Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
  • A61B5/026—Measuring blood flow
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
  • A61B5/02007—Evaluating blood vessel condition, e.g. elasticity, compliance
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
  • A61B5/021—Measuring pressure in heart or blood vessels
  • A61B5/0215—Measuring pressure in heart or blood vessels by means inserted into the body
  • A61B5/02152—Measuring pressure in heart or blood vessels by means inserted into the body specially adapted for venous pressure

Definitions

• the present invention relates to a microcatheter and to a diagnostic method for in vivo measurements of blood pressure in vessels, and in particular to blood pressure measurements in individual arteries by means of a pressure sensitive sensor mounted on a guide wire while simultenously using an infusion catheter for continuous infusion of a vasodilator agent in the form of diagnostic fluid with a specific infusion range.
• Coronary pressure measurements have recently received renewed interest, partly due to technical innovations (such as the development of pressure- measuring angioplasty guidewire) and theoretical progress (such as the concept of pressure derived fractional flow reserve).
• Fractional flow reserve is the ratio of maximal flow in the myocardial region affected by a stenosis to maximal flow in that same region if the stenosis were absent.
• pressure derived FFR can be used as a surrogate for a stress test for on-line clinical decision making in the catheterization laboratory.
• values ⁇ 0.75 are most often associated with exercise-inducible myocardial ischemia, while values > 0.75 exclude objective signs of ischemia during exercise.
• the accuracy of FFR for that purpose is approximately 95% which is higher than that of any single non-invasive test taken alone.
• Maximal coronary hyperaemia is beneficial in producing accurate, reproducible measurements. In a normal artery there should be no pressure gradient between the aorta and the distal artery resulting in a FFR value of 1. Pullback of the pressure wire can be used to determine which of two or more serial stenoses is more functionally significant. As stated, the achievement of maximal hyperaemia is beneficial for the accurate determination of FFR. Otherwise the pressure gradient across a stenosis will be underestimated. As may be appreciated, maximum distal pressure (DPmax) and the distal coronary pressure (Pd) are directly proportional to the arterial pressure (Pa) but only in conditions where maximal hyperemia has been secured. Therefore, changes in systemic blood pressure during maximum hyperemia are accompanied by proportional changes in DPmax. If maximum hyperemia is not completely achieved, patients may be undertreated.
• DPmax maximum distal pressure
• Pd distal coronary pressure
• the available pharmacological agents for inducing maximal coronary hyperaemia can be given by intracoronary injection (ic) or intravenous infusion (iv).
• intracoronary adenosine some specific pitfalls are present which may lead to underestimation of the maximum gradient and overestimation of FFR.
• the available pharmacological agents for inducing maximal renal hyperaemia are papaverine [2] whereas adenosine induces vasoconstriction and UTP induces vasodilation ⁇ ]
• U.S. Patent Application No. US 20070078352 is directed to a system for measuring coronary flow reserve (CFR), wherein a known amount of saline is injected as a bolus and is this bolus is used for measurements of blood flow (CFR) by continuous thermodiiution.
• CFR coronary flow reserve
• This document describes a catheter that has side holes which are not optimal for drug delivery and can only be used for iv hyperemic agent infusion in order to perform both FFR and CFR measurements. The infusion rate range by which this catheter allows for IC infusion of saline is not disclosed.
• the intraarterial systemic pressure can be measured continuously with a transducer and a miniaturized pressure-gradient wire system (PressureWire; St. Jude Medical or Volcano combo wire). Pressures can be recorded using a fiber-optic pressure sensor located laterally and 3 cm from the distal end.
• Pressure wire modulates an optical reflection with pressure-induced elastic movements. This pressure wire thus replaces a standard 0.018-inch guide wire.
• the induction of a pressure difference (index) is achieved by intraarterial infusion of a vasodilator agent such as adenosine, papaverine, adenosine-tri-phosphate, dopamine, nitric oxide or uridine triphosphate(UTP).
• a catheter system e.g.
• the catheter comprises a intraarterial artery Infusion catheter for hyperemic agent and an FFR catheter in the same catheter.
• the infusion catheter comprises a tubular member having a circumferential side wall and an opening at its distal end so for discharging a vasodilator agent.
• the circumferential side wall is impermeable to the vasodilator agent and, in particular, does not comprise any openings or other outlets that would allow the vasodilator agent to be discharged.
• the only opening for discharging the vasodilator agent is adapted to discharge the vasodilator agent in a longitudinal direction of the tubular member, thereby improving the drug delivery.
