CN102309785A - Method for improving regional citric acid anticoagulation - Google Patents

Abstract

The invention belongs to the field of blood purification and relates to a method for improving the regional citric acid anticoagulation, in particular to the method for improving the regional citric acid anticoagulation based on a mathematical model. The method comprises two stages of quantificational calculation of calcium supplement amounts for citric acid anticoagulation, namely, in the first stage, quantificationally calculating the sum of in-vitro circulation clearing amount and in-vivo accumulation amount of calcium, and in the second stage, quantificationally calculating the in-vitro circulation clearing amount of the calcium only required to be supplemented. By the method, the infusion speeds of the citric acid and the calcium during regional citric acid anticoagulation during continuous renal replacement therapy (CRRT) can be quantificationally calculated, and the application range of the regional citric acid anticoagulation is greatly expanded. Corresponding application and verification are performed on critical patients requiring regional citric acid anticoagulation CRRT treatment. A result shows that the method is safe and effective and can stabilize in-vivo and in-vitro accumulation ionized calcium level in a proper range; the service life of a filter is prolonged; and the monitoring times are obviously reduced.

Description

The local citric acid anticoagulant of a kind of improvement method

Technical field

The invention belongs to the blood purification field, relate to a kind of local citric acid anticoagulant method of improvement, this method proposes the method that the two-stage accurate quantification calculates the amount of replenishing the calcium according to citric acid in the continuous renal replacement therapy process and calcium dynamics mathematical model.This method can be used for the local citric acid anticoagulant of quantification of continuous renal replacement therapy.

Background technology

Equipment for continuous renal replacement therapy (Continuous Renal replacement Therapy; CRRT) be superior to numerous advantages of CHD with it; As: better control solution equilibria, hemodynamic stability is slowly removed solute stably; Help replenishing and removing part inflammatory mediator etc. of intestinal peripheral hyperalimentation, be applied to more and more widely take place in critical illness patient's the treatment of acute renal failure.Yet for the patient with high-risk bleeding tendency, effectively extracorporeal circulation anticoagulant technology remains the clinical difficult problem of puzzlement.For these patients, if it is fatal hemorrhage to adopt whole body heparinization anticoagulant meeting to cause.

Local citric acid anticoagulant has been proved has definite external anticoagulation, and can avoid the exposure and the accumulation of heparin during the long-time anticoagulant heparin CRRT.The advantage that local citric acid anticoagulant has comprises: reduce the relevant hemorrhage complication of dialysis, improve the permeability of dialyser, improve the biocompatibility of dialyser, prolong the filter life-span.In addition, citric acid can suppress the complement of calcium ion mediation and the activation of inflammatory cell.There is research to disclose safety and the effectiveness when adopting local citric acid anticoagulant and the anticoagulant of Low molecular heparin whole body when a random contrast clinical trial has compared CRRT; Result of study shows that the citric acid anticoagulant can reduce mortality in said patients, and for operation, merge pyemia, multiple organ dysfunction syndrome patient that SOFA is high is especially benefited.The reduction that researcher is analyzed mortality rate not only can reduce hemorrhage risk with the citric acid anticoagulant, maybe be also to reduce inflammatory reaction relevant with citric acid.

Yet the severe complication that possibly occur in the citric acid anticoagulant process like metabolic alkalosis and acidosis, hypernatremia, hypocalcemia or hypercalcemia etc., makes and should technology still fails extensive use clinically.Joannidis in 2009 writes articles on Critical Care Medicine and points out, many local citric acid anticoagulation regimens of having delivered have certain area and condition limitation at present, and the citric acid anticoagulant implements to press for standardization.

The rapid change situation of blood calcium in the body is depended in the enforcement of effective and safe local citric acid anticoagulation regimens to a great extent, because hypocalcemia directly jeopardizes patient's life, and hypercalcemia will cause the anticoagulant failure.For fear of the generation of untoward reaction, be necessary to monitor the concentration of ionized calcium in the body and in time regulate the speed of replenishing the calcium, but also therefore make local citric acid anticoagulant CRRT complex operation, the treatment cost increases.

