては螺旋状、交互螺旋状などの対掌形状、含異常形状、含衝突形状、含チャンネル形状、小円鋸形状、フックまたはホーン形状、迷路形状などがある。伝熱要素を形成する金属要素、要素または化合物は配置時にそのような形状をとれるように充分に延展性でなけらばならない。
【０６３９】
「配置」なる表現が使われているが、これは金属や被覆がマンドレルまたは伝熱要素の層上に施与されるプロセスも含む概念である。例えば配置は、ＣＶＤ、ＰＶＤ、スパタリング、ＭＢＥ、結晶または非結晶材料「成長」形状、スプレーコーチング、電気メッキ、ＥＣＤなどがある。ＥＣＤや電気メッキなどは帯電加工品を使う利点があり、帯電が加工品を道具に固定するのに利用できる。一般に伝熱要素を混合誘発形状のマンドレルを有するように形成する。マンドレルを金属層または一連の層（つまり伝熱要素）で被覆して、マンドレルを溶解させる。
【０６４０】
伝熱要素形成はマンドレル形成で始まる。例えばＡｌ６０６１などのアルミを使いＴ６熱処理をする。アルミはカセイソーダで容易に溶解または濾過できるので便利である。伝熱要素の軸に沿って孔を形成すると濾過が速くなる。マンドレルはＣｉｔｉｚｅｎ Ｓｗｉｓｓ Ｓｃｒｅｗ Ｍａｃｈｉｎｅなどで機械加工して製造する。またマンドレルは、プラスチックやワックスや低融点熱可塑性プラスチックなどから出来ている時には、射出成形によることもできる。その他にもレーザーによる加工（外面のみ）およびハイドロ加工などもある。
【０６４１】
マンドレルがいかに形成されようとも、重要なのは平滑な表面仕上げと外部構造を有していることであり、これで伝熱要素は平滑となる。マンドレルが平滑となるとその周りにアトラウマチック（ａｔｒａｕｍａｔｉｃ）な装置を形成できる。また平滑だと金属被覆（伝熱要素）の周辺への簡単な配置が可能となり、均一な熱伝導、バイオコーチングの均一な厚さ、アトラウマチックな形状などが可能となる。
【０６４２】
図７３に被覆層を示す。一般に金属からなる機械層７２４とバイオ相容層７２６とがある。層７２４は基本的な熱伝導性要素である。層７２４は熱伝導を行って冷却を与え、材料が配置できる限りではその熱伝導率は約０．１〜４Ｗ／ｃｍ−Ｋである。層７２４に使える金属としてはＮｉ、Ｃｕ、Ａｕ、Ａｇ、Ｔｉ、Ｔａ、ニチノール、ステンレス、これらの混合物などがある。
【０６４３】
機械層の厚さは約２ｍｉｌ未満として蛇行した血管を通過するに充分な可撓性を与えるべきであるが、これは関連する金属タイプと血管の蛇行とにより左右される。タイプとしては貴金属が使える。あるものは有害なバイオ相容性を有しているが、それぞれ異なる製造法である。例えばＡｕ伝熱要素はＡｕがＡｌマンドレルには粘着しないのでシード層を必要とする。Ｎｉは有用である。Ｃｕも有用で高伝導性であるが、配置される血管の形状に倣い易い。
【０６４４】
Ｎｉが基本的な伝熱要素を形成するものと仮定する。Ｎｉは血液相容性ではない。相容性層７２６が図７３に示すように機械層７２４上に配置する。相容性層はウレタン、ポリウレタン、テフロン（登録商標）、潤滑被覆、ヘパリンなどのアンチスロンボジェニック（ａｎｔｉｔｈｒｏｍｂｏｇｅｎｉｃ）被覆、Ａｕなどの貴金属、これらの組合せなどである。
【０６４５】
ここでひとつ難しいのは、サリンなどの作動流体を使うと機械層の腐蝕が起きることであり、Ｎｉの機械層７２４の場合にはサリンが特に腐食性である。したがってサリンに対して非腐食性である保護層７２２を与えてやる。例えば保護層はＡｕからなる。Ａｕ保護層はアルミマンドレルに付着し難い。したがって必要ならＡｕ層の施与前にＣｕ層をマンドレルに施与する。マンドレルの溶解に続いてＣｕ層もエッチングされる。保護層は一般に貴金属または不活性金属であり、テフロン（登録商標）などのポリマーでもよい。
【０６４６】
これに代えて、マンドレルの除去または溶解に続いて、保護層７２２を真空蒸着してもよい。マンドレル除去により残された孔は蒸発した気体または液体化学物が通過できる。かくして材料は伝熱要素内部に施与できて、施与された材料は上記したようなポリマー、非侵蝕性または非極性ポリマー、貴金属などである。
【０６４７】
図７４では機械層７２４上にバイオ相容性層７２６とヘパリン／潤滑層７２８があり、これらが結合してひとつのバイオ相容性層を形成している。これに代えて、バイオ相容性層は「シード」層であってもよく、これがヘパリン／潤滑層７２８の機械層７２４への結合を高める。シード層は例えばヘパリンである。ヘパリン／潤滑層は一例に過ぎず、両者は別個・一緒に施与されてもよい。ヘパリンが要らないこともある。
【０６４８】
図７５に種々の金属について起きる問題を示す。例えば全体がＮｉからなる機械層７２４はその多孔性の故に破断圧力が低過ぎて図７４の保護層７２２がこれに関連してくる。該機械層は数個の層に分けられ、該層７２４ａ、７２４ｃはＮｉなどの第１の材料からなり、層７２４ｂは両層の間に配置されている。この層７２４ｂはＣｕなどの第２の材料からなり、これらの層の組合せが機械的な「サンドイッチ」構造を構成している。Ｃｕ層はＮｉ層中の「ピンホール」を塞ぐのである。
【０６４９】
表Ｉに有用な実施例を示すが、バイオ相容性コーチングはＡｕ層であるが、これは特別な例である。この表は図７５に関連する。
【０６５０】
【表１】

【０６５１】
層１０２〜１０８のグループ全体の厚さは約１ｍｉｌであり、ニッケルと銅とは他の要素の痕跡を含んでいるが有害性はない。この発明は以上の実施例に限定されるものではない。
【０６５２】
【表２】