• the aortic pressure signal is recorded proximal to the infusion catheter so pressure measurements do not have to be interrupted for administration of the drug. Therefore, the drug could then be administered continuously without using the stopcock to register Pa again, avoiding care should be taken to be sure that the correct value is taken for Pa at the correct moment (peak hyperemia, minimal distal pressure) by checking the FFR screen for the lowest possible FFR and highest possible CFR.
• the catheter comprises a first lumen for infusing the vasodilator agent, and a second lumen for advancing a wire-mounted pressure sensor.
• the catheter may be embodied as a double- lumen catheter.
• the separate lumen allow maximal drug delivery to the coronary artery and permit accurate measurements of the aortic pressure.. If a guiding catheter with side holes is used, an unpredictable part of the hyperemic drug will be spilled in the ascending aorta. As a consequence, the measurements may be unreliable, as mean arterial pressure may be underestimated and intracoronary FFR overestimated.
• kits comprising an intracoronary infusion and FFR catheter disclosed herein and a pre-specified amount of uridine triphosphate (with or without Nitric oxide and/or in combination with one or more other medicaments) or another vasodilator agent.
• Embodiments of the method described herein enhance the medical usefulness of blood flow measurements, and in particular provide absolute values of blood flow and pressure measured through application of the continuous intracoronary infusion of UTP in a patient who suffers from a coronary disease that can be related to normal blood flow values for this particular patient.
• a method of measuring coronary blood flow comprising the following steps: positioning of a guide-wire mounted infusion lumen and pressure sensor at a distal position in a coronary artery of a patient, in such a way that the positioning of an infusion catheter in the coronary artery is proximally (upstream) of the distal pressure sensor, but distal to the proximal pressure sensor, measurement of resting pressure by both a proximal and a distal pressure sensor to get a baseline FFR value of 1 , hereafter initiate a continuous infusion of a hyperemic diagnostic agent such as UTP with known infusion rates through the infusion catheter, and calculation of absolute coronary proximal and distal pressure according to a calculated index on the known and measured quantities.
• a hyperemic diagnostic agent such as UTP with known infusion rates
• Embodiments of the method comprises the preferred induction of a steady state hyperemia with hyperemic agents in the patient, such that the obtained absolute coronary flow is the maximum absolute coronary flow (post occlusion hyperemia).
• the blood flow increase due to the infusion of a hyperemic agent is measured by the same combined guide wire mounted pressure sensor as is used for infusing the hyperemic agent.
• the actual guide wire is placed in the pressure sensor lumen.
• the positioning of the pressure sensor guide wire and infusion catheter is usually accomplished through a guide catheter that has been inserted into the patient's aorta, and the method can be supplemented with a corresponding step.
• the method comprises the following steps: positioning of a guide wire mounted pressure sensor at a distal position in a coronary artery of a patient, positioning the infusion lumen in the coronary artery such that the distal end of the infusion catheter is located proximally (upstream) of the pressure sensor, inducting steady state hyperemia by intracoronary infusion of hyperemic agent through the intracoronary mounted catheter in the patient, measuring the blood pressure difference by the two pressure sensors, calculation of FFR index according to a formula based on the known and measured quantities, valued as a ratio of the measured hyperemic aortic pressure and the measured distal coronary pressure, and calculating a related FFR value.
• the method for calculating FFR values is disclosed in e.g.
• the method further comprises inducing a steady state hyperemia in the patient before and after hyperemia, and measurement is calculated so that the coronary blood flow is the maximum coronary blood flow. This may occur by infusing a hyperaemic agent in increasing concentration until the largest possible pressure drop across a stenotic vessel is observed in either the renal or coronary artery. The infusion can be in either continuous or bolus fashion.
• the sensor guide wire as well as the infusion catheter is introduced into the coronary artery via a guide catheter inserted into the patient's aorta, and the hyperemic aortic pressure is measured by a pressure transducer e.g. a pressure transducer connected to the guide catheter or a second pressure transducer connected to the sensor guide wire or to the infusion catheter.
• the method can further include the following steps: positioning of a balloon arranged on a catheter in the coronary artery such that the balloon is positioned proximally (upstream) of the guide wire moulted pressure sensor, inflating the balloon to create total occlusion of the coronary artery, and measuring the coronary wedge pressure by the pressure sensor.
• the balloon is then deflated, and - like in the previous method - the FFR can be measured by the same guide wire after the angioplasty by the mounted sensors as is used for measurements prior to the angioplasty.
• the method further comprises the step of retracting the first pressure sensor along a vessel in case of either uni- and/or multi-vessel artery disease; and measuring the pressure at at least three locations.