During local citric acid anticoagulant in the body homeostasis of blood calcium mainly receive two big factor affecting, be the increase of citric acid concentration in the body on the one hand, be the extracorporal dialysis removing of calcium on the other hand.The starting stage of treatment, because a large amount of Citric acid calcium complex forms and have part to be removed by extracorporal dialysis simultaneously, so the concentration of free calcium can reduce in the body.This effect is particularly evident for the patient of abnormal liver function (citric acid dysbolismus in the body) or when using no calcium displacement liquid or dialysis solution.Citric acid concentration reaches stable state in body, originally is released and returns the calcium pond by the ionized calcium of citric acid chelating, only exists this moment the dialysis of extracorporeal circulation calcium to remove approach; If still replenish calcium with the starting stage speed of replenishing the calcium; Hypercalcemia will certainly take place, influence therapeutic effect, even jeopardize the patient.

Summary of the invention

The objective of the invention is to overcome the defective that prior art exists; A kind of local citric acid anticoagulant method of improvement is provided; This method proposes the method that the two-stage accurate quantification calculates the amount of replenishing the calcium according to citric acid in the continuous renal replacement therapy process and calcium dynamics mathematical model.This method can be used for the local citric acid anticoagulant of quantification of continuous renal replacement therapy.

The present invention proposes the technical scheme of the quantitative Analysis of two stage of the citric acid anticoagulant amount of replenishing the calcium; The quantitative Analysis that comprises two stage of the citric acid anticoagulant amount of replenishing the calcium; Wherein, Phase I quantitative Analysis calcium extracorporeal circulation removing amount and body accumulation amount sum, the removing amount of the calcium extracorporeal circulation that the second stage quantitative Analysis only need be replenished.

Particularly, the present invention removes the mathematical model that kinetics and internal metabolism kinetics have made up local two stages of a citric acid anticoagulant calculating amount of replenishing the calcium according to the extracorporeal circulation of citric acid and calcium, and it comprises following two stages:

The phase I amount of replenishing the calcium calculation mathematic model is:

The second stage amount of replenishing the calcium calculation mathematic model is:

$\mathrm{<figure-callout\; id="2"\; label="Qca"\; filenames="HSA00000173237200012.png,HSA00000173237200022.png"\; state="\{\{state\}\}">Qca</figure-callout>}2=\frac{\mathrm{fa}\&times;\mathrm{CcaT}\_\mathrm{art}\&times;\mathrm{Qp}\&times;\mathrm{Quf}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$

The present invention passes through test sample; Concrete extracorporal dialysis through citric acid level, calcium level, calcium in the body during the local citric acid anticoagulant patient CRRT treatment of mensuration is removed; Obtain two significant coefficients in the mathematical model, wherein can filter the ratio that calcium accounts for total calcium is 0.87, promptly obtains coefficient a (fa).In conjunction with having remarkable positive correlation between the citric acid concentration in calcium level rising and the body, equation of linear regression is: △ Cca-bound (t)=0.062+0.778 * Ccit (t) promptly obtains coefficient b (fb).

The technical scheme of the quantitative Analysis of two stage of the citric acid anticoagulant amount of replenishing the calcium of the present invention,, realize through following method and step:

(1) model construction

Blood calcium has three kinds of existence forms in the body: free calcium (accounting for the 45-50% of total calcium), protein-bound calcium (account for total calcium 40%) combines calcium (accounting for the 10-15% of total calcium) with citric acid and phosphate.Under the physiological conditions, the three keeps poised state.During the citric acid anticoagulant, citric acid is from the input of extracorporeal circulation arterial end, and this balance is broken, and a large amount of ionized calciums behind the citric acid infusion point are formed the Citric acid calcium complex by the citric acid chelating.Free calcium and Citric acid calcium can freely pass through filter membrane, and albumen calcium can not pass through fenestra, are meant free calcium and Citric acid calcium so can filter calcium during the citric acid anticoagulant.Along with citric acid concentration in the body increases, combine the ca proportion rising, the form that part ion calcium changes Citric acid calcium into " is accumulated ".Therefore, the present invention will replenish the calcium and be divided into two stages, and the phase I also need extraly be replenished the calcium with the citric acid chelating except that needing to replenish the calcium of dialysis removing; When citric acid concentration reaches stable state in the body, be released into the body circulation with the calcium of citric acid chelating, get into the second stage of replenishing the calcium this moment, the calcium that only needs added body outer circulation dialysis to remove.