【０６５３】
【表３】

【０６５４】
【表４】

【０６５５】
【表５】

【０６５６】
【表６】

【０６５７】
【表７】

【０６５８】
【表８】

【０６５９】
【表９】

【図面の簡単な説明】
【０６６０】
この発明そのものはもとより、この発明の新規態様は、以下の説明とともに、添付図面の参照により、よく理解されるであろう。以下で類似の参照記号を類似箇所に対応して使用する。
【図１】上大動脈内で使用した伝熱要素の実施例を示した説明図である。
【図２】低体温治療法で、大流量器官の優先的冷却実施方法を示したグラフである。
【図３】時間の関数としての、乱流定常（ステディ）状態における速度を示すグラフである。
【図４】時間の関数としての、動脈内における血流速度を示すグラフである。
【図５】動脈血流と類似の、時間の関数としての、脈打ち状態にある乱流定常状態における血流速度を示すグラフである。
【図６】動脈内における乱流誘発伝熱要素を示す立面図である。
【図７】一定圧力傾斜で駆動される定常状態のポアジーユ流れを示す速度プロファイル図である。
【図８】心臓パルスの継続時間平均した動脈内血流の速度プロファイル図である。
【図９】動脈内に平滑な伝熱要素を挿入後の心臓パルスの継続時間平均した、動脈内血流の速度プロファイル図である。
【図１０】この発明による、ひとつの実施例である伝熱要素の説明図である。
【図１１】均一壁面温度における、長い加熱パイプに沿って流れる空気流の、ヌッセルト数（Ｎｕ）と、レイノルズ数（Ｒｅ）の関係を示すグラフである。
【図１２】この発明による、ひとつの実施例である伝熱要素の立面図である。
【図１３】図１で示した伝熱要素の長手方向断面図である。
【図１４】図１で示した伝熱要素の横方向断面図である。
【図１５】図１で示した伝熱要素の、血管内での使用状況を示す斜視図である。
【図１６】隣接セグメント間に一列に並んだ長手方向リッジを有する、この発明によるもうひとつの伝熱要素を示す斜視図である。
【図１７】隣接セグメント間に、若干オフセット（回転ずれ）した長手方向リッジを有する、この発明によるもうひとつの、伝熱要素を示す斜視図である。
【図１８】図１６、または図１７で示した伝熱要素の、横方向断面図である。
【図１９】この発明による代わりの伝熱要素を、切り欠いた様子を示す斜視図である。
【図２０】図５で示した伝熱要素の、横方向断面図である。
【図２１】この発明の原理による、伝熱要素を採用した実施例であって、さらにサイド・バイ・サイド（横に並んだ）管腔配列構成の、カテーテルのさらなる実施態様を示す正面断面図である。
【図２２】図２１で示したカテーテルの、図２１の２２−２２線に沿っての、断面図である。
【図２３】この発明による、さらに別の伝熱要素と、管腔配列構成を採用したカテーテルの正面断面図である。
【図２４】この発明による、なおさらに別の伝熱要素と、管腔配列構成を採用したカテーテルの正面断面図である。
【図２５】この発明の原理による、伝熱要素を採用した、もうひとつの実施例であって、この発明の別の実施態様による。サイド・バイ・サイド管腔配列構成を採用した、カテーテルの、もうひとつの実施態様を示す正面断面図である。
【図２６】図２５で示した伝熱要素の、図２５の２６−２６線に沿っての断面図である。
【図２７】動脈内に配置した、この発明の実施例としての、膨張可能な乱流誘発伝熱要素を示す、説明的側面図である。
【図２８】動脈内に配置した、この発明による、代わりの実施例としての、表面積増加テーパーと、乱流誘発形状を採用した、膨張可能な乱流誘発伝熱要素を示す説明図である。
【図２９】図２３の実施例で採用すると良い、テーパー付きジョイントを示す。
【図３０】この発明による、第２の代わりの実施例としての、表面積増加テーパーと、乱流誘発形状を採用した、乱流誘発伝熱要素を示す説明図である。
【図３１】図２８の実施例としての伝熱要素で採用すると良い、乱流誘発表面形態の、一形式を示す説明図である。図３１では、スパイラル（らせん）形状を示す。
【図３２】この発明による、代わりの実施例としての、表面積増加テーパーを採用する、伝熱要素を示す説明図である。
【図３３】図２７の実施例で採用すると良い、別タイプの乱流誘発表面形態を示す、説明図である。図３３では、一連のジグザグ配置の突起を示す。
【図３４】図３３の実施例で示した、伝熱要素の横方向断面図である。
【図３５】患者の共通頚動脈内に配置した、この発明による装置の斜視図である。
【図３６】構造詳細部を追加した、図３５で示した装置の斜視図である。
【図３７】図３６で示した装置の、線３−３に沿っての横断面図である。
【図３８】図３０で示した装置の、冷却流体の流路を示す、部分的長手方向断面図である。
【図３９】ひとつの実施例として、患者の全身冷却を行ない次に身体を再加温する患者に低体温法を施すために使用中の伝熱要素の図式的描写である。
【図４０】ひとつの実施例として、患者の脳冷却と脳から帰る咽喉静脈内の血液を加温するために使用中の伝熱要素の図式的描写である。
【図４１】ひとつの実施例として、患者の脳冷却を行なう一方、脳から帰る咽喉静脈内の血液に温かい生理的食塩水を注入する様子を示す伝熱要素の図式的描写である。
【図４２】器官から帰る静脈中の血液を加温するために使用できる、ひとつの実施例としての外部加温装置の図式的描写である。
【図４３】もうひとつの実施例として、患者の全身冷却を行ない、次に身体を再加温する患者に低体温法を施すために使用中の伝熱要素の図式的描写である。
【図４４】加温毛布（ブランケット）と熱調節薬剤とを用いるこの発明による代表的方法を示すフローチャートである。
【図４５】メペリジン分子を示す。
【図４６】モルヒネ分子を示す。
【図４７】プロジン（＋）異性体分子を示す。
【図４８】プロジン（−）異性体分子を示す。
【図４９】フェンタニル分子を示す。
【図５０】ヒドロキシ・アリル・プロジン（＋）異性体分子を示す。
【図５１】ピセナドール（＋）異性体分子を示す。
【図５２】ピセナドール（−）異性体分子を示す。
【図５３】トラマドール分子を示す。
【図５４】ネフォパム分子を示す。
【図５５】この発明によるひとつの実施例としての、身体冷却のための伝熱要素使用法の図式的描写である。
【図５６】この発明による代表的方法を示す、フローチャートである。
【図５７】この発明により構成した、マニフォルドを有するカテーテルを示す。
【図５８】図５７で示した、カテーテルの断片的部分を拡大して示す。
【図５９】この発明の実施例により構成した循環セットを含む、伝熱カテーテルシステムの斜視図である。
【図６０】図５９で示した循環セットとともに使うと良い、カテーテルの先端部の実施例を示す側立面図とともに、伝熱カテーテルの先端部の実施例を示す断面図である。
【図６１】この発明による、ある実施例で採用すると良い、バルブの説明図である。
【図６２】図４８で示した、循環セットの説明図である。
【図６３】この発明による、循環セットで使うと良い、使い捨て式（ディスポーザブル）熱交換器を示す、分解斜視図である。
【図６４】図５２で示した、熱交換器の断面図である。
【図６５】図６３で示した、熱交換器のマニフォルド部分を示す斜視図である。
【図６６】図６３で示した、熱交換器のマニフォルド部分を示す斜視図である。
【図６７】この発明の実施例により構成した、温度、および圧力センサーを示す斜視図である。
【図６８】図６７で示した、温度、および圧力センサーを示す分解斜視図である。
【図６９】図６７で示した、温度、および圧力センサーを示す分解側立面図である。
【図７０】図６７で示した、温度、および圧力センサーを示す分解斜視図であって、図６８で示したのとは、別の視点から見た図である。
【図７１】図５９で示した、循環セットのポンプについて、ポンプのモーター速度対時間の関係を示す代表的グラフである。
【図７２】図５９で示した循環セットの、１０Ｆ伝熱カテーテル用モーターと、１４Ｆ伝熱カテーテル用モーターとの、圧力対ポンプモーター速度の代表的関係を示すグラフである。
【図７３】この発明による実施例としての、伝熱要素の壁を構成する層（レイヤー）であって、この発明による方法で形成された層を示す、図式的描写である。
【図７４】この発明による第２実施例としての、伝熱要素の壁を構成する層（レイヤー）であって、この発明による方法で形成された層を示す、図式的描写である。
【図７５】この発明による第３実施例としての、伝熱要素の壁を構成する層（レイヤー）であって、この発明による方法で形成された層を示す、図式的分解描写である。
【図７６】予報的温度アルゴリズムを、実施するために使用すると良い、システムを示す。
【図７７】カテーテル装着型伝熱要素の位置付け（ポジション）を示す、伝熱要素とカテーテル間の、ジャンクションを示す。
【図７８】ポンプの作動サイクルを示す。
【図７９】ポンプのふたつの作動サイクルを示し、予報的温度アルゴリズムを採用すると、図７８で示したよりも、より高度な作動サイクルが達成されることを示す。
【図８０】制御温度を予報する、ひとつのグラフ的方法を示す。
【図８１】時間に関する、測定前と、測定後の面積比の関係を示す。
【図８２】制御温度を予報する、もうひとつの方法を示す。
【図８３】制御温度予報法を実施できるシステムを示す。
【図８４】図８１で示した、面積のグラフを示す。
【図８５】制御温度予報法を実施できる、もうひとつのシステムを示す。
【図８６】図８５で示した、実施例で使用すると良い、比較器スイッチを示す。
【符号の説明】
【０６６１】
１００：血流
１０２、２１０：伝熱要素
１０４：熱伝導セグメント
１０７：作動流体
１２２：血液
１２４：管腔【Technical field】
[0001]
Continuation application information. This application is a continuation-in-part of each of the United States patent applications listed below. That is, US patent application Ser. No. 09 / 650,940 filed on Aug. 30, 2000 (ie, August 30, 2000, and so forth) with the title of the invention, "Selective Organ Hypothermia and its Apparatus." US patent application Ser. No. 09 / 785,243, filed on Feb. 16, 01, entitled "Fluid circulating hypothermia and its apparatus"; U.S. patent application Ser. No. 09 / 566,531 filed on Aug. 8, 2001; filed on Aug. 1, 2001 under the title of "Inflatable Catheter for Heating and Cooling Selective Organs and How to Use It". U.S. patent application Ser. No. 09 / 71,124, filed on Nov. 16/00, filed on 11/16/00, entitled "Cryogenic Thrombolysis, and Low Temperature Thrombolysis Treatment, for Selective Organ Temperature Control." No. 09 / 621,051 filed on 21/21/00 under the title of "Method and Apparatus for Selective Organ Cooling Application"; Title of the Invention "Specific agents such as thrombolytic agents" Patent Application No. 09 / 800,159 filed on 3/6/01 in "Apparatus and Method for Arranging and Controlling Temperature"; U.S. patent application Ser. No. 09 / 292,532 filed on 15/99; U.S. patent application Ser. No. 09 / 379,295, filed on Aug. 23/99 with the title of "Method of Manufacturing Heat Transfer Elements for In Vivo Cooling". No. 09 / 885,655 filed on 6/20/01 with the title of "Inflatable Heat Transfer Device"; 3 / the title of the Invention "Method and Apparatus for Selective Organ Cooling Application." U.S. Patent Application Serial No. 09/2 filed on 28/01 US patent application Ser. No. 09 / 797,028 filed on Feb. 27, 01, entitled "Selective Organ Cooling Catheter with Guidewire Device and Temperature Monitoring Device". US Patent Application Ser. No. 09 / 607,799, filed on Jun. 30, 2001, entitled "Selective Organ Cooling Apparatus and Method"; US Patent Application, filed Mar. 3, 000, entitled "Catheter Lumen Design" No. 09 / 519,022; U.S. patent application Ser. No. 10 / 082,964, filed on Feb. 25/02 under the title of "Method of Determining Effective Calorie when Using Body or Organ Cooling Catheter" US patent application Ser. No. 09 / 539,932, filed Mar. 31/00 on “Medical Procedures”; US patent application Ser. No. 09 / 658,950, filed on Sep. 11/00 with the title “Medical Procedures”; US patent application Ser. No. 09 / 373,112, filed 8/11/99, entitled "Method and Apparatus for Controlling the Temperature of Patients"; Title: Circulating Set for Temperature Controlled Catheter and Use Thereof US patent application Ser. No. 10 / 007,545 filed on Nov. 6, 2001; US patent application Ser. No. 10 / 005,416, filed on Nov. 7, 2001 with title of Invention "Method and Apparatus for Controlling Heat Generation"; US patent application Ser. No. 10 / 117,733 filed 4/4/02 under the title of "Method of Manufacturing Heat Transfer Element for In Vivo Cooling", which is entitled "Optimal Reheating Method ( Strategy) is a conversion of US Patent Application No. 60 / 311,589, filed 8/9/01; filed on 8/15/01 with the title of invention "Control Method for Hypothermia Application" US Patent Application Serial No. 60/31 U.S. Patent Application No. 60 / 316,057, filed on Aug. 29, 01, entitled "Control of Hypothermia", 8/31, entitled "New Anti-Seismic Agent and Its Prescription Plan" U.S. Patent Application No. 60 / 316,922 filed on Jan. 14, 2001; U.S. Patent Application No. 60 / 322,945 filed on Sep. 14, 2001 under the title of "New Anti-Seismic Agent and Its Prescription Plan"; U.S. patent application Ser. No. 60 / 328,259 filed 10/01/01 with the title "Single operator replaceable coaxial cooling catheter"; U.S. Patent Application No. 60 / 328,320 filed on Sep. 9/01; all of which are incorporated herein by reference.
[Patent Document 1]
US Patent Application No. 09 / 650,940
[Patent Document 2]
US Patent Application No. 09 / 785,243
[Patent Document 3]
US Patent Application No. 09 / 566,531
[Patent Document 4]
U.S. Patent Application Serial No. 09 / 757,124
[Patent Document 5]
U.S. patent application Ser. No. 09 / 714,749.
[Patent Document 6]
US Patent Application No. 09 / 621,051
[Patent Document 7]
US Patent Application No. 09 / 800,159
[Patent Document 8]
US patent application Ser. No. 09 / 292,532
[Patent Document 9]
US Patent Application No. 09 / 379,295
[Patent Document 10]
US Patent Application No. 09 / 885,655
[Patent Document 11]
US Patent Application No. 09 / 246,788
[Patent Document 12]
US Patent Application No. 09 / 797,028
[Patent Document 13]
US Patent Application No. 09 / 607,799
[Patent Document 14]
US Patent Application No. 09 / 519,022
[Patent Document 15]
US Patent Application No. 10 / 082,964
[Patent Document 16]
US Patent Application Serial No. 09 / 539,932
[Patent Document 17]
US Patent Application No. 09 / 658,950
[Patent Document 18]
US Patent Application No. 09 / 373,112
[Patent Document 19]
US Patent Application No. 10 / 007,545
[Patent Document 20]
US Patent Application No. 10 / 005,416
[Patent Document 21]
US Patent Application No. 10 / 117,733
[Patent Document 22]
US Patent Application No. 60 / 311,589
[Patent Document 23]
US Patent Application No. 60 / 312,409
[Patent Document 24]
US Patent Application No. 60 / 316,057
[Patent Document 25]
US Patent Application No. 60 / 316,922
[Patent Document 26]
US Patent Application No. 60 / 322,945
[Patent Document 27]
US Patent Application No. 60 / 328,259
[Patent Document 28]
US Patent Application No. 60 / 328,320
[0002]
Field of the invention. The present invention relates generally to reducing, increasing, and controlling the temperature of a human body. More particularly, the present invention relates to a method for controlling the temperature of the human body and an intravascular device therefor.
[Background Art]
[0003]
Background information. Organs within the human body, such as the brain, kidneys, and heart, are maintained at a constant temperature of about 37 ° C. Hypothermia can be defined clinically as keeping the core body temperature below 35 ° C. Hypothermia is sometimes subdivided according to its severity. The fact that the core body temperature is in the range of 33 ° C. to 35 ° C. is referred to as a mild (mild) hypothermia method. A core body temperature in the range of 28 ° C. to 32 ° C. is referred to as a modal (medium) hypothermia method. The fact that the core body temperature is in the range of 24 ° C to 28 ° C is referred to as a severe (severe) hypothermia method.
[0004]
Hypothermia is uniquely effective in reducing brain injury caused by nervous system trauma and may eventually play an important role in emergency brain resuscitation. Experimental evidence has demonstrated that: Performing cerebral cooling improves the results after systemic, focal, or traumatic ischemic symptoms. For this reason, as with other organs, it is advisable to induce and use hypothermia for the purpose of reducing the effects of certain parts of the trauma on the brain.
SUMMARY OF THE INVENTION
[0005]
The device according to the present invention may include a heat transfer (ie, heat transfer) element used to cool blood flowing in the blood vessel.
[0006]
The heat transfer element includes, by way of example only, first and second elongated, articulated segments, each segment having a turbulence-inducing outer surface. A flexible joint may join the first and second elongated segments. An inner lumen may be disposed within the first and second elongated segments, the inner lumen being capable of delivering pressurized working fluid to the end of the first elongated segment.
[0007]
In addition, the first and second elongated segments may have a turbulence-inducing inner surface for turbulence induction of the pressurized working fluid flowing therethrough.
[0008]
When placed in an artery or vein, a turbulence-inducing outer surface may be used to induce turbulence in the free stream of blood.
[0009]
This turbulence inducing outer surface may be used to induce a turbulence intensity of 0.05 or more in the free flow of blood.
[0010]
In one embodiment, the flexible joint includes a bellows section (bellows section), which not only increases flexibility but also allows axial compression of the heat transfer element.
[0011]
In one embodiment, the turbulence-inducing outer surface of the heat transfer element includes one or more spiral ridges.
[0012]
Adjacent segments of the heat transfer element may be spiraled in opposite directions to enhance turbulence. For example, a first elongated segment includes a spiral ridge having one or more counterclockwise twists, and a second elongated segment includes a spiral ridge having one or more clockwise twists.
[0013]
Of course, conversely, the first elongate segment may include one or more clockwise spiral ridges and the second elongate segment may include one or more counterclockwise spiral ridges. The first and second elongated, articulated segments may be made of a highly thermally conductive material.
[0014]
The heat transfer device may also include a coaxial delivery catheter wherein the inner catheter lumen has a further inner coaxial lumen and is joined to the first and second heat transfer segments, respectively.
[0015]
A working fluid supply configured to dispense pressurized working fluid may be connected to the inner catheter lumen.
[0016]
The working fluid supply device may be configured to create a pressurized working fluid at a temperature of about 0 ° C. and a pressure of about 5 atmospheres or less. The working fluid may be isolite, physiological saline, D5W, or the like.
[0017]
As yet another embodiment, the heat transfer device may include three or more elongated, articulated heat transfer segments, each heat transfer segment connecting an additional elongated heat transfer segment, an additional flexible heat transfer segment. And a turbulence-inducing outer surface.
[0018]
In one such embodiment, and by way of example only, the first and third elongated heat transfer segments include a clockwise spiral ridge and the second elongated heat transfer segment includes one or more counterclockwise It is desirable to include a direction spiral ridge. Of course, alternatively, the first and third elongated heat transfer segments may include counterclockwise spiral ridges, and the second elongated heat transfer segment may include one or more clockwise spiral ridges.
[0019]
The turbulence-inducing outer surface of the heat transfer element may optionally include a surface coat, or anti-clot treatment.
[0020]
The present invention also provides for the insertion of a flexible, thermally conductive cooling element into the inferior aorta from a remote location and applying body warming means to prevent tremors associated with the cooling blanket means. Assume the body cooling method.
[0021]
The method further includes circulating the working fluid through a flexible, thermally conductive cooling element to reduce body temperature. This flexible, thermally conductive heat transfer element absorbs about 25, 50, or more than 75 watts of heat.
[0022]
The method also includes inducing turbulence in the free blood flow in the artery or vein. One embodiment includes inducing blood turbulence in the vascular system with a high turbulence intensity of about 0.05 or greater.
[0023]
This circulation consists of inducing a mixed flow in the working fluid through a flexible, thermally conductive heat transfer element. The pressure of the working fluid may be maintained at about 5 atmospheres or less.
[0024]
Cooling or warming may consist of circulating the working fluid through the inner lumen of the catheter and outside the coaxial lumen. In one embodiment, the working fluid remains liquid throughout the cycle. The working fluid may be water-soluble.
[0025]
The invention also contemplates a cooling or warming catheter that includes first and second catheter shafts therein.
[0026]
The catheter also includes a cooling or warming tip to enter the circulation from the first lumen and exit the circulation from the second lumen, to transfer heat to or from the working fluid, and the tip is inserted into a blood vessel. A turbulence-inducing structure on the chip that, when activated, creates turbulence in the free flow. This tip may be used to induce turbulence in the working fluid.
[0027]
The catheter, when inserted into a vessel feeding an organ, can remove at least about 25 watts of heat from the organ while cooling the tip with a working fluid that remains liquid within the catheter.
[0028]
Alternatively, when inserted into a blood vessel feeding an organ, the catheter may remove at least about 50, or 75 watts of heat from the organ while cooling the tip with an aqueous working fluid.
[0029]
In another embodiment, a cooling or warming catheter has first and second lumens therein, enters the circulation from the first lumen, exits the circulation from the second lumen, and circulates. Includes a catheter shaft that cools or warms the tip used for heat transfer to or from the working fluid, and a turbulence inducing mechanism on the tip that can induce turbulence when the tip is inserted into a blood vessel And good.
[0030]
The present invention also provides a temperature control device comprising a flexible catheter, having an inflatable balloon near the end of the catheter, which can be inserted into an artery or vein through the patient's vascular system. it can.
[0031]
The invention also encompasses methods used to cool, warm, or regulate such devices.
[0032]
After placement in a blood vessel, one embodiment of the present invention is directed to a method in which the heat exchange balloon is adapted to supply a working fluid, such as saline, Isolite, D5W, or other similar fluid, or a combination thereof, within the catheter. Includes one device, inflated by pressure, through the cavity.
[0033]
The heat exchange balloon has one or more blood flow paths passing therethrough from the balloon base side to the balloon end side.
[0034]
When this heat exchange balloon is inflated and contacts the wall of the artery in which it is located, each blood flow path has an inlet on one side of the heat exchange balloon and an outlet on the other side of the heat exchange balloon. To allow blood to continue to flow through the arteries even after the balloon is inflated.
[0035]
The blood flow tube may be made of a material having a relatively high thermal conductivity, such as a thin metal-coated polymer, for example, a film having one or more vapor-deposited surfaces.
[0036]
Alternatively, the blood flow tube may be made of a metal-added polymer film.
[0037]
Further, to maximize the cooling capacity of the heat exchange device, the entire heat exchange balloon may be made of such a material.
[0038]
After inflating the heat exchange balloon, the saline solution cooled by the external cooler continues to circulate through the blood flow tube through the heat exchange balloon and returns from the balloon through the return lumen in the catheter.
[0039]
This cools the blood flow tube, which in turn cools the blood flowing therethrough. The cooled blood then flows through the selected organ and cools that organ.
[0040]
The device may also include a guidewire lumen that performs navigation functions for the catheter through the patient's vascular system.
[0041]
In one embodiment, the present invention is directed to a catheter system that changes blood temperature by heat transfer to or from a working fluid.
[0042]
The system includes an inflatable inlet lumen and an outlet lumen. The outlet lumen is joined with the inlet lumen to transfer working fluid between the two. The outlet lumen has a structure for inducing turbulence in the blood and / or working fluid when inflated.
[0043]
Variations on this system include one or more of the following: The inlet and outlet lumens may be made of a flexible material such as latex rubber.
[0044]
The outlet lumen may have a spiral-like structure that, when inflated, induces turbulence in the working fluid and tapers in a segmented or non-segmented manner.
[0045]
The diameter of the inlet lumen and the outlet lumen may decrease in a distal direction such that when inflated, the inlet lumen and the outlet lumen are tapered.
[0046]
In order to provide shape and strength even when contracted, it is preferable to arrange a wire in the entrance lumen or the exit lumen.
[0047]
The thickness of the outlet lumen when inflated is preferably about 1/2 mil or less. The length of the inlet lumen may be in the range of about 5-30 cm.
[0048]
If the exit lumen has a helical shape, the diameter of the helix when inflated should be about 8 mm or less. The outer diameter of the spiral of the outlet lumen when inflated is preferably in the range of about 2 mm to 8 mm, and is preferably tapered in the range of about 1 mm to 2 mm.
[0049]
In segmented embodiments, the length of the segment may be in the range of about 1 cm to 10 cm. The radius of the inlet lumen and the outlet lumen when inflated is preferably in the range of about 0.5 mm to 2 mm.
[0050]
The outlet lumen may further include at least one surface morphology and / or an internal morphology, wherein the surface morphology induces turbulence in the fluid adjacent to the outlet lumen and the internal morphology induces turbulence in the working fluid. .
[0051]
The surface morphology may include one or more helical turns or spirals formed in the outlet lumen. Adjacent helical rotations may employ reverse helical rotations.
[0052]
Alternatively, or in combination, the surface feature may be a series of zig-zag ridges formed in the outlet lumen.
[0053]
The turbulence inducing exit lumen may be used to induce turbulence when placed in the artery and inflated in the free flow of blood. The strength of the turbulence is preferably about 0.05 or more. The turbulence-inducing outlet lumen may be inflated and placed in an artery throughout the entire period of the cardiac cycle or used for turbulence induction for at least 20% of the cardiac cycle period.
[0054]
The system further includes a coaxial delivery catheter having an inner catheter lumen joined to the inner lumen, a working fluid supply configured to dispense a working fluid, and a discharge joined to the inner catheter lumen. Including.
[0055]
The working fluid supply may be configured to produce a pressurized working fluid having a temperature in the range of about -3C to 36C and a pressure of about 5 atmospheres or less. If blood warming is desired, higher temperatures may be employed.
[0056]
The turbulence-inducing outlet lumen may include a surface coating or treatment such as heparin (a type of polysaccharide) to prevent clot formation. It is preferable to join a stent (stainless steel mesh tube) to the distal end of the entrance lumen. The system may be employed to cool or warm a volume of tissue, rather than blood.
[0057]
In embodiments employing a tapered, helical exit lumen, the taper of the exit lumen allows the exit lumen, smaller than its initial radius, to be placed within the artery.
[0058]
The outlet lumen may be tapered in a segmented manner. Each segment may be separated by a joint, which may have a smaller diameter than either of the adjacent segments.
[0059]
In another embodiment, the invention is directed to a method of changing blood temperature by heat transfer. The method includes inserting the inflatable heat transfer element into an artery or vein, and further including inflating the inflatable heat transfer element with a working fluid therein. The temperature of this working fluid usually depends on its blood temperature.
[0060]
The method further includes inducing turbulence in most of the free flow of blood by flowing the working fluid through the turbulence inducing passage, and inducing turbulence in the working fluid. The expandable heat transfer element may have a structure that induces turbulence when inflated.
[0061]
In another embodiment, the invention is directed to a method of treating the brain. This brain treatment involves inserting a flexible heat transfer element into the artery from a remote location, circulating the working fluid through the flexible heat transfer element, inflating it, and changing the temperature of the whole body. Includes treatments that selectively alter only the temperature of certain organs without modification. Desirably, the flexible, thermally conductive heat transfer element absorbs about 25, 50, or more than 75 watts of heat. The artery may be a common carotid artery or a combination of a common carotid artery and an internal carotid artery.
[0062]
In another embodiment, the invention is directed to a method of cooling an organ within a patient's body. In this organ cooling method, a catheter having a diameter of 5 mm or less is inserted into a blood vessel supplying blood to the organ, and free-flow turbulence is induced in the blood flow flowing on the surface of the catheter. Methods include cooling the catheter to remove heat from the blood and cooling only that organ without substantially lowering the temperature of the whole body.
[0063]
In one embodiment, the cooling method removes at least about 75 watts of heat from the blood. In another embodiment, the cooling method removes at least about 100 watts of heat from the blood. The human brain is a good organ to be cooled.
[0064]
The circulation further includes passing the working fluid through a coaxial lumen from the inlet lumen and out of the outlet lumen. The working fluid is preferably a liquid at or below its boiling point and, moreover, an aqueous solution.
[0065]
Advantages of the invention include one or more of the following.
[0066]
Heat transfer element design criteria described above: small diameter when contracted, large diameter when expanded, excellent flexibility, increased heat transfer element surface area and increased turbulence to increase heat transfer efficiency , Creating the ability for the heat transfer element to successfully achieve the selective cooling or warming of a particular organ.
[0067]
The problems associated with the external circulation of blood are eliminated because the blood is cooled in blood vessels or in vivo.
[0068]
Also, only one arterial vascular cannula (drainage) is required, which can be performed on an easily accessible artery, such as the femur, subclavian or brachial artery.
[0069]
Eliminating the use of cold perfusate (fluid from the organs) eliminates the problems associated with excessive fluid accumulation. In addition, rapid cooling to the correct temperature can be achieved. Moreover, the patient's treatment is hassle-free, and the patient can easily continue to take care during the heat transfer process.
[0070]
The device and method can be easily combined with other devices and techniques to provide aggressive and diversified treatments.
[0071]
Other advantages of the present invention include devices for warming or cooling the surrounding fluid in a blood vessel, and solve the above-mentioned problems.
[0072]
The device comprises an elongated catheter body, a heat transfer element located at the distal end of the catheter body, and an elongate supply lumen and a heat transfer element having a hydraulic diameter used to pump working fluid into the heat transfer element. An elongated return lumen having a hydraulic diameter for use in returning the working fluid, wherein the ratio of the hydraulic diameter of the return lumen to the hydraulic diameter of the supply lumen is substantially equal to 0.75.
[0073]
Implementations of the above-described embodiments of the present invention may include one or more of the following.
[0074]
The supply lumen may be located substantially inside the return lumen.
[0075]
One set of the supply lumen and the return lumen may have a substantially unitary cross-sectional shape.
[0076]
One set of the supply lumen and the return lumen may have a substantially annular cross-sectional shape.
[0077]
The supply lumen may have a certain general cross-sectional shape, and the return lumen may have a certain general cross-sectional shape different from the general cross-sectional shape of the supply lumen.
[0078]
The catheter device (assembly) includes an integrated elongated bi-lumen body having a first lumen for receiving a guidewire and a second lumen comprising either a supply lumen or a return lumen. .
[0079]
This bi-lumen body has a substantially “eight-shaped” cross-sectional shape.
[0080]
The first lumen has a substantially circular cross section and the second lumen has a substantially annular cross section.
[0081]
The heat transfer element includes means for inducing mixing of the fluid around the circumference.
[0082]
The apparatus further includes a means for inducing the working fluid between the wall jet inducing means or the heat transfer element and the working fluid to further enhance the heat transfer effect.
[0083]
The heat transfer element includes an inner tip, the supply lumen having a first means for delivering a working fluid to the inner tip of the heat transfer element, and a transfer means at one or more points proximal to the tip of the heat transfer element. Second means for delivering a working fluid inside the thermal element.
[0084]
Another aspect of the invention includes a catheter device that can be inserted into a selected vessel within a patient's vascular system.
[0085]
The catheter device includes an elongated supply lumen and an elongated return lumen. The elongate supply lumen is for use with the elongate catheter body, including an operating element having an interior at the distal end of the catheter body, and for pumping working fluid into the interior of the tip having a hydraulic radius. Also, the elongated return lumen is used for returning working fluid from inside the operating element having a certain hydraulic radius. Moreover, the ratio of the hydraulic radius of the return lumen to the hydraulic radius of the supply lumen is substantially equal to 0.75.
[0086]
Any of the techniques described above with respect to one embodiment of the present invention can be applied to another embodiment of the present invention.
[0087]
Moreover, implementations of the invention may include one or more of the following.
[0088]
The operating element may include a heat transfer element for transferring heat to or from the working fluid.
[0089]
The heat transfer element may include means for inducing mixing in the surrounding fluid.
[0090]
The operating element may include a catheter balloon that is inflated by the working fluid.
[0091]
Another embodiment of the present invention includes an apparatus for warming or cooling surrounding fluid within a blood vessel.
[0092]
The device includes an elongated catheter body, a heat transfer element including an interior located at the distal end of the catheter body, an integrated elongated bi-lumen body disposed within the catheter body, a guidewire and Either a supply lumen that includes a first lumen for receiving the second lumen and sends working fluid inside the heat transfer element, or a return lumen for sending working fluid back from inside the heat transfer element. And a third lumen consisting of either a supply lumen for sending working fluid inside the heat transfer element or a return lumen used to send working fluid back from inside the heat transfer element. And
[0093]
Implementations of the invention may include one or more of the following.
[0094]
The catheter body includes an inner wall, the integrated bi-lumen body includes an outer wall, and the third lumen substantially comprises an inner wall of the catheter body and an outer wall of the bi-lumen body. Stipulated.
[0095]
Both the catheter body and the bi-lumen body are extruded. The bi-lumen body is located substantially within the third lumen.
[0096]
The second lumen has a substantially unitary cross-sectional shape.
[0097]
The third lumen has a substantially annular cross-sectional shape.
[0098]
The second lumen has a certain general cross-sectional shape, and the third lumen has a certain general cross-sectional shape different from the general cross-sectional shape of the second lumen.
[0099]
The bi-lumen body has a substantially figure eight cross-sectional shape.
[0100]
The first lumen has a substantially circular cross-sectional shape, and the second lumen has a substantially unitary cross-sectional shape.
[0101]
The heat transfer element includes means for inducing mixing in the surrounding fluid.
[0102]
The apparatus further includes wall jet inducing means or means for mixing the working fluid more strongly to further enhance the heat transfer effect between the heat transfer element and the working fluid.
[0103]
The heat transfer element includes an inner tip, the supply lumen includes a first means for delivering a working fluid to the inner tip of the heat transfer element, and a heat transfer element at one or more points proximal to the tip of the heat transfer element. Second means for feeding the working fluid into the inside of the body.
[0104]
Another embodiment of the present invention includes a catheter device that can be inserted into a selected blood vessel within a patient's vascular system.
[0105]
The catheter device includes an active element including an elongated catheter body, including an inner side disposed at the distal end of the catheter body, an integrated elongated bi-lumen body disposed within the catheter body, a guidewire, a second lumen, A second tube comprising either a first lumen for receiving the working fluid and a return lumen used to deliver working fluid inside the working element or a return lumen used to send working fluid back from inside the working element. A third lumen comprising either a supply lumen for delivering working fluid inside the working element, or a return lumen used to send working fluid back from inside the working element.
[0106]
Another embodiment of the invention includes a method of making a catheter device for warming or cooling surrounding fluid in a blood vessel.
[0107]
The method includes extruding an elongated catheter body; including arranging a heat transfer element, including an interior disposed at a distal end of the catheter body; and for receiving a guidewire and a second lumen. A first lumen and a second lumen, either a supply lumen for delivering working fluid inside the heat transfer element, or a return lumen used to send working fluid back from inside the heat transfer element; Including providing an integrated bi-lumen body; substantially providing a third lumen to be formed within the elongated catheter body. The third lumen comprises either a supply lumen for pumping working fluid inside the heat transfer element, or a return lumen used to return working fluid from inside the heat transfer element.
[0108]
Implementations of the invention may include one or more of the following.
[0109]
The second lumen has a hydraulic diameter, the third lumen has a hydraulic diameter, and the ratio of the hydraulic diameter of the second lumen to the hydraulic diameter of the third lumen is substantially. It is equal to 0.75.
[0110]
Providing the integrated elongate bi-lumen body substantially within the elongate catheter body includes simultaneously extruding the integrated bi-lumen body within the elongate catheter body.
[0111]
Another embodiment of the present invention includes a method of making a catheter device.
[0112]
The method includes extruding an elongate catheter body; including locating an active element, including an interior disposed at a distal end of the catheter body; a first method for receiving a guidewire and a second lumen. An integrated type including one lumen and a second lumen consisting of either a supply lumen for delivering working fluid to the inside of the working element or a return lumen used to send working fluid back from inside the working element. Extruding an elongated bi-lumen body; substantially providing an integrated bi-lumen body such that a third lumen is formed within the elongated catheter body, wherein the third lumen is operative. It consists of either a supply lumen that feeds working fluid inside the element, or a return lumen that is used to send working fluid back from inside the working element.
[0113]
Another embodiment of the present invention includes an apparatus for warming or cooling the surrounding fluid in a blood vessel.
[0114]
The device includes an elongate catheter body, a heat transfer element including an interior disposed at a distal end of the catheter body, and an inner tip, and an inner portion defining at least a first heat transfer segment and a second heat transfer segment. And at least one elongate supply lumen including at least one elongate supply lumen disposed within the catheter body, and first means for delivering a working fluid to an inner tip of the first heat transfer segment; A second means for delivering a working fluid to the inner tip of the thermal segment.
[0115]
In an embodiment of the invention, a second working fluid delivery means is used to deliver working fluid to the inside of the heat transfer element near the midpoint of the heat transfer element.
[0116]
Another embodiment of the present invention includes an apparatus for warming or cooling surrounding fluid in a blood vessel.
[0117]
The device includes an elongate catheter body, includes a heat transfer element disposed at a distal end of the catheter body, and an inner tip and an inner portion, wherein at least one elongate supply lumen disposed within the catheter body; At least one elongate supply including first means for distributing the working fluid to an inner end of the element, and second means for delivering the working fluid inside the heat transfer element at one or more points proximal to the distal end of the heat transfer element. Includes lumen.
[0118]
In an embodiment of the invention, a second working fluid delivery means is used to deliver working fluid to the inside of the heat transfer element near the midpoint of the heat transfer element.
[0119]
Another embodiment of the present invention includes an apparatus for warming or cooling surrounding fluid in a blood vessel.
[0120]
The device includes an elongated catheter body, including a heat transfer element disposed at a distal end of the catheter body, and an inner tip and an inner portion defining at least a first heat transfer segment and a second heat transfer segment. And a first elongate supply lumen disposed within the catheter body, ending at a location near the inner end of the heat transfer element and distributing working fluid to the inner end of the heat transfer element; and a catheter body. A second elongate supply lumen disposed therein, the second means terminating near an end of the heat transfer element and distributing working fluid to an inner portion of the heat transfer element near the end of the heat transfer element.
[0121]
In an embodiment of the invention, a second working fluid delivery means is used to deliver working fluid to the inside of the heat transfer element near the midpoint of the heat transfer element.
[0122]
Another embodiment of the present invention includes an apparatus for warming or cooling the surrounding fluid in a blood vessel.
[0123]
The apparatus includes an elongated catheter body, wherein a heat transfer element disposed at a distal end of the catheter body includes an inner tip, the inner portion comprising at least a first heat transfer segment inner portion and a second heat transfer segment inner portion. And a first elongate supply lumen disposed within the catheter body, terminating at an inner end of the first heat transfer segment, and for distributing a working fluid inside the first heat transfer segment. A first means, and a second elongate supply lumen disposed within the catheter body, the second means terminating near a distal end of the heat transfer element and for distributing the working fluid inside the second heat transfer segment. Including.
[0124]
In an embodiment of the invention, a second working fluid delivery means is used to deliver working fluid to the inside of the heat transfer element near the midpoint of the heat transfer element.
[0125]
Another embodiment of the present invention includes an apparatus for warming or cooling surrounding fluid in a blood vessel.
[0126]
The device includes an elongated catheter body, wherein a heat transfer element disposed at a distal end of the catheter body includes an inner tip, the inner portion of the working fluid to enhance a heat transfer effect between the heat transfer element and the working fluid. Used for induction of mixing. The heat transfer element includes at least a first heat transfer segment, a second heat transfer segment, and an intermediate segment between the first heat transfer segment and the second heat transfer segment, wherein one elongate supply lumen is disposed within the catheter body. , Used to pump the working fluid inside the heat transfer element. The supply lumen element includes a circular outer surface, a portion of which is defined by the outer surface of the supply lumen element and the inner portion of the heat transfer element, wherein an elongate return lumen extends from the inside of the heat transfer element to the working fluid. Used to send back. Moreover, the distance between the inner portion of the heat transfer element and the outer surface of the supply lumen element near the intermediate segment is less than or equal to the distance between the inner portion of the heat transfer element and the outer surface of the supply lumen element near the first heat transfer segment. .
[0127]
Implementations of the invention may include one or more of the following.
[0128]
The distance between the inner portion of the heat transfer element and the outer surface of the supply lumen element proximate the intermediate segment is set such that the working fluid has at least a characteristic flow resulting from a flow in some transitional nature.
[0129]
The intermediate segment includes an inner diameter that is less than or equal to the inner diameter of the first or second heat transfer segments.
[0130]
The supply lumen includes an outer diameter proximate the intermediate segment that is greater than an outer diameter proximate the first heat transfer segment or the second heat transfer segment.
[0131]
The supply lumen element is comprised of a multi-lumen element.
[0132]
The supply lumen element includes a supply lumen having a hydraulic diameter, and the return lumen has a hydraulic diameter equivalent to 0.75 times the hydraulic diameter of the supply lumen.
[0133]
The middle segment includes a flexible bellows joint.
[0134]
Another embodiment of the present invention includes an apparatus for warming or cooling surrounding fluid in a blood vessel.
[0135]
The device includes an elongated catheter body, wherein a heat transfer element disposed at a distal end of the catheter body includes an inner tip, the inner portion being activated to enhance a heat transfer effect between the heat transfer element and the working fluid. Used to induce fluid mixing. One elongate supply lumen is located within the catheter body and is used to pump working fluid inside the heat transfer element. An elongated return lumen is disposed within the catheter body and is used to return working fluid from inside the heat transfer element. Means for inducing mixing of the working fluid are arranged within the heat transfer element to further enhance the heat transfer effect between the heat transfer element and the working fluid.
[0136]
Implementations of the invention may include one or more of the following.
[0137]
The supply lumen element consists of a multi-lumen element having a circular outer surface. The supply lumen element includes a supply lumen having a hydraulic diameter, and the return lumen has a hydraulic diameter corresponding to 0.75 times the hydraulic diameter of the supply lumen.
[0138]
Another embodiment of the present invention includes an apparatus for warming or cooling the surrounding fluid in a blood vessel.
[0139]
The device includes an elongated catheter body, wherein a heat transfer element disposed at a distal end of the catheter body includes an inner tip, the inner portion of the working fluid to enhance a heat transfer effect between the heat transfer element and the working fluid. Used for induction of mixing. One elongate supply lumen is disposed within the catheter body and is used to pump working fluid inside the heat transfer element. An elongated return lumen is disposed within the catheter body and is used to return working fluid from inside the heat transfer element. Mixing enhancement means are disposed within the heat transfer element and are used to mix the working fluid to further enhance the heat transfer effect between the heat transfer element and the working fluid.
[0140]
Implementations of the invention may include one or more of the following.
[0141]
The supply lumen element comprises a multi-lumen element having a circular outer surface. The supply lumen element includes a supply lumen having a hydraulic diameter and the return lumen has a hydraulic diameter approximately equal to the hydraulic diameter of the supply lumen.
[0142]
A fourteenth embodiment includes a method of warming or cooling the surrounding fluid in a blood vessel.
[0143]
The method includes providing, within the bloodstream of a blood vessel, a device for warming or cooling fluid surrounding the blood vessel, the device comprising an elongate catheter body, and a transfer device disposed at a distal end of the catheter body. The heat element includes an inner tip, which is used to induce mixing of the working fluid to enhance the heat transfer effect between the heat transfer element and the working fluid. One elongate supply lumen is located within the catheter body and is used to pump working fluid inside the heat transfer element. An elongated return lumen is disposed within the catheter body and is used to return working fluid from inside the heat transfer element. Mixing enhancement means are disposed within the heat transfer element and are used to further enhance the heat transfer effect between the heat transfer element and the working fluid; using the supply lumen and the return lumen to remove the working fluid. Flow to and along the inner portion of the heat transfer element; by generating a mixture between the inner portion and the working fluid used to induce mixing of the working fluid, a transfer between the working fluid and the heat transfer element is generated. Exerts a thermal function; exerts an additional heat transfer function between the working fluid and the heat transfer element by exerting further mixing of the working fluid with the mixing enhancing mechanism and the inner part; between the heat transfer element and the working fluid Heat is transferred between the blood flow and the heat transfer element.
BEST MODE FOR CARRYING OUT THE INVENTION
[0144]
Overview. In the following description, the term “pressure conduction” refers to a state between two points in a flowing or non-flowing fluid. When pressure is applied to one point, if there is pressure conduction between the two points, the second point will someday feel the effect of the pressure. Any number of valves or elements can be placed between the two points, and if the above test is met, the two points are in pressure conduction. For example, any number of pipe fittings can be placed between the two pipes for an inflow fluid in the pipes, and the points in each pipe are in pressure conduction as long as the open circuit is maintained.
[0145]
One or two processes and one or two piece devices can be used to induce therapeutic hypothermia to lower the body temperature intravascularly. A cooling element can be placed in a vein, such as a high-flow venous space, to absorb heat from blood flowing into the heart. This heat transfer causes cooling of the blood flowing in the heart and blood vessels. Such methods and devices can be used therapeutically to induce artificial hypothermic conditions.
[0146]
The heat transfer element that systematically cools the blood must provide the required rate of heat transfer to produce the desired cooling effect throughout the blood vessel. This can be up to 300 watts or more, depending at least in part on the patient's weight and vascular flow rate. The heat transfer element can be provided with a surface structure to increase the rate of heat conduction. The surface structure and other components of the heat transfer element will be described in detail below.
[0147]
One problem with hypothermia as a treatment is that the patient's thermoregulatory defense has begun and attempts to spoil hypothermia. Methods and devices for reducing this thermoregulatory response can also be used. For example, the patient can be covered with a thermal blanket, which makes the patient more comfortable.
[0148]
Thermoregulatory drugs can also be used to lower the trigger point at which a patient's thermoregulatory system attempts to defend. Such agents are described in more detail below. Methods using body temperature regulators, thermal blankets and heat transfer elements are also described in detail below.
[0149]
Anatomical arrangement. The internal pharyngeal vein is a vein that drains the brain directly. The external and internal throats meet at the base of the neck. The internal pharyngeal vein associates with the subclavian vein to form the brachiocephalic artery, which drains into the superior vena cava. As shown in FIG. 1, the superior vena cava drains into the right atrium of the heart. The superior vena cava supplies blood from the body web to the heart.
[0150]
Cooling elements can be placed in the superior vena cava, inferior vena cava, veins feeding into the superior vena cava, and the heart to cool the body. The physician attempts to access the superior vena cava percutaneously by placing the catheter subcutaneously or into the internal and external pharyngeal vein. The blood cooled by the heat transfer element is processed by the heart and given to the body in an oxygen infusion form to be used as a conductive medium for cooling the body. The lungs have a very low heat capacity and the flowing blood cannot be reheated much.
[0151]
The vasculature, by its very nature, provides preferential blood flow to high blood flow organs such as the brain and heart. Thus, these organs are preferentially cooled by the process shown in FIG. FIG. 2 is a graph showing measured temperature versus cooling time. This graph shows the effect of placing a cooling element in the superior vena cava of a sheep. The core temperature measured by the esophageal probe is shown in curve 14. Brain temperature is shown by curve 12.