• This operation may be referred to as a pu!l back maneuver and performed e.g. as described in Pressure-Derived Fractional Flow Reserve to Assess Serial Epicardial Stenoses theoretical Basis and Animal Validation by Bernard De Bruyne et al, circulation, 2000.
• FFRpred FFR of each stenosis separately (ie, as if the other one were removed) from arterial pressure (Pa), pressure between the 2 stenoses (Pm), distal coronary pressure (Pd), and coronary occlusive pressure (Pw).
• Pa arterial pressure
• Pm pressure between the 2 stenoses
• Pd distal coronary pressure
• Pw coronary occlusive pressure
• the interaction between 2 stenoses is such that FFR of each lesion separately cannot be calculated by the equation for isolated stenoses (Pd/Pa during hyperemia) applied to each separately but can be predicted by more complete equations taking into account Pa, and Pd.
• Advantages of using a micro catheter for the FFR diagnostic method in patients with coronary artery disease include
• microcatheter secures ostial infusion instead of infusion into aorta which results in less systemic spill over;
• adenosine versus UTP: The preferred hyperemic agent used today for inducing coronary hyperemia is the naturally occurring nucleoside adenosine.
• IC intracoronary
• CFR coronary flow reserve
• IV Intravenous
• IV continuous adenosine infusion has also been validated as a standard method for the induction of coronary hyperemia for FFR measurements [5].
• An intracoronary bolus of ATP or adenosine (20 to 40 g) induced a similar degree of hyperemia as in intracoronary bolus of 20 mg papaverine in humans.
• intracoronary ATP and adenosine often fail to induce true steady-state hyperemia.
• the IC continuous UTP infusion method by using either a guide wire or an IC microcatheter is safe and useful for inducing optimal coronary hyperemia without any additional procedure.
• UTP can therefore be used in all patients following normal guidelines for FFR use.
• the present invention relates to different aspects including the device described above and in the following, and corresponding methods, uses and/or product means, each yielding one or more of the benefits and advantages described in connection with one or more of the above- mentioned aspects, and each having one or more embodiments
• FIG. 1 schematically illustrates an example of a combined catheter with a single infusion and pressure wire lumina.
• FIG. 2 schematically illustrates an example of a combined catheter with two different lumina, one for infusion and one for a pressure wire.
• FIG. 3 schematically illustrates a kit comprising a hyperemic agent (e.g. UTP optionally with NO), a combined catheter and an infusion pump.
• a hyperemic agent e.g. UTP optionally with NO
• FIG. 4 is a schematic illustration of a human with coronary artery disease in which there is inserted a combined catheter positioned in order to perform the steps included in the method described herein.
• FIG 5. is a graph showing IC UTP versus IC adenosine in an equimoiar concentration comparison during FFR measurements, illustrating the difference in maximal hyperemia by use of UTP in comparison to adenosine.
• UTP is more effective than adenosine with regard to lowing FFR in comparison to adenosine during continuous intracoronary infusion using a microcatheter.
• the maximal coronary blood flow in a coronary artery of a patient who is in a state of maximal hyperemia with UTP infusion can be calculated from previously described equations, e.g. as mentioned in detail in US 2007/0078352. It is applicable in a situation where a patient is set in a state of hyperemia such that the incoming blood flow cannot be increased further pharmacologically.
• fractional flow reserve FFR
• the concept of inducing maximal hyperemia is desirable in order to get an accurate FFR because only at maximal hyperemia are pressure and flow comparative which is the basis for the calculations.
• the true maximal hyperemic response in a human subject can be achieved during post occlusion episodes, where several compound/metabolites that are discharged from the endothelial cells and myocardial cells participate in the response.
• pharmacological agents are used to simulate this response it is not the true maximum, as shown in FIG. 5 where it is clear that UTP is superior to adenosine for resembling post occlusion hyperemia as much as possible.
• FIG. 1 schematically illustrates an example of a combined catheter with a single infusion and pressure wire lumen.
• the catheter comprises an infusion catheter 100 having a single lumen with an open distal end 113 through which a hyperemic agent may be infused into a coronary.
• a hyperemic agent may be infused directly into the coronary; furthermore as the opening 1 3 is provided at the distal end face of the infusion catheter, and as the infusion catheter does not have any lateral openings, the hyperemic agent is infused in the longitudinal direction of the infusion catheter, thus allowing a more efficient infusion of hyperaemic agent.
• the catheter comprises a wire 101 movably arranged inside the infusion catheter 100 such that the wire can be caused to slide in its longitudinal direction in and out of the distal opening 113 of the infusion catheter.