The amount of replenishing the calcium calculation mathematic model of the present invention is based on that the following characteristics of citric acid and Citric acid calcium propose: be distributed in extracellular fluid, molecular weight little, remove through dialysis easily.Because the conversion in extracellular liquid calcium and the body between the calcium storage pool is extremely complicated and can not directly measure, therefore model of the present invention does not relate to the conversion of this part calcium.

The Derivation of Mathematical Model process of the calculating amount of replenishing the calcium of the present invention is following:

1. total calcium concentration of dilution CVVH dialyser inlet before calculating:

$\mathrm{CcaT}\_\mathrm{In}=\frac{\mathrm{CcaT}\_\mathrm{Art}\&times;\mathrm{QP}}{(\mathrm{QP}+\mathrm{Qcit}+\mathrm{Qsub})}$ (formula 1)

Wherein: CcaT_in: the dialyser total calcium concentration (mmol/L) that enters the mouth; CcaT_art: total calcium concentration (mmol/L) before the dialyser inlet of arterial end citric acid infusion point back; Qp: citric acid infusion point prerolandic artery Rolando end plasmaflux; Qp=Qb * (1-Hct) * (1-protein concentration/100), Hct: hematocrit value (%), Qcit: citric acid infusion velocity (L/h); Qsub: displacement liquid speed (L/h)

Supposing to account for through the filtered calcium of dialyzer clearance total ca proportion is coefficient a (fa), then the filtered calcium concentration (CcaF_in) of citric acid infusion point back dialyser inlet:

$\mathrm{CcaF}\_\mathrm{In}=\mathrm{Fa}\&times;\mathrm{CcaT}\_\mathrm{In}=\frac{\mathrm{Fa}\&times;\mathrm{CcaT}\_\mathrm{Art}\&times;\mathrm{Qp}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$ (formula 2)

2. calculate dialysis and remove calcium:

Caflux=Quf * S * CcaF_in (formula 3)

Wherein: Caflux: calcium amount (mmol) is removed in dialysis; S: sieve coefficient, S=(1-protein binding mark) ≈ 1

Formula (2) is obtained dialysis for people's formula (3) removes the calcium mathematical formulae:

$\mathrm{Caflux}=\frac{\mathrm{Fa}\&times;\mathrm{CcaT}\_\mathrm{Art}\&times;\mathrm{Qp}\&times;\mathrm{Quf}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$ (formula 4)

Wherein: Quf: ultrafiltrate flow (L/h)

3. combine in the calculating body calcium increase concentration through the time change:

Suppose to combine in the body relation between calcium increase concentration and the citric acid concentration to represent, combine the increase concentration (△ Cca_bound (t)) of the basic combination calcium of calcium to be during t in the mesosome with coefficient b (fb):

Δ Cca_bound (t)=fb * Ccit (t) (formula 5)

Extracellular fluid percentage of liveweight ratio is 21%.(Qca_bound) can be expressed as in conjunction with the calcium amount:

Qca_bound=fb * Ccit (t) * body weight (kg) * 21% (formula 6)

Citric acid concentration (Ccit (t)) is used J.Yee in the body, and the citric acid pharmacokinetic parameter is predicted in the liver cirrhosis of reports such as the citric acid pharmacokinetics model of propositions such as S.Frinak and B.Szamosfalvi and Kramer and the non-liver cirrhosis critical patient body.Citric acid pharmacokinetics model:

$\mathrm{Csys}\left(t\right)=C\left(0\right)\&CenterDot;e-[(\mathrm{Kf}+\mathrm{Kb})\&CenterDot;\frac{t}{V}]+\frac{G}{(\mathrm{Kf}+\mathrm{Kb})}\&times;(1-e-[(\mathrm{Kf}+\mathrm{Kb})\&CenterDot;\frac{t}{V}\left]\right).$

Citric acid pharmacokinetic parameters: clearance rate CLb=710ml/min in the non-liver cirrhosis critical patient body; Apparent volume of distribution Vd=29; Half-life t1/2=36min; Citric acid pharmacokinetic parameters: clearance rate CLb=340ml/min in the liver cirrhosis critical patient body; Apparent volume of distribution Vd=27; Half-life t1/2=69min.

