RU2571505C1 - Method for assessing level of unfractionated heparin induced anticoagulation in haemodialysis in patients with acute renal injury - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: performing a haemodialysis procedure in the periods of time: prior to administration of unfractionated heparin, then 10, 30, 60 minutes after a bolus, then 10 minutes after another bolus, and 5 minutes before the haemodialysis procedure is completed, is accompanied by performing a low-frequency piezothromboelastography and measuring blood viscosity parameters, as follows: t1 is the A1 achievement time (min); t2 is the time of an amplitude A increase by 100 units (min); TAC is a thrombin activity constant defined as the time from the end of a reaction period to the amplitude A increase by 100 units from the minimum amplitude for the reaction period (relative units), and calculated by formula: TAC = 100/(t2-t1). If TAC after the UFH bolus administration is 2-3 times less than the reference, the anticoagulation level is considered optimum.

EFFECT: using the invention enables providing more effective heparinisation control and reducing the investigation time.

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Description

The invention relates to medicine and can be used to assess the level of anticoagulation with unfractionated heparin during the hemodialysis procedure in patients with acute kidney damage.

The problem of controlling the level of heparinization during the hemodialysis procedure is relevant, since in patients with acute renal damage (AKI) requiring renal replacement therapy (RRT), various disorders are detected in all parts of the blood aggregation regulation system (RASK).

The hemodialysis procedure itself makes a certain contribution to the degree of hemostasis disorders. This is due to a number of reasons: pumping blood circulation causes a turbulent blood flow; high shear rates; contact of blood with foreign surfaces of the dialysis circuit, the membrane of the mass exchanger-dialyzer, air in traps; mechanical trauma to blood cells with a peristaltic pump; level of ultrafiltration, leading to thickening of the blood.

The result is “clogging” of the dialyzer capillaries, the formation of blood clots in various air traps, up to complete thrombosis of the dialysis circuit with the loss of 150-250 ml of the patient’s blood, in mild cases from moderate to significant deterioration in the cleansing ability of the hemodialysis procedure.

The basis of thrombotic complications within the dialysis circuit is the activation of platelets and leukocytes, followed by the release of tissue factor and the activation of the “external” and “internal” blood coagulation pathways, which ultimately leads to prolapse of fibrin strands with the formation of complete platelet-fibrin thrombi inside the dialysis circuit. Thus, the use of anticoagulants to prevent activation of the coagulation cascade during hemodialysis is usually necessary, the invention and the current state of hemodialysis are directly related to the discovery and use of anticoagulation agents [3].

Unfractionated heparin (UFH) is still one of the most used anticoagulants for hemodialysis both in world practice and in our country. Advantages of UFH: good knowledge of the pharmacological properties of the drug by clinicians; low cost; relatively short and predictable period of action; the presence of an effective antidote - protamine sulfate; practically developed systems for controlling anticoagulant action.

At the same time, UFH has a number of significant drawbacks: dependence on the level of antithrombin content; non-specific binding to acute phase blood proteins in the presence of a systemic inflammatory reaction; interpersonal sensitivity to UFH; the development of heparin-induced thrombocytopenia, especially type 2. This led to the creation of new anticoagulant agents, such as direct thrombin inhibitors, synthetic prostaglandins and anticoagulation schemes limited only by the dialysis circuit (calcium-citrate anticoagulation without systemic anticoagulation, the control of which requires a powerful laboratory base and significant financial costs).

Thus, in world practice during hemodialysis in patients with AKI, UFH remains the predominant anticoagulant [4].

However, the use of UFH in hemodialysis is associated with systemic anticoagulation and balancing between thrombosis of the extracorporeal circuit and the development of hemorrhagic complications in the patient.

Considering the narrow “therapeutic window” of the anticoagulant effect of UFH, at which the risk of hemorrhagic complications in patients with AKI is minimized, when conducting HD, methods for controlling its optimal dosage, that is, balancing between the adequacy of anticoagulation and, accordingly, the quality of hemodialysis and the risk of bleeding in a patient, are especially relevant. [5].