[0152]
Throughout all experiments, brain temperature appears to drop more rapidly than core body temperature. This effect is believed to be due to the preferential supply of blood to the brain and heart. This effect can be further accentuated if a thermoregulatory effect such as vasoconstriction occurs to concentrate blood supply to the core vasculature system and from the peripheral vasculature system.
[0153]
Heat conduction. When the heat transfer element is inserted approximately concentrically into an artery or vein, the heat transfer between the surface of the heat transfer element and the blood is forced convection. Convection depends on the movement of the fluid that conducts heat. Forced convection occurs when an external force causes movement in the fluid. In the case of arterial or venous flow, heating of the heart causes movement of blood around the heat transfer element.
[0154]
The magnitude of the heat transfer rate is proportional to the surface area of the heat transfer element, the temperature difference, and the heat transfer coefficient of the heat transfer element.
[0155]
The acceptability of the artery or vein where the heat transfer element is located is limited in diameter and length. Thus, the surface area of the heat transfer element must be constrained to avoid significant obstruction of the arteries and veins, and the heat transfer element must easily pass through the blood vessel. For placement in the superior vena cava via the external throat, the cross-sectional diameter of the heat transfer element is limited to about 5-6 mm and its length is limited to approximately 10-15 cm. For placement in the inferior vena cava, the cross-sectional diameter of the heat transfer element is limited to approximately 6-7 mm and the length is approximately 25-35 cm.
[0156]
Reducing the surface temperature of the heat transfer element increases the temperature difference. However, the minimum allowable surface temperature is limited by the properties of the blood. As the blood approaches freezing, it forms an ice occlusion plug in the blood, which stagnates downstream, resulting in severe local anemia injury. Moreover, reducing the temperature of the blood increases its speed, resulting in a slight decrease in the convective heat transfer coefficient.
[0157]
In addition, the increased velocity of the blood results in an increased pressure effect in the arteries, jeopardizing blood flow to the brain. When such a danger occurs, it is advantageous to limit the minimum allowable surface temperature of the heat transfer element to approximately 5 ° C. This results in a temperature difference between the blood flow and the heat transfer element of approximately 32 ° C. For other physiological reasons, there is a limit on the maximum allowable surface temperature of the heating element.
[0158]
The mechanism by which the convective heat transfer coefficient is increased is complicated. However, it is well known that the convective heat transfer coefficient increases with the level of "mixing" or "turbulent" kinetic energy in the fluid stream. It is advantageous, then, for the blood stream to have a high degree of mixing in contact with the heat transfer element.
[0159]
Blood flow has a much more stable flow in the superior vena cava than in arteries. However, blood flow in the superior vena cava still has a high degree of inherent mixing or turbulence. The Reynolds number in the superior vena cava is, for example, in the range of 2000 to 5000. Thus, blood cooling in the superior vena cava benefits from raising the level of mixing of the heat transfer elements, but this benefit is substantially less than with intrinsic mixing.
[0160]
A thin boundary layer forms during the heart cycle. The boundary layer occurs near the heat transfer element and adjacent to the wall of the artery or vein. Each boundary layer is about the same thickness as the boundary layer that occurs on the wall of the artery when there is no heat transfer element. Free flow regions are also created in the annular ring around the heat transfer element. The heat transfer elements used in such vessels reduce the formation of such viscous boundary layers.
[0161]
Characteristics of heat transfer element. The intravascular heat transfer element must be flexible and capable of being placed in the vena cava or artery. The flexibility of the heat transfer element is an important property. This is because the heat transfer element is inserted into a vein such as the external throat and first accesses the vena cava through a series of one or more branch vessels. Further, the heat transfer element is ideally formed from a highly thermally conductive material, such as a metal, to promote heat conduction.
[0162]
The use of a high thermal conductivity material increases the heat transfer between the working fluid and the blood in the heat transfer element at a given temperature difference. This facilitates the use of a high temperature coolant or a low temperature fluid in the heat transfer element and allows for the use of a safer working fluid, such as water or saline. High heat conductive materials such as metals tend to be hard. Therefore, the design of the heat transfer element should promote flexibility in naturally flexible materials.
[0163]
When placed in the superior vena cava to reduce body temperature to about 30-34 ° C., the cooling element is estimated to absorb at least about 300 watts of heat. These temperatures are believed to be appropriate to benefit from the hypothermia method described above. The power removed determines how quickly the target temperature is reached. For example, in a beating therapy where it is desired to lower the brain temperature, the brain temperature is reduced by about 4 ° C. per hour in a 70 kg person, and 330 watts are removed.
[0164]
In one embodiment of the invention, a modular design is used. This design creates a spiral blood flow and creates a certain level of mixing in the blood flow by periodically forcing sharp changes in the direction of the coiled blood flow. Abrupt changes in flow direction are achieved using a series of two or more heat conducting segments. Each segment includes one or more spiral ridges.
[0165]
The periodic rapid change in the direction of the blood flow swirl to induce strong free-flow turbulence is found in general clothes washing machines. The washing machine rotor initially rotates in one direction, causing laminar flow. When the rotor suddenly reverses direction, significant turbulent kinetic energy is generated throughout the wash tub as the changing flow causes turbulent motion in the garment / water slurry. Such a surface structure also increases the area of the heat transfer element and increases the heat transfer.
[0166]
A heat transfer element with a smooth surface could provide the desired amount of heat transfer. However, as noted above, the convective heat transfer coefficient increases with the level of turbulent kinetic energy in the fluid flow. If the flow through the smooth heat transfer element thus does not conduct enough heat, it is advantageous to bring the turbulent or mixed blood flow into contact with the heat transfer element.
[0167]
The graph of FIG. 3 shows a steady state turbulent flow. The vertical axis is flow velocity, and the horizontal axis is time. The average velocity of the turbulence is shown by line 118. The actual instantaneous flow rate is shown by curve 116.
[0168]
Under steady pressure conditions, the flow in the pipe is characterized by a balance between viscous strain and steady pressure gradient. Such a flow is called Poiseuille flow. The velocity diagram of FIG. 7 shows a steady state Poiseuille flow driven by a steady pressure gradient.
[0169]
The velocity of the fluid flowing through the pipe is shown in FIG. 7 by a parabolic curve and a corresponding velocity vector. The velocity of the fluid in contact with the wall is zero. The boundary layer is the area of flow in contact with the pipe surface where viscous stress predominates. In the Poiseuille flow in a stable state, a boundary flow is generated until all the pipes are included. That is, the thickness of the boundary layer in FIG. 16 is １ ／ of the pipe.
[0170]
Under Poiseuille flow conditions, the Reynolds number, the ratio of initial force to viscous force, can be used to characterize the turbulent kinetic energy present in the flow. For Poiseuille flow, the Reynolds number must be greater than about 2300 to cause a transition from laminar to turbulent.
[0171]
Further, if the Reynolds number is greater than about 2000, the boundary layer becomes "tripped". Tripping is a process in which small disruptions in the boundary layer can create turbulent conditions. The receptivity of the boundary layer to "tripping" is proportional to the Reynolds number and is nearly zero for Reynolds numbers less than 2000.
[0172]
In comparison to steady state Poiseuille flow, blood flow in the arteries is pulsed because it is induced by a heart beat. The description of this pulsation in connection with FIGS. 5 to 19 below is for the case where the heat transfer element has been inserted into the artery.
[0173]
The graph of FIG. 4 shows the velocity of blood flow in the artery as a function of time. A beating heart provides a pulse flow of approximately 0.5-1 second duration. This is known as the heart cycle. The horizontal axis in FIG. 4 represents time in seconds, and the vertical axis represents the average velocity of blood in cm / sec.
[0174]
Although very high velocities are reached at the peak of the pulse, high velocities occur in only a small part of the cycle. In fact, in the carotid artery, the blood velocity goes to zero at the end of the pulse and temporarily reverses.
[0175]
Due to the relatively short duration of the heart vein, blood flow in arteries does not occur in classic Poiseuille flow. The velocity diagram in FIG. 8 shows the blood flow rate in the artery averaged for the heart beat. The boundary layer where the flow velocity decays from free flow to zero is very thin, typically 1/6 to 1/20 of the artery diameter, whereas in Poiseuille flow conditions it is 11/2 of the artery diameter.
[0176]
When the flow in the artery is more stable than the pulsation as described above, a transition from laminar flow to turbulent flow occurs when the Reynolds number exceeds about 2000. However, in pulsatile arterial flow, the Reynolds number fluctuates during the cardiac cycle, as does the flow velocity. Due to the high stability and acceleration of the free flow in the pulsating flow, the critical value of the Reynolds number at which the mode of unstable motion grows into turbulence is probably around 9000.
[0177]
Blood flow in the artery in question is stratified over more than 80% of the cardiac cycle. In FIG. 4, the blood takes about time t.₁~ T_TwoOver a small portion of the systolic flow, which is less than 20% of the duration of the cardiac cycle. If the heat transfer element is placed in an artery, heat conduction will be facilitated for a short period of time. However, to conduct the heat necessary to selectively cool the brain, in arterial embodiments, turbulent kinetic energy should be generated in the bloodstream and throughout the cardiac cycle. Should be maintained.
[0178]
A thin boundary layer is formed during the cardiac cycle. The boundary layer is formed on the surface of the smooth heat transfer element. The velocity diagram shown in FIG. 9 is the blood flow velocity in the artery after the insertion of the smooth heat transfer element and is averaged over the heart beat. In the figure, the diameter of the heat transfer element is about 1/2 of the artery diameter. The boundary layer occurs near the heat transfer element and near the artery wall.
[0179]
Each boundary layer has a thickness approximately equal to the thickness of the boundary layer occurring on the wall of the artery without heat transfer elements. The free flow region occurs in an annular ring around the heat transfer element. Blood flow through such a smooth heat transfer element conducts sufficient heat to achieve the desired temperature control.
[0180]
One way to increase the rate of heat transfer is to create a turbulent boundary layer on the surface of the heat transfer element. However, turbulence in a very thin boundary layer does not generate enough kinetic energy to provide the required heat conduction velocity. Therefore, in order to induce a heat transfer rate sufficient to increase the heat transfer rate sufficient to cool the brain, a stirring mechanism that rapidly changes the direction of the speed vector must be used. This creates a high level of turbulence intensity in the free stream, thereby sufficiently increasing the rate of heat transfer.
[0181]
Ideally, this turbulence intensity is maintained over a significant portion of the cardiac cycle. Furthermore, turbulent kinetic energy is ideally generated not only in the boundary layer, but throughout the free flow. The graph shown in FIG. 5 shows the velocity of continuous turbulence under beating conditions as a function of time, resulting in optimal heat transfer in the arterial blood flow.
[0182]
Time t in FIG.₁~ T_TwoFor short intervals of the turbulence velocity variation, the turbulence velocity variation is what is seen over the cycle. These speed fluctuations are seen in free flow. The turbulence intensity shown in FIG. 5 is at least 0.05. In other words, the instantaneous speed fluctuation deviates from the average speed by at least 5%. Ideally, turbulence or mixing is generated throughout the cardiac cycle, but turbulence or mixing is as low as 75%, only 50%, or as low as 30%, or as low as 20% of the heart cycle. If still maintained, the benefits of turbulence will be obtained.
[0183]
In one embodiment, a modular design is used to produce the desired level of turbulence intensity or mixing in the free flow of blood during the entire cardiac cycle. This design creates a spiral blood flow, producing high levels of mixing in the free stream.
[0184]
The non-declining azimuthal velocity in the flow results in instability, as the fluid's azimuthal velocity swirls in a tube that decays towards a static outer boundary, and the inner fluid spontaneously interacts with the fluid near the wall. Which is similar to Taylor cells in pure azimuthal flow between the rotating inner cylinder and the static outer cylinder.
[0185]
This instability results from the lack of any opposition to the centripetal acceleration of fluid particles moving along the spiral path, and the pressure in the tube is a function of longitudinal position only. In one embodiment, the apparatus of the present invention provides an azimuthal velocity inside the generated pipe flow so that as the fluid descends longitudinally through the pipe, there is a continuous flow between the flow core and the periphery. Fluid replacement occurs.
[0186]
This fluid exchange enhances heat transfer and effectively increases the convective heat transfer coefficient more than in an unstirred pipe stream. Turbulence is possible if the induced azimuthal velocity is high enough, but a large exchange of this fluid need not be turbulent.
[0187]
FIG. 6 is a perspective view of such a turbulent or mixing induced heat transfer element in an artery. In this embodiment, turbulence or mixing is further enhanced by forcibly and periodically changing the direction of the vortex flow. Turbulent or mixed flows are seen at point 120 in the free flow region. Abrupt changes in flow direction are achieved through the use of a series of two or more heat transfer elements, each consisting of one or more spiral ridges. Ideally, the segments are close enough together to prevent flow re-stratification between the segments.
[0188]
The use of periodic abrupt changes in the direction of blood flow vortex to induce strong free-flow turbulence or mixing is seen in clothes washing machines. The washing machine rotor first rotates in one direction, causing laminar flow. When the rotor suddenly reverses direction, significant turbulent kinetic energy is formed as the changing flow causes random turbulent mixing motions in the garment / water slurry.
[0189]
Such cooling or heating according to one embodiment of the present invention is shown in FIG. The vessel wall 132 through which the blood flow 100 passes is shown. A catheter 130 is positioned within the blood flow 100 to affect blood temperature. The catheter 101 has an inlet lumen 126 for providing the working fluid 107 and an outlet lumen 124 for discharging the working fluid 128. The function of each lumen is, of course, opposite to that described. The reverse configuration is particularly advantageous if the purpose is to heat the blood rather than cool the blood.
[0190]
The heat transfer in this system is governed by the following mechanism. (1) Convective heat transfer from blood 122 to outlet lumen 124. (2) conduction through the wall of the outlet lumen 124; (3) Convective heat transfer from outlet 3 lumen 124 to working fluid 128. (4) conduction through the working fluid 128; (5) convective heat transfer from the working fluid 128 in the outlet lumen 124 to the inlet lumen 126 and (6) conduction through the wall of the inlet lumen 126.
[0191]
Once the lumen and working fluid materials are selected, the conduction heat conduction depends only on the temperature gradient. Convective heat transfer, on the other hand, depends on the motion of a fluid that conducts heat. Forced convection results when the heat transfer surface comes into contact with a fluid whose movement is being induced (or forced) by pressure gradients, regional fluctuations or other forces. In the case of arterial flow, the beating heart provides an oscillating pressure gradient, forcing movement of blood in contact with the heat conducting surface. The invention also uses turbulence to enhance forced convection heat transfer.
[0192]
The speed Q of convective heat conduction is S (the area of the heat transfer element in direct contact with the fluid), ΔT = T_b−T_s(Surface temperature T of heat transfer element_sAnd free flowing blood temperature T_bTemperature gradient between h) and h_c(Translation)_cThere is a line at the top of. The same applies hereinafter. ) (Average convective heat transfer coefficient over the heat transfer region). h_cIs called "surface coefficient of heat conduction" or "convective heat conduction coefficient".
[0193]
The magnitude of the rate of heat transfer Q to and from the fluid stream can be increased by manipulating the parameters as described above. Practical constraints constrain those parameters and how well they can be manipulated. For example, the internal diameter of a common carotid artery is in the range of 6-8 mm. To avoid vascular occlusion, the diameter of the heat transfer element located there cannot exceed much 4 mm. In addition, the length of the heat transfer element is also limited, and the length is limited to about 10 cm for placement in the carotid artery. This estimate is based on the length of a common carotid artery, ie, 8-12 cm.
[0194]
The same applies to use in a venous system.
[0195]
Therefore, the area value S is constrained by physical constraints due to the size of the artery in which the device is placed. Although surface structures such as fins can be used to increase the area of the heat transfer elements, those structures alone do not provide sufficient area for the normally required rate of heat transfer. According to one embodiment of the present invention, described below, a beveled heat transfer element is used, which is large in size but adapted to small arteries and veins. Because the device is inflatable, it can be inserted in a deflated state into an artery or vein to minimize invasion. Once the device is positioned, it can be expanded to increase area and increase heat transfer rate.
[0196]
Some will try to change the magnitude of the heat transfer rate by changing ΔT. (ΔT = T_b−T_s) Is the surface temperature T of the heat transfer element._sCan be changed by changing. The permissible surface temperature of the heat transfer element is limited by the characteristics of the blood. Blood temperature is fixed at about 37 ° C, and blood freezes at approximately 0 ° C. As blood approaches freezing, ice embolisms form in the blood, causing it to stagnate downstream and cause severe local anemia damage.
[0197]
Further decreasing the temperature of the blood increases its speed, h_cValue decreases slightly. The increased velocity of the blood causes a pressure drop in the blood vessels, making the blood flow dangerous. Due to the suppression described above, it is advantageous to limit the surface temperature of the heat transfer element to approximately 1-5 ° C. This results in a maximum temperature difference between the blood flow and the heat transfer element of approximately 32-36 ° C.
[0198]
h_cSome will try to change the magnitude of the heat transfer rate by changing the temperature. Then the value of the convective heat transfer coefficient h_cSuppression is reduced. h_cThe mechanism by which the value of is increased is complex. However, for a fixed average speed value h_cOne way to increase turbulence is to increase the level of turbulent kinetic energy in the fluid stream.
[0199]
Heat conduction velocity Q without fluid flow_no-flowIs proportional to ΔT. Surface temperature T of heat transfer element_sAnd free flowing blood temperature T_bIs timed to the dispersion constant k and inversely proportional to the thickness δ of the laminar flow.
[0200]
The magnitude of the improvement of the heat conduction by the fluid flow is the ratio of the heat conduction velocity of the fluid flow to the heat conduction velocity without the fluid flow N = Q_flow/ Q_no-flow= H_cIt can be estimated by taking / (k / δ). This ratio is called the Nusselt number ("Nu"). For convective heat transfer between the blood and the heat transfer element surface, a Nusselt number of 30 to 80 has been found to be appropriate for use in selective cooling of various organs in the human body. The Nusselt number generally depends on some other numbers, such as Reynolds number, Warmersly number, and Prandtl number.
[0201]
A turbulent kinetic energy can be induced using a stirring-type mechanism that rapidly changes the direction of a velocity vector to increase the heat conduction velocity. The level of the turbulence thus formed is represented by the turbulence intensity θ. Is defined as the root mean square of the fluctuation speed divided by the average speed. Such a mechanism can create high levels of turbulence intensity in free flow, thereby increasing the rate of heat transfer. This turbulence intensity is ideally maintained for a significant portion of the cardiac cycle and ideally formed throughout the free flow, not just in the boundary layer.
[0202]
In any case, turbulence occurs for a short period of the heart cycle. In particular, the blood flow becomes turbulent between small portions in the descending systolic flow. This portion is less than 20% of the cardiac cycle period. When the heat transfer elements are arranged concentrically in the artery, the heat transfer rate is increased for this short period.
[0203]
For those variations in general, the turbulence intensity is at least 0.05. In other words, the instantaneous speed fluctuation deviates from the average speed by at least 5%. Ideally, turbulence is formed throughout the heart cycle, but turbulence benefits from turbulence as low as 75%, 50% or 30% or 20% of the heart cycle. It is.
[0204]
U.S. Patent No. 6,096,068 ("Selected Organ Cooling Catheter and Uses Thereof") discloses a heat transfer element that can be advantageously used to heat or cool an organ or volume. The heat transfer element is formed from a high heat conductive material such as a metal. Metallic heat transfer elements provide a high degree of heat conduction due to their high thermal conductivity. Bellows have a high degree of articulation to reduce the inherent rigidity of metal. The size of the device has been minimized, for example, to less than 4 mm to avoid obstruction of blood flowing into the arteries.
[Patent Document 29]
U.S. Pat. No. 6,096,068
[0205]
FIG. 11 shows the dependence of the Nusselt number on the Reynolds number for a fluid flowing through a long duct, for example air flowing through a long heating pipe at a uniform wall temperature. Although the figure shows this relationship for different fluids through different structures, it is believed that this relationship also exists for blood flow through blood vessels. It is shown that when the Reynolds number is less than a certain number (about 2100 in this case), the flow becomes laminar.
[0206]
In the Reynolds number range between other sets (2100-10000 in this case), a transition from laminar to turbulent occurs. The flow of this situation is called transitional. Mixing due to the heat transfer element of the present invention results in at least a transitional flow. At other Reynolds numbers (above about 1000 in this case), the flow is completely turbulent.
[0207]
The type of flow that occurs is important. This is because in laminar flow through the duct there is no warming by vortex motion and no mixing of cold fluid particles. So the only possible heat conduction is by conduction. Since most fluids have small thermal conductivity, the coefficient of thermal conductivity in laminar flow is relatively small. In transitional and turbulent flows, mixing occurs through vortices, causing warmer fluids to be transported to cooler regions and vice versa.
[0208]
Even small motion compared to perfect turbulence, the mixing motion significantly accelerates the heat transfer, and above a certain Reynolds number a significant increase in the heat transfer coefficient occurs. It is about 2100 in the graph of FIG. It is at this point that the Nusselt number increases dramatically from the figure. A different number of sets will be measured for blood flow through an artery or vein. However, at least the Nusselt number in the transition region is important for high heat conduction.
[0209]
apparatus. In one embodiment of the cooling element of the present invention shown in FIG. 12, the heat transfer element 102 has a series of extended articulating segments or modules 134, 104, 106. Although these segments are shown in this embodiment, more than two segments can be used in the present invention. As shown, a first extending heat conducting segment 134 is located at a distal end of the heat transfer element 102.
[0210]
The mixing-inducing outer surface of segment 134 has four parallel spiral ridges 138 and four parallel spiral grooves 136 therebetween. One, two, three or more ridges 138 may be used. In this embodiment, ridge 138 and groove 136 are left-handed, which is referred to herein as counter-clockwise spiral rotation as it travels toward the end of heat transfer segment 134.
[0211]
The first heat-conducting segment 134 is connected to the second heat-conducting segment 104 by a first bellows portion 140, thereby providing flexibility and compressibility. The second heat transfer segment 104 has one or more spiral ridges 144 and one or more grooves 142 therebetween. Ridge 144 and groove 142 have a right or clockwise twist as they travel toward the end of heat transfer segment 104.
[0212]
Second heat conducting segment 104 is coupled to third extending heat conducting segment 106 by a second bellows portion 108. The third heat transfer segment 106 has one or more spiral ridges 148 and one or more grooves 146 therebetween. Ridge 148 and groove 146 have a left or counterclockwise twist as they move toward the end of heat transfer segment 106.
[0213]
The continuous heat conducting segments 134, 104, 106 of the heat transfer element 102 alternate between left and right twists. The left or right twist of a particular segment is not significant, as long as adjacent segments have opposite spiral twists.
[0214]
In addition, the rounded contours of the ridges 138, 144, 148 cause the heat transfer element 102 to assume a relatively atraumatic shape, thereby minimizing the potential for damage to the vessel wall. The heat transfer element of the present invention may have a few or more heat conducting segments.
[0215]
Bellows portions 140, 108 are formed from a seamless, non-porous material such as metal and are impermeable to gas, which is particularly important depending on the type of working fluid circulating through heat transfer element 102. Because of its structure, the bellows section can bend, expand and contract to increase flexibility and facilitate passage through blood vessels. Because of the bellows portion, the heat transfer element can be axially compressed, thus limiting trauma when its end hits the vessel wall. The bellows section can also tolerate very low temperatures without loss of behavior. In another embodiment, the bellows can be replaced by a flexible polymer tube, which is adhered between the heat conducting segments.
[0216]
The outer surface of the heat transfer element 102 can be formed of a metal and can contain a very thermally conductive material, such as nickel, which promotes heat conduction. Alternatively, metals such as stainless steel, titanium, aluminum, silver, and copper may be used, and may or may not be subjected to a coating or treatment for enhancing biological compatibility or suppressing blood clots.
[0217]
Suitable biocompatible coatings include, for example, gold, platinum or polymeric paraline. The heat transfer element 102 can be manufactured by plating a thin metal layer on a mandrel having a suitable pattern. Thus, the heat transfer element can be mass-produced at low cost. This is important for a disposable medical device.
[0218]
Since the heat transfer element can be present in the blood vessel for as long as 24-48 hours or more, it is desirable that the surface of the heat transfer element be treated so that no clots form. In particular, the bellows portions 140, 108 may be treated. This is because blood flow stagnation occurs in the vortex, causing a clot to form and stick to the surface to form a thrombus.
[0219]
One way to avoid thrombus formation is to attach an antithrombotic agent to the surface of the heat transfer element. For example, heparin is known to inhibit clot formation and is known to be effective for biocoaching. Alternatively, ions such as nitrogen may be bombarded on the surface of the heat transfer element. Nitrogen impact hardens and smoothes the surface and prevents sticking of solidified clots. Other coatings that provide good properties include lubricated coatings. Lubricating coating on the catheter associated with the heat transfer element facilitates placement, for example, in the vena cava.
[0220]
FIG. 13 shows a longitudinal cross-section of the heat transfer element according to one embodiment of the present invention, taken along line 2-2 in FIG. 12, with some internal contours omitted. Inner tube 150 forms inner and outer lumens 158, 156 within heat transfer element 102. Once the heat transfer element is positioned within the blood vessel, a working fluid, such as sarin or other aqueous solution, is circulated through the heat transfer element.
[0221]
Fluid flows into the inner lumen 158 through the delivery catheter. At the end of the heat transfer element, the working fluid exits the lumen and enters the outer lumen 156. As the working fluid flows through the lumen 156, heat is conducted from the working fluid to the outer surface 152 of the heat transfer element.
[0222]
Because the heat transfer element is formed from a highly conductive material, the temperature of the outer surface 152 will be very close to the temperature of the working fluid. Forming tube 150 in an insulating divider thermally isolates lumen 158 from lumen 156. For example, insulation is achieved by forming longitudinal air channels in the walls of the insulation tube 150. Alternatively, tube 150 may be formed from a non-thermally conductive material, such as polytetrafluoroethylene or another polymer.
[0223]
It is important to note that the same mechanism that governs the rate of heat transfer between the outer surface 152 of the heat transfer element and the blood also governs the rate of heat transfer between the working fluid and the inner surface 154 of the heat transfer element. is there. The heat transfer properties of the inner surface are particularly important when using a liquid that leaves water, sarin or other liquid as the working fluid. Other coolants, such as freon, cause nucleate boiling to form a mixture by different mechanisms.
[0224]
Salin is a safe working fluid because it is non-toxic and does not form a gas embolism if leaked, which would occur with the use of boiling coolant. Since the mixing in the working fluid is enhanced by the internal shape of the heat transfer element, the working fluid is distributed by the heat transfer element at a warmer temperature and achieves the required cooling rate. Similarly, the mixing in the working fluid is also enhanced by the internal shape of the heat transfer element, so that the working fluid is distributed at a lower temperature by the heat transfer element and achieves the required heating rate.
[0225]
This has many beneficial implications in the need for insulation along the length of the catheter shaft. The diameter of the catheter shaft can be reduced due to the reduced need for insulation. Due to the enhanced heat transfer characteristics of the inner surface of the heat transfer element 102, the working fluid can be distributed to the heat transfer element at low speed and low pressure. The high pressure stiffens the heat transfer element and presses against the walls of the blood vessel, masking a portion of the outer surface 152 of the heat transfer element from blood. Due to the enhanced heat transfer properties achieved by the alternating spiral ridges 138, 144, 148, the working fluid pressure will be less than 5, 3, 2, or 1 atmosphere.
[0226]
FIG. 14 is a cross-sectional view of the heat transfer element taken along line 3-3 in FIG. This is a five leaf embodiment, and FIG. 12 is a four leaf embodiment. As described above, the number of leaves may be any number. FIG. 14 clearly shows the structure of the heat transfer element. Inner lumen 158 is defined by insulating tube 150 and outer lumen 156 is defined by the outer surface of insulating tube 150 and the inner surface 154 of the heat transfer element. In addition, the spiral ridge 144 and the spiral groove 142 are shown in FIG. Although four ridges and grooves are shown, the number may vary. Heat transfer elements with one to eight or more ridges are conceivable.
[0227]
FIG. 15 shows a heat transfer element 102 used in a blood vessel, showing one spiral leaf per segment. As the blood advances, starting from the proximal end of the heat transfer element (not shown), the first spiral heat transfer segment 134 induces a counterclockwise rotational inertia in the blood. When the blood reaches the second segment 104, the direction of rotation of the inertia is reversed and mixing occurs in the blood. When the blood reaches the third segment 106, the rotational direction of the inertia is reversed again. Abrupt changes in flow direction actively rearrange and randomize the velocity vectors to ensure mixing throughout the blood flow.
[0228]
During such mixing, the velocity vector of the blood becomes more random and possibly perpendicular to the axis of the blood vessel. Thus, the majority of the warm blood in the blood vessels is in active contact with the heat transfer element, and is largely cooled directly by contact rather than by heat conduction through the adjacent laminar flow of blood.
[0229]
In FIG. 12, the heat transfer element is designed to satisfy the above design rules. First, the heat transfer element 102 is flexible and formed from a highly thermally conductive material. Flexibility is provided by the segmental distribution of the bellows portions 140, 108, providing a joint mechanism. The bellows are of a known spiral design to provide flexibility. Second, the outer surface area 152 is increased by the use of spiral ridges 138, 144, 148 and spiral grooves 136, 142, 146.
[0230]
The ridge also allows the heat transfer element to assume an atromatic shape, minimizing the potential for damage to the vessel wall. Third, the heat transfer elements are designed to promote internal and external mixing. The direction of the grooves can be reversed between segments by a modular or segment design.
[0231]
The alternating swirl creates an alternating flow and mixing occurs in the blood in a manner similar to the mixing motion created by the washing machine rotor switching back and forth. This movement promotes mixing and enhances the rate of heat transfer. The alternating swirl design also provides advantageous mixing or turbulent kinetic energy of the working fluid flowing therethrough.
[0232]
FIG. 16 shows a third embodiment of the heat transfer element of the present invention, wherein the heat transfer element 160 comprises a series of extending articulated segments or modules 162. The first heat transfer segment 162 is located at the proximal end of the heat transfer element 160 and is a smooth circular cylinder as shown in FIG. Alternatively, it may have a turbulence-inducing or mixing-inducing outer surface. The outer surface shown in FIG. 16 has a plurality of parallel longitudinal ridges 164 and parallel longitudinal grooves 168 therebetween. One, two, three or more ridges may be used. The ridge and the groove are parallel to the axis of the first heat conduction segment 162.
[0233]
The first heat conducting segment 162 is coupled to the second heat conducting segment 162 by a flexible portion, such as the first bellows portion 166, which provides flexibility and compressibility. Alternatively, the flexible portion may be a simple flexible tube similar to the heat conducting segment of FIG. 9, but is flexible. The second heat conducting segment 162 also has a plurality of parallel longitudinal ridges 164 and parallel longitudinal grooves 168 therebetween. The ridge and the groove are parallel to the axis of the second heat conducting segment 162.
[0234]
The second thermally conductive segment 162 is coupled to the third thermally conductive segment 162 by a flexible portion, such as a second bellows portion 166 or a flexible tube, wherein the segment 162 comprises a plurality of parallel longitudinal ridges 164. And a parallel longitudinal groove 168 therebetween, with the ridge and groove parallel to the axis of segment 162. Further, in this embodiment, adjacent heat conducting segments 162 of heat transfer element 160 have mutually aligned longitudinal ridges 164 and mutually aligned longitudinal grooves 168.
[0235]
In addition, due to the rounded contour of the ridge, the heat transfer element 160 has an atraumatic shape to minimize the potential for injury to the vessel wall. The heat transfer element 160 may have a few or more heat conducting segments 162.
[0236]
Bellows portion 166 is formed from a seamless, non-porous material such as metal and is impervious to gas, which is particularly important depending on the type of working fluid circulating through heat transfer element 160. Bellows portion 166 can be bent, stretched, or compressed due to its structure, increasing the flexibility of the heat transfer element and making it easier to pass through the blood vessel. The bellows portion also allows axial compression of the heat transfer element, which can limit trauma if the end of the heat transfer element hits the vessel wall. Also, extremely low temperatures can be tolerated without impairing the behavior.
[0237]
FIG. 17 shows a fourth embodiment of a heat transfer element, wherein the heat transfer element 170 comprises a series of articulated extending segments or modules 172 wherein the first heat transfer segment 172 is Located at the proximal end. The turbulence-inducing or mixing-inducing outer surface of segment 172 has a plurality of parallel ridges 174 and parallel grooves 176 therebetween. There may be one, two, three or more ridges. The ridge and groove are parallel to the axis of the first segment 172.
[0238]
The first heat conducting segment 172 is connected to the second heat conducting segment 172 by a first flexible portion, such as a bellows portion 178, which provides flexibility and compressibility. Alternatively, the flexible portion may be a simple flexible tube very similar to the heat conducting segment shown in FIG. 9, but is flexible. The heat-conducting segment 172 also has a plurality of parallel longitudinal ridges 174 and parallel grooves 176 therebetween. These ridges and grooves are parallel to the axis of second heat conducting segment 172.
[0239]
The second thermally conductive segment 172 is coupled to the third thermally conductive segment 172 by a second flexible portion, such as a bellows portion or a flexible tube, and includes a plurality of parallel longitudinal ridges 174 and a parallel longitudinal ridge therebetween. It has grooves 176, which ridges and grooves are parallel to the axis of the third segment 172. Furthermore, adjacent heat-conducting segments have their longitudinal ridges 174 angularly offset from one another, as well as the grooves 176. This misalignment of the ridges and grooves promotes turbulence or mixing of blood flowing outside the heat transfer element 170.
[0240]
The heat conduction segment 180 shown in FIG. 18 is a description of the segments 162 and 172, and shows the coaxial structure of the segment 180. Inner lumen 182 is defined by insulating tube 184 and outer lumen 190 is defined by the outer surface of tube 184 and the inner surface 192 of segment 180. In addition, parallel ridges 186 and parallel grooves 188 are shown, wherein the ridges and grooves are square (FIG. 18) or triangular (FIGS. 16, 17) cross-sections. The ridges and grooves are formed only on the outer surface of the segment 180 with the cylindrical inner surface 192.
[0241]
Alternatively, ridges and grooves can be formed on inner surface 192 to promote turbulence or mixing in the working fluid. Although six ridges and grooves are shown, the number can be varied. When a smooth outer surface is required, a smooth outer inner surface is provided to the outer tube of the segment 180 similarly to the inner tube 184. Alternatively, the outer tube of the segment may be a smooth outer surface and a ridged inner surface such as inner surface 192.
[0242]
The outer surface 196 of the heat transfer element 194 shown in FIG. 19 has a series of axially staggered projections 198, which are shown in FIG. 20 (cross-section taken along line 6-6 in FIG. 19). Explicitly. When the blood flows along the outer surface, it collides with one of the projections 198 and a turbulent wake is formed behind the projection. As blood separates and swirls along the first protrusion, the turbulent wake encounters the next protrusion, preventing re-laminarization of the flow and forming more mixing. Thus, the velocity vectors are randomized and mixing is formed not only in the boundary layer but also over the majority of the free flow. This has a mixing effect on the internal working fluid flow.
[0243]
The working fluid circulates through the inner lumen 200 defined by the insulating tube 202 and reaches the end of the heat transfer element 194. The working fluid then conducts heat across the outer lumen 204 to the outer surface 196 of the heat transfer element. The inner surface of the heat transfer element, like the outer surface, induces turbulence in the working fluid. As shown in FIG. 20, the inner protrusions may be aligned with the outer protrusions 198 or may be offset.
[0244]
One embodiment of the catheter 206 shown in FIGS. 21 and 22 has a catheter body 208 with a heat transfer element 210 at its distal end 212. Catheter 206 has a number of lumens 214 to distribute fluid into or out of heat transfer element 210 and to place catheter 206 within a blood vessel with a guidewire. The heat transfer element 210 has a turbulence inducing recess 218 on the outer surface 252. The same recess may be provided on the inner surface 220, but is not shown. The heat transfer element 210 has four indentations 218.
[0245]
In some embodiments, multiple elements are connected by flexible connectors or bellows. FIG. 21 shows only a single heat transfer element. Alternatively, the heat transfer element as described above can be replaced by the heat transfer element 212. Alternatively, a multi-lumen configuration may be used to distribute fluid to or from actuation elements other than heat transfer elements, such as catheter balloons (dilatation balloons).
[0246]
Catheter 206 has a number of integral extended lumens, such as bi-lumen body 222, which has a first lumen body 226 and a second lumen body 228. The bi-lumen body 222 has a substantially octagonal (FIG. 22) cross-section and the outer surface 224 has the same shape. The inner surface 230 of the first lumen body 226 defines a first lumen or guidewire lumen 232, the guidewire lumen having a substantially circular cross section.
[0247]
Inner surface 230 is coated with a lubricating material to facilitate catheter 206 slipping over the guidewire. Lumen body 226 further has a first outer surface 242 and a second outer surface 244. Lumen 232 receives the guidewire and places catheter 206 in the blood vessel along the guidewire in a known manner. In the figure, the guide wire lumen 232 is not coaxial with the catheter body 208, but both may be coaxial.
[0248]
The second lumen body 228 has first and second inner surfaces 246,248. These, like the second outer surface 244 of the lumen body 226, together define a second lumen or supply lumen and are substantially uniform in cross section. Lumen 228 further has an outer surface 252. The lumen 250 has a cross-sectional area A_Twohave. Lumen 250 supplies working fluid to the interior of heat transfer element 210 to provide temperature control of the blood flow or volume as described above.
[0249]
Lumen 228 terminates near distal end 236 of catheter 206, leaving sufficient space for working fluid to exit lumen 250. So it contacts the inner surface 220 of the heat transfer element 210 to conduct heat.
[0250]
The lumen body 228 is illustrated as a single supply lumen and terminates near the distal end of the catheter to distribute working fluid at the distal end, but has one or more outlet openings 256 near the distal end and the interior of the heat transfer element. One or more outlet openings 258 may be provided near the center along the length. This configuration improves the heat transfer characteristics of the heat transfer element because the same temperature working fluid is distributed separately to each segment 104, 106 inside the heat transfer element 210 instead of continuously. Although two heat conducting segments 104, 106 are shown, the number of segments is not limited.
[0251]
In other embodiments, openings may be provided at one or more locations along the interior length of the heat transfer element in addition to the one or more openings 256 at the end of the heat transfer element.
[0252]
The supply lumens 260, 262 of the embodiment shown in FIG. 24 define lumens 264, 266 to supply working fluid to the inner surface of the heat transfer element 210. Lumen 260 terminates near end 236 of catheter 206 and distributes working fluid to the end of heat transfer element 210. Lumen 262 also distributes the working fluid to heat transfer segment 104 along the interior of heat transfer element 210 ending near the end, eg, at the center. Alternatively, lumen 262 may terminate anywhere along the length of heat transfer element 210, and two or more lumens 262 also terminate along the length to distribute working fluid at various locations. You can do it.
[0253]
21 and 22, the bi-lumen body 222 is desirably extruded from a material such as polyurethane or Pebax. The bilumen body is co-extruded with the catheter body 208, and in other embodiments, the lumen body 226 and the lumen body 228 are formed separately and welded or joined together.
[0254]
The third or return lumen 238 provides a return path for the working fluid and is defined by the inner surface 220 of the heat transfer element 210, the inner surface 240 of the catheter body 208, and the outer surface 224 of the bi-lumen body 222. The pressure drop of the working fluid through the lumen is such that lumen 238 is the hydraulic diameter D of lumen 250._TwoHydraulic diameter D equal to 0.75 of_ThreeWas decided to be minimized. But D_ThreeD_TwoThe pressure drop that occurs when the ratio to is substantially 0.75 (ie, 0.75 ± 0.10) works well.
[0255]
For flow through the cylinder, the hydraulic diameter D of the lumen is equal to four times the cross-sectional area of the lumen divided by the wetted perimeter, and the wetted perimeter is the fluid path and tube through the lumen. The entire perimeter of the area defined by the intersection with the plane perpendicular to the long axis of the cavity. The wetted perimeter for the return lumen 238 has an inner wetted perimeter (by the outer surface 224 of the bi-lumen body 222) and an outer wetted perimeter (by the inner surface 240 of the catheter body 208).
[0256]
The wetted perimeter for supply lumen 250 has only an outer wetted perimeter (by inner surfaces 246, 248 of bi-lumen body 222). That is, the wetted perimeter of the lumen is determined by the number of boundary surfaces that define the lumen. The third lumen 238 recirculates the working fluid disposed on the inner surface of the heat transfer element 210 back to an external reservoir or fluid supply in a known manner.
[0257]
In another embodiment, third lumen 238 is a supply lumen and second lumen 250 is a return lumen. Therefore, "first", "second", and the like are merely expressions for convenience. In some embodiments, body 222 includes multiple lumens. In addition, the lumen can be used as a supply and / or double-flow lumen for other devices, such as an imaging device, or for purposes such as inflating a catheter balloon or dispensing medication.
[0258]
The heating or cooling efficiency of the heat transfer element 210 can be optimized by maximizing the flow rate of the working fluid through the lumens 250, 238 and minimizing the heat transfer between the working fluid and the supply lumen. In the present invention, the hydraulic diameter D of the return lumen 238_ThreeHydraulic diameter D of the supply lumen 250_TwoBy setting the ratio to 0.75, the flow rate of the working fluid is maximized and the pressure drop can be minimized. However, this ratio may be substantially 0.75 ± 10-20%.