4. the phase I mathematical model (Qca1) of replenishing the calcium:

(formula 7)

5. the second stage mathematical model (Qca2) of replenishing the calcium:

$\mathrm{<figure-callout\; id="2"\; label="Qca"\; filenames="HSA00000173237200012.png,HSA00000173237200022.png"\; state="\{\{state\}\}">Qca</figure-callout>}2=\frac{\mathrm{Fa}\&times;\mathrm{CcaT}\_\mathrm{Art}\&times;\mathrm{Qp}\&times;\mathrm{Quf}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$ (formula 8)

(2) modelling verification

The present invention includes the critical patient that 32 examples (median age 56.1 years old) need the continous blood purification treatment in, and wherein 17 routine patient's datas are used to solve the mathematical model coefficient of replenishing the calcium.In 15 routine patient CVVH treatments, carried out verifying (Huashan Hospital Affiliated To Fudan Univ ethics audit scheme 2009-98), all object of study signature Informed Consent Forms.

The result shows, in the 15 routine critical patient RCA-CVVH treatments, uses the two stages amount of replenishing the calcium computational mathematics models guidance of the present invention and replenishes the calcium.Mathematical model of the present invention instructs the result who replenishes the calcium to confirm, calculates the gained amount of replenishing the calcium safety, effective.Ion calcium concentration does not have rapid fluctuation in the body, stable being controlled in the ideal range.Treat in 24 hours, none filter is changed because of blood coagulation takes place.In addition, in the end in the 5 routine patient treatment processes, adopt this method to save frequent ionized calcium monitoring, monitor blanking time above 6 hours (as shown in Figure 6).

The present invention has produced significant beneficial effect than prior art, has following advantage:

The infusion velocity of citric acid and calcium during local citric acid anticoagulant when the inventive method can quantitative Analysis goes out CRRT; Avoid in the past clinically can only " trial-and-error method " or each center can only use the defective of fixed solution, expanded local citric acid anticoagulant range of application greatly.Critical patient through needs being implemented local citric acid anticoagulant CRRT treatment carries out application corresponding and checking.The result confirms, the inventive method safety, effective can make in the body to be stabilized in the OK range with the extracorporeal circulation ionized calcium level, filter significant prolongation in service life, and significantly reduce the monitoring number of times.

Description of drawings

Fig. 1 shown 1-6 hour citric acid infusion point back of treatment and preceding ionized calcium, the albumen calcium of displacement liquid and can filter the percentage ratio that calcium accounts for total calcium (be respectively 9.65%-15.61%, 11.63%-13.22%, 85.36%-94.54%).

Fig. 2. show Bland-Altman method extracorporal dialysis removing relatively actual and model prediction calcium, do not had system's bias (P=0.654) between the two.

Fig. 3 is the increase of combination calcium and the relation of the interior citric acid concentration of body.

Fig. 4 has shown classical " trial-and-error method " local citric acid anticoagulant result.After treatment 3 hours, carrying out property of ion calcium concentration rising in the body, and exceed ideal scope gradually.Wherein, the infusion of 5% calcium chloride of shade histogram graph representation model presumes, first three hour is with 100% expression; Represent with 70% after three hours; The actual speed of replenishing the calcium of white histogram graph representation, the actual speed of replenishing the calcium exceed predicts the speed 20%-80% that replenishes the calcium.

Fig. 5 has shown " compromise method " local citric acid anticoagulant method; The speed of promptly initially replenishing the calcium is according to replenish the calcium mathematical model (formula 7) prediction of phase I; Get into the second stage of replenishing the calcium when treating three hours; The speed of replenishing the calcium that progressively slows down, but still a little more than the second stage speed of replenishing the calcium that mathematical model predicts of replenishing the calcium.Ion calcium concentration also is progressively ascendant trend in the display body as a result, and finally exceeds ideal range.Wherein the shade rectangular histogram is represented the 5% calcium chloride infusion velocity predicted, and white rectangular histogram is represented the actual speed of replenishing the calcium, after three hours actual replenish the calcium speed the theory speed of replenishing the calcium exceed 10%-20%.

Fig. 6 is shown as the local citric acid anticoagulant method of implementing according to model prediction.The result confirms this mathematical model safety, effective.Ion calcium concentration does not have rapid fluctuation in the body, stable being controlled in the ideal range.Treat in 24 hours, none filter is changed because of blood coagulation takes place.The shade histogram graph representation theory speed of replenishing the calcium wherein.