A known method of controlling anticoagulation of UFH during hemodialysis in patients with AKI by determining the activated partial thromboplastin time (APTT). A blood sample is taken in a test tube with sodium citrate, which binds calcium ions, without which blood does not coagulate. Further, a platelet-poor blood plasma is obtained from a blood sample by centrifugation. To activate the internal coagulation pathway, an activator, such as kaolin, and phospholipids, such as cephalin, are added to the plasma sample, after which a calcium chloride solution is added in order to get rid of the anticoagulant effect previously created by citrate. Measure the time before the formation of a clot. However, the method based on the determination of APTT is subjected to significant criticism, which is due to: the presence of significant preanalytical and analytical errors, the lack of standardization of various reagents, the need to contact the central laboratory, and a significant delay in the time for receiving the results. At the same time, there are imported devices that measure APTT in the (Point-of-Care-Testing) mode, but there are also problems in their practical use: the high cost of consumables and limited access to them due to the lack of domestic counterparts [6].

Closest to the proposed method is the control of anticoagulation of UFH during hemodialysis in patients with AKI, which consists in determining the activated coagulation time of whole blood - ABC test. The ABC test was first described by Paul Hattersley in 1966. At first, the method was manual, then devices were created to automatically run the ABC test, which made it more convenient. Actalyke automated test systems use pre-filled reagents with disposable test tubes to which a blood sample is added; the test tube is then installed in a device in which the tube is rotated and heated to 37 ° C (+ 0.5 ° C) until the fibrin clot is mechanically detected. After detecting the clot, the test is stopped, an audible signal sounds, and the result of the ABC test (in seconds) appears on the instrument’s light display [1].

ABC is mainly used in cardiac surgery for cardiopulmonary bypass using high-dose anticoagulation, and recently a whole line of devices and tube sets with activators has appeared: for high-dose, moderate-dose and low-dose anticoagulation in (Point-of-Care-Testing) mode. However, significant criticism of this technique for controlling low-dose anticoagulation of the use of ABC during hemodialysis remains due to the low sensitivity of this technique in conditions of acute hemodialysis [2].

A new technical problem is to increase the sensitivity and information content of the method, convenience, cost reduction, simplification of the method.

To obtain a new technical result in the method of assessing the level of anticoagulation with unfractionated heparin during hemodialysis in patients with acute kidney damage by examining the patient’s blood, in periods of time: before administration of unfractionated heparin, then 10, 30, 60 minutes after the first bolus, then after 10 minutes after a second bolus and 5 minutes before the end of hemodialysis, low-frequency piezothromboelastography is performed and the viscosity characteristics of the blood are measured: t1 is an indicator that reflects the time to reach genia A1 (min); t2-indicator, reflecting the time during which the amplitude And increases by 100 units (min); KTA is the constant of thrombin activity, which is defined as the time elapsed from the end of the reaction period to an increase in the amplitude by 100 relative units from the level of the minimum amplitude for the reaction period (rel. Units) and is calculated by the formula:

KTA = 100 / (t2-t1).

and with a CTA value after administration of a bolus of UFH, 2-3 times less than the initial one, the level of anticoagulation is considered optimal.

The method is as follows. When hemodialysis is performed in a patient for periods of time: before the introduction of unfractionated heparin, then 10.30, 60 minutes after the bolus, then 10 minutes after the second bolus and 5 minutes before the end of hemodialysis, whole unstabilized venous blood is sampled under standardization of the process , with a silicone syringe of 2 ml in volume without applying a filament of a cubital vein in an amount of 0.45 ml, which is then placed in a cuvette of a device of a hardware-software complex for clinical diagnostic tests for 5-10 seconds studies of the rheological properties of blood (ARP-01M "Mednord", Registration certificate N ФСР 2010/09767 dated December 30, 2010), with which the following indicators are evaluated by the method of low-frequency piezothromboelastography:

t1 is an indicator reflecting the time to reach A1 (min).

t2 is the time during which the amplitude A increases by 100 units (min).