[0259]
By minimizing the contact area between the bi-lumen body 222 and the working fluid as the working fluid passes through the supply lumen, heat transfer losses can be minimized in the supply lumen. The area of the supply lumen body with which the supplied working fluid contacts is smaller than that of coaxial or concentric lumens used in the past. This is because the supplied working fluid only contacts the inside of a certain lumen body as compared with the case where the working fluid contacts the inside of a certain lumen body and the outside of another lumen body. Thus, heat conduction losses are minimized in the multiple lumen body 222 embodiment.
[0260]
The supply lumen 250 and the double flow lumen 238 can have other cross-sectional shapes than shown, yet maintain the desired hydraulic diameter ratio of substantially 0.75.
[0261]
The catheter 206 shown in FIGS. 25 and 26 has a supply / double flow lumen, and the hydraulic diameter ratio of the double flow lumen to the supply lumen is substantially equal to 0.75. The same reference numerals are used for the same elements as in FIGS.
[0262]
The illustrated catheter 206 has a number of lumen configurations 214 ', which communicate working fluid with the interior 216 of the heat transfer element 210 so that the catheter can be placed in a blood vessel over a guidewire. The lumen configuration 214 'has a bi-lumen body 222', but is slightly different from the bi-lumen body 222 shown in FIGS. 21 and 22 and has a circular outer surface instead of the octagonal outer surface 224. I have. Thus, third lumen 238 'has a circular cross section.
[0263]
Maintaining the hydraulic diameter ratio of the dual-flow lumen 250 'to the supply lumen 238' at 0.75 maximizes the flow rate of the working fluid through the multi-lumen configuration 214 '.
[0264]
In addition, the annular double-flow lumen 238 'increases the convective heat transfer coefficient in the heat transfer element 210, especially near the intermediate segment or bellows portion 268. Working fluid passing through the double-flow lumen between the outer surface 224 'of the bi-lumen body and the inner surface 220 of the heat transfer element encounters a constraint 270 due to the projection of the bellows portion 268 into the flow path. However, in other embodiments, the bi-lumen body 222 'can also form the constraint 270 by being thicker in its longitudinal region. The distance between the bi-lumen body and the bellows portion is such that the properties resulting from the working fluid flow are at least transmissive.
[0265]
For a particular working fluid flow rate (cc / sec), the average flow rate through the constraint 270 is greater than the flow rate through the annular double-flow lumen 238 'of the heat transfer segment 104, 106 of the heat transfer element 210. If the flow velocity through constraint 270 is high enough, wall jet 272 will be directed into interior 220 of heat transfer segment 104. Wall jet 272 increases the coefficient of heat transfer in heat transfer segment 104. 3 because they enhance the mixing of the working fluid along the interior of the heat transfer segment 104.
[0266]
Increasing the velocity of the jet 272 by increasing the working fluid flow rate or reducing the size of the constraint 270 increases the average turbulence intensity across the swirl heat transfer segment 104 with the transition closer to the jet outlet. . Thus, in addition to that caused by the interior 220 of the heat transfer segment 104, the outer surface 224 'of the bi-lumen body 222' near the bellows 268 and the inner surface of the bellows provide heat transfer between the heat transfer element 210 and the working fluid. Enhance. In other embodiments, the heat transfer element can have a larger number of heat conducting segments, and the number of intermediate segments, (the number of heat conducting segments minus one), is also large.
[0267]
The multi-lumen configuration 222 described in FIGS. 21 and 22 does not increase the convective heat transfer coefficient as much as the multi-lumen configuration 222 'described in FIGS. This is because the working fluid preferentially flows through the return lumen 238 near the junction of the first lumen 226 and the second lumen 228. Thus, the high speed working fluid has greater contact with the outer surface 224 of the bi-lumen body 222 and less contact with the interior 220 of the heat transfer element 210. In contrast, the annular return lumen 238 'of the multi-lumen configuration 222' makes the working fluid axisymmetric so that significant working fluid flow contacts the entire area of the swirl segment equally.
[0268]
On the other hand, the heat transfer element of the present invention can also be formed from a flexible material such as latex rubber, the high degree of flexibility of which is conventionally provided by articulated structures. The rubber also allows the heat transfer element to be foldable and can be easily inserted into the artery when deflated. Insertion and positioning can be performed efficiently using a guide catheter or guide wire. Following insertion and positioning in the desired artery, the heat transfer element is expanded and used with a suitable working fluid, such as sarin, water, perfluorocarbon, or the like.
[0269]
Heat transfer elements made of flexible materials generally have significantly less thermal conductivity than those made of metal. The device compensates for this by increasing the area available for heat transfer. There are two ways to do this. That is, whether to increase the cross-sectional area or the length. In the former, the device is configured to be large when inflated. The device is inserted into the artery when deflated. In fact, the device can be as large as the arterial wall as far as the passage of blood is possible. This is because the flexibility of the device prevents damage to the arterial wall even in contact.
[0270]
For the latter, the device is made longer. One approach is to incline to accommodate smaller radius end arteries. Also, the reduced thermal conductivity compensates by reducing the thickness of the heat transfer element walls.
[0271]
Some embodiments use heat transfer elements that create a free flow of blood and a high degree of turbulence in the working fluid. The turbulence is generated by forcing the working fluid to swirl to provide a swirling barrier in the blood. In another embodiment, the spiral barrier is inclined. Also, the inclined expandable heat transfer element has a surface structure that causes turbulence.
[0272]
As an example, the surface structure has a spiral shape. In another example, the surface structure has staggered protrusions. In both embodiments, the design forces blood to follow a tortuous path as it passes through the artery, forcing a high degree of turbulence in the free flow of blood. This tortuous path causes the blood to experience severe acceleration resulting in turbulence.
[0273]
In a third embodiment, the slope of the expandable heat transfer element provides sufficient additional area to provide sufficient heat transfer. In all embodiments, the expansion is performed by a working fluid such as water or sarin.
[0274]
In FIG. 27, the heat transfer element 272 is constituted by an inlet lumen 276 and an outlet lumen 274, and the outlet lumen 274 has a spiral shape surrounding the pipe-shaped lumen 276. The name of the lumen is not limited. Lumen 276 may function as an outlet and lumen 274 may function as an inlet. The heat transfer element can heat (distribute heat) and cool (remove heat) the desired area.
[0275]
The heat transfer element 272 is rigid but flexible and can be inserted into a blood vessel using a guide catheter. Alternatively, a device that guides the guidewire through the heat transfer element may be used to assist in placement within the artery. The heat transfer element has an expansion length L and a spiral diameter D_C, Tube diameter d and spiral angle α. For example, D_CIs about 3.3 mm and d is about 0.9 mm to 1 mm. Of course, the pipe diameter d need not be constant. For example, the diameter of lumen 276 may be different from that of lumen 272.
[0276]
The shape of lumen 274 in FIG. 27 is a spiral, which presents a cylindrical obstruction in cross-section to the blood flow. Such obstacles tend to form turbulence in the free flow of blood. In particular, the form of turbulence forms a von Karman vortex downstream of the cylindrical obstacle in the wake of the blood flow.
[0277]
Typical expandable materials are not highly thermally conductive, and are significantly less thermally conductive than metallic heat transfer elements as described above. In the present invention, differences in thermal conductivity can be compensated for in at least two ways. Thinner materials and larger areas for heat transfer elements. For the former, the thickness is less than about 1/2 mil for proper cooling.
[0278]
Thin inflatable materials (especially large in area) require a structure such as a wire and have a substantially inflatable portion inside to achieve the proper shape when inflated. Although the wire 282 is shown in FIG. 27, it is advantageous to place it in an inflatable material because it performs such a function.
[0279]
Another consideration is the swirl angle α, which is determined to optimize blood swirl around the lumens 274, 276 to enhance heat transfer. Of course, the angle α must also be determined to optimize the swirling motion of the working fluid in the lumens 274,276. By forming a secondary motion, the swirling motion of the working fluid in the lumen increases turbulence in the working fluid. In particular, the swirling motion of the fluid in the pipe induces two counter-rotating secondary flows. In this system, h_cIs obtained, which is indicated by the Nusselt number Nu being about 10 or more.
[0280]
In another embodiment shown in FIG. 28, the heat transfer element 286 has an increased area, and increasing the area of the expandable material increases the heat conduction. The heat transfer element 272 has a series of coils of different coil diameters or spirals of different tube diameters. The tube diameters need not necessarily be different, but commercially available systems have different tube diameters. The heat transfer element 272 may be continuously or segmentally inclined.
[0281]
In this embodiment, the area is increased in two ways. First, the overall area-to-volume ratio is increased by using a small diameter lumen. Second, the distal end 312 is inserted deeper into the artery than the embodiment of FIG. 27 using a progressively smaller (ie, beveled) lumen.
[0282]
In the embodiment of FIG. 28, the first coil segment 288 has a length L₁And diameter D_C1have. The segment has a diameter d₁Inlet lumen 296 and diameter d₁'Outlet lumen 298. The outlet lumen need not drain immediately into the inlet lumen. In FIG. 28, apart from the inlet lumen adjacent the end 312 of the heat transfer element 286 that feeds directly to the corresponding outlet lumen, the inlet lumen of each segment feeds the inlet lumen of the subsequent segment.
[0283]
In some embodiments, each inlet lumen provides working fluid to a corresponding outlet lumen. In this case, a separate lumen must be provided to drain each outlet lumen or from each outlet lumen to the adjacent outlet lumen. This embodiment has the advantage that opposite convolutions can be imparted to each successive segment. The opposite swirl increases the turbulence of the passing working fluid.
[0284]
The second coil segment 290 has a length L_TwoWith diameter D_C2It is. The segment has a diameter of d_TwoInlet lumen 300 and diameter d_Two'Outlet lumen 302. The third coil segment 292 has a length L_ThreeWith diameter D_C3It is. The segment has a diameter of d_ThreeInlet lumen 304 and diameter d_Three'Outlet lumen 306. Similarly, the fourth coil segment 294 has a length L_FourWith diameter D_C4And the diameter is d_FourInlet lumen 308 and diameter d_Four'Outlet lumen 310. The diameter of the lumen, especially that of the lumen near the distal end 312, is large enough to not constrain the working fluid inside. The number of lumens is not specified as needed.
[0285]
FIG. 29 shows the connection between the two lumens 296 and 300. The two lumens are connected by a joint 314. The structure of the joint changes depending on stress, hardness and the like. The advantage of this embodiment is due to the smaller diameter of the end segment. The heat transfer element of FIG. 28 can be arranged in a smaller working space than that of FIG. For example, in the treatment of brain trauma, a cooling device is placed in the patient's internal carotid artery. The common carotid artery supplies the internal carotid artery. Some patients do not fit into the heat transfer element internal carotid artery of FIG.
[0286]
The second, third, and fourth segments fit, but similarly the first coil segment of the heat transfer element of FIG. 28 does not fit into the internal carotid artery. In the embodiment of FIG. 28, the first segment remains in the common carotid artery and the smaller diameter segment (second, third, fourth) can be placed in the internal carotid artery. In fact, in this embodiment D_C1Is as large as 5 to 6 mm. The total length of the heat transfer element 286 is, for example, about 20 to 25 cm, but when placed in a large blood vessel such as the inferior vena cava, the role of such consideration is small.
[0287]
The area in the embodiment of FIG. 28 is substantially larger than that in FIG. 27, and the heat conduction is significantly enhanced. For example, the increase in area is more than three times the area of the device. An additional advantage of both embodiments is that the spiral shape allows for a traumatic insertion into a cylindrical cavity such as an artery. Nu in this embodiment is 1 to 50.
[0288]
The embodiment of FIG. 30 seeks to induce turbulence by a specific surface structure. In particular, the illustrated heat transfer element 314 has an inlet lumen (not shown) and an inflatable outlet lumen 328 with four segments 316, 318, 320, 330. Segment 346 is near proximal end 326 and segment 330 is near distal end 322. The segment has a radius that decreases in a proximal to distal direction. As in the case of FIG. 28, the reduced radius structure facilitates insertion of the heat transfer element into a small working space such as a small artery.
[0289]
The heat transfer element 314 has a number of surface structures 324 in which the heat transfer element 314 is subjected to various hardening treatments or manufactured by injection molding, for example. The curing process provides a wavy or corrugated surface on the outside of the heat transfer element, and a similar surface can be applied on the inside. In the embodiment shown in FIG. 31, a manufacturing process for providing a spiral surface structure is adopted, and as a result, Nu is about 1 to 50.
[0290]
In the embodiment shown in FIG. 33, heat transfer element 356 has a plurality of protrusions 360 on outlet lumen 358 surrounding inlet lumen 364. The working fluid circulates through the inlet lumen to the end of the heat transfer element to expand the heat transfer element. The working fluid then conducts heat from the outer surface 358 of the heat transfer element across the exit coaxial lumen 366. The internal structure of the heat transfer element induces turbulence of the working fluid in the same manner as the external structure.
[0291]
The outer surface 358 of the heat transfer element is covered by a series of corrugated protrusions 360. The undulation of the protrusion is shown in FIG. 34 taken along line 8-8 in FIG. The height of the protrusion, d, to induce free-flow turbulence_pIs greater than the thickness of the boundary layer that occurs when a smooth heat transfer element is introduced into the blood stream. When blood flows along the outer surface, it collides with one projection and forms turbulence.
[0292]
As the blood separates and rotates along the side of the first protrusion, it collides with other protrusions in the passage, preventing flow re-stratification and creating more turbulence. Thus, the velocity vectors are randomized to form free flow turbulence. As with the other embodiments, this configuration induces turbulence effects on the internal cooling flow. Nu in the case of FIG. 33 is about 1 to 50. Other shapes such as spirals, spirals, spirals, protrusions, various polygons, pyramids, tetrahedra, and wedges cause turbulence.
[0293]
In some situations, sufficient heat transfer to cool the blood is obtained with only the increased area without additional turbulence formation. The heat transfer element 332 shown in FIG. 32 has inlet / outlet lumens 334, 336. The inlet lumen provides the working fluid to the heat transfer element, and the outlet lumen drains the working fluid therefrom. This function may be reversed. The heat transfer element is further divided into five segments, but may be somewhat more.
[0294]
These segments are segments 338, 340, 342, 344, 346. Segment 338 has a first maximum radius R₁And the following is the corresponding segment radius. Segment 346 has a second minimum radius. The length of the segment 338 is L₁And the following is the corresponding segment length.
[0295]
The inclined segments can be replaced with purely inclined (non-segmented), but the former is more difficult to manufacture. In each case, the heat transfer element is a small artery or radius R due to the inclined shape.₁Can be placed in less than an artery. Thus, a sufficient area is provided even in very small arteries to provide the required heat transfer.
[0296]
The area, that is, the size of the device, is effective in providing the necessary heat conduction. Exemplary dimensions for a three-segment slope are L₁= 10cm, R₁= 2.5mm, L_Two= 10cm, R_Two= 1.65mm, L_Three= 5cm, R_Three= 1 mm. Such a heat transfer element has a total length of 25 cm and an area of 3 × 10^-Fourm^TwoIt is. In the embodiment of FIG. 32, the heat conduction speed is improved up to about 300% only by the increased area S.
[0297]
In some embodiments, at least one turbulence inducing area structure is formed inside the outlet lumen 336. This area structure can induce turbulence in the working fluid, increasing convective heat transfer velocity in the same manner as described above.
[0298]
Another variation is to reduce the joint diameter between segments (not shown). For example, the intumescent material can be formed such that joints 348, 350, 352, 354 are slightly smaller in diameter than inlet lumen 334. In other words, the heat transfer element 332 takes on an inclined "sausage" shape.
[0299]
In all embodiments, the intumescent material can be formed from a seamless, non-porous material, and thus is impermeable to gas. Impermeableness is particularly important depending on the type of working fluid circulating in the heat transfer element. For example, the expandable material is a rubber material such as latex or a material that exhibits the same properties when expanded. The use of flexible materials allows the heat transfer element to bend, stretch and contract, making it more mobile in blood vessels. The material also allows for axial compression of the heat transfer element, limiting trauma when the end of the heat transfer element strikes the vessel wall. The material should be selected to allow heat in the range of -1 to 37 ° C (and more in the case of blood heating) and without loss of behavior.
[0300]
Since the heat transfer element stays in the blood vessel for as long as 24-48 hours or more, it is desirable to apply a treatment to the surface of the heat transfer element to avoid the formation of clots. One way to prevent thrombus formation is to attach an antithrombotic agent to the surface of the heat transfer element. For example, it is known that heparin suppresses clot formation and is useful for biocoating.
[0301]
In FIG. 27, the guide catheter is located near the area to be cooled and heated, and the heat transfer element is supplied to the area through the guide catheter. Alternatively, the heat transfer element may be part of the guide catheter. A portion of the interior of the guide catheter may be formed, for example, in a return lumen for the working fluid. In any case, the flexibility of the heat transfer element makes the movement of the heat transfer element significantly more convenient.
[0302]
Once the location of the heat transfer element 272 is determined, a working fluid, such as an aqueous solution such as sarin, is circulated through the heat transfer element to expand. Fluid flows from the delivery catheter to the inlet lumen 276. At the end 280 of the heat transfer element, the working fluid exits the lumen 276 and enters the outlet lumen 274.
[0303]
In the embodiment of FIG. 30, as in FIG. 33, the working fluid exits the inlet lumen and enters an inflatable outlet lumen 328 with segments 316-330. As the working fluid flows through the lumen 328, heat is transferred from the surface of the heat transfer element 314 to the working fluid. Since the heat transfer element is formed from a very thin material, the temperature of the outer surface will be very close to the temperature of the working fluid.
[0304]
Working fluids that can be employed in the device include water, sarin, and other fluids that remain liquid at operating temperatures. Other coolants, such as freon, can cause nucleation boiling and form turbulence by different mechanisms. Because it is non-toxic, sarin is a safe coolant, and leaking it does not form a gas embolus as with the use of a boiling coolant.
[0305]
By increasing the turbulence in the coolant, the coolant can be distributed to the heat transfer element at a warmer temperature while maintaining the required heat transfer rate. In particular, the working fluid can be distributed to the heat transfer element at a low flow rate and a low pressure due to the enhanced heat transfer characteristic of the internal structure. The high pressure stiffens the heat transfer element and presses against the walls of the blood vessel, protecting a portion of the heat transfer element from blood. Such pressure does not harm the walls of the blood vessel as the flexibility of the inflated device increases. As the heat transfer characteristics increase, the working fluid pressure can be distributed below 5, 3, 2, 1 atmosphere.
[0306]
In some embodiments, the turbulence intensity created by the heat transfer element is greater than 0.05, creating a desired level of turbulence in whole blood during a whole cardiac cycle. The turbulence intensity is 0.055, 0.06, 0.07 to 0.10 or 0.20 or more.
[0307]
As shown in FIG. 35, the cooling device 368 has a flexible multilumen catheter 370, an inflatable balloon 372, and a plurality of blood channels 16 through the balloon. The balloon is shown inflated and is at a selected location in the carotid artery CC.
[0308]
The balloon 372 is mounted near the distal end of the catheter, the catheter having at least a cooling fluid supply lumen 380 and a cooling fluid return lumen 382, which lumen 380 is preferably located in the return lumen. are doing. The catheter may also have a guidewire lumen 384 for passage of a guidewire 386.
[0309]
The balloon is formed from a flexible material, such as a polymer, and is cylindrical when inflated to include a proximal end 374 and a distal end 378. The balloon also has a plurality of tubular blood passages 376 that penetrate from the proximal end to the distal end, and the tube walls of the flow passages constitute a heat conducting surface to conduct heat from blood to the cooling fluid.
[0310]
The flexible material of the conduit 376 may be at least partially a metal layer, such as a film coated on the inside, outside, or both, with a thin metal layer to assist the heat conduction of the passage walls. Alternatively, the conduit can be formed of a metal-added polymer film.
[0311]
In addition, the remainder of the balloon 372 can be coated internally, externally, or both with a thin metallized layer or a metal-added polymer film. The proximal end 374 and distal end 378 of the balloon can also be configured as heat conducting surfaces, and conduct heat from the blood to the cooling fluid. The guidewire lumen 384 of the catheter 370 can also penetrate the balloon from proximal to distal.
[0312]
As shown in FIG. 36, each conduit 376 has a proximal port 388 on the proximal end face 390 of the balloon 372 and a distal port 392 on the distal end face 394. A cooling fluid supply port 396 near the end of the lumen 380 supplies a cooling saline solution from a cooler (not shown) to the interior of the balloon 372 surrounding the passage 376. Cooling fluid return port 398 in lumen 382 returns the sarin solution from inside the balloon to the cooler. The relative positions of the cooling fluid ports 396, 398 may be selected to create a flow opposite to the direction of blood flow, if necessary.
[0313]
FIG. 37 shows the general arrangement of the blood flow path 376, lumen 380, lumen 382, and lumen 384 in the outer wall 400 of the balloon. FIG. 38 shows a device 368 having a longitudinal section through the balloon wall 400 and an array of ports 396, 398 in the balloon 372.
[0314]
In effect, the deflated balloon 372 rides over the guidewire 386 and passes through the patient's vascular system over the distal end of the catheter 370. The placement of the guidewire and balloon can be monitored by fluoroscopy with a radiopaque marker (not shown). When the balloon is positioned at a desired location in an artery within a selected organ, such as the carotid artery, which the balloon supplies to the brain, a fluid, such as a sarin solution, is delivered through lumen 380.
[0315]
This fluid flows through port 396 into the interior of the balloon surrounding conduit 376 to inflate balloon 372. The balloon can be shaped to assume a cylindrical shape during unconstrained inflation, but essentially follows the shape of the artery in which it is inflated. When the balloon is inflated, the blood flow path 376 is opened to assume the illustrated tubular shape.
[0316]
When the balloon is properly inflated, blood flows through the blood flow channel 376 into the artery CC as indicated by the arrow in FIG. The size and number of blood channels 376 are set to provide a desired amount of heat conducting surface and maintain proper blood flow through artery CC.
[0317]
A return flow to the cooler is formed to allow cooling fluid to flow through port 398 and lumen 382 to the cooler. This allows the cooling fluid to flow continuously inside the balloon around the blood flow path 376. The return flow is adjusted to keep the balloon inflated and to allow circulation of the cooling fluid to occur. The sarin solution is cooled in the cooler to maintain the desired temperature inside the balloon and to provide the desired temperature drop to the blood passing through line 376. The flow of cooled blood through the artery provides the desired amount of cooling to the selected organ. The cooling fluid is then removed from the balloon through catheter 370, causing the balloon to deflate and withdraw device 368 from the patient's vascular system.
[0318]
Temperature sensing. Guidewires are also used to help load the device. The tip of the guidewire is or is part of a temperature monitor. The temperature monitor measures the temperature upstream or downstream of the heat transfer element and the catheter depending on the direction of blood flow relative to the monitor. For this, for example, a thermistor or a thermocouple is used.
[0319]
In one embodiment, a thermocouple is mounted on the end of the guidewire. For the temperatures considered in blood cooling and heating, most thermocouples are of type T, E, J, K, G, C, D, R, S, B.
[0320]
A thermistor may be attached to the end of the guidewire. This is a thermally sensitive resistor, and its resistance changes when the body temperature changes. Due to their sensitivity, thermistors are advantageous for monitoring the temperature of blood flow through a cooling device.
[0321]
Thermistors commonly used for monitoring body fluid temperature have a high resistance negative temperature coefficient ("NTC"). Ideally, its operating temperature is in the range of 25-40 ° C. Potential thermistors include polymer or ceramic active elements. Ceramic thermistors are most desirable because they have the most reproducible temperature measurements.
[0322]
Most properly sized thermistors are encapsulated in a protective material, such as glass, and are no larger than about 15 mils for easy attachment of the guidewire and easy insertion into blood vessels. You can use a large thermistor if necessary. Various thermistors can be used depending on the desired size, structure, temperature resolution, and the like.
[0323]
The signal from the temperature monitoring device is fed back to the working fluid source to control the temperature of the working fluid emerging therefrom. In particular, a catheter is connected to the source of working fluid. The proximal end of the supply lumen defined by the supply tube is connected to an outlet port to a source of working fluid. The return lumen defined by the return pipe is also connected to the inlet port to the source of working fluid. The working fluid source can control the temperature of the working fluid exiting the outlet port. A signal from the circuit is input to the source of working fluid at the inlet. The signal comes from a temperature monitoring device, such as a thermocouple or guidewire tip.
[0324]
The signal can advantageously be used to change the temperature of the working fluid from the source if necessary, for example, if the temperature monitoring device senses that the temperature of the blood flowing in the patient's supply vessel is below the optimal value Then, a signal is sent to the working fluid source to increase the temperature of the outgoing working fluid. The reverse is true if the temperature of the blood flowing through the blood vessels is above the optimal value.
[0325]
How to use simultaneous cooling and heating. FIG. 39 shows an embodiment used for cooling and heating a patient's body. The illustrated hypothermic device preferably includes a first working fluid supply 404, a first supply catheter 406, and a cooling element 102 for supplying a cooling fluid, such as water, alcohol, or a halogenated hydrocarbon. The catheter 406 has a substantially coaxial structure. An internal lumen in catheter 406 receives coolant from the supply. The coolant goes through the catheter 406 to the cooling element 102, which functions as the cooling tip of the catheter.
[0326]
At the distal end of the cooling element, the coolant exits the insulated inner lumen and traverses the cooling element, reducing the temperature of the cooling element. The coolant is then drained or recirculated across the outer lumen of catheter 406. Catheter 406 is flexible and of sufficiently small diameter that its distal end can be inserted percutaneously into an accessible blood vessel, such as the patient's external throat vein, as shown in FIG. The catheter is sufficiently long so that at the distal end of the catheter, the cooling element 102 can be placed through the patient's vasculature into the superior vena cava, inferior vena cava (not shown) or other blood vessel.
[0327]
Methods for inserting a catheter into a patient and passing the cooling element 102 are well known. The placement of the heat transfer element 102 in the throat vessels can be done directly. This is because the throat vessels are close to the surface. The catheter stays in the oropharynx and enters the superior vena cava and even into the right atrium.
[0328]
Although the working fluid supply 404 is shown as an example of a cooling device, other devices and working fluids can be used. For example, freon, perfluorocarbon, water or sarin can be used to provide cooling. The cooling element can absorb more than 300 watts of heat from the bloodstream and absorb more than 100, 150, 170 watts from the brain.
[0329]
FIG. 39 shows a heating element 410 as a heating blanket, which generally comprises a forced hot air blower, which blows warm air through the gaps in the blanket toward the patient. This type of heating occurs through the patient's skin and depends in part on the patient's area. As shown, the heated blanket provides comfort over most of the patient. Also, the face and head do not need to be covered, and the patient can breathe easily.
[0330]
Heated blankets are used for various purposes and avoid vasoconstriction by warming the patient. Also, the patient becomes more comfortable, for example, the core body temperature is reduced, and the patient feels comfort at a surface skin temperature of 5 ° C as well. Convulsions due to whole body hypothermia can also be avoided. If the physician has other variables adjusted (amount of heating), controlling the temperature of the patient is easier. The heating element may be, for example, that proposed in US patent application Ser. No. 09 / 292,532.
[0331]
FIG. 40 shows an embodiment of selective cooling, which cools the brain of a patient and heats blood flowing back from the brain in the throat blood vessels. The selective organ hypothermia device has a first working fluid supply 420 (preferably a cooling liquid such as water, alcohol or a halogenated hydrocarbon), a delivery catheter 418 and a cooling element 102. The catheter has a coaxial structure. An inner coaxial lumen in the catheter receives coolant from the supply 420, and the coolant passes through the catheter to the cooling element, which acts as a cooling tip for the catheter.
[0332]
At the end of the cooling element, the coolant exits the lumen and traverses the cooling element, reducing the temperature of the cooling element. The coolant is then drained or recirculated across the outer lumen of catheter 418. The catheter is flexible and has a sufficiently small diameter and its distal end is inserted into an accessible artery, such as the femoral artery of the patient. The catheter 418 is sufficiently long to allow the cooling element to pass through the patient's vascular system at the distal end of the catheter and be placed in an artery inside the patient. This insertion technique is well known.
[0333]
Although the working fluid supply device 420 is shown as an example of the cooling device, other devices and working fluids may be used, such as freon, perfluorocarbon, water, and sarin. The cooling element can absorb and provide more than 75 watts of heat to the bloodstream, and can be as high as 100, 150, 170 watts or more. The cooling element, 4 mm in diameter and about 10 cm in length, usually uses a cooled sarin solution, the surface temperature of the heat transfer element is about 5 ° C., and is pressurized to 2 atmospheres, which draws about 100 watts of energy from the bloodstream. Can be absorbed. Less than 60, 50, 25 watts of heat can be conducted using small size heat transfer elements for the organelle.
[0334]
FIG. 40 shows a second working fluid supply 416 that supplies a hot liquid such as water, a supply catheter 414, and a heating element 412 (which may be the same as the cooling element 102). The catheter has a coaxial structure. The inner coaxial lumen in the catheter receives warm fluid from a supply 416. The fluid passes through the catheter to the heating element 412, which acts as the heating tip of the catheter.
[0335]
At the end of the heating element 41, the fluid exits the inner lumen and raises the temperature of the heating element across the heating element 412. The fluid is then drained or recirculated across the outer lumen. The catheter 414 is flexible and has a sufficiently small diameter that its end can be inserted into an accessible vein such as the left throat vein, as shown in FIG. Alternatively, the heating element may be an electrical resistance heater controlled by controller 416.
[0336]
The placement of the heating element 412 in the throat vein can be done directly. Because it is close to the surface. The catheter stays in the oropharynx and reaches into the superior vena cava and even into the right atrium. Throat vein catheters are known. Instead of heating the blood in the pharyngeal vein with the heating element 412, a warm sarin solution can be injected into the pharyngeal vein from the supply 422 via the catheter 420, as shown in FIG. This is advantageous because sarin is often required as a maintenance fluid (1000-2500 cc / day).
[0337]
Heating can also be applied externally to the patient. A heating blanket covering the whole body may be used as the heating means, and local heating of the vein returning from the organ being cooled is also possible. FIG. 42 shows a neck fastener 426 that keeps the patient's head stationary. Immobilize the head to prevent movement of the cooling element or prevent damage to the supply artery by the cooling element. The neck fastener has one or more heating elements 428 that are placed directly on the left and right throat veins and flow through the skin into the throat vein to heat the blood. The heating element can be heated by a circulating fluid, or an electrical resistance heater may be used. Temperature control is maintained by the working fluid supply or controller 424.
[0338]
An exemplary course of treatment. 1. The patient is first examined, resuscitated and stabilized. 2. The procedure is performed in an angiography room or operating room with fluoroscopy. 3. Determine the vessel diameter and blood flow using ultrasound or angiography in the superior vena cava and external throat and select a catheter with an appropriately sized heat transfer element. 5. After examining the veins, the patient is disinfected and infiltrates the accessed area of the femoral artery with lidocaine.
[0339]
6. Insert a guidewire into the superior vena cava by inserting a cannula into the external throat. The arrangement of the guide wire is confirmed by fluoroscopy. 7. The imaging catheter is placed on a guidewire and, if necessary, the contrast medium is injected intravenously for further examination of the tissue. 8. Alternatively, a cannula may be inserted into the external throat to place the 10-12.5 French (f) introducer sheath. 9. A guide catheter is placed in the superior vena cava. Once positioned, the tissue is further examined by distributing the contrast media directly. 10. A cooling catheter is placed in the superior vena cava via a guide catheter or on a guide wire.
[0340]
11. If necessary, check the arrangement by fluoroscopy. 12. Alternatively, the cooling catheter shaft may be sufficiently pressurized and twisted to be placed in the superior vena cava without the aid of a guidewire or guide catheter. 13. The cooling catheter is connected to a pump circuit filled with sarin and free of bubbles. The pump circuit has a heat exchange part, which is immersed in a line connected to a water bath and a peristaltic pump. The water bath is cooled to approximately 0 ° C. 14． Cooling is started by starting the pump mechanism. Sarin in the catheter is circulated at 5 cc / sec. Salin is cooled to approximately 1 ° C. through a heat exchanger in a cooling water bath. 15. Subsequently, the sarin enters the cooling catheter and is distributed to the heat transfer element. Sarin is heated to approximately 5-7 ° C. while passing through the inner lumen of the catheter shaft to the end of the heat transfer element.
[0341]
16. The sarin then flows back through the heat transfer element and into contact with its inner surface. It is further heated in the heat transfer element to 12-15 ° C, during which heat is absorbed from the blood and the blood is cooled to 30-35 ° C. During this time, the patient is heated by an external heat source such as a heating blanket. 17． The cooled blood continues to cool the body further. It is estimated that it takes less than one hour to cool the brain to 30-35 ° C. 18. The heated sarin returns to the outer lumen of the catheter shaft and returns to the water bath where it is cooled to 1 ° C. 19. The pressure drop along the circuit is estimated to be between 1 and 10 atmospheres. 20. Cooling can be adjusted by increasing or decreasing the flow rate of sarin. By monitoring the sarin temperature drop along the heat transfer element, the flow can be adjusted to achieve the desired cooling effect. 21. The catheter is left in place to provide cooling, for example, for 6 to 48 hours.
[0342]
In FIG. 43, the heat transfer element 102 is placed in the superior vena cava 110 from the axillary vein, not the external throat. Suitable veins for percutaneous insertion of heat transfer elements include femoral vein, internal pharyngeal vein, subclavian vein and other veins of the same size and location. Other suitable veins for placement of the heat transfer element include the inferior vena cava, superior vena cava, femoral vein, internal pharyngeal vein, and other veins of the same size and location.
[0343]
In the heart shown in FIG. 1, the heat transfer element 102 is disposed in the superior vena cava 110 and has a rotating spiral groove 104 and a counter-rotating spiral groove 106. There is a bellows 108 between the grooves, which is believed to increase the number of Nusselt in the superior vena cava by about 5-80.
[0344]
Usage in thermoregulators. While the above describes a mechanical method of reheating a patient that minimizes the harm of the hypothermia, there are also processes for administering anti-vasoconstrictor and anti-seismic drugs. Such drugs minimize the effects of vasoconstriction which impede heat transfer and prevent cooling of the patient. In general, hypothermia causes strong thermoregulatory defenses throughout the body. Such drugs also increase metabolic rates to dangerous levels and suppress reactions such as tremors that can damage cardiac-risk patients.
[0345]
Drugs that induce thermoregulatory tolerance can be used to limit the effectiveness of thermoregulatory defenses during hypothermia treatment. For example, there are various drugs such as clonidine, meperidine, a mixture thereof, propofol, magnesium, and dexmethomidine.
[0346]
Certain drugs constrain thermoregulation approximately in proportion to their narcotic nature. Volatile anesthetics (such as isoflurane and desflurane), propofol and the like more effectively suppress thermoregulation than opioids (which are more effective than midazolam and central alpha agonists). The combination of clonidine and meperidine synergistically reduces vasoconstriction and tremor. It also synergistically reduces vasoconstriction and tremor gain and maximum intensity. The thermoregulatory activity is sufficiently suppressed to allow cooling of the central catheter to 32 ° C. without excessive hypotension, activation of the autonomic nervous system, sedation and danger of respiration. These drugs are particularly important in initiating thermoregulatory defense. For example, vasoconstriction begins at a temperature that is only half a degree below normal body temperature. Shivering begins at a point one degree below vasoconstriction.
[0347]
The blood is lowered at a temperature at which the thermoregulatory reaction does not start. For example, the thermoregulatory reaction starts at 1 to 1 and 1/2 degrees below the normal temperature. If normal body temperature is 37 ° C, the reaction will take place at 35 ° C. The thermoregulator lowers the temperature of the thermoregulation threshold to 33 ° C. The use of a heating blanket can cool the patient more. For example, to lower the patient's temperature from 33 ° C. to 31 ° C. (2 ° C. difference), two 5 ° C. or 10 ° C. elevated surface temperatures occur on the patient's skin, and the patient “feels” cooling above 2 ° C. There is no.
[0348]
FIG. 44 shows a combination of a thermoregulatory method and a heating blanket, where the patient's normal body temperature fluctuates as well as the thermoregulation threshold. As shown, the patient begins with a normal body temperature of 37 ° C and a typical thermoregulation threshold of 35 ° C (step 432). In other words, at 35 ° C., the patient starts shaking and vasoconstriction. A thermoregulator is administered (step 434) to suppress the thermoregulatory response and change the threshold to, for example, 35 ° C. This new value is shown in step 436.
[0349]
The heat transfer element is then placed in a high flow vein, such as the superior or inferior vena cava (step 438). Cooling occurs to lower the blood temperature (step 440). The cooling mode is as described above. Upon cooling, the patient experiences a hypothermia and achieves a temperature of, for example, 33 ° C. (step 442). More cooling can be done at this stage, but the thermal regulation threshold is kept at 33 ° C., so tremors and vasoconstriction can be harmful. This completes the procedure. Alternatively, additional medication may be applied to further lower the thermoregulation threshold.
[0350]
As another method for lowering the heat regulation threshold, a heating blanket is used. A general rule of thumb is that patient comfort remains steady as long as a heating blanket 5 ° C. warmer than the skin is applied to a substantial portion of the patient's area, even if the temperature is reduced by 1 ° C. (Step 444). A blanket of 10 ° C (warm than skin temperature) is applied for a 2 ° C reduction in body temperature. This is the upper limit of blanket temperature, as blankets hotter than about 42 ° C. will harm the patient's skin.
[0351]
Next, the patient's body temperature is continuously decreased by the heating blanket, and the temperature of the heating blanket is increased by 5 ° C. (step 448) to reduce the body temperature by 1 ° C. (step 446). The physician determines whether to continue cooling after each body temperature is reduced (step 450). After cooling, another procedure is performed if necessary (step 452) and the patient is reheated (step 454). It is important that the two thermoregulation reaction reduction methods can be performed independently. In other words, either the thermoregulator or the heating blanket can be used without using the other. The flow chart of FIG. 44 can be used omitting steps 434 or 444 and 448.
[0352]
Vasoconstriction treatment. FIG. 2 shows the hyperperfusion organ response to hypothermia more rapidly than peripheral circulation. This reaction can be maintained and improved by employing a cooling blanket rather than a heating blanket as a method of performing the hypothermia method. The cooling blanket vasoconstricts the blood vessels in the peripheral circulation, directing blood flow to the heart and brain.
[0353]
This method uses separate vasoconstrictors to affect the posterior hypothalamus so that the heart and cerebral circulation proceed unobstructed and vasoconstrict the peripheral circulation. Such drugs include alpha receptor type drugs. Such drugs and cooling blankets enhance reflux exchange and force cooling to the heart and brain. Such drugs and blankets, which generally provide sufficient cooling to cause a massive percutaneous vasoconstrictor response, force cooling blood flow toward the brain and heart (ie, the "central" volume). The term "peripheral circulation" or "peripheral vasoconstriction" refers to a portion of the vasculature that serves the legs, arms, muscles, skin, and the like.
[0354]
Antiseismic drugs and prescriptions. Other thermoregulators are described. Meperidine is a phenylpiperazine class analgesic and is known to bind to opiate receptors. Meperidine is used to treat postoperative anesthesia and tremors caused by low temperatures, and is also used to treat chills with administration of amphotericin B.
[0355]
Meperidine is also used to control tremor when hypothermia is clinically induced. Hypothermia protects tissues from damage during beating or local anemia that occurs during a heart attack. It is important to be able to cool the patient without inducing general anesthesia requiring an intubation procedure. High doses of meperidine are required to cool conscious patients. Cooling of the patient is accomplished with a cooling blanket (water or air) or an alcohol bath.
[0356]
Cooling can also be achieved by irrigation of the body cavity (pouch, stomach, intestine, peritoneum). The most effective way to cool a patient for therapeutic purposes is to use an intravascular catheter. The intravascular cooling catheter has a heat exchange area, which exchanges heat with blood. The absorption of heat from the blood by the heat exchange area will cool the body. Mixing or turbulence occurs on or near the heat exchange area to enhance heat transfer by the intravascular method. The heat exchange of this catheter is characterized by inducing turbulence or mixing.
[0357]
Tremor is regulated by the hypothalamus of the brain. This regulation generally regulates body temperature by controlling heat production and heat loss. Heat production above basal metabolic levels is caused by tremors. Heat loss can be prevented by vasoconstriction, reducing blood flow to the skin / perimeter. The set point for normal body temperature in the hypothalamus is approximately 37 ° C. As the body cools, it reaches a threshold at which vasoconstriction and tremors occur.
[0358]
Vasoconstriction occurs approximately 0.5-1.0 ° C. below the set point, and shivering occurs 1.0-1.5 ° C. below the set point. The intensity of the tremor increases in proportion to the difference from the threshold to the maximum intensity. Meperidine lowers the threshold for shivering, but has little effect on gain and maximum intensity. The decrease in the tremor threshold is proportional to the serum concentration of meperidine; the higher the serum concentration, the greater the decrease in the threshold. Meperidine is considered to have a special anti-seismic effect, especially because it reduces the tremor threshold by as much as twice the vasoconstriction threshold. In addition, it prevents or manages tremors better than the administration of other opioid and other analgesics.
[0359]
The anti-seismic effect of meperidine (reducing the tremor threshold) may not be related to opiate receptor binding. Meperidine is known to have many non-opioid effects, including anticholinergic and local anesthetics. Furthermore, the anti-seismic effect of meperidine is not antagonized by naraxone (opiate receptor antagonist). In addition, other opiates, such as morphine, pentazocine, and nalbuphine, have low or no anti-seismic activity.
[0360]