• the wire 101 comprises a pressure sensor 102 at its distal end.
• the infusion catheter 100 may have a diameter sufficiently small to allow insertion into a coronary, e.g. no larger than 4 Fr or 1.35 mm in diameter.
• the infusion catheter may be sufficiently long to allow advancement of the catheter from a patient's groin to a patient's heart, e.g. the catheter may be 175 cm long.
• the pressure sensor 102 may have a pressure range of -30 to +300 mmHg and a pressure accuracy of +/-1 mmHg plus ( ⁇ 50 mmHg)+/-3% (>50 mmHg) and a frequency response of DC to 25 Hz
• the catheter is inserted into the coronary artery to be investigated, e.g. as illustrated in fig. 4.
• the catheter may be introduced via a guide catheter inserted into either the radial or femoral artery.
• pressure measurements are performed with the guide-wire mounted sensor 102.
• a suitable guide wire mounted sensor is, for example, manufactured and sold by Volcano Corporation under the registered trademark Combowire® or the St. Jude Medical produced PressureWire® Sensor, and is described in the U.S. Pat. No. 6,343,514 and Re 35,648.
• the sensor signals representing the measured pressures may be processed in a device for monitoring, calculating and displaying the measured variables.
• a device is sold under the registered trademark RadiAnalyzer® by Radi Medical Systems AB, and is described in U.S. Pat. No. 6,565,514.
• F!G. 2 schematically illustrates an example of a combined catheter with two different lumina, one for infusion and one for a pressure wire.
• the catheter comprises a double lumen microcatheter 107 providing two separate lumina 104 and 105, respectively.
• the two lumina function as an infusion lumen 104 and a pressure wire lumen 105, respectively, and have respective open ends 113a and 113b.
• the pressure wire lumen which may be made from a flexible material; in some embodiments it may be pre-shaped in a J-form so as to facilitate insertion.
• the infusion lumen 104 has an open distal end 113a through which a hyperemic agent may be infused into a coronary artery as described in connection with fig. 1 ; furthermore the opening 113a is provided at the distal end face of the infusion catheter, and the infusion catheter does not have any lateral openings.
• the catheter comprises a wire 101 movably arranged inside the pressure wire lumen 105 such that the wire can be caused to slide in its longitudinal direction in an out the distal opening 113b of the pressure wire lumen 105.
• the wire 101 comprises a pressure sensor 102 at or proximal to its distal end, e.g. a pressure sensor as described in connection with fig. 1.
• a pressure sensor 102 at or proximal to its distal end, e.g. a pressure sensor as described in connection with fig. 1.
• the pressure sensor 102 may be located close the distal end of the pressure wire thus leaving a dead end pressure wire 100.
• the end of the pressure wire may be made of and/or coated with an x-ray sensitive material so as to facilitate identification of the tip in x-ray images. It will be appreciated, however, that the pressure sensor may alternatively be positioned directly at the end of the wire. Hence, the distal pressure sensor is capable of being repositioned along the artery whereas the infusion catheter is a "dead end" on the combined catheter.
• the catheter 107 may have a diameter sufficiently small to allow insertion into a coronary, e.g. no larger than 4 Fr or 1.35 mm in diameter.
• the infusion catheter may be sufficiently long to allow advancement of the catheter from a patient's groin to a patient's heart, e.g. the catheter may be 175 cm long.
• the pressure wire and infusion lumina may have the same or different diameter.
• the catheter may comprise a second pressure sensor 106 positioned upstream of the opening 113a of the infusion lumen.
• the pressure sensor 105 may be of the same or a similar type of the distal pressure sensor 102.
• the pressure sensor 106 may be positioned on the pressure wire lumen as shown in fig. 2, and/or on the infusion !umen and/or the combined catheter 107.
• the catheter may further comprise or be used in combination with a guide catheter 108 facilitating insertion of the combined microcatheter 107.
• fig. 2 shows an example of a combined catheter with two different lumina one for infusion and one for a pressure wire.
• the catheter is constructed in such a way that it consists of two separate lumina: a fixed infusion catheter lumen and a lumen with a movable pressure wire where the guide wire can pass through. This is created in such a way that one can slide the pressure wire in and out whereas the infusion catheter is stable.
• Examples of catheters described herein do not have side holes. In the case of multiple stenosis in the same vessel, the sliding pressure wire will thus be able to extend itself across several lesion without affecting the infusion lumen.
• the guide wire is applied trough the pressure lumen.
• Fig. 3 schematically shows a system for determining a blood flow/pressure index (FFR) using intracoronary infusion of a hyperemic agent into an individual artery of a patient, e.g. a human or mammal.