KTA is the thrombin activity constant, defined as the time elapsed from the end of the reaction period to an increase in the amplitude by 100 relative units from the level of the minimum amplitude for the reaction period (rel. Units), the KTA equation has the form

KTA = (100 / t2-t1).

and with a CTA value after administration of an NFH bolus, 2-3 times less than the initial one, the level of anticoagulation during hemodialysis in patients with acute kidney damage is considered optimal.

The method is based on the results of an analysis of clinical trial data. The authors conducted a comparative assessment of the dynamics of changes in "CTA", ABC and APTT in healthy volunteers (n = 30) and patients with AKI (n = 30) requiring acute hemodialysis (HD), with informed consent. Definition of aPTT - APTV reagent Technology Standard (Russia), Thrombotimer 2 BehnkElektronik apparatus (Germany), ABCS on ActalykeMiniIIc apparatus tested with MAX-ACT HelenaLaboratories systems (USA). In healthy volunteers, indicators were determined before and 10 minutes after iv administration of UFH 5 units, from venous blood. In patients, the initial recording of NPTEG on the ARP 01M Mednord apparatus was performed from the systemic circulation before hemodialysis. Subsequent blood sampling during hemodialysis was performed from the port of the venous (return line) located after the dialyzer. The bolus anticoagulation mode, the initial bolus at the rate of 25-50 units / kg, the repeated bolus at the rate of 10-15 units / kg, on average after 90 minutes [7].

If necessary, additional boluses were introduced (no more than two). Empirically, based on clinical observations of patients with AKI, control points were determined for monitoring the proposed method parameters during hemodialysis: initial determination before heparin administration, then 10, 30, 60 minutes after the first bolus, then 10 minutes after the second bolus and 5 minutes before the end of hemodialysis. The total time of hemodialysis (HD) is 3-4 hours (3 hours 40 minutes ± 20 minutes). Quantitative data are presented as Me [LQ; UQ] (where Me is the median, LQ is the lower quartile, UQ is the upper quartile, p is the achieved significance level). The following indicators were evaluated:

t1 is an indicator reflecting the time to reach A1 (min).

t2 is the time during which the amplitude A increases by 100 units (min).

KTA is a constant of thrombin activity, is defined as the time elapsed from the end of the reaction period to an increase in the amplitude values by 100 relative units from the level of the minimum amplitude value for the reaction period (rel. Units) and is calculated by the equation:

CTA = (100 / t2-t1).

and with a CTA value after administration of an NFH bolus, 2-3 times less than the initial one, the level of anticoagulation during hemodialysis in patients with acute kidney damage is considered optimal.

The dynamics of changes in indicators determined by various methods: CTA, ABC and APTT when monitoring the anticoagulant effect of UFH in healthy volunteers and in acute hemodialysis are presented in table 1.

Example No. 1. Patient P. 72 years old was admitted O. Surgery, Tomsk Regional Clinical Hospital with a diagnosis of Duodenal ulcer, bleeding in the gastrointestinal tract, hemorrhagic shock. An emergency operation was performed laparotomy, duadenoplasty. In the postoperative period, the patient was treated in the intensive care unit, on the second day the patient developed acute kidney damage, anuria, azotemia, as a result of the hemorrhagic shock. This condition required an emergency start of renal replacement therapy in the form of acute hemodialysis.

Clinical and biochemical studies were conducted before hemodialysis No. 1. Hb - 88 g / l, erythrocytes 2.6 * 10 ¹² , leukocytes 11.5 * 10 ⁹ , urea 24 mmol / l, cretinin 456 μmol / l, K 5.6 mmol / l, Na - 134 mmol / l, IPT - 87%, fibrinogen - 4.5 g / l, APTT - 34s, ATIII - 82%. A study of the rheological properties of blood according to the proposed method was also carried out: by the method of low-frequency piezotromboelastography using the ARP-01M Mednord hardware-software complex, and t1 was determined, an indicator reflecting the time to reach A1 (min), t2 is the time for which amplitude A increases by 100 units (min) and the CTA is calculated.