In FIG. 45, the meperidine molecule 456 is structurally significantly different from morphine 458 or its derivative in FIG. 46, which may explain the different effects. The use of meperidine has many undesirable side effects, most of which are affinity for opiate receptors. The worst is respiratory sedation, which can be fatal, and is related to its affinity for delta opiate receptors. Blockade of the delta opiate receptor by antagonists reduces or eliminates opioid-induced respiratory sedation.
[0361]
In addition, meperidine is metabolized in the liver by n-demethylation to produce metabolized nor-meperidine. Nor-meperidine is known to have central nervous system toxicity and causes seizures. Meperidine cannot be used in patients with renal failure or impairment due to the rapid formation of metabolites of normeperidine. In addition, due to complications such as convulsions and hyperthermia, meperidine cannot be used in patients taking monoamine oxidase inhibitors.
[0362]
Prozin (α, β) (FIGS. 47, 48, molecules 460, 462) is structurally very similar to meperidine. They both bind to opiate receptors with great affinity. Unlike meperidine, prozine has chirality, and the chirality molecule has at least one asymmetric atomic center, which causes a mirror image of the base molecule and can be superpolymerized on the base molecule. The various base molecules and mirror images are called enantiomers.
[0363]
Chiral molecules are optically active, and each enantiomer can rotate the plane of polarized light in equal but opposite directions, clockwise and counterclockwise, plus or minus. When one enantiomer rotates the plane of polarization by +10 degrees {(+) enantiomer}, the opposite enantiomer rotates the light by -10 degrees {(-) enantiomer}. For example, two prozines (α, β) differ at the position of the 3-methyl group. The chiral atom center is at the carbon to which the 3-methyl group is attached resulting in various mirror image species.
[0364]
Chemical reactions that make up chiral molecules often form racemic mixtures containing portions of each enantiomer. Racemic mixtures containing equal proportions of each enantiomer are optically inactive.
[0365]
Binding to an opiate receptor is known to be stereoselective. That is, one enantiomer has much greater receptor affinity than the other, for example, the (-) isomer of morphine has much greater opiate receptor affinity than the (+) isomer. I have. In the case of α and β prozines, the (+) isomer has much greater receptor affinity than the (−) isomer.
[0366]
Due to structural similarities, it is reasonable to assume that prozine has a similar anti-seismic effect to meperidine. This is a reasonable assumption since fentanyl (molecule 464 in FIG. 49), an opioid analgesic that is structurally related to meperidine, also has an anti-seismic effect. Fentanyl also has opiate-related side effects such as respiratory sedation.
[0367]
An ideal anti-seismic medication or prescription has strong anti-seismic efficiency with small respiratory sedation and other side effects. One successful method is to use meperidine, fentanyl or other opioids with anti-seismic effects in combination with delta-opioid receptor antagonists. Nartrindole or naltriben are competitive antagonists at the delta receptor and interfere with respiratory sedation by fentanyl.
[0368]
Induction of hypothermia in a conscious patient using an intravascular cooling catheter can be accomplished using a drug formulation containing an opiate such as fentanyl or meperidine in combination with a delta receptor antagonist such as naltrindole.
[0369]
Molecules that are structurally similar to meperidine but cannot bind to opiate receptors or have antagonistic effects on opiate receptors often have anti-seismic effects but have opiate-related respiratory sedation Absent. This is because the anti-seismic effect is mediated through different receptors. This ideal anti-seismic molecule exists in the form of the (-) isomer of α or β prozine. The ratio of opiate efficiency (+/-) between the enantiomeric forms of α and β prozine is at least 10 to 30 times.
[0370]
Due to their structural similarity to meperidine, they often retain anti-seismic efficiency; in a similar example, dextromethorphan is a morphine-based chemical and inhibitor (antitussive). Dextromethorphan, a (+) methoxy enantiomer of (-) levorphanol, retains the antitussive effect of a morphine derivative (ie, (-) levorphanol), but has analgesia, respiratory sedation, poisoning, etc. The other opiate effect has been lost.
[0371]
In addition, it can interfere with the opiate receptor affinity of the (+) isomer of α, β prodin. To achieve this, hydroxyl (especially at the m position) is added to the phenyl ring. This is true in the case of strong analgesic α-allylprozine where 3-methyl is replaced by an allyl group (molecule 466 in FIG. 50). Furthermore, the opiate activity of the (+) β-prozine isomer is remarkably reduced by n-propyl or allyl substitution of the 3-methyl group. These changes to the (+) isomer of the prodine molecule that suppress opium activity have little effect on anti-seismic activity due to structural similarity to meperidine.
[0372]
Cis-picenadol, 1,3 dimethyl-4-propyl-4-hydroxyphenyl piperidine (cis 3-methyl, 4-propyl) is a phenyl piperidine compound, and the (-) enantiomer is an opiate receptor (FIG. 51). Molecules 468, 470). Due to its structural similarity to meperidine, this (-) enantiomer has anti-seismic activity with some respiratory sedation. This resemetic mixture of opioids has a ceiling effect on respiratory sedation when used in animals. This ceiling effect makes resetic picenadol a better anti-seismic than meperidine. The enantiomer of tramadol (molecule 472 in FIG. 53) has reduced opiate activity that could reduce the tremor threshold.
[0373]
Alpha-prozin has been used as an analgesic under the brand name Nicentil in therapeutics. This drug is supplied as a racemic mixture. The racemic mixture can be separated into two pure isomers, the (-) isomer being used as anti-seismic medication. Such separation can be achieved by high-performance liquid chromatography (HPLC) using a chiral static phase. The enantiostatic phase is cellulose based and is provided as Chiralcells OD and OJ.
[0374]
Novel anti-seismic or threshold-lowering drugs or prescriptions are therapeutic treatments that induce hypothermia in patients. The patient is first diagnosed with a regional anemia injury, such as a beating or heart attack. An intravascular cooling catheter or blanket is applied to the patient. Patients are injected intravenously with new anti-seismic drugs such as (-) α-prozin. Alternatively, meperidine or fentanyl in combination with a delta opiate antagonist may be administered.
[0375]
Buspirone can also be administered in combination with any of the above formulations, as it is known to increase the anti-seismic effect of meperidine. The patient is cooled below 32-35 ° C. During the maintenance of cooling, which lasts 12-48 hours, the administration of anti-seismic drug or prescription begins to maintain a certain plasma concentration. Maintain plasma concentration using a new anti-seismic injection. Upon completion of cooling, the patient is reheated and dosing is stopped.
[0376]
Another ideal anti-seismic agent is nefopam (molecule 474 in FIG. 54), which is widely used as an analgesic, especially outside the United States. Although not analogous to meperidine, they have similar structural and morphological properties, such as having a phenyl group attached to the N-methyl ring, with the phenyl group preferring the equatorial position. Like meperidine, nefopam prevents post-operative tremors and tremors associated with amphotericin B administration.
[0377]
However, nefopam has few respiratory depression side effects and is not metabolized into neurotoxic compounds. Injectable nefopam is a racemic mixture. Analgesic activity is in the (+) enantiomer. The (-) enantiomer is a selective anti-seismic drug and is superior to the racemic form. Combining nefopam with intravascular catheter-based cooling induction has successfully performed therapeutic hypothermia.
[0378]
Combinations of the above compounds or combinations thereof with other drugs are desirable because they reduce tremors and lower thresholds. This reduces the dosage and side effects required for any drug. For example, nefopam can be combined with (−) α-prozine, meperidine, thorazine, buspirone, clonidine, tramadol or other agents to achieve the desired effect. The same combination can be made with (-) α-prozin. There are many other combinations and three drugs can be combined. These combinations can be used for therapeutic purposes together with terminal vascular or surface hypothermia induction.
[0379]
Dependence on enzyme temperature. The above techniques and devices provide for effective cooling and heating of fluids such as blood. Heating / cooling occurs either in the affected blood vessel or in a blood vessel in fluid communication therewith. “Fluid communication” between two blood vessels refers to a state where there is a supply between one blood vessel and another blood vessel. One application of such equipment and technology is coagulation lysis. However, other types of enzyme activation can also be advantageously induced. The following method can be applied to other devices and technologies as long as the blood can be heated and cooled.
[0380]
As described above, the enzyme is administered to the patient in a drug or intravenous mode for coagulation lysis. These enzymes are already occurring in vascular plasma in addition to natural ones. The activity of the enzyme is at least partially regulated by controlling the ambient temperature. In the method of the present invention, the enzyme is selectively controlled by controlling the environmental temperature. The controlled enzyme allows selective thrombolysis by selective vascular hypothermia in the manner detailed below.
[0381]
There have been several reports on the preparation of animals and clots at various temperatures, as described below, with appropriate temperature formulations for thrombolysis being mentioned with certainty. However, the mechanism by which the environmental temperature controls thrombolysis has not been well characterized. The following are some suggested mechanisms, which are speculative and do not limit the method of the invention.
[0382]
These mechanisms depend to some extent on known mechanisms for fibrinolysis, in particular plasminogen is an inert precursor of plasmin. Plasmin is an enzyme that dissolves clots (ie, attached peptide bonds in fibrin), and plasminogen binds to fibrin and is converted to plasmin when activated by a suitable enzyme such as tPA, UK, SK. Plasminogen can also be activated in solution. α_TwoInhibitors such as antiplasmin soften plasmin by almost instantaneously inactivating plasmin released from the fibrin surface. α_Two-Antiplasmin can inactivate even plasmin bound to the fibrin surface, but this takes about 10 seconds.
[0383]
There are also mechanisms related to the activity of the inhibitor, α_Two-The activity of antiplasmin is reduced at low temperatures and less effective in inactivating plasmin. In this case, more plasmin can be used to dissolve the clot and fibrinolysis is enhanced.
[0384]
A related effect is the level of plasmin relative to the level of plasminogen, where elevated plasmin levels increase the level of plasminogen circulating in solution. Furthermore α_Two-When the activity of antiplasmin decreases, α_TwoThe level of plasminogen is increased because antiplasmin binds to plasminogen; α_Two-Less antiplasmin results in less binding.
[0385]
Increased plasminogen levels suggest other mechanisms for clot dissolution. For example, plasmin attaches to single-chain urokinase ("scu-PA" or "pro-UK") to form UK. That is, pro-UK is a precursor of UK. Pro-UK such as tPA cannot efficiently activate plasminogen in solution, but plasminogen bound to fibrin can be easily activated. Increasing plasminogen together with the body's UK, tPA or similar enzymes supplied intravascularly results in more localized (direct at the location of the clot) fibrin lysis.
[0386]
Another suggested mechanism is the increase in plasminogen, where UK can activate plasminogen in solution and bound to fibrin. Increased levels of plasminogen, together with the body's own or delivered intravascularly, result in local dissolution of fibrin and enhanced activation of plasminogen in solution.
[0387]
Other suggested mechanisms result from putative binding of plasmin to fibrin. Plasmin retains binding to fibrin for long periods in hypothermic conditions. Thus, a longer time is available to dissolve the coagulum and increase the overall fibrinolysis.
[0388]
The hypothermia temperature at which increased fibrinolysis occurs has not been fully elucidated, but at 25 ° C and below coagulated mass samples benefited. For a human body, 30 to 32 ° C. is considered appropriate, and this is adopted in the present invention.
[0389]
The method of the present invention also allows the cooling organ to be reheated from a low temperature, such as 30 ° C, for which the temperature is about 20-37 ° C depending on the patient, condition, hypothermia temperature, and the like. Reheating has the benefit of increasing the rate of coagulation dissolution. Further, the temperature circulating in the blood in the blood vessel is changed from the hypothermia method temperature to the reheating temperature. Thus, the rewarming regime is repeated to enhance fibrinolysis.
[0390]
Experimental example 1 (no drug). The effect of temperature on fibrinolysis was discussed. The control group was studied but the drug was not used. In studies using coagulated mass samples, dissolution was studied at temperatures ranging from 25 to 41 ° C. In the absence of drug, an increase in clot dissolution was seen in the lower temperature range. This study can be extended to humans and enhances fibrinolytic activity at low temperatures.
[0391]
Experimental example 2 (no drug). In another study of the effect of temperature on fibrinolysis, clot dissolution in dogs was studied with clot temperatures ranging from 20-36 ° C. The dog's temperature was reduced from room temperature to low. Subsequent to the low temperature period, a slow reheating period was provided. There was an increase in coagulation dissolution at lower temperatures than at higher temperatures. In particular, maximum fibrinolytic activity occurred early in the rewarming period, i.e., from 20 to about 25C. It can be spread to humans and the fibrinolytic activity is increased at low temperatures, especially during rewarming.
[0392]
The advantage in these examples is that the clot dissolution takes place in a simple manner and does not require drugs. It also has the advantage that the blood temperature drops and lysis occurs, while the cells are protected from local anemia. Clot dissolution and cooling occur simultaneously to provide an effective and aggressive dual treatment. If dual treatment is employed, a cooling catheter can be inserted into both femoral arteries for metastasis to the brain. One catheter cools the brain and the other cools the blood from the arteries to the clot. The latter has a good effect as described above. In some cases, the nature and extent of the coagulum is such that dissolution only occurs with drug intervention. In that case, a thrombolytic drug is introduced to induce fibrinolysis.
[0393]
While these drugs are effective in treating thrombus, cooling the brain as a separate neuroprotective measure is also effective. The effectiveness of both treatments is enhanced the earlier they are performed, and it is desirable to do both at the same time. Thus, hypothermia is induced as a neuroprotective measure, and also clot lysis.
[0394]
The drawback of this approach is that the techniques are interdependent, with drugs depending on enzymes in activity and enzymes on temperature. In fact, as is known from previous work, the enzymatic activity of certain thrombolytics on clot samples is temperature dependent. In other words, their effect on coagulation or thrombolysis varies with the temperature range. In general temperature-specific enzymes, maximum activity occurs at the optimum temperature. For known thrombolysis, the optimal temperature is about 37 ° C., which is normal human body temperature.
[0395]
Above a certain temperature, the enzyme is denatured and becomes inactive, so that the enzyme activity is dramatically reduced. Below a certain temperature, the enzyme becomes deficient in the energy required to bind to the substrate, thereby reducing enzyme activity. Thus, for example, if there is brain or other tissue at a different temperature from normal body temperature during hypothermia, it is desirable to use the isoform of the enzyme, which has an optimal operating temperature in hypothermia. . Such isoforms that are effective at different temperatures are said to have an "operating temperature" at different temperatures or within different temperature ranges.
[0396]
Here, "inform" will be described. When a first enzyme catalyzes a reaction at a first temperature and a different enzyme catalyzes the same reaction at a second temperature, the different enzymes are called "isoforms" of the first enzyme. For patients undergoing hypothermia, physicians prefer to use the low temperature isoform, and for patients whose body temperature has already increased, they prefer to use the high temperature isoform. The enzyme form has an optimal activity curve at or near the desired temperature. Known enzymes and methods for enzyme selection are described below.
[0397]
Experimental example 3 (SK). The effect of temperature on the fibrinolytic activity of the SK mixture was studied, and the clot was treated with a mixture of plasminogen (2 mg) and SK (100 IU) in a total volume of 15 ml PBS. The temperature of the coagulum was raised to 24-37 ° C. and it was found that heating improved the fibrinolytic activity. In other words, heating from hypothermia to normothermic increased clot dissolution treated with SK.
[0398]
It is believed that such trends are accurately spread to patients. Patients are administered drugs, such as streptokinase, and experience hypothermia using the devices or methods described above. In particular, a cooling catheter is placed in the artery that supplies blood to the thrombotic vessels, and the SK mixture is distributed through the separation lumen of the catheter. Coolant or working fluid is supplied to the cooling catheter to cool the catheter and cool the blood near the heat transfer element located at the distal end of the catheter. This cooling step induces turbulence in the blood flowing through the blood vessels and / or working fluid. The SK is delivered through a separate drug delivery lumen and the patient is re-warmed. The reheating step is performed by passing a warm sarin solution as the working fluid.
[0399]
Experimental Example 4 (TPA). The effect of temperature on the fibrinolytic activity of tPA was studied, and the coagulum was treated with 2.5 μg / ml tPA and cultured at various temperatures (eg, 37, 25, 10, 0, −8 ° C., etc.). Was. Plasminogen activation was relatively high at low temperatures (eg, 0, -8 ° C) and low at high temperatures. In other words, for tPA, cooling from normal body temperature to hypothermia increased fibrinolytic activity.
[0400]
Such trends are accurately spread to patients. In this case, the patient experiences a hypothermia using the above-described device placed in an artery receiving tPA and supplying blood to the thrombus vessels. The catheter has a separate lumen through which the tPA is delivered. A coolant or working fluid is supplied to the catheter to cool the catheter and adjacent blood. This cooling step induces turbulence in the blood and / or working fluid flowing through the blood vessels. The tPA is distributed through a separate dose plumbing lumen. In this case, the patient is not re-warmed until the drug distribution is complete or the thrombus is dissolved.
[0401]
Experimental Example 5 (TPA). The effect of temperature on the fibrinolytic activity of tPA was studied, and the clot was treated with tPA at a concentration of 0.3, 1.0, 3.0 μg / ml and incubated at various temperatures of 24-40 ° C. Was. At all concentrations, the amount of clot dissolution was correlated with temperature. However, contrary to the results of Example 4, the amount of coagulum dissolution at lower temperatures was less than at higher temperatures. Heating was presumed to enhance the activation of plasminogen by tPA, and such heating was presumed to have a similar effect on patients. This improvement was also observed in UK and SK systems.
[0402]
Further studies are needed to determine the optical process. In any case, the present invention is employed to provide better heating and cooling. To enhance the activation of plasminogen by tPA, a warm sarin solution is supplied to a catheter of the type described above. The solution transfers heat to the blood in the heat transfer element. A suitable temperature for the solution in the heat transfer element is about 38-74C.
[0403]
Experimental Example 6 (UK). The effect of temperature on the fibrinolytic activity of UK was studied, and the coagulum was treated with a mixture of UK at 4 ° C and 28 ° C. The introduction of UK into the clot induced a certain amount of fibrinolytic activity. Heating to 28 ° C. resulted in a secondary phase of activity, converting all plasminogen to plasmin and increasing fibrinolytic activity. In other words, heating from a very low temperature (4 ° C.) to a hypothermia temperature (28 ° C.) resulted in increased clot dissolution. It is thought that such a tendency can spread to patients. This experimental example is similar to Experimental Example 3 because of the re-warming step, and a similar process can be employed when treating a patient.
[0404]
This example demonstrates how a temperature changer and drug can be combined to provide cooling and thrombolysis at the same time. This combination provides a power dual therapy, which can be employed to aggressively treat a beating or other similar disability. When dual therapy is employed, a cooling catheter is inserted into the femoral artery to reach the brain for neuroprotection. If a temperature increase is desired, a heating catheter is used.
[0405]
Drugs can be distributed with other catheters. Alternatively, the heating and cooling catheter may have a lumen for drug distribution therein, for example, the lumen is coaxial with the catheter and is located along the centerline of the catheter and the heat transfer element. .
[0406]
Alternatively, the lumen may be located along a portion of the wall of the outlet lumen, the dosing lumen having an outlet at the tip of the heat transfer element. One example is disclosed in, for example, U.S. patent application Ser. No. 09 / 215,040, in which such drug dispensing catheters deliver drugs or enzymes into blood vessels containing thrombus or into blood vessels in fluid communication with thrombus vessels. Especially useful for:
[Patent Document 30]
US Patent Application No. 09 / 215,040
[0407]
In addition to the above-mentioned known drugs, enzyme activity can be achieved at temperatures other than normal body temperature using similar techniques and appropriate isoforms of enzymes. One way to select suitable isoforms for those enzymes is to study in cold climates. For example, SK is a bacterial enzyme, and bacteria live in a variety of different temperature environments. It is common to find and select enzymes for a process or temperature by finding bacteria that live in an environment with the desired temperature.
[0408]
As another example, the polymerase chain reaction is a polynucleotide amplification process that requires enzymes that can withstand high heat, and these enzymes are found in bacteria that live in hot springs and sea bottom craters. Thus, bacteria that survive in a room temperature or arctic environment have an enzyme equivalent to the desired enzyme. That is, SK that can survive in a hypothermic environment.
[0409]
On the other hand, tPA and UK are recombinant human enzymes, and tPA and UK are altered to maintain activity at low temperatures. For example, the protein dorsal column is altered to exhibit higher tPA or UK activity at lower temperatures.
[0410]
Such "temperature specific" enzymes or drugs are advantageously used to localize their effects. Certain enzymes or drugs may be dangerous for use due to systemic effects. For example, certain thrombolytics are administered sparingly due to the risk of bleeding. Danger exists because current drugs are active at temperature working temperatures that are within the blood temperature range of the vascular system and because the drug soaks into the entire vascular system. The blood temperature range of the vascular system is said to be within a first temperature range and is said to have an average temperature at the first temperature. Drugs administered to dissolve thrombi also reduce clots in the vascular system and increase the risk of bleeding. However, such effects are not limited to thrombotics.
[0411]
The present invention provides such a method of reducing systemic risk, which allows the use of an appropriate isoform of the enzyme to enable enzyme activity at temperatures outside the normal body temperature range (eg, the first temperature range described above). And In other words, for cooling, the working temperature range of certain enzymes is the hypothermic temperature. Such enzymes do not work in the first temperature range. For example, a thrombolytic isoform dissolves clots if the blood temperature is hypothermic, but does not produce a fibrinolytic effect if the blood temperature is not hypothermic.
[0412]
Enzymes or drugs of this type are advantageously used in the present invention, for example, a heat transfer element is placed in a blood vessel upstream of the vicinity of the site where a clot has formed, cooling the nearby blood and cooling the nearby blood. The hypothermia temperature is reached. The isoform of the hypothermia drug is distributed proximate and has a working temperature at the hypothermic temperature. The isoform then dissolves the clot.
[0413]
Thrombolytics do not produce fibrinolytic activity in parts of the blood vessel that are not at hypothermia temperatures, the rest of the body. The advantage of this method is that it can be used with very strong thrombolytic agents to effectively dissolve the clot, and there is no need to worry too much about the above fibrinolytic side effects throughout the rest of the body. The present invention is not limited to the above devices and techniques.
[0414]
Furthermore, although the invention has been described primarily with reference to a lysis system, the lysis of blood clots in blood vessels results from beating or myocardial infarction. However, the method of the invention can also be applied to alter the activity of an enzyme at normal temperature. Further, the invention is applicable to cooling solids such as the volume of tissue rather than the static volume of blood flow or blood. It is further applicable when heating blood or tissue, especially when heating in certain enzymes enhances the desired activity. The present invention is not limited to the drug treatment as described above.
[0415]
Additional treatment. For additional therapies from thermoregulators, the methods and devices of the present invention perform prominently in the treatment of various disorders, including cytotoxicity, and the optimal rewarming strategy is described below.
[0416]
Beating. The devices and methods of the present invention increase the fibrinolysis of the clot by cooling the blood flowing through the arteries and provide a significant reduction in platelet activity at reduced temperatures using blood cooling. . Although the actual method is unknown, such a reduction occurs by suppressing enzyme function. Reducing platelet aggregation and improving fibrinolysis will reduce or eliminate the current dependence on drugs such as tPA and Leopro.
[0417]
Myocardial infarction. Vein cooling as described above also provides many benefits to patients suffering from myocardial infarction. Currently there are three areas for treating myocardial infarction. Thrombolysis or stenting is used to create a return. Oxygen supply is increased by providing oxygen directly to the patient and vasodilation with nitrate. Oxygen demand is reduced by reducing heart rate and blood pressure.
[0418]
The devices and methods of the present invention provide an advantageous combination with those treatments. For example, providing the heart with cooled blood can reduce the heart's oxygen demand. The cooled blood cools the inner chamber of the heart from the inside. The heart with myocardial infarction beats fast because it is excited. However, chilled blood induces a slow heart rate state that reduces oxygen demand by the heart itself.
[0419]
High fibrinolysis as described above to establish regurgitation and oxygenation can dissolve clots and distribute more blood flow and oxygen to the heart. Platelet aggregation can also be reduced as described above. In addition, induction through the subendocardium, cooling the heart, reduces metabolic activity of the entire heart and protects the subendocardium from cell damage.
[0420]
Backflow often damages cells with reperfusion injury. Neutrophil activation occurs as part of reperfusion injury. Hypothermia can suppress such activation and can reduce reperfusion injury. Thus, a single device can provide a variety of treatments, and thus the "beta-blocker" drug currently employed to reduce heart rate, especially in patients suffering from infarction, may be useful in patients undergoing hypothermia treatment. No need to apply.
[0421]
Restenosis. In addition, the present invention can be applied to the treatment of a stenotic artery. Stenotic arteries are blood vessels that have narrowed due to the formation of tissue and / or plaque atheroma. Stenotic vessels are treated with angioplasty or stents that widen the arteries. The vessel wall may be injured during the procedure, and such injuries often cause an inflammatory response (20-50%), resulting in restenosis of the blood vessels after a period of time (6-12 months or years) .
[0422]
Hypothermia is known to moderate the inflammatory response, for example, the first step in restenosis is the migration of macrophages or leukocytes to the area of injury. Hypothermia can suppress this migration and can also suppress the reactions and processes caused by molecules acting in an autocrine or paracrine manner. It is also possible to suppress the release of growth factors (at the site of injury) such as PDGF and EGF that act in such a manner.
[0423]
CV rewarming / surgery. The present invention uses hypothermia protection to allow a physician to perform a cardiac bypass procedure, while avoiding the disadvantages associated with conventional external cardiopulmonary bypass systems and aortic clamp procedures. The heat transfer element is disposed in a blood vessel of the body and can cool the living body by contacting blood.
[0424]
The heat transfer element is located in an arterial or venous vessel. One preferred location for the heat transfer element is the inferior aorta, with a diameter in the range of 15-25 mm. The placement of the heat transfer element at this location may be via the femoral vein.
[0425]
FIG. 55 shows a heat transfer element for cooling a patient's body. The illustrated device preferably includes a working fluid supply 476 for supplying a cooled aqueous solution, a supply catheter 478, and a heat transfer element 102. The catheter is substantially coaxial in that the coaxial lumen receives coolant from a supply.
[0426]
The coolant passes through the catheter to the heat transfer element, which acts as a cooling tip for the catheter. At the end of the heat transfer element, the coolant exits the lumen and traverses the heat transfer element, reducing the temperature of the heat transfer element surface. It is then drained or recirculated across the outer lumen of the catheter.
[0427]
The catheter is flexible and has a sufficiently small diameter that its distal end can be inserted percutaneously into an accessible blood vessel (the right femoral vein in the figure). The catheter is sufficiently long that the heat transfer element at the distal end of the catheter can pass through the patient's vascular system and be placed in the relevant vessel (here, the inferior vena cava). Methods of inserting a catheter into a patient and delivering it into a selected artery or vein are known. In the illustrated embodiment, the narrowest blood vessel encountered in the process of the heat transfer element reaching the inferior aorta is the femoral artery, which has a diameter of 5-8 mm. The diameter of the heat transfer element is therefore about 4-5 mm.
[0428]
To obtain the benefits associated with hypothermia during a cardiac bypass procedure, it is desirable that the temperature of the blood flowing through the body be less than 35 ° C, more preferably 30-35 ° C, and most preferably 32 ± 2 ° C. If the blood flow rate in the inferior vena cava is approximately 2.5-4 l / min, and more typically 3.5 l / min, the heat transfer element will absorb 200-300 watts of heat in the vein to achieve the desired Gives a cooling effect. The cooling time is approximately 15 to 30 minutes.
[0429]
Cooling the body below 35 ° C. has various favorable effects. First, cooling induces bradycardia in the heart. A heartbeat corresponding to about ／ of a normal heartbeat has a temperature of 32 ± 2 ° C. Although the present invention facilitates surgery during a beating heart procedure by slowing the beating, this technique is well known. For example, for beating heart surgery, see Benetti et al., "Coronary Reversalization With Artificial Conducts Via a Small Thoroughcology and Assisted by Thorough Physiology Worldwide Physiological Wrap-Up. Europatum, 4 (1): 22-24 (1995), and "Coronary Surgery Without Cardiopulmonary Bypass" by Westaby, British Heart Journal, March 1995, and the like.
[Non-patent document 1]
Benetti et al, "Coronary Revivalization With Artificial Conducts Via a Small Thorakotomy and Assisted by Thoroughcorporation. Europatum, 4 (1): 22-24 (1995)
[Non-patent document 2]
Westby "Coronary Surgery Without Cardiopulmonary Bypass" British Heart Journal, March 1995
[0430]
"Direct myocardial reversalization with extracorporal circulation" by Benetti et al., "Experience in 700 patents",,,,, et al. Thorac. Surg. 54: 1085-92 (1992), and Fanning et al., "Reoperable coronary artery bypass grafting with cardiopulmonary bypass", Ann. Throac. Surg. 55: 486-89 (1993).
[Non-Patent Document 3]
Benetti et al "Direct myocardial reversalization with out extracorporal circulation.Experience in 700 patents", Chest, 100 (2): 316-16 (1991).
[Non-patent document 4]
Pfister et al, "Coronary artery bypass cardiopulmonary bypass," Ann. Thorac. Surg. 54: 1085-92 (1992).
[Non-Patent Document 5]
Fanning et al, "Reperative coronary artery bypass grafting with cardiopulmonary bypass", Ann. Throac. Surg. 55: 486-89 (1993).
[0431]
In addition, general anesthesia associated with cardiac bypass techniques often involves vasodilation in the patient, which reduces organ perfusion and increases the risk of local anemia. However, this effect can be accommodated by the hypothermia method introduced by the present invention, and vasoconstriction is promoted.
[0432]
Body cooling also protects organs from local anemia due to low circulatory flow rates or embolization, such as (1) intermittent arrest and restart of the heart or (2) circulatory support with a small internal pump when the heart is arrested And other measures are known. These techniques allow a physician to operate on a stationary or nearly stationary heart. However, each of these techniques puts patients at risk from local anemia. However, by reducing the patient's body temperature to the preferred temperature of 32 ± 2 ° C. in accordance with the present invention, the oxygen demands of body tissues and thus the risk of local anemia associated with the treatment are reduced.
[0433]
Techniques have been provided to alter the duration of the heartbeat and cardiac arrest, using drugs such as beta blockers to stop or nearly stop the heart, and use a pacemaker to beat the heart as needed. One example of such a system is Corvascular, Inc. , Palo Alto, CA.
[0434]
Other techniques include electrical stimulation of the vagus nerve to momentarily stop or slow the heart (US Pat. Nos. 5,913,876 and 6,006,134). U.S. Pat. No. 5,913,876 discloses that if one or more pacemakers, such as a Pace port-Swan pulmonary artery catheter, were inserted into a patient's heart by conventional techniques and the heart slowed after the neural stimulation signal was turned off. Healed and used to keep the heart beat during surgery. Each technique involves a circulating flow rate that is significantly lower than normal cardiac output.
[Patent Document 30]
U.S. Pat. No. 5,913,876
[Patent Document 31]
U.S. Patent No. 6,006,134
[0435]
However, local anemia due to low circulation flow rates can be reduced by the present invention. In particular, prior to adjusting the patient's heartbeat, a heat transfer element is inserted into the patient's blood vessels to reduce body temperature, preferably to 32 ± 2 ° C. Reducing body temperature reduces oxygen demand and reduces the risk of local anemia. Furthermore, the reduction in body temperature according to the invention is accompanied by vasoconstriction, which reduces the risk of proper organ perfusion and thus local anemia.
[0436]
The invention is useful in connection with techniques where the heart is arrested or nearly halted and the in-vivo pump assists in circulation. For example, some techniques provide circulatory support during cardiac bypass by a pump placed in the patient's aortic valve. For example, M. S. Sweeney, "The Hemopump in 1997: A Clinical, Political, and Marketing Evolution," Ann. Thorac. Surg. Vol. 68, p. See 761-3.
[Non-Patent Document 6]
M. S. Sweeney, "The Hemopump in 1997: A Clinical, Political, and Marketing Evolution", Ann. Thorac. Surg. , 1999, Vol. 68, p. 761-3
[0437]
In this reference, esmolol, a short-acting beta blocker, is administered in cardiac bypass to make the heart quiet during surgery. The patient's own lungs are used for oxygenation using Medtronic Hemopump® for circulatory support. The core of the Hemopump has a small, rapidly rotating Archimedes screw. The pump is made of stainless steel and is attached to a silicone rubber inlet cannula. The cannula is placed across the aortic valve and not in the left ventricle.
[0438]
A pump is mounted on the catheter to facilitate placement in the operative position. For example, it is usually inserted into the femoral artery of the thigh and guided to the left ventricle. Once in place, the cannula rides on the blood and pumps it, pumping the blood through the aorta and into circulation. The pump is driven by creating a pulsed electromagnetic field, which rotates a permanent magnet and the Archimedes screw works. Power is supplied from a console outside the patient, and pumping is axial and continuous (ie, not pulsating).
[0439]
Due to the design of the HemoPump, rotation speeds of 10,000 to 20,000 rpm are used to produce a blood flow of less than about 4 liters per minute (depending on the model), but without significant hemolysis. For details, see M.E. C. Sweeney and O.M. H. Frazier, "Device-supported myocardial reversalization; safe help for sick hearts", Ann. Thorac. Surg. 1992, 54: 1065-70 and U.S. Pat. No. 4,625,712.
[Non-Patent Document 7]
M. C. Sweeney and O.M. H. Frazier, "Device-supported myocardial reversalization; safe help for sick hearts", Ann. Thorac. Surg. 1992, 54: 1065-70
[Patent Document 32]
U.S. Pat. No. 4,625,712
[0440]
These techniques often place patients at risk for local anemia with circulating flow rates (less than about 4 l / min) below normal cardiac output (often about 5 l / min). By lowering the patient's body temperature to the preferred range of 32 ± 2 ° C. in accordance with the present invention, the blood vessels constrict and the tissue oxygen demand is reduced, organ perfusion is increased, and the risk of local anemia is reduced for a given circulatory output. You.
[0441]
In this invention, the heat transfer element is placed in the inferior vena cava via the femoral vein. In contrast, in Hemopump, it is placed in the left ventricle via the femoral vein. Thus, the heat transfer element and Hemopump can be placed in the body with minimal intrusion.
[0442]
In the present invention, hypothermia is administered to conscious or half conscious patients, for example, when the patient suffers from a heartbeat and the hypothermia is introduced into the brain to reduce local anemia injury. In practice, the whole or part of the patient, generally an organ, is cooled. For example, in whole body cooling, a heat transfer element is placed in a vein, more preferably in the inferior vena cava, to perform whole body cooling.
[0443]
To regulate the temperature of a selected area intravascularly, a heat transfer element is positioned in the supply artery of the area to absorb or provide heat from blood flowing to the area. The heat transfer element is small enough to be placed in the supply artery so that sufficient blood flow reaches the area to avoid local anemia injury. By placing the heat transfer element in the supply artery, the temperature of the area is controlled and has less effect on the rest of the body.
[0444]
Taking the brain as an example, the carotid artery supplies blood to the head and brain, from which the internal carotid artery branches and supplies blood directly to the brain. Heat transfer elements are placed in the carotid artery or both the carotid and internal carotid arteries to selectively cool the brain. The carotid artery has an inner diameter of 6-8 mm and a length of 80-120 mm. The heat transfer element in any artery must be much larger than 4 mm in diameter to avoid occluding blood vessels (causing local anemia injury).
[0445]
Undesirable side effects can occur when hypothermia is introduced into a patient. For example, hypothermia activates the sympathetic nerves in conscious or half-conscious patients, causing a pronounced norepinephrine response. Norepinephrine binds to beta positions, including those in the heart, causing the heart to beat violently and rapidly, often causing cardiac arrhythmias and focal myocardial anemia. However, according to the invention, a beta blocker is administered to the patient. Without being bound by theory, beta-blockers counteract norepinephrine as described above and are generally administered at the beginning, preferably just prior to patient cooling.
[0446]
Preferred β blockers for this purpose include β1 blockers, β1β2 blockers and αβ1β2 blockers. Preferred β1 blockers include acebutolol, atenolol, betaxolol, bisoprolol, esmolol and metoprolol. Preferred β1β2 blockers include carteolol, nadolol, penbutrol, pindolol, propranolol, sotalol, timolol. Preferred αβ1β2 blockers include carvedilol and labetalol.
[0447]
The high demands of hypothermia on conscious or half-conscious patients are also alleviated, for example, by heating blankets. However, vasoconstriction limits the heating capacity of the heating blanket. Without being bound by theory, it is believed, for example, that the production of norepinephrine active α-receptor in peripheral blood vessels causes vasoconstriction. According to the present invention, vasoconstriction can be counteracted, preferably by treating the patient with an alpha blocker before the onset of cooling. Preferred alpha blockers include labetalol and carvedilol. In many cases, once the medical task is completed, it is desirable to use the heat transfer element to bring the body to a normal temperature, ie, 37 ° C.
[0448]
In addition, in the present invention, the hypothermia can be induced in a patient in need of neuroprotection due to local anemia by placing the heat transfer element in the blood vessel of the patient. To enhance neuroprotection by induced hypothermia, one or more therapeutic agents are administered to the patient, including (a) antipyretic agents, (b) free radical scavengers, and / or (c) N-methyl-D. -Aspartame receptor antagonists.
[0449]
Preferred antipyretics for the purpose of this invention include those having anti-inflammatory and antipyretic properties, such as dipyrone. Dipyrone has disappeared and emerged from the market in the United States, but is available from Hoechst AG.
[0450]
Determination of effective dosage forms, dosages, and dosage frequencies to aid neuroprotection by hypothermia is well known in the art. If the local anemia condition involves beating and fever, antipyretics are administered until the risk of fever is reduced, generally at least three days after hypothermia has ceased.
[0451]
Preferred free radical scavengers for the purposes of this invention include trirazad and pharmaceutically active salts thereof, and trirazad mesylate, a free radical scavenger and lipid peroxidant inhibitor, is manufactured by Upjohn under the tradename FREEDOX, Improve survival and functional outcome in male patients with subarachnoid hemorrhage. Effective dosage forms, dosage amounts, and dosing frequencies to aid neuroprotection by hypothermia are known to those skilled in the art.
[0452]
Preferred N-methyl-D-aspartame receptor antagonists for the practice of this invention include dextromethorphan, MgCl 2_Two, Memantine, and more preferably dextromethorphan, a pharmaceutically active salt thereof.
[0453]
Dextromethorphan is commonly found in syrup form and is available from a variety of sources, with the preferred dosage being 10-30 mg orally every 4-8 hours orally for at least 3 days. Pharmaceutical forms, dosage amounts, and dosage frequencies effective for supporting neuroprotection by the hypothermia method are known to those skilled in the art.
[0454]
The above therapeutic agents can be combined, for example, a free radical scavenger and an N-methyl-D-aspartame receptor antagonist are co-administered with the hypothermia method. The method of the present invention is suitable for various regional anemia neurological conditions, such as local anemia of the spinal cord, regional anemia including beating, and the like.
[0455]
The need for neuroprotection in local anemia states arises in various ways. In some cases, the patient experiences an unexpected local anemia disorder, such as physical trauma associated with a car accident or a local anemia disorder resulting from a pathological event such as a beating. In such conditions, it is desirable to administer the therapeutic agent within 6 to 12 hours after the hypothermia has been induced and the patient has experienced a local anemia disorder.
[0456]
Patients may also be at risk for focal anemia due to medical procedures such as cardiac surgery and brain surgery including aneurysms, in which case hypothermia is introduced and the therapeutic agent is Is desirably administered prior to therapeutic treatment.
[0457]
In addition, in some cases, it may be desirable to attach a stent to the distal end of the heat transfer element, which is used to open an artery damaged by atheroma prior to heat transfer. In addition, the device may dispense a drug such as a clot lysing compound (tissue plasminogen activator ("tPA"), urokinase, pro-urokinase, streptokinase, etc.) or a neuroprotective agent (a selective neurotransmission inhibitor). Also used for. In addition to therapeutic uses, the device is also used to destroy tissue, such as cryosurgery.
[0458]
Fever. A one or two step process and one or two piece device for lowering body temperature intravascularly to treat fever is used. A cooling element is located within the high-flow vein, such as the vena cava, to absorb heat from the blood flowing to the heart. This heat conduction cools the blood flowing through the heart, thus cooling all blood vessels. Such methods and devices are used therapeutically to treat fever.
[0459]
The heat transfer element that cools the blood systematically provides the necessary heat transfer rate to produce the desired cooling effect throughout the blood vessel. This can be up to 300 watts or more, depending at least in part on the patient's weight and blood flow velocity. The surface structure is used for the heat transfer element to increase the heat conduction speed. These are described in detail below.
[0460]
One problem with the heat treatment due to cooling is that the cause of the patient's heat loss is cooling, which requires a high power device.
[0461]
The superior vena cava is an example. The following veins are expected to be suitable for percutaneously inserting the heat transfer element: femurs, internal throat, subclavian and other veins of the same size and location. Inferior vena cava, superior vena cava, thigh, internal throat, and other veins of the same size and location are also expected to be suitable for placement of heat transfer elements. Arteries may also be employed if selective fever treatment is desired for a particular organ or body region.
[0462]
To treat a fever patient, the heat transfer element is placed in a vein such as the thigh, IVC, SVC, subclavian, braichiocephalic, or throat. It is also placed in the artery for further selective heat reduction.
[0463]
The amount of cooling to be performed is determined as a first approximation by the cooling rate. The amount of cooling is proportional to the difference between the body temperature and the temperature of the heat transfer or cooling element. If the blood temperature is 40 ° C and the temperature of the cooling element is 5 ° C, the blood temperature is 38 ° C and the temperature of the cooling element is 5 ° C. The extraction power is greater than if it were kept. The cooling or cooling rate is generally maximum early in the cooling operation, and when the body temperature begins to approach the target temperature, generally normal body temperature or 37 ° C., the cooling rate decreases because the temperature difference is no longer great.
[0464]
In any case, once the patient has reached normal body temperature, it is difficult to guess whether the patient is still fevery or has reduced fever without cooling treatment. The present invention makes this determination possible.
[0465]
First, the extraction power is calculated from the temperature difference between the working fluid supply and the working fluid return. In particular
[0466]
(Equation 1)