The specific embodiment

The local citric acid anticoagulant of embodiment 1CRRT mathematical model is set up

1) calculate total calcium concentration that preceding dilution CVVH dialyser enters the mouth:

$\mathrm{CcaT}\_\mathrm{In}=\frac{\mathrm{CcaT}\_\mathrm{Art}\&times;\mathrm{QP}}{(\mathrm{QP}+\mathrm{Qcit}+\mathrm{Qsub})}$ (formula 1)

Wherein: CcaT_in: the dialyser total calcium concentration (mmol/L) that enters the mouth; CcaT_art: total calcium concentration (mmol/L) before the dialyser inlet of arterial end citric acid infusion point back; Qp: citric acid infusion point prerolandic artery Rolando end plasmaflux; Qp=Qb * (1-Hct) * (1-protein concentration/100), Hct: hematocrit value (%), Qcit: citric acid infusion velocity (L/h); Qsub: displacement liquid speed (L/h)

Supposing to account for through the filtered calcium of dialyzer clearance total ca proportion is coefficient a (fa), then the filtered calcium concentration (CcaF_in) of citric acid infusion point back dialyser inlet:

$\mathrm{CcaF}\_\mathrm{In}=\mathrm{Fa}\&times;\mathrm{CcaT}\_\mathrm{In}=\frac{\mathrm{Fa}\&times;\mathrm{CcaT}\_\mathrm{Art}\&times;\mathrm{Qp}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$ (formula 2)

2) calculate dialysis and remove calcium:

Caflux=Quf * S * CcaF_in (formula 3)

Wherein: Caflux: calcium amount (mmol) is removed in dialysis; S: sieve coefficient, S=(1-protein binding mark) ≈ 1

Formula (2) is obtained dialysis for people's formula (3) removes the calcium mathematical formulae:

$\mathrm{Caflux}=\frac{\mathrm{Fa}\&times;\mathrm{CcaT}\_\mathrm{Art}\&times;\mathrm{Qp}\&times;\mathrm{Quf}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$ (formula 4)

Wherein: Quf: ultrafiltrate flow (L/h)

3) calculate combine in the body calcium increase concentration through the time change:

Suppose to combine in the body relation between calcium increase concentration and the citric acid concentration to represent, combine the increase concentration (△ Cca_bound (t)) of the basic combination calcium of calcium to be during t in the mesosome with coefficient b (fb):

Δ Cca_bound (t)=fb * Ccit (t) (formula 5)

Extracellular fluid percentage of liveweight ratio is 21%.(Qca_bound) can be expressed as in conjunction with the calcium amount:

Qca_bound=fb * Ccit (t) * body weight (kg) * 21% (formula 6)

Citric acid concentration (Ccit (t)) is used J.Yee in the body, and the citric acid pharmacokinetic parameter is predicted in the liver cirrhosis of reports such as the citric acid pharmacokinetics model of propositions such as S.Frinak and B.Szamosfalvi and Kramer and the non-liver cirrhosis critical patient body.Citric acid pharmacokinetics model:

$\mathrm{Csys}\left(t\right)=C\left(0\right)\&CenterDot;e-[(\mathrm{Kf}+\mathrm{Kb})\&CenterDot;\frac{t}{V}]+\frac{G}{(\mathrm{Kf}+\mathrm{Kb})}\&times;(1-e-[(\mathrm{Kf}+\mathrm{Kb})\&CenterDot;\frac{t}{V}\left]\right).$

Citric acid pharmacokinetic parameters: clearance rate CLb=710ml/min in the non-liver cirrhosis critical patient body; Apparent volume of distribution Vd=29; Half-life t1/2=36min; Citric acid pharmacokinetic parameters: clearance rate CLb=340ml/min in the liver cirrhosis critical patient body; Apparent volume of distribution Vd=27; Half-life t1/2=69min.

4) drawing the phase I mathematical model (Qca1) of replenishing the calcium is:

The second stage mathematical model (Qca2) of replenishing the calcium:

$\mathrm{<figure-callout\; id="2"\; label="Qca"\; filenames="HSA00000173237200012.png,HSA00000173237200022.png"\; state="\{\{state\}\}">Qca</figure-callout>}2=\frac{\mathrm{fa}\&times;\mathrm{CcaT}\_\mathrm{art}\&times;\mathrm{Qp}\&times;\mathrm{Quf}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$

The ratio that the filtered calcium that extracorporeal circulation arterial end citric acid infusion point afterwards records before the displacement liquid accounts for total calcium is 87 ± 1%, promptly obtains coefficient a (fa).This ratio does not prolong with treatment time and changes, and between different patients, does not have significant change yet.