• the system comprises a combined catheter 301 , e.g. as described in connection with fig. 1 or 2, an infusion pump 302 for injecting a hyperaemic agent such as UTP, NO or a combination thereof, and a signal processing device 303.
• the combined catheter comprises one or two pressure sensors (not explicitly shown).
• the measured pressure signals by the pressure sensor(s) are fed into the signal processing device for signal processing and calculation of the FFR and output and/or recording of the calculated FFR.
• the pressure wire and/or a sensor lumen 305 of the combined catheter is connected to the signal processing device.
• the infusion pump is connected to an infusion catheter 304 of the combined catheter.
• an embodiment of the method described herein may begin with the introduction of a guide catheter 108 into the patient's aorta, as is well-known in the field.
• a conventional guide wire can be employed to facilitate the introduction of the guide catheter, as also is well-known in the field.
• the combined catheter 107 including the guide-wire mounted pressure sensor 102 is subsequently introduced into the guide catheter, and is then advanced out of the end of the guide catheter and into a specific coronary artery until the openings 113a,b and the proximal pressure sensor 106 are positioned at a proximal position in the coronary artery.
• the pressure wire 101 may then be further advanced into the coronary artery until the distal pressure sensor 102 is located at a distal position in the coronary artery.
• the specially designed infusion lumen 04 is parallel to the pressure lumen 105 but positioned next to the sensor lumen but in such a way that the infusion is released out of the opening 113a distal to the proximal pressure sensor 106 but proximal to the distal pressure sensor 102.
• the guide wire runs in the sensor lumen 105, and is advanced in this lumen distal to a stenosis.
• the open end of the infusion catheter 113a is thus outside the end of the guide catheter and is located proximally (upstream) of the distal pressure sensor 102 in the specific coronary artery.
• a guide catheter is usually used in coronary interventions, it is not an absolute necessity for practicing the present invention, and the invention, as defined by the claims, comprises embodiments wherein a guide catheter has been dispensed with.
• a guide wire with or without a sensor mounted thereon, an infusion catheter, or a combination of both, may be utilized to locate a specific coronary artery without the assistance of a guide catheter; or a guide catheter could be removed before the FFR measurements begins.
• the effects of hyperemic agent fluid is measured at the downstream pressure sensor 102.
• the infusion catheter without side holes ensures a coaxial flow even in the case of high infusion rates. If the steps of the above method are conducted in a patient suffering from a flow restricting disease, such as a stenosis, the measured coronary flow will apparently be the momentary flow, which consequently depends on the present state of the stenosis.
• a medical intervention such as a PTCA is usually undertaken, and such operation involves the creation of total occlusion and the FFR can then simultaneously be measured without any extra efforts.
• Embodiments of the method described herein may be summarized as comprising at least the steps of: (I) positioning a pressure sensor combined with an infusion catheter mounted at a distal portion of a guide wire or other member at a distal position in a coronary artery of a patient, (2) positioning the combined catheter in the coronary artery such that the distal end of the infusion catheter is located proximaliy (upstream) of the distal pressure sensor, (3) measuring the blood pressure at proximal and distal locations in the individual coronary artery, (4) infusing a hyperemic agent such as adenosine , nitric oxide or UTP with a known rate into the coronary artery by the infusion catheter, (5) measuring the pressure at the distal and proximal location (6) calculating the FFR by an equation based on the known and measured quantities.
• a hyperemic agent such as adenosine , nitric oxide or UTP
• the method may also comprise the step of inducting steady state hyperaemia in the patient before the pressure measurements are done, such that the calculated blood flow is the maximum coronary blood flow, which is the clinically most relevant type of coronary blood flow, in practise, the method may often start with the introduction of a guide catheter into the aorta of the patient, and the infusion catheter and the sensor guide is then introduced via this guide catheter.
• the calculation of some FFR values may require knowledge of the so-called wedge pressure, which, by definition, can only be obtained at total occlusion of the coronary artery. Total occlusion can be artificially induced by inflating a balloon provided at a balloon catheter introduced into the coronary artery, for example via the above-mentioned guide catheter.
• the method above can therefore be supplemented with the steps of inducing total occlusion and measuring the wedge pressure.
• the distal coronary pressure is equal, or almost equal, to the aortic pressure, and the wedge pressure can be neglected in the different calculations.
• Tonino PA De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN,
• Tuzcu EM Anderson WD, Abizaid AA, Mintz GS, Yeung AC, Kern MJ, Yock PG: Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements.

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