[0467]
Where P_catherterIs the extraction power, M is the flow rate of the working fluid, C_fIs the heat capacity of the working fluid and ΔT is the temperature difference between the working fluid entering the catheter and the working fluid leaving the catheter. Therefore P_catherterCan be easily calculated by measuring the weight of the circulating fluid and the temperature difference between the working fluid entering the catheter and the working fluid exiting the catheter. The power removed by the catheter approximates the power lost by the patient's body.
[0468]
Generally, a body with a temperature T₀No closed form solution is known for the power P required to cool (or heat) the chiller. One approximation is an exponential assumption.
[0469]
(Equation 2)

[0470]
Taking the derivative of each side with respect to temperature,
[0471]
(Equation 3)

[0472]
Taking the inverse of each side
[0473]
(Equation 4)

[0474]
Or
[0475]
(Equation 5)

[0476]
Where ΔT is the temperature difference from the nominal temperature and ΔP is the measured power. An approximation is obtained by assuming that the relationship is linear. The power series is equally expanded and the linear term is maintained. In any case integration, linear relationships, rearrangement:
[0477]
(Equation 6)

[0478]
Here, the constant of proportionality has a unit of watt / ° C., and the constant α can be determined using two points where T and P are unknown and known during the treatment. One is when treatment was started (when the patient had temperature T and the catheter extracted power P). The other point is T = T₀, P = P₀Obtained at the time. Then, both P and T are obtained by the following equations.
[0479]
(Equation 7)