(the P value is respectively P=0.091, P=0.116) not have dependency between the citric acid concentration in total calcium concentration and total calcium/ionized calcium ratio and the body; In conjunction with having remarkable positive correlation (r=0.7, P＜0.001) between the citric acid concentration in calcium level rising and the body, equation of linear regression is: △ Cca-bound (t)=0.062+0.778 * Ccit (t), so obtain coefficient b (fb).

Embodiment 2 modelling verifications

1) testing research object: 32 examples (median age 56.1 years old) the incomes Huashan ICU of hospital acute renal failure needs the critical patient of continous blood purification treatment, 28 male wherein, 4 women.SOFA scoring meansigma methods is 11.9 ± 3.4 before the treatment.The acute renal failure reason comprises kidney ischemia (n=11,34.4%), renal tubules poisoning (n=5,15.6%) and Combination (n=16,50.00%).Most of patient need implement the citric acid anticoagulant because of acute hemorrhage, thrombocytopenia, coagulation disorders.Study in preceding 24 hours all patients infusion blood product or promoting the circulation of blood slurry replacement therapy are not arranged.17 routine patient's datas are used to solve the mathematical model coefficient of replenishing the calcium.Model is verified in 15 routine patient CVVH treatments.This research approach is through the audit approval of Huashan Hospital Affiliated To Fudan Univ Ethics Committee (ethics audit scheme 2009-98), all object of study signature Informed Consent Forms.

2) continuous renal replacement therapy therapeutic scheme

Use the continuous kidney replacement therapy of German Bei Lang machine, high pass PS membrane HIPS15 dialyser.All object of study vascular access are the femoral vein double channel catheter.Dilution continuous vein-vein hemofiltration (CVVH) treatment pattern before adopting, blood flow is arranged on 150-200ml/min, displacement liquid flow 2.5L/h or 4L/h.Displacement liquid speed, CVVH treatment number of times and treatment time formulate according to the conditions of patients needs.Record blood flow, displacement liquid flow, ultrafiltration flow before each blood sampling.

3) citric acid anticoagulation regimens

4% liquor sodii citratis is imported before extracorporeal circulation arterial end dialyser with 3.7mmol/L blood flow speed.2.5L/h replacement liquid prescription is Na ⁺121mmol/L, K ⁺3.2mmol/L, Mg ²⁺0.75mmol/L, Cl ^-109mmol/L, HCO ₃ ^-7mmol/L, glucose 250mg/dL.The 4L/h replacement liquid prescription is Na ⁺121mmol/L, K ⁺3.2mmol/L, Mg ²⁺0.75mmol/L, Cl ^-109mmol/L, HCO ₃ ^-18mmol/L, glucose 250mg/dL.

4) scheme of replenishing the calcium

5% calcium chloride solution is imported from the extracorporeal circulation vein end.

Adopt following three kinds of schemes of replenishing the calcium:

Scheme 1 (trial-and-error method): according to scheme and this dialysis center experience of prior art report; The present invention's speed setting of will initially replenishing the calcium is the 1mmol/L blood flow; Ionized calcium level in the 2-4 hour monitoring body; And constantly the adjustment speed of replenishing the calcium makes proper interior ionized calcium level maintain 1.0-1.2mmol/L, and the extracorporeal circuit ionized calcium maintains 0.25-0.30mmol/L.

Scheme 2 (compromise method): calcium additional is divided into two stages.The speed of initially replenishing the calcium is according to the phase I mathematical model prediction of replenishing the calcium.According to citric acid pharmacokinetics result in the body; Three hour of the external infusion citric acid of non-liver cirrhosis patient; Citric acid concentration reaches stable state basically in the body, so the present invention is chosen in three hour of treatment and gets into the second stage of replenishing the calcium, and the speed of replenishing the calcium slowed down than the phase I.From security consideration, in the present embodiment, on the basis of model prediction, improved the speed of replenishing the calcium slightly.

Scheme 3 (modelling): use the mathematical model prediction of replenishing the calcium of the present invention two stages that and guided and replenish the calcium.