[0480]
An example of this is shown in the flowchart of FIG. A patient in a hospital or the like generates heat (step 480). In general, patients develop fever as a result of a disease requiring hospitalization, for example, most patients in an ICU exhibit fever.
[0481]
A catheter carrying a heat transfer element is inserted (step 482) and the initial power P_startIs extracted and the body temperature T_startIs measured (step 484) and treatment is started (step 486). The treatment continues (step 488), and P and T are measured periodically and continuously (step 490). Normal body temperature T = T where the measured T is usually about 37 ° C.₀Is compared with (step 492). T is T₀If greater, treatment continues (step 488), where T is T₀T is smaller than T = T₀At power P₀Is measured (step 494).
[0482]
By the above equation, T_start, P_start, P₀, T₀Is determined from α (step 496), and from α, T_start, P_start, P₀, T_{0 ,}T_{absence of cooling}Can be determined (step 498). Then T_{absence of cooling}Is T₀Is compared with (step 500). T_{absence of cooling}> T₀If so, the patient is still generating sufficient power due to metabolism that produces fever if treatment is interrupted, and treatment is continued (step 502). T_{absence of cooling}<= T₀If so, the patient no longer generates sufficient power due to metabolism that produces fever if treatment is interrupted, and treatment is interrupted (step 504). In the above, various changes are possible.
[0483]
The manifold of the present invention is shown at 506 in FIG. Manifold 506 is connected at end 508 to three lumen catheters 104 that circulate fluid for various purposes. The present invention describes a heat transfer catheter in which fluid is circulated to cool or heat a patient. A strain relief sleeve 514 prevents the catheter 512 from twisting near the distal end 508 of the manifold 506.
[0484]
The three catheters 512 shown in FIG. 58 have an outer tube 530, an intermediate tube 538, and an inner tube 534, and the catheter has a guidewire space or lumen 540 defined by the inner surface of the tube 534. Outer annular lumen 542 is defined between the inner surface of outer tube 530 and the outer surface of intermediate lumen 538. Inner annular lumen 536 is defined between the inner surface of intermediate tube 538 and the outer surface of inner tube 534.
[0485]
In operation, once the catheter 512 is positioned, an aqueous solution such as sarin circulates through the catheter and flows into the inner annular lumen 536 and exits the lumen at the distal end of the catheter into the outer annular lumen 542. enter. If the catheter is used for heat transfer, it is formed from a highly conductive material so that the temperature of the outer surface approaches the temperature of the working fluid. To avoid loss of thermal energy from the working fluid in the lumen 536, an insulating layer is placed in the catheter 512. In some cases, the lumen 542 is insulated, except where heat is directly applied to the body by contact.
[0486]
In FIG. 57, manifold 506 has a first manifold 518, which provides access to lumen 536 via port 524. Also, a second manifold 516 of manifold 506 provides access to lumen 542 via port 522. First manifold 518 also has a guidewire entry port 526, which provides access to lumen 540 for the guidewire (not shown). When loaded, the guidewire flows through the central shaft 521 through the manifold. The port 526 is beveled so that it can be inserted without obstruction. At the proximal end of the first manifold 518 is a luer fitting 520.
[0487]
console. The heat transfer catheter system 544 of FIG. 59 includes a heat transfer catheter 546, a control system 548, and a circulation set 550 housed in the control system. The control system is equipped with an output display 552 and an input key 554 to facilitate user interaction with the control system. A hood 556 is supported on the control unit case 558 to cover the circulation set.
[0488]
The catheter 568 of FIGS. 60 and 61 may be a hypothermic catheter capable of intravascular regulation of the temperature of a patient's body or organ. The heat transfer element 562 of the catheter is located distally and has a supply lumen 564 and a return lumen 566, the ends of both lumens terminating at the distal end of the heat transfer element and the proximal end of the supply pipe. Terminating at lumen port 570, the return lumen terminates at catheter handle 573.
[0489]
The heat transfer element 562 is disposed in a patient's blood vessel to transfer heat with surrounding blood flowing along the heat transfer element to regulate the temperature of the patient's body or organ. Similarly, heat transfer elements can be used in tissue to transfer heat to and from the tissue. In the latter case, heat is mainly distributed by conduction.
[0490]
The heat conduction catheter 568 may be used for cooling the brain, and the temperature is controlled by cooling and heating the organ or the whole body. The carotid artery supplies blood to the head and brain. The internal carotid artery branches from the carotid artery to supply blood to the forebrain. Heat transfer element 562 is placed in the carotid artery or both the carotid and internal carotid arteries via the femoral artery or other vascular pathway. The heat transfer fluid supplied, cooled, and circulated by the circulation set 550 causes the heat transfer element to extract heat from the carotid or internal carotid artery. This cools the brain and reduces the effects of disability on the brain.
[0490]
Although the catheter 568 is described as having a heat transfer element 562, other types of heat transfer elements can be used. Although the circulatory set has been described in connection with a heat transfer catheter, it can be used in connection with catheters other than hypothermia or heat transfer catheters. The circulation set can also be used with a catheter that supplies and / or circulates fluid within the catheter.
[0492]
Circulation set. The circulation set 550 shown in FIGS. 59 and 62 includes one or more of a fluid reservoir 574, a pump 576, a filter 578, a heat exchanger 580, a temperature and pressure sensor unit 584, a supply line 586, and a return line 588. The supply lumen port 570 and the return lumen portion are connected to the supply / return line of the circulation set 550. The supply and return lines preferably include one or more tubes, connectors, etc., to connect the components of the set 550 to the ports 570,572. The circulation set feeds, filters, circulates, and monitors the temperature and pressure of the heat transfer fluid for catheter 546. This is described in detail below.
[0493]
Fluid reservoir. Fluid reservoir 60 is a modified 250 ml PVCIV bag. The fluid reservoir 574 can be filled with a working fluid such as sarin, freon, perfluorocarbon, and the like. The working fluid is preferably a non-ionic fluid to prevent the working fluid from causing EMI interference with other electronics in the operating room, ie, D5W, D5W with 1.5% glycerin, sorbitol-mannitol. , Ringer's solution and the like.
[0494]
Fluid reservoir 574 is used to prioritize lines 586, 588, lumens 564, 566 of system 544 and has a supply or inlet tube 590 that is opposite inlet 592 from the return lumen 588. The end or outlet 594 communicates with the reservoir inlet 596. The reservoir also has a return or outlet tube 598 which communicates at one end with the supply line 586 and at the other end or inlet 602 with the inside 596 of the reservoir.
[0495]
Reservoir 574 has a mechanism 604 to expel, evacuate, or remove air from system 544, which mechanism is used to remove air from lines 586, 588, lumens 564, 566, and a polycarbonate removal spike 608. Needle-free polycarbonate valve 606 provided with Removal of air from system 544 is important in maximizing pressure in system 544, maximizing heat transfer of heat transfer element 562, and preventing air from entering the blood due to catheter breakage.
[0496]
The outlet 594 of the supply pipe 590 is located closer to or near the mechanism 604 than the inlet 602 of the return pipe 598 so that air bubbles supplied by the pipe 598 are not removed by the mechanism 604 and the return pipe 598 is not removed. Suppress direct entry into The deaeration cycle will be described in detail below.
[0497]
The fluid reservoir supplies working fluid to the system 544 without recirculation, where the supply tube 590 and the mechanism 604 are not present. The mechanism 604 is located outside the reservoir 574 within the circulation set 550. The pump 576 may be disposable, and the plastic micropump is discarded with other disposable parts after use. Pump 576 is used to draw the heat transfer fluid from the reservoir and circulate the fluid through lines 586,588, lumens 564,566. The pump need not be disposable.
[0498]
filter. Filter 578 is preferably a 5μ filter housed in a male and female container to remove impurities from the circulating heat transfer fluid. The circulation set 550 may have one or more filters or the filters may be part of a set part.
[0499]
Heat exchanger. 59 and 62, the heat exchanger 580 is a stainless steel tube 582 and is disposed in a second heat transfer fluid tank 560 which is a biocompatible fluid such as Galden or ethylene glycol. In this example, the tube 582 is It is located in a heat transfer fluid. A second heat exchanger (not shown) is located in control unit vessel 558 to regulate the temperature in vessel 560 to control the temperature of the heat transfer fluid in system 544. The heat exchanger is a renewable non-disposable wet heat exchanger.
[0500]
63-66, a dry heat exchanger 610 having a disposable heat exchanger body 612 is used in the circulation set 550, and the heat exchanger body 612 is removably secured in the mold bodies 614, 616; The heat exchanger mold bodies 614, 616 are formed from a thermoplastic insulating material and have serpentine grooves 618. One end of the groove ends at an inlet groove 620 and the other end ends at an outlet groove 622. The access channel accommodates access tubes 626, 628 of heat exchanger body 612 and corresponding tubes (not shown) for connection to supply line 586.
[0501]
The heat exchanger mold bodies 614, 616 may have one or more ports. Each mold body may have one or more recesses instead of the grooves 618, and the recesses constitute a reservoir through which the heat exchange fluid flows. The first and second heat exchange surfaces 624, 632 are located on the inner surface of the mold body, which are stamped stainless steel pieces, which are joined to the inner surface of the mold body and heat exchange passages 634 (FIG. 64) therebetween. Is composed. The surface desirably has serpentine grooves 636, and each groove may have other shapes. The surface insulates the heat exchanger body 612 from the heat exchange fluid flowing through the heat exchange path, making the heat exchanger "dry" and preventing fluids such as ethyl alcohol from contacting the outer surface of the heat exchanger body.
[0502]
Preferably, the heat exchanger body 612 is formed from an IV bag and has inlet and outlet tubes 628, 626 welded to the bag body 630.
[0503]
In use, the heat exchanger 610 is opened by separating the mold bodies 614, 616, the heat exchanger body 612 is placed therebetween, and the heat exchanger is closed by bringing both mold bodies together. When the heat exchanger is closed, the heat exchanger body follows the shape of the groove 636, forming a corresponding serpentine flow path 638 in the heat exchanger body. As the working fluid flows through the flow path, heat transfer occurs between the heat transfer fluid and the heat exchanger surfaces 624, 632 between the surface and the fluid in the flow path. After use, the heat exchanger body is opened by separating the mold bodies 614, 616 and discarded with other disposable parts in the circulation set.
[0504]
The heat exchanger 610 is dry since it does not come into contact with liquid, and is not as difficult to use as the coil heat exchanger 580 disposed in the liquid tank. Since the heat exchanger body 612 is inexpensive, it may be discarded after use. Alternatively, two heat exchangers may be stacked on each other in a "two-storey bus" shape to use a common heat exchanger mold body. The heat exchanger 610 may comprise a bag having a meandering or other built-in passage, or may comprise a meandering or other stainless steel tube.
[0505]
Temperature and pressure sensors. 67-70 measure the temperature and pressure before the heat transfer fluid in supply line 586 enters catheter 568, and after the heat transfer fluid in return line 588 leaves the catheter. It is used to measure the temperature and pressure of the fluid. This measurement is important to determine the pressure of the fluid passing through the catheter and the heat transfer occurring in the heat transfer element 562 of the catheter. Heating or cooling efficiency of the heat transfer element can be optimized by maximizing the pressure or velocity of the working fluid through the catheter.
[0506]
The temperature / pressure sensor 584 can be used to measure only temperature or pressure, and can also measure other physical property values of the working fluid. The temperature / pressure sensor 584 has two main components, a multiple, fixed, non-disposable temperature / pressure sensor electronics 640 and a single, disposable temperature / pressure sensor block 642. 67-68, the temperature and pressure sensor electronics 640 has a base 644, a latch 646 supported thereon by pins 648, and the base has an upper surface 664 and a skirt 666. The upper surface and the skirt define a receiving area 668 for the block. The substrate includes first and second pressure transducer holes 670, 672 containing first and second pressure transducers 674, 676 and first and second thermocouple holes containing first and second thermocouples 682, 684. 678 and 680.
[0507]
The pressure transducer and thermocouple are connected to electronics on the underside of the substrate, which is connected to the control system 548. The base ramp 650 terminates at a shoulder 652. The latch catch 654 is biased outwardly to engage the shoulder when the latch is mounted on the base. The latch releaser 656 is operated by the user with his / her finger to remove the catch 654 from the shoulder.
[0508]
The polycarbonate substrate 658 of the temperature / pressure sensor block 642 in FIGS. 69 and 70 has first and second lumens 660 and 662, which are the first and second pressure transducer wells 698 and 700 (FIG. 69). ) And first and second thermocouple wells 702, 704. The central holes 706 of the wells 698, 700 have lumens 660, 662, an inner annular ridge 708, an outer annular recess 710, and an annular wall 712. Central holes 714 in wells 702, 704 communicate with lumens 660, 662, inner annular recess 716, outer annular ridge 718, and annular wall 720.
[0509]
The pressure transducer wells 698, 700 include an O-ring seal 686 fixed on the outer annular recess 710, a pressure sensor diaphragm 688 fixed on the seal, an inner annular ridge 708, and a pressure sensor bush 690 fixed on the annular wall 712. On the diaphragm. Each thermocouple well 702, 704 includes an O-ring seal 692 secured to a recess 716, a sensor connection tube 694 secured to the seal and extending into a central bore 714, and a temperature sensor bush secured to an annular wall 720. 696 on the sensor connection tube.
[0510]
Temperature and pressure sensors 584 are combined by matching block 642 to electronics 640, and transducers 674,676 and thermocouples 682,684 associate with corresponding transducer wells 698,700 and thermocouple wells 702,794. I do. Latch 646 is then journaled on the locking portion and catch portion 654 engages shoulder 652 of base 644. As a result, the block body 642 is locked to the electronic body 640.
[0511]
After the circulation set 550 or one operation using the circulation set 550 is completed, the block body 642 is preferably removed from the electronic body and discarded. For this purpose, the catch is released from the shoulder by pulling the release body 656. The block is discarded along with the other disposable components, leaving only the electronics for reusable components. Due to the structure of the block body described above, the production is inexpensive and disposable, and the electronic body can be reused without contamination of other parts.
[0512]
Air displacement mechanism 604 evacuates system 544 from lines 586,588 and lumens 564,566. This deflation maximizes the pressure in the system, maximizes heat transfer in heat transfer element 562, and reduces air entry into the patient's bloodstream. The mechanism 604 is used during the expelling phase before each use of the system 544, which is important for identifying the catheter being used and for early detection of system problems.
[0513]
In the method shown in FIGS. 71 and 72, the pressure in the circulation set is read to automatically identify the catheter connected to the circulation set 550 or the heat transfer element of the catheter. FIG. 71 shows the relationship between pump motor speed versus expulsion, idle and the operating cycle of catheter system 544, where motor speed indicates the flow rate in system 544. In the expulsion operation, the flow velocity gradually increases in clear steps.
[0514]
In FIG. 72, each catheter (10F, 14F, etc.) or the heat transfer element connected to the catheter has a unique flow resistance, ie, pressure versus flow response. Once the inlet pressure of the catheter 568 and the pump speed are measured during the expulsion cycle, a slope is drawn through the measured data points and the slope is calculated. FIG. 72 shows diagonal lines for the 10F and 14F catheters attached to the circulation set 559. The catheter or heat transfer element of the catheter used in conjunction with the circulation set 548 can be automatically identified by comparing the diagonal line to a list of similar diagonal lines obtained empirically.
[0515]
After automatically identifying that the catheter is being used, the control system 26 provides corresponding appropriate parameters for operation of the catheter 568. If the calculated slope does not match that of the reference catheter, the slope is used to determine whether a problem, such as a fluid leak, has occurred in system 544.
[0516]
The closed circuit control of the heat treatment performed by the system requires feedback of a temperature signal indicative of the condition of the patient to be treated, which signal is input to the PID type control algorithm along with the target temperature of the treatment and is erroneously input to the patient. Regulates the energy supplied to and removed from the
[0517]
In such a system, the servo gain is set and the maximum system power is distributed with approximately 0.2C servo error. A PID controller having a zero coefficient for the integration / pull-out period provides a proportional linear drive signal at a power of 0% (servo error = 0C) to 100% (servo error = 0.2C or more).
[0518]
Choosing the right physiological site for this feedback signal acquisition is important for successful treatment. Since the thermal changes induced by the system are applied directly to the patient's core, the control signal preferably represents the thermal state (temperature) of the central component. In current therapeutically accepted temperature monitoring tasks, core temperature is obtained with the esophagus, nasal passages, tympanic membrane, capsule, and rectal probe.
[0519]
All of these represent the temperature of the patient in equilibrium with the environment (unless exposed to rapid temperature changes), while sac and rectal temperatures, etc., reflect the response of the core during rapid core temperature change intervals. Delay. In addition, the esophagus, nasal passages, and eardrum probes can be used for severely sedated patients, but are not practical for uncomfortable or slightly sedated or conscious patients. In some cases, a temperature monitor in the terminal esophagus is appropriate for a core body temperature monitor and provides a feedback signal for controlling induction and maintenance of hypothermia. However, esophageal temperature monitoring, including heartbeat and AMI patients in some patients, is not practical because the patient is conscious.
[0520]
Other monitor parts such as the tympanic cavity and sac can be used. However, such monitoring sites are not ideal. For example, a tympanic temperature probe can be uncomfortable and pulled out of the monitor. When this happens, at room temperature the patient temperature is already measured as hypothermic and the system shuts down. The bladder temperature probe does not represent the dynamic temperature changes occurring in the wick in real time. There is a noticeable time delay (a delay of 20-40 minutes), which does not represent the true core temperature under the influence of 1-2 ° C.
[0521]
Inducing and controlling hypothermia in conscious patients requires reliable and accurate monitoring sites that are not overly intrusive. The pulmonary artery (PA) temperature sensor placed in a Swan-Ganz pulmonary artery catheter is a reliable monitoring site, but requires other invasive catheterizations not shown to beating patients. Alternatively, a central nervous system catheter can measure the temperature of blood entering the right atrium, but is too noxious.
[0522]
Sensors mounted inside the catheter can address such issues without the need for a separate intrusive temperature probe and assure a precise control temperature measurement due to the central placement of the catheter in the IVC. Since the temperature of the inside and outside environment of the catheter during surgery generally differs from 10 to 40 ° C., it is difficult to obtain an accurate control temperature from a catheter-mounted probe such as a thermistor due to the presence of a heating / cooling heat transfer fluid in the catheter. , The heat transfer fluid is stopped and the treatment is temporarily interrupted.
[0523]
After fluid is stopped, an indefinite period of time elapses before thermal equilibrium or relaxation of the catheter with the environment. Interruption of the treatment to obtain the control temperature compromises the accuracy of the controller. Predictive algorithms have been developed to allow for the calculation of useful control temperatures, eliminating the need for perfect equilibrium and patient core temperature measurements. The method of predicting the equilibrium temperature is based on the hypothesis function of the relaxation history. By measuring the temperature of the catheter "coolant" returning to the console, the power distributed and consumed by the catheter heat exchanger can be determined and estimated. For example
[0524]
(Equation 8)

[0525]
This power is directly affected by the temperature of the patient, with less power being distributed at the hot core temperature than at the cold core temperature. Generally, the power delivered is proportional to the temperature gradient between the patient's blood temperature and the heat exchanger temperature.
[0526]
(Equation 9)

[0527]
By going from a patient temperature of 37-33 ° C, the power is reduced by approximately:
[0528]
(Equation 10)

[0529]
By monitoring the increase or decrease in power delivered and absorbed by the catheter, a useful control temperature or at least a blood temperature can be indirectly estimated. By knowing the starting patient temperature (eg, an IR ear thermometer allows the physician to enter a value corresponding to the patient temperature) and programming at the desired patient temperature, the device can cool and heat the patient. By monitoring the upstream temperature change, the device can be controlled to the desired hypothermic regime.
[0530]
The console 750 of FIG. 76 can measure the temperature of the catheter “coolant” or working fluid in both directions, ie, the temperature T of the fluid 752 supplied to the catheter._SAnd the temperature T of the fluid 754 returning from the catheter_RIt is. This temperature can be measured at console 750, for example, with a thermistor pin mediating a disposable circulating set. Another way to measure the temperature (ie, the catheter coolant return temperature) is to place a temperature sensor 756 in the heat transfer element 758 in the return lumen 760. This makes the temperature measurement more accurate.
[0531]
Coolant return temperature T in the catheter in HTE 762_RBy measuring the instantaneous power, the instantaneous power supplied to and absorbed by the bloodstream can be measured. This power is proportional to the actual blood temperature. In the cooling mode, the blood temperature decreases and the power delivered to the catheter decreases due to the small temperature gradient. This is the same in the reheating mode. As the patient is heated, less power is distributed to the bloodstream, and this relationship is approximated as:
[0532]
(Equation 11)

[0533]
The console 750 measures the instantaneous power delivered and absorbed by the catheter 762 and monitors the change in power delivered during cooling and heating to provide a new control temperature if the initial temperature is known. Can be predicted and estimated. Therefore, the following relationship exists.
[0534]
(Equation 12)

[0535]
From this relationship, “change in catheter power” changes to “change in blood temperature”. For example, if the blood flow changes dramatically during this period, the efficiency of the catheter heat exchanger will change. High cardiac output increases power absorption and distribution.
[0536]
To correct this effect, catheter coolant flow is stopped and HTE equilibrates with blood temperature. At this equilibrium, the temperature sensor on the HTE is measuring blood temperature. This measurement is used to correct estimates for future blood temperature predictions. It is necessary to determine how often the pumps need to be stopped and the algorithms that provide real-time blood temperature prediction need to be readjusted. Where T_SIs the temperature of the coolant entering the catheter, T_RIs the temperature of the coolant returning from the catheter, T_BIs the blood temperature indirectly estimated by stopping the flow of coolant through the catheter.
[0537]
This method estimates the blood temperature between the "delivery" state and the return state. The variable determines the estimation level. First, the pump is "stopped" for a predetermined period of time to reach equilibrium with the blood flowing around the HTE.
[0538]
For example, it takes 60-120 seconds for the HTE exit sensor to reach the equilibrium temperature with the flowing blood. In addition, the steady state temperature can be predicted using an estimation algorithm. For example, in FIG. 78, the temperature measured by the catheter mounted thermistor at the time of full pump operation is, for example, 10 C at time t = 0. When the pump is turned off at this time, the measured temperature rises along curve 766 to the equilibrium temperature. When the pump is restarted at time t = 1, the temperature cools along curve 768. Duty cycle is defined by:
[0539]
(Equation 13)

[0540]
A good duty cycle is, for example, greater than 90%, which is achieved if the foreseeable algorithm can reduce the amount of time the pump is turned off. According to the control temperature prediction algorithm shown in FIG. 79, the temperature can be measured in a short time, the “stop” time of the pump can be reduced, and the cycle as described above can be increased. The following illustrates the principle of changing the patient temperature for at least a predetermined time without having to constantly monitor the patient temperature.
[0541]
During the maximum drive period by the system, the patient core temperature can move, for example, the average cooling rate is 5 ° C / hr and the average heating rate is 2 ° C / hr. If these values are maintained for 10 minutes, the body temperature changes as follows.
[0542]
[Equation 14]

[0543]
After this initial period (10 minutes), the algorithm samples more rapidly as it approaches the desired target, eg, if the patient's initial temperature is 37 ° C and the final temperature is 33 ° C and changes by 4 ° C, the device Predicts that a minimum of 30-45 minutes is required to induce a 4 ° C core temperature change. The apparatus thus starts cooling at maximum power for 30 minutes and then shuts down and checks the temperature.
[0544]
At temperatures near the set point, sampling is more frequent, and the sampling algorithm shown in Table I shows that when the difference between the patient target temperature and the target control or plan or measured blood temperature decreases, the frequency of pump stoppages and the measured temperature will decrease. be changed. Tables III and IV show a detailed analysis of the rates.
[0545]
A temperature sensor located in the HTE. Experimental example 1. A thermocouple 756, such as the “T” type of FIG. 77, is coupled to the proximal end 764 of the catheter's HTE 762 (eg, 14 fr. HTE) to bring the system to the maximum cooling stage and allow the HTE temperature sensor 756 to reach a temperature of approximately 18 ° C. Measuring. When the circulation pump is stopped, the temperature of the temperature sensor rises exponentially to 37.4 ° C., and the time constant is approximately 10 to 20 seconds. The actual temperature read as a function of time is shown in Table II. If the pump is stopped for 30 seconds, the temperature sensor approaches the final value of about 0.3 ° C., and if the pump is stopped for 20 seconds, the temperature sensor decreases the final value by about 0.7 ° C.
[0546]
Prediction algorithm. Determination of time constant. The time constant of the reaction is proportional to the amount of sarin trapped in the HTE, 24 cm 14 fr. HTE substantially includes:
[0547]
(Equation 15)

[0548]
24 cm 9 fr. HTE substantially includes:
[0549]
(Equation 16)

[0550]
Therefore, 9fr. The dual element HTE is:
[0551]
[Equation 17]

[0552]
Thus, 9 fr. For catheters, the "pump off" time is reduced by approximately 10-15 seconds.
[0553]
Experimental example. 1. Enter the desired "target temperature" and, if necessary, the speed. 2. Temperature = T from HTE temperature sensor_{p (o)}And the pump is "stopped" for, for example, 30 seconds. 3. The device calculates a "servo error".
[0554]
(Equation 18)

[0555]
4. The cooling / heating time is determined according to the size of E (O) (Table V). 5. Stop pump at end of heating / cooling period. 6. Temperature data is captured from the HTE temperature sensor at, for example, a 0.1 second sampling rate. For 9 fr, 15 seconds of data capture, 14 fr. For 30 seconds of data capture. 7. Estimate the control temperature and display value. This value is input to the temperature control servo loop. 8. Start pump based on servo error (Table VI). Here is:
[0556]
[Equation 19]

[0557]
Alternatively, the pump power may be proportional to the servo error. The determination of the time to drive the system before the pump stops is as follows, where T₀(T) is the initial patient temperature, T_TIs the target temperature, and the maximum cooling / heating rate is as follows.
[0558]
(Equation 20)

[0559]
One approach to determining the target control temperature is as follows. FIG. 80 shows the index T (t). The area A1 is T (t) for the first 10 seconds, and the area A2 is T (t) for the next 10 seconds. The assumption is as follows.
[0560]
(Equation 21)

[0561]
A1 and A2 can be measured numerically, from which B can be calculated. A search table can be created for easy reference (Table VII). In FIG. 81, each of the regions A1 and A2 includes a 12-second collection time. When B is determined from the search table, A can be calculated from the following.
[0562]
(Equation 22)

[0563]
The magnitude of the correction can be calculated as follows.
[0564]
(Equation 23)

[0565]
In FIG. 82, A1 and A2 include unequal times, but are as follows.
[0566]
[Equation 24]

[0567]
A1_{12 sec}= Get x for A2.
[0568]
(Equation 25)

[0569]
Solving x for some B creates a lookup table, which defines the range of possible time constants for a given catheter. An apparatus as shown in FIG. 83 is used for the above implementation. Temperature sensor temperature T (t) is measured by switch 780 when the pump is shut off (step 768). Although a 0.1 second sampling interval is shown, this can be changed.
[0570]
The calculation of A1 / A2 continues (step 770), and B is determined from the search table (step 772). A is then calculated (step 774), from which ΔT or the correction factor is calculated (step 776). The target temperature T () is then determined (step 778). These quantities are shown in FIG.
[0571]
The steps in the state diagram shown in FIG. 85 turn on the system (step 730) and perform the desired data entry. At the time of input, the catheter size, target temperature, time or speed of cooling / heating, etc. are input. The catheter and associated circulatory set are connected to each other and to the console.
[0572]
The system is then cleaned (step 734), put into a "stop" mode (step 736), and the catheter is inspected / inserted. If necessary, the system enters patient temperature mode, and the catheter mounted thermistor determines the patient temperature (step 738). In this case, a delay of several "X" seconds occurs (step 740), the temperature is measured, and averaging is performed over Y seconds (step 744). X is, for example, in the range of 0 to 24 seconds or more depending on the catheter size. Various temperatures are measured or determined during X followed by Y. T_HTE(T), T (t)_CONTROL, T (t)_MONITORAnd so on. These are preferably acquired at a frequency such as 10 Hz, for example, and the average patient temperature trend over time can be approximated by the average trend of HTE temperature.
[0573]
(Equation 26)

[0574]
The patient temperature is then displayed, for example, for 2 seconds (step 746), then the run mode is entered (step 742), and the patient is cooled and heated. The servo error is determined (step 744), and once the size of the servo error is determined, a safe time to execute in the maximum cooling / heating mode is determined (step 748). After this time, the system pump is stopped, and the control temperature protruding mode is entered (step 782). The system is shut down and the time is 10 to 45 seconds, such as 15 seconds or 30 seconds, for example, and the spike temperature is the basis for future calculations and is displayed if necessary.
[0575]
As an example, during the hypothermia induction period, the pump is stopped approximately three to five times, each for about 15 to 30 seconds, and a new patient temperature estimate is made. The total cooling time is several minutes longer than the average cooling time.
[0576]
FIG. 86 shows a comparator switch. When the switch 788 is closed, integration of the area A1 by the integrator 784 starts, and when the switch 790 is closed, integration of the area A2 by the integrator 786 starts.
[0577]
In a different theoretical mode, the temperature is set to T to model the transition behavior of the catheter immediately after the internal fluid flow stops.₀And stable axial fluid flow (steady temperature T_CConsider a simple (axisymmetric) cylindrical system immersed in (away from the cylinder at). If the internal temperature of the cylinder changes over time but is uniform in each longitudinal section, assuming that the longitudinal change in temperature in the cylinder is smaller than the temperature difference between the cylinder and the surroundings, the temperature change in each section of the cylinder The time speed of is given below.
[0578]
[Equation 27]

[0579]
Where α is a constant that depends on the material properties of the cylinder and surrounding fluid and the kinematics of the external flow region. This simplified analysis suggests that the transition signal from the catheter-mounted temperature sensor correlates to a morphological function.
[0580]
[Equation 28]

[0581]
Where T_∞Is the equilibrium temperature and C is the T from the starting temperature (which is always unknown for data with non-negligible noise)._∞Is dependent on the material properties of the catheter and the heat transfer fluid and the kinematics of the surrounding environment. If the range of α can be narrowed empirically, a series of binary least-squares fits the function, and eq. The form of T is T_∞Is sufficient to determine
[0582]
T_∞To determine the flow rate, the fluid flow in the catheter is first stopped, after a short period of time the transitional motion disappears, and the n temperature value T from the embedded thermistor_iAre acquired at a rate of 1 / Δt, where Δt is the time interval between adjacent (stationary) samples. Data T_iTo avoid non-linear systems due to the direct application of the least squares method to functions having the form and eq2, α is specified and the resulting 2-D linear system is solved. Specific catheter size by in vivo evaluation of catheter behavior
[0583]
(Equation 29)

[0584]
, The error between the temperature data and the eq2 form function is defined for a particular α by:
[0585]
[Equation 30]

[0586]
Where α_min<Α_j<Α_maxIt is. In fact, ε (α) is α_jT in the sequence_∞And the domain minimized for C and specified in eq3 is:
[0587]
[Equation 31]

[0588]
If the discrete representation of the resulting function ε (α), where ε represents the minimum of ε for a particular α, has a unique minimum in the domain specified in eq3, the data T_i(T) that gives the best fit to the assumed function form of_∞, C, α) is defined by the value of α with a minimum in ε (α). The number of samples m is chosen to give a sufficient solution of the function ε (α). Each α_jThe minimum error ε (α_j) Gives the corresponding T_{∞ , j}And C_jIs obtained by obtaining two derivatives.
[0589]
(Equation 32)

[0590]
This must be zero, indicating eq6 in matrix form
[Equation 33]

[0591]
[Equation 34]

[0592]
(Equation 35)

[0593]
Each T_∞Solving for and C gives:
[0594]
[Equation 36]

[0595]
Once T_∞And C, ε (α_j) Is calculated in eq4, and finally T (corresponding to the least square error between the temperature data and the function in the form of eq2) and the corresponding T_∞And C are defined as the minimum values of the discrete representation of the function ε (α).
[0596]
If the function ε (α) does not have a specific minimum or if the minimum in ε (α) is greater than a certain limit, the result of the above process is ignored and the temperature of the embedded thermistor is The equilibrium temperature T_∞Is obtained. Failure of the system identification algorithm indicates that the catheter placement was improper (eg, optimal α_minIf smaller, the catheter does not have proper external blood flow, indicating that the placement is a branch vein rather than an IVC).
[0597]
Alternatively, if it cannot be assumed that α is steady over each treatment period, each stage of control signal acquisition (including the first stage after following the “execute” command) is used as the system identification. (Where α is T_∞And C). It is then assumed that α has been combined as in equation 6, and then the specified intervals Δα, T_∞, C are calculated and the following is minimized in a least-squares manner:
[0598]
(37)

[0599]
Equation eq6. Each α in the domain determined by ε (α)_jA function is defined for and if the limits in eq6 are chosen correctly, the function gets a minimum during the domain of Eq. This minimum value defines the time constant α and then T_∞And C best fit least least squares to a function of the form expressed in Equation 5 using n of the temperature relaxation data. If the function ε is calculated with a relatively small Δα, the minimum value of ε (α) is determined by a simple selection algorithm. Alternatively, a quadratic form is assumed and the minimum is determined analytically. This method can be performed faster due to the associated cost of the quadratic curve compared to the additional evaluation of Equation 15.
[0600]
Add primary linear period. The basic exponential model as described above is based on the assumption that the temperature of the external environment (e.g., blood in IVC) is steady for a time during which the embedded thermistor can equilibrate with the environment. Generally, the temperature of the external environment is not steady over this time.
[0601]
While the catheter is working (e.g., in cooling mode), various components of the body (identified based on blood flow per body weight) or specific blood flows are dynamic and may be removed by the catheter. Heat comes preferentially from those tissues, for which the specific blood flow is maximal. When coolant flow in the catheter ceases, body components attempt to equilibrate. Tissue with high blood flow is warmer than tissue with low blood flow because the internal heat of the body is redistributed. Since the redistribution of heat occurs primarily through convective transport by blood, the temperature around the catheter must change as the components approach equilibrium.
[0602]
The blood temperature near the catheter changes over the time the catheter equilibrates with the surroundings, but the functional form of the change is unknown. For simplicity, it is assumed that the time scale during a temperature change is greater than the time scale associated with temperature relaxation in the catheter. Body temperature changes are described in the Taylor series.
[0603]
[Equation 38]

[0604]
Where T_extIs the ambient temperature, and t = 0 is when heat flow through the catheter stops. Based on the above assumption, the time Δt during which temperature data is obtained from the embedded thermistor is “small” compared to the time during which a significant change in body temperature occurs. The change in external temperature is accurately modeled by a simple linear function. It is not unreasonable to add a linear component to the functional form of eq2 to model the changing temperature of the external environment.
[0605]
[Equation 39]