6) laboratory detects

Basic hematocrit value and serum albumin concentration send chemical examination to measure before the treatment.Sampling time point for treatment before, in back 8 hours of the treatment per hour, before per 12 hours of treatment back, treatment finish.Sampled point is before the extracorporeal circulation arterial end citric acid infusion, behind the citric acid infusion and before the displacement liquid, vein loop, ultrafiltrate.Each sampling time point is collected the 1.5ml whole blood sample at above four sampled points respectively, and separated plasma also is kept at-80 ℃ of refrigerators, is used to measure citric acid concentration, total calcium, non-protein binding calcium concentration.Use in the quick biochemistry analyzer monitoring of the i-STAT body and change with external ionized calcium.

Citric acid concentration adopts HPLC (HPLC) to measure: high performance liquid chromatograph is Agilent 1100 (USA), under the 210nm wavelength, detects BIAO and BEN citric acid concentration.Intraassay coefficient of variation is 6.8%, and the interassay variation coefficient is 11.3%.

Total calcium, non-protein binding calcium concentration adopt the improvement OCPC method (OCPC) of world health organisation recommendations to measure.Add the OCPC reagent that 800ul contains 8-hydroxyquinol (final concentration 0.25g/L) in the 10ul BIAO and BEN.Under the 570nm wavelength, detect total calcium concentration.Then sample being placed the molecular weight cutoff is Deproteinization in the albumen ultra-filtration centrifuge tube of 3000Da, measures non-protein binding calcium concentration.Intraassay coefficient of variation is 7.6%, and the interassay variation coefficient is 12.3%.

7) statistical analysis

Data are represented with mean ± standard deviation.Independent sample adopts the t check.Adopt Pearson and/or Spearman method to carry out correlation analysis.Difference between model predication value and the measured value as statistic of test, is carried out paired data t check.Adopt the concordance of Bland-Altman analytic process evaluation model predictive value and measured value.P＜0.05 is remarkable significant difference.

The result shows:

(1) can filter ca proportion:

The average blood plasma flow is 101 ± 13ml/min.The displacement liquid flow velocity is respectively 2.5L/h (n=12) and 4L/h (n=33).Set ultrafiltration volume according to the conditions of patients needs, average ultrafiltration rate is 322 ± 279ml/h.The ratio that the filtered calcium that extracorporeal circulation arterial end citric acid infusion point afterwards records before the displacement liquid accounts for total calcium is 87 ± 1%.This ratio does not prolong with treatment time and changes (P=0.767), and between different patients, does not have significant change (P=0.994) yet.Thereby draw the filtered ca proportion coefficient a (fa) of mathematical model of the present invention.Fig. 1 has shown 1-6 hour citric acid infusion point back of treatment and preceding ionized calcium, the albumen calcium of displacement liquid and can filter the percentage ratio that calcium accounts for total calcium.

(2) measured value and predictive value are removed in the extracorporal dialysis of calcium:

Dialyser is 0.43 ± 0.31mmol/h to the removing amount of calcium in unit interval.Dialyser is 0.38 ± 0.30mmol/h to the theory removing amount of calcium in the unit interval that draws according to model (formula 8).Bland-Altman analyzes and shows no system bias (P=0.654) (as shown in Figure 2) between actual value and the predictive value.

(3) relation that calcium concentration and citric acid are accumulated in the body:

Citric acid Css measured value is 0.38 ± 0.10mmol/L in the body.According to Yee, the citric acid metabolic kinetic model that S.Frinak and B.Szamosfalvi propose obtains citric acid Css predictive value 0.37 ± 0.06mmol/L.Bland-Altman that analyze to show measure with body prediction in the citric acid Css do not have system's bias (P=0.74).

Correlation analysis showed: do not have between total calcium concentration and total calcium/ionized calcium ratio and the interior citric acid concentration of body dependency (the P value is respectively P=0.091, P=0.116, n=42); In conjunction with calcium level rise with the interior citric acid concentration of body between have remarkable positive correlation (r=0.7, P＜0.001, n=42) (as shown in Figure 3), equation of linear regression is: △ Cca-bound (t)=0.062+0.778 * Ccit (t), so obtain coefficient b (fb).

(4) three kinds of scheme effects of replenishing the calcium show:

1. scheme 1 (trial-and-error method):

Adopt this method in the 3 routine RCA-CVVH treatments.Treat after 3 hours carrying out property of ion calcium concentration rising (as shown in Figure 4) in the body.The self-examination calcium scheme of replenishing the calcium, we find theory that the actual speed of replenishing the calcium the is higher than model prediction far away speed of replenishing the calcium.Though, still be difficult to ionized calcium in the body is controlled in the ideal range stably according to monitoring ion calcium concentration repeatedly and in time having regulated the speed of replenishing the calcium.Finally, hypercalcemia is inevitable, causes extracorporeal circulation anticoagulant failure then.If improve the citric acid infusion amount simply, will cause easily that citric acid is accumulated in the body.