[0606]
Where β is the unknown rate of change in external temperature that occurs in the body after heat cessation by the catheter.
[0607]
The calculation of the best-fit function using the eq12 form to the temperature data obtained from the embedded thermistor is the same as described for the simple three-dimensional model. α is assumed to be a series of values, and the resulting linear least squares problem for the error is a triple (T_∞, C, β). The solution has the least α and its associated least squared error (T_∞, C, β).
[0608]
Higher order changes in body temperature. The above-described method for the hypothetical functions given to eq2 and eq12 can be applied to various other forms together with the linear / nonlinear improvement added to the basic exponential model.
[0609]
Temperature estimation error and accuracy. The ability of the system to control to the desired set point or target temperature includes cooling power, degree of thermal disturbance (described below), temperature measurement accuracy in the catheter, patient temperature driving force during sampling when the pump is stopped, estimation Limited by the accuracy of the algorithm.
[0610]
From neurosurgical treatment experience, even when a convection heating blanket is used during hypothermia maintenance, the cooling power required to maintain the hypothermia at 33 ° C. is about 20 times the maximum power of the system. %. With a servo gain of 0.2C for 100% power, a load of 20% gives a servo type 1 offset of 20% X 0.2C = 0.04C error. For a 9fr catheter having a 14fr capability of about 65%, it gives an offset error during hypothermia maintenance of approximately 30% X0.2C = 0.06C. In the treatment of beating and acute myocardial infarction, the steady state load during maintenance is about the same, or about 0.06 C offset, which extracts heat from the patient and balances the patient's maintained metabolic fever by surface heating. It is necessary to make it.
[0611]
The accuracy of the thermistor is, for example, +/- 0.1 C with 100% reliability (4 standard deviations) in a temperature range of 32 to 42C. The electronic and signal processes are specified at +/- 0.1 C (95% reliability = + /-2 SD) and cover initial adjustments, dynamic temperature range, drift, and degradation considerations. Hardware temperature channel adjustments are checked and re-adjusted if necessary, eg, annually. Thermistor and hardware signal conditioning and process accuracy are comparable to commercially available disposable sensors and devices used in hospital operating rooms and intensive care settings for monitoring patient temperatures.
[0612]
During the temperature sensor data collection period (approximately 30 seconds for 9fr and approximately 60 seconds for 14fr equipment), the patient can reheat due to retained metabolic heat and interruption of heat extraction. The maximum reheat rate observed was less than about 1.5 C / hr or nearly 0.025 C / 60 sec.
[0613]
The last source of error is the ability to predict the final value of the sensor's temperature response to a one-step input of the temperature estimation algorithm. Error sensitivity analysis was performed by changing the sampling time and comparing the estimated temperature to the actual temperature. For a 20 second sampling point (24 seconds total for the pump in "stop" mode), the standard deviation of the error was 0.1C. Reducing the sampling point to 15 (total of 19 seconds of pump down) increased the standard deviation of the error to 0.18C. Increasing the sampling point to 25 (total of 29 seconds) reduced the standard deviation to 0.7C. A 20-point algorithm was chosen for an optimal compromise of the accuracy of the time versus estimation.
[0614]
Temperature measurement and estimation accuracy include various components that are considered to be statistically independent sources of error (see Table VIII), and these error sources combine to give a maximum expected error of, for example, about 0.51C. (95% confidence). Taking the root mean square error (ie, the RMS error) is about 0.26C.
[0615]
Potential thermal disturbance. One purpose of a closed circuit servo controller is the ability to maintain control during various load conditions. This ability is expressed as the maximum thermal power that eliminates the disturbance, what amount of energy is drawn to the magnitude of a particular servo error, or defined as servo gain, in a feedback control for control stability. The controller response may have an intentional delay or lead of the controller.
[0616]
Because the patient's response to thermal input is generally slow over several hours, no additional volume or phase compensation in the controller is required for optimal stability. A key component of loop stability is the servo gain level, which is selected in the range of 500-800 watts per degree C of error, based on which the catheter is selected. Clinical experiments demonstrate that at this servo gain level, the problem of instability will be a little or zero with minimal steady state servo error and good response.
[0617]
Latent heat agitation is an IV injection of a room temperature (cold) fluid. For a steady infusion rate of 1.4 ml / min (2 liters per 24 hours) of 20C fluid, this represents a heat input rate of about 2 watts. To correct for this steady state thermal disturbance, the system generates a servo error of approximately (2 watts) / (600 watts / C) or 0.003C. Since 2 watts is within the scope of the present invention, this disturbance is well controlled.
[0618]
A further challenge to thermal agitation is rapid bolus injection of fluid (eg, 250 ml in 5 minutes). If the fluid is not heated to body temperature, for an equivalent energy input of about 70 watts for 5 minutes, this represents an infusion rate of about 1 cc / sec at 20C. Reducing the temperature of an average patient (70 Kg) by 1 ° C. requires about 70-85 watts per hour. The bolus has the effect of lowering 5/60, 0.083 C of 1 ° C., which is within the controllability of the present invention.
[0619]
In actual treatment, convection or electric heating blankets are used for patient comfort and tremor suppression, and the temperature of the blanket and how much the patient's body contacts the blanket determine the energy transfer from the patient to the room. Sessler et al estimated that the blanket prevented heat loss to the environment of 20-50 watts by the blanket. Maintaining 50 watts of heat requires current systems to extract an additional 50 watts of cooling to maintain thermal balance. Servo errors are within the capabilities of the motion system at 50 watts / 600 watts / C = 0.083C. In summary, thermal disturbances as described above are within the capability of a closed circuit control system to keep the target temperature within 0.5C.
[0620]
Control algorithms may be used to control the rate at which heat is extracted from the body by the catheter. The algorithm is implemented in hardware, software or a combination. The gain factor used by the algorithm depends on the available heat of the body or organ being cooled. Therefore, it is important to determine the effective heat quantity, so that the appropriate gain factor is calculated for the feedback control algorithm.
[0621]
The weight of the body being cooled (whole body or organ) is estimated by relating the power removed by the catheter to the power lost by the body. The power removed by the catheter is given by:
[0622]
(Equation 40)

[0623]
Where M is the flow rate (cc / s) of the fluid circulating in the catheter, c_fIs the heat capacity of the fluid and ΔT is the temperature difference between the working fluid entering and exiting the catheter. By measuring the flow rate and temperature difference of the circulating fluid, P_catheterCan be easily calculated. The power removed by the catheter determined by equation (1) is equal to the power lost by the patient's body.
[0624]
(Equation 41)

[0625]
P_catheterIs the power lost by the patient's body and has a value calculated by equation (1), m is the effective heat of the body being cooled and C_bIs the heat capacity of the body and ΔT / Δt is the temperature change of the weight being cooled per hour. Therefore, the effective heat of the body being cooled is as follows.
[0626]
(Equation 42)

[0627]
Since all variables in equation (3) are known or measurable, an effective amount can be determined. The weight thus calculated is the effective heat and represents the part of the body from which power has been removed (ie, the cooled part), and the temperature change in equation (3) is the temperature change of the cooled body part. Represents For example, for whole body cooling, the change in core body temperature is measured and the weight is calculated by equation (3). Generally, for whole body cooling, if the patient is vasoconstricted, the effective amount will represent about 50% of the total body weight. If the patient is vasodilated, the effective dose will be close to total body weight.
[0628]
If, instead, a selected organ such as the brain is cooled, the temperature change used in equation (3) is the temperature change of the organ, which is largely thermally insulated from the rest of the body. At least a little can be assumed. The effective amount determined in this case is comparable to the weight of the organ. If the organ to be cooled is the brain, the catheter is placed in the carotid artery, the internal carotid artery or both. The temperature change used in equation (3) is measured by inserting a temperature sensor into the brain or via an eardrum sensor. All are commercially available.
[0629]
Experimental example. For whole body cooling in animals, catheters were inserted into the femoral vein, inferior vena cava, right atrium, and superior vena cava. The working fluid was circulated at a flow rate of 5 cc / sec to start cooling, and the temperature difference between the fluid entering and exiting the catheter was 17 ° C. The power extracted by the catheter was 354 watts.
[0630]
Body core temperature was measured through the esophagus, cooling started after 20 minutes, the rate of change of core temperature was measured for about 10 minutes, and the average temperature change was about 4 ° C./hr. From equation (3) above, the effective heat was m = 354 watts / (. 965 watts / kg · ° C.) (10 ° C./hr)=37 kg. The total weight of the animals was 53 kg and the effective weight was 69% of the total weight.
[0631]
Reheating by process. The adoption of the hypothermic method has special needs and priorities, as does the rewarming method. This will be described below.
[0632]
Neurosurgery. A common goal in neurosurgery is to quickly reheat a patient from a hypothermic temperature (eg, about 33 ° C.) to a slightly lower temperature (eg, about 35.5 ° C., wick). Reheating rates greater than about 2.5 ° C. can be achieved in less than one hour. Rewarming occurs when extubating in the operating room, as a typical closing time is about 60 minutes. A neurological examination is then performed on conscious patients. This uses an esophageal temperature probe, but other probes or sensors may be used.
[0633]
Neurosurgery method. 1. Cover the patient with 1-2 layers. 2. The temperature of the bath through which the working fluid flows for heat exchange is about 50 ° C. A sufficient temperature drop occurs between this and the blood temperature so that the blood temperature does not rise above 42 ° C. 3. The target temperature for the control system is programmed to about 35.5 ° C. 4. After the target temperature has been reached, the patient is transferred to the PACU / ICU and reheated appropriately, such as with a convection air blanket.
[0634]
Beating. A common goal in beating is, for example, to gradually re-warm the patient from a hypothermic temperature (about 33 ° C) to a “normal” temperature (about 36.5 ° C, wick) over about 12-24 hours. is there. The ICP desirably minimizes rebound, and the patient is kept comfortable without shaking or chills. A sac temperature probe is used for this, but other probes may be used.
[0635]
Beating method. 1. Warm the patient to about 41 ° C. by aggressive re-warming to prevent tremors. An electric or convection air blanket is used for this heating. 2. The console performs control reheat to meet the target temperature ramp function. In other words, a ramp value is entered by the nurse, which ramp is the rate at which the patient is reheated. A controller in the console matches the true speed with the programmed ramp. The ramp is determined by the rise time of the patient's body temperature desired by the physician and the amount of rise required to reach normal or pre-normal body temperature (36.5 ° C). 3. Patients are given anti-seismic drugs such as meperidine. 4. After reaching the target temperature, the patient is transferred to the PACU / ICU and reheated by conventional techniques such as a convection air blanket.
[0636]
Cardiovascular surgery. The goal of cardiovascular surgery is, for example, to maintain normal body temperature during the initial preoperative period following isolation from cardiopulmonary bypass for the first 24 hours after surgery. It is desirable to re-warm and re-warm and maintain the patient's temperature in the operating room to at least about 36 ° C during the last 30-45 minute closure. To complicate this, there is a 1-2 ° C drop after separation from the CPB pump, usually due to redistribution and heat loss to the surroundings. It is desirable not to use active surface reheating during closure or within the ICU. This uses an esophageal temperature probe or PA catheter in the manner described below, but other types of probes and sensors may be used.
[0637]
Cardiovascular surgery method. 1. The heat transfer element and the catheter are inserted first. 2. A CV process is performed. 3. When the patient leaves the pump, the system is started in reheat mode and the patient target temperature is set at 36.5 ° C. 4. If necessary or after the patient reaches the target temperature, remove the catheter from the console and transfer the patient to the ICU. 5. Reconnect the patient to the console and continue reheating with conventional means such as a convection air blanket. 6. Normal body temperature maintenance is continued for the next 24 hours or for the time specified by the physician.
[0638]
Manufacturing method of heat transfer element. The outer surface of the heat transfer element, as a complex shape, induces mixing of the surrounding blood flow and induces mixing of the working fluid within the heat transfer element. Such a shape is called a "mixing-induced shape", examples of which include spiral, alternating spiral, antipodal, abnormal-containing, collision-containing, channel-containing, small circular saw, hook or horn shapes. , Maze shapes and the like. The metal element, element or compound forming the heat transfer element must be sufficiently ductile to take such a shape upon placement.
[0639]
The term "arrangement" is used, and is a concept that also includes the process by which metal or coating is applied to a mandrel or layer of a heat transfer element. For example, configurations include CVD, PVD, sputtering, MBE, crystalline or non-crystalline material “grown” shapes, spray coating, electroplating, ECD, and the like. ECD, electroplating, etc. have the advantage of using charged workpieces, which can be used to fix the workpiece to tools. Generally, the heat transfer element is formed to have a mandrel with a mixing-inducing shape. The mandrel is coated with a metal layer or a series of layers (ie, heat transfer elements) to dissolve the mandrel.
[0640]
Heat transfer element formation begins with mandrel formation. For example, T6 heat treatment is performed using aluminum such as Al6061. Aluminum is convenient because it can be easily dissolved or filtered with sodium hydroxide. Forming holes along the axis of the heat transfer element speeds filtration. The mandrel is manufactured by machining with a Citizen Swiss Screw Machine or the like. When the mandrel is made of plastic, wax, low melting point thermoplastic, or the like, injection molding can be used. In addition, there are laser processing (only the outer surface) and hydro processing.
[0641]
Whatever the shape of the mandrel, it is important to have a smooth surface finish and external structure, so that the heat transfer element is smooth. When the mandrel is smooth, an atraumatic device can be formed around it. In addition, the smoothness enables easy arrangement around the metal coating (heat transfer element), and enables uniform heat conduction, uniform thickness of bio-coating, and atraumatic shape.
[0642]
FIG. 73 shows the coating layer. There is a mechanical layer 724 and a biocompatible layer 726, typically made of metal. Layer 724 is the basic thermally conductive element. Layer 724 conducts heat to provide cooling and has a thermal conductivity of about 0.1-4 W / cm-K as long as the material can be placed. Metals that can be used for layer 724 include Ni, Cu, Au, Ag, Ti, Ta, Nitinol, stainless steel, and mixtures thereof.
[0643]
The thickness of the mechanical layer should be less than about 2 mils to provide enough flexibility to pass through tortuous vessels, depending on the metal type involved and the tortuous nature of the vessels. Precious metals can be used as the type. Some have harmful biocompatibility, but each is a different manufacturing method. For example, an Au heat transfer element requires a seed layer because Au does not stick to the Al mandrel. Ni is useful. Cu is also useful and highly conductive, but tends to follow the shape of the vessel being placed.
[0644]
It is assumed that Ni forms a basic heat transfer element. Ni is not blood compatible. A compatible layer 726 is disposed on the mechanical layer 724 as shown in FIG. Compatible layers include urethane, polyurethane, Teflon, lubricating coatings, antithrombogenic coatings such as heparin, precious metals such as Au, combinations thereof, and the like.
[0645]
One difficulty here is that when a working fluid such as sarin is used, corrosion of the mechanical layer occurs. In the case of the mechanical layer 724 of Ni, sarin is particularly corrosive. Therefore, a protective layer 722 that is non-corrosive to sarin is provided. For example, the protective layer is made of Au. The Au protective layer hardly adheres to the aluminum mandrel. Therefore, if necessary, a Cu layer is applied to the mandrel before the Au layer is applied. Following dissolution of the mandrel, the Cu layer is also etched. The protective layer is generally a noble or inert metal, and may be a polymer such as Teflon.
[0646]
Alternatively, the protective layer 722 may be vacuum deposited following removal or dissolution of the mandrel. The holes left by mandrel removal allow the passage of evaporated gas or liquid chemicals. Thus, the material can be applied inside the heat transfer element, the applied material being a polymer as described above, a non-erodible or non-polar polymer, a noble metal or the like.
[0647]
In FIG. 74, there is a biocompatible layer 726 and a heparin / lubricating layer 728 on the mechanical layer 724, which combine to form one biocompatible layer. Alternatively, the biocompatible layer may be a “seed” layer, which enhances the bonding of the heparin / lubricating layer 728 to the mechanical layer 724. The seed layer is, for example, heparin. The heparin / lubricating layer is only one example, and both may be applied separately or together. Sometimes heparin is not needed.
[0648]
FIG. 75 illustrates problems that occur with various metals. For example, the mechanical layer 724 made entirely of Ni has a rupture pressure too low due to its porosity, and the protective layer 722 of FIG. 74 is associated with this. The mechanical layer is divided into several layers, the layers 724a and 724c are made of a first material such as Ni, and the layer 724b is disposed between the two layers. This layer 724b is made of a second material such as Cu, and the combination of these layers constitutes a mechanical "sandwich" structure. The Cu layer closes "pinholes" in the Ni layer.
[0649]
Table I shows a useful example where the biocompatible coating is an Au layer, which is a special case. This table relates to FIG.
[0650]
[Table 1]

[0651]
The total thickness of the group of layers 102-108 is about 1 mil, and nickel and copper contain traces of other elements but are not harmful. The present invention is not limited to the above embodiment.
[0652]
[Table 2]

[0653]
[Table 3]

[0654]
[Table 4]

[0655]
[Table 5]

[0656]
[Table 6]

[0657]
[Table 7]

[0658]
[Table 8]

[0659]
[Table 9]

[Brief description of the drawings]
[0660]
The novel aspects of the invention, as well as the invention itself, will be better understood with reference to the following drawings, together with the following description. In the following, similar reference symbols are used corresponding to similar parts.
FIG. 1 is an explanatory diagram showing an embodiment of a heat transfer element used in the superior aorta.
FIG. 2 is a graph showing a method for preferentially cooling a high-flow organ in a hypothermia therapy.
FIG. 3 is a graph showing velocity in a steady state of turbulence as a function of time.
FIG. 4 is a graph showing blood flow velocity in an artery as a function of time.
FIG. 5 is a graph showing pulsatile steady-state turbulent blood flow velocity as a function of time, similar to arterial blood flow.
FIG. 6 is an elevation view showing a turbulence-induced heat transfer element in an artery.
FIG. 7 is a velocity profile diagram showing a Poiseuille flow in a steady state driven at a constant pressure gradient.
FIG. 8 is a velocity profile diagram of arterial blood flow averaged over the duration of a cardiac pulse.
FIG. 9 is a velocity profile diagram of arterial blood flow averaged over the duration of a cardiac pulse after a smooth heat transfer element is inserted into an artery.
FIG. 10 is an explanatory view of a heat transfer element according to one embodiment of the present invention.
FIG. 11 is a graph showing the relationship between Nusselt number (Nu) and Reynolds number (Re) of an air flow flowing along a long heating pipe at a uniform wall temperature.
FIG. 12 is an elevational view of one embodiment of a heat transfer element according to the present invention.
FIG. 13 is a longitudinal sectional view of the heat transfer element shown in FIG. 1;
FIG. 14 is a transverse sectional view of the heat transfer element shown in FIG. 1;
FIG. 15 is a perspective view showing a state of use of the heat transfer element shown in FIG. 1 in a blood vessel.
FIG. 16 is a perspective view showing another heat transfer element according to the present invention having a row of longitudinal ridges between adjacent segments.
FIG. 17 is a perspective view of another heat transfer element according to the present invention having slightly offset longitudinal ridges between adjacent segments.
FIG. 18 is a transverse sectional view of the heat transfer element shown in FIG. 16 or FIG. 17;
FIG. 19 is a perspective view showing a state in which a substitute heat transfer element according to the present invention is cut away.
FIG. 20 is a transverse sectional view of the heat transfer element shown in FIG. 5;
FIG. 21 is a front cross-sectional view of a further embodiment of a catheter employing a heat transfer element and further in a side-by-side lumen arrangement in accordance with the principles of the present invention. It is.
FIG. 22 is a cross-sectional view of the catheter shown in FIG. 21, taken along line 22-22 of FIG. 21.
FIG. 23 is a front cross-sectional view of a catheter employing yet another heat transfer element and a lumen arrangement according to the present invention.
FIG. 24 is a front cross-sectional view of a catheter employing yet another heat transfer element and a lumen arrangement according to the present invention.
FIG. 25 is another embodiment employing heat transfer elements according to the principles of the present invention, according to another embodiment of the present invention. FIG. 9 is a front cross-sectional view of another embodiment of a catheter employing a side-by-side lumen arrangement.
26 is a cross-sectional view of the heat transfer element shown in FIG. 25, taken along line 26-26 of FIG.
FIG. 27 is an illustrative side view showing an inflatable turbulence-inducing heat transfer element as an embodiment of the present invention positioned within an artery.
FIG. 28 is an illustration of an alternative embodiment of an inflatable turbulence induced heat transfer element employing a surface area increasing taper and a turbulence induced shape in an artery according to the present invention.
FIG. 29 illustrates a tapered joint that may be employed in the embodiment of FIG.
FIG. 30 is an illustration showing a turbulence induced heat transfer element employing a surface area increasing taper and a turbulence induced shape as a second alternative embodiment according to the present invention.
FIG. 31 is an illustration showing one form of turbulence-inducing surface morphology that may be employed in the example heat transfer element of FIG. 28. FIG. 31 shows a spiral (spiral) shape.
FIG. 32 is an illustration showing an alternative embodiment of a heat transfer element employing a surface area increasing taper according to the present invention.
FIG. 33 is an illustration showing another type of turbulence inducing surface configuration that may be employed in the embodiment of FIG. 27. FIG. 33 shows a series of projections in a zigzag arrangement.
FIG. 34 is a transverse sectional view of the heat transfer element shown in the embodiment of FIG. 33.
FIG. 35 is a perspective view of a device according to the present invention positioned within a common carotid artery of a patient.
FIG. 36 is a perspective view of the device shown in FIG. 35 with additional structural details.
FIG. 37 is a cross-sectional view of the device shown in FIG. 36, taken along line 3-3.
FIG. 38 is a partial longitudinal cross-sectional view of the apparatus shown in FIG. 30, showing the flow path of the cooling fluid.
FIG. 39 is a schematic depiction of a heat transfer element being used to provide a hypothermia to a patient undergoing full body cooling and then rewarming the patient, in one embodiment.
FIG. 40 is a schematic depiction of a heat transfer element being used to cool a patient's brain and warm blood in the throat vein returning from the brain, as one example.
FIG. 41 is a schematic depiction of a heat transfer element showing infusion of warm saline into blood in the throat vein returning from the brain while cooling the brain of a patient, as one example.
FIG. 42 is a schematic depiction of an exemplary external warming device that can be used to warm blood in a vein returning from an organ.
FIG. 43 is a schematic depiction of a heat transfer element in use to provide hypothermia to a patient undergoing full body cooling of the patient and then re-warming the body, as another example.
FIG. 44 is a flow chart illustrating an exemplary method according to the present invention using a heating blanket and a thermoregulator.
FIG. 45 shows a meperidine molecule.
FIG. 46 shows a morphine molecule.
FIG. 47 shows prozin (+) isomer molecules.
FIG. 48 shows prozin (−) isomer molecules.
FIG. 49 shows a fentanyl molecule.
FIG. 50 shows hydroxy allyl prozin (+) isomer molecule.
FIG. 51 shows a picenadol (+) isomer molecule.
FIG. 52 shows a picenadol (−) isomer molecule.
FIG. 53 shows a tramadol molecule.
FIG. 54 shows a nefopam molecule.
FIG. 55 is a schematic depiction of the use of a heat transfer element for body cooling, according to one embodiment of the present invention.
FIG. 56 is a flowchart illustrating an exemplary method according to the present invention.
FIG. 57 shows a catheter having a manifold constructed in accordance with the present invention.
FIG. 58 shows an enlarged fragmentary portion of the catheter shown in FIG. 57.
FIG. 59 is a perspective view of a heat transfer catheter system including a circulating set constructed in accordance with an embodiment of the present invention.
FIG. 60 is a cross-sectional view of an embodiment of the distal end of a heat transfer catheter, along with a side elevation view of an embodiment of the distal end of the catheter, which may be used with the circulating set shown in FIG. 59.
FIG. 61 is an illustration of a valve that may be employed in certain embodiments according to the present invention.
FIG. 62 is an explanatory diagram of the circulating set shown in FIG. 48.
FIG. 63 is an exploded perspective view showing a disposable heat exchanger that may be used in a circulating set according to the present invention.
FIG. 64 is a cross-sectional view of the heat exchanger shown in FIG. 52.
FIG. 65 is a perspective view showing a manifold portion of the heat exchanger shown in FIG. 63.
FIG. 66 is a perspective view showing a manifold portion of the heat exchanger shown in FIG. 63.
FIG. 67 is a perspective view showing a temperature and pressure sensor configured according to an embodiment of the present invention.
FIG. 68 is an exploded perspective view showing the temperature and pressure sensor shown in FIG. 67.
FIG. 69 is an exploded side elevational view showing the temperature and pressure sensors shown in FIG. 67.
70 is an exploded perspective view showing the temperature and pressure sensors shown in FIG. 67, and is a view seen from a different viewpoint from that shown in FIG. 68.
FIG. 71 is a representative graph showing pump motor speed versus time for the circulating set of pumps shown in FIG. 59.
FIG. 72 is a graph showing an exemplary relationship between pressure and pump motor speed for the 10F and 14F heat transfer catheter motors of the circulating set shown in FIG. 59.
FIG. 73 is a schematic depiction showing layers constituting a wall of a heat transfer element, as an embodiment according to the invention, formed by the method according to the invention;
FIG. 74 is a schematic depiction showing a layer constituting a wall of a heat transfer element according to a second embodiment of the present invention, the layer formed by the method according to the present invention;
FIG. 75 is a schematic exploded depiction showing a layer constituting a wall of a heat transfer element according to a third embodiment of the present invention, the layer formed by the method according to the present invention;
FIG. 76 illustrates a system that may be used to implement a predictive temperature algorithm.
FIG. 77 shows the junction between the heat transfer element and the catheter, showing the position of the catheter-mounted heat transfer element.
FIG. 78 shows an operating cycle of the pump.
FIG. 79 illustrates two operating cycles of the pump, and illustrates that employing the predictive temperature algorithm achieves a higher operating cycle than that shown in FIG. 78.
FIG. 80 illustrates one graphical method for predicting a control temperature.
FIG. 81 shows the relationship between time and the area ratio before and after measurement.
FIG. 82 illustrates another method for predicting a control temperature.
FIG. 83 shows a system that can implement a controlled temperature forecasting method.
FIG. 84 shows a graph of the area shown in FIG. 81.
FIG. 85 illustrates another system in which a controlled temperature forecasting method can be implemented.
86 shows a comparator switch shown in FIG. 85 and which may be used in the embodiment.
[Explanation of symbols]
[0661]
100: blood flow
102, 210: heat transfer element
104: heat conduction segment
107: Working fluid
122: Blood
124: lumen

Claims (42)

A catheter having a supply / return lumen for supplying / returning the working fluid between the heat transfer element and the heat transfer element at the distal end is inserted into a patient's blood vessel, and the catheter is inserted between the catheter and the heat transfer element. Circulates a working fluid at a temperature different from the patient's temperature, receives a signal from a temperature sensor attached to one of the supply and return lumens, determines a control temperature based on the signal, and uses the control temperature. A method for controlling a thermal therapy dosage comprising controlling the temperature of a working fluid. In stopping and receiving the circulation of the working fluid, the first time interval is passed, data is collected from the temperature sensor during the second time interval, and the first time interval is passed and the data collection is activated. The method of claim 1, wherein the fluid circulation stop is continued. The method of claim 1, wherein the temperature sensor is selected from the group consisting of a thermistor, a thermocouple, and combinations thereof. The method of claim 3, wherein the temperature sensor is two thermistors and receives a safety monitor signal from one of the thermistors. The method according to claim 4, wherein the circulation of the working fluid is stopped when the value of the control temperature measured by the safety monitor signal falls outside a predetermined range. The method according to claim 5, wherein the predetermined range is 31 to 37C. The method of claim 2, wherein no data is collected during the first time interval. The method of claim 7, wherein data is collected at a predetermined frequency during the second time interval. The method of claim 2, wherein the first time interval is between about 5 and 15 seconds. The method of claim 9, wherein the first time interval is about 10-12 seconds. The method of claim 2, wherein the second time interval is between about 10 and 30 seconds. The method of claim 11, wherein the second time interval is between about 15 and 25 seconds. The method of claim 1, wherein the temperature sensor is located in the polymer tube in the supply or return lumen. The method of claim 1, wherein the temperature sensor is located in the return lumen. 14. The method according to claim 13, wherein the polymer is a polyamide. The method of claim 2, wherein the first time interval is approximately the same length as the second time interval. The method of claim 2, wherein the first and second time intervals are different lengths of time. 3. The method according to claim 2, wherein the signal values are integrated over a first time interval with respect to time to derive a first region. 19. The method of claim 18, wherein signal values are integrated over a second time interval with respect to time to derive a second region. 3. The method according to claim 2, wherein the second time interval is at least one minute. (Working fluid stopping circulation) / ((sum of working fluid stopping circulation) + (working fluid circulating time)) is greater than about 90%. Item 3. The method according to Item 2. The method of claim 1, wherein the working fluid is circulated and the control temperature is not determined for a predetermined period of time based on a difference between a current patient temperature and a target patient temperature. 23. The method of claim 22, wherein the temperature of the working fluid is lower than the current patient temperature and the predetermined time is greater than about 30 minutes. 23. The method of claim 22, wherein the temperature of the working fluid is higher than the current patient temperature and the predetermined time is greater than about 15 minutes. 23. The method of claim 22, wherein the predetermined time is directly proportional to a difference between a current patient temperature and a target patient temperature. The method of claim 22, wherein circulating the working fluid comprises circulating the working fluid at a maximum pump speed. 23. The method of claim 22, wherein circulating circulates the working fluid at a pump speed power proportional to a difference between a current patient temperature and a target patient temperature. The predetermined time is determined by ((initial patient temperature)-(sum of target patient temperatures) + (constant)) / (maximum rate of temperature change associated with desired thermal treatment). 23. The method according to claim 22. 29. The method of claim 28, wherein the desired thermal treatment induces hypothermia. 29. The method of claim 28, wherein the desired thermal treatment is a rewarming procedure. The method of claim 19, wherein the first region is divided by the second region to calculate a value that is a function of an exponential time constant. The method of claim 31, wherein a search table is formed as a function of a time constant and a result of dividing the first region by the second region. The method of claim 32, further comprising determining a magnitude of the exponential function using the first region, the second region, and the time constant. Determining the magnitude of the exponential function based on the signal from the temperature sensor measured at the end of the second time interval, the magnitude of the exponential function, and the time constant of the exponential function. 34. The method according to claim 33. To determine the magnitude of the exponential function, estimate the time constant range for the exponent and calculate the error value that is a function of the time constant by performing the least squares fit method between the collected data and the exponent for each range of the time constant 3. The method of claim 2, wherein the characteristic value of the time constant is determined by minimizing an error value. 36. The method of claim 35, further comprising using a unique value of the time constant to determine the planned control temperature. The method of claim 35, further comprising determining a magnitude of the exponent. The method of claim 35, further comprising determining a primary linear element and adding the primary linear element to an index to determine a planned control temperature. 39. The method of claim 38, further determining a higher order component and adding the higher order component to the exponent to determine a planned control temperature. The method of claim 1, further comprising administering to the patient an anti-seismic agent. A computer program, located on a computer readable medium, for causing a machine to receive a signal from a temperature sensor mounted on one of a supply / return lumen through which a working fluid is flowing, and based on the signal. A computer program for determining a control temperature and controlling a temperature of a working fluid using the control temperature. A computer program, located on a computer readable medium, causing a machine to receive a signal from a temperature sensor mounted on one of a supply / return lumen through which a working fluid is flowing, and the working fluid to flow. Stopping a first time interval, collecting data from a temperature sensor during a second time interval, determining a control temperature based on the collected data, and using the control temperature to determine a temperature of the working fluid. A computer program characterized by being controlled.

Images