2. scheme 2 (compromise method):

Adopt this method in the 5 routine RCA-CVVH treatments; The speed of promptly initially replenishing the calcium is according to replenish the calcium mathematical model (formula 7) prediction of phase I; Get into the second stage of replenishing the calcium when treating three hours, the speed of replenishing the calcium that progressively slows down, but still a little more than the second stage speed of replenishing the calcium that mathematical model predicts of replenishing the calcium.As shown in Figure 5, ion calcium concentration is progressively ascendant trend in the body.

3. scheme 3 (modelling):

In the 15 routine critical patient RCA-CVVH treatment, use the two stages of the present invention mathematical model of replenishing the calcium and instruct and replenish the calcium.The result confirms this mathematical model safety, effective.Ion calcium concentration does not have rapid fluctuation in the body, stable being controlled in the ideal range.Treat in 24 hours, none filter is changed because of blood coagulation takes place.In addition, in the end in the 5 routine patient treatment processes, adopt this method to save frequent ionized calcium monitoring, monitor blanking time above 6 hours (Fig. 6).

Claims (6)

1. improve local citric acid anticoagulant method for one kind; It is characterized in that; It comprises the quantitative Analysis of two stage of the citric acid anticoagulant amount of replenishing the calcium; Wherein, phase I quantitative Analysis calcium extracorporeal circulation removing amount and body accumulation amount sum, the removing amount of the calcium extracorporeal circulation that the second stage quantitative Analysis only need be replenished.

2. by the local citric acid anticoagulant of the described improvement of claim 1 method, it is characterized in that the described phase I amount of replenishing the calcium is calculated as follows:

Wherein: Qcal: the phase I speed (mmol/ hour) of replenishing the calcium; Fa: dialyser can filter calcium and account for total ca proportion coefficient; CcaT_art: total calcium concentration (mmol/L) before the dialyser inlet of arterial end citric acid infusion point back; Quf: ultrasiltrated rate (L/h); Qp: citric acid infusion point prerolandic artery Rolando end plasmaflux; Qcit: citric acid infusion velocity (L/h); Qsub: displacement liquid speed (L/h); Fb: combine calcium to increase the coefficient between concentration and the citric acid concentration in the body; Ccit: citric acid concentration (mmol/L) in the body.

3. by the local citric acid anticoagulant of the described improvement of claim 1 method, it is characterized in that the described second stage amount of replenishing the calcium is calculated as follows:

$\mathrm{Qca}2=\frac{\mathrm{fa}\&times;\mathrm{CcaT}\_\mathrm{art}\&times;\mathrm{Qp}\&times;\mathrm{Quf}}{(\mathrm{Qp}+\mathrm{Qcit}+\mathrm{Qsub})}$

Wherein: Qca2: the second stage speed (mmol/ hour) of replenishing the calcium; Fa: dialyser can filter calcium and account for total ca proportion coefficient; CcaT_art: total calcium concentration (mmol/L) before the dialyser inlet of arterial end citric acid infusion point back; Quf: ultrasiltrated rate (L/h; Qp: citric acid infusion point prerolandic artery Rolando end plasmaflux; Qcit: citric acid infusion velocity (L/h); Qsub: displacement liquid speed (L/h).

4. by the local citric acid anticoagulant of the described improvement of claim 1 method; It is characterized in that described dialyser can filter calcium and account for and combine calcium to increase the extracorporal dialysis removing amount acquisition of citric acid level, calcium level and the calcium of coefficient (fb) through measuring local citric acid anticoagulant test sample book between concentration and the citric acid concentration in total ca proportion coefficient (fa) and the body.

5. by the method for claim 4, it is characterized in that described coefficient a (fa) is 0.87; Described coefficient b (fb) obtains through equation of linear regression △ Cca-bound (t)=0.062+0.778 * Ccit (t).

6. by the method for claim 4, it is characterized in that, described test sample book for patient CRRT treatment during the extracorporal dialysis removing amount of the interior citric acid level of body, calcium level and calcium.

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