The patient's CTA before the administration of UFH was 12.99 pu, 10 minutes after administration of a bolus of 1 thousand units. UFH indicator did not change, which indicated the insufficiency of the selected dose (see Fig. 1). After an additional introduction of 2.5 thousand units UFH KTA decreased to 5.56 p.u. at 60 minutes (2.3 times from the original), which confirmed the presence of an optimal interval for the change of CTA against heparinization by 2-3 times. However, by 130 minutes, the figure again rose to 8.93 pu (1.5 times), which was the reason for the introduction of a second bolus of 3.5 thousand units. UFH. By 175 min, 5 min before the end of the DG, the CTA index reached 32.26 pu, i.e. 2.5 times higher than the original (Fig. 1).

The patient satisfactorily underwent hemodialysis. Subsequently, after two weeks, the patient noted the stage of recovery of diuresis, a total of 11 hemodialysis procedures were performed. The early start of dialysis therapy contributed to a fairly rapid restoration of renal function, and optimal anticoagulation under the control of heparinization using the proposed method avoided hemorrhagic complications in the near postoperative period.

Example No. 2. Patient S. 64 years old was admitted to the department. Toxicology of Tomsk Regional Clinical Hospital, transferred from an infectious diseases hospital, where acute acute nonspecific gastroenteritis developed acute respiratory infections (ARI), which was caused by the use of unspecified alcohols.

Upon receipt of the diagnosis: poisoning with unspecified heavy alcohol, hepatopathy, AKI, anuria, which required the initiation of PST in the form of hemodialysis.

As an example, heparinization control at DG No. 16

Clinical and biochemical studies before hemodialysis №16

Hb - 94 g / l, red blood cells 3 * 10 ¹² , platelets 196 * 10 ⁹ , IPT - 74%, fibrinogen - 4.0 g / l, APTT - 40 s, ATIII - 81%, urea - 14.9 mmol / l, creatinine 486 μmol / L, K - 3.4 mmol / L, Na - 131 mmol / L. A study of the rheological properties of blood according to the proposed method was also carried out: by the method of low-frequency piezotromboelastography using the ARP-01M Mednord hardware-software complex, and t1 was determined, which reflects the time to reach A1 (min), t2 is the time for which the amplitude And increases by 100 units (min), and the calculation of the CTA.

The initial CTA was 52 pu, 10 minutes after the administration of an UFH bolus of 3.5 thousand units. CTA became equal to 7.8 p.u. (decreased 6.7 times), which indicated a somewhat excessive heparinization. In FIG. Figure 2 shows that the anticoagulant activity remained sufficient up to 100 min, amounting to 9.26 pu for 40 min, 10.75 for 70 min (exceeding the initial value by 3 or more times). When the value of KTA was fixed at 32.26 o.u., it was decided to introduce an additional bolt of UFG of 1 thousand units, since it left the optimal interval of change in KTA (2-3 times), amounting to only 1.6 times. After that, for 130 minutes, the CTA was 20.14 p.u. (a change of 2.6 times from the original), which was optimal, and by 180 min 13.16 p.u. (almost 4 times) (see Fig. 2).

Diuresis recovery was noted 5 weeks after receipt. A total of 23 hemodialysis was performed. On the 54th day from the moment of receipt for further rehabilitation he was transferred to Dep. nephrology.

Thus, the proposed method allows for effective monitoring of the most adequate heparinization, without leaving the patient’s bed, reduces the study time, is available for use in the health care system.

Information sources

1. Test system Actalyke MINI II, Instructions for use. http://www.hd13.ru/article/60/ (prototype).

2. Nikolaev A.Yu., Milovanov Yu.S. Treatment of renal failure. Moscow, MIA, 1999.

3. Davenport, A. What are the anticoagulation options for intermittent hemodialysis? NatRev. Nephrol. 7, 499-508 (2011).

4. “UchinoS. BellomoR. MorimatsuH. MorgeraS. SchetzM. TanI. BoumanC. MacedoE GibneyN. TolwaniA. Oudemans-vanStraatenH. RoncoC. KellumJA. Continuous renal replacement therapy: a worldwide practice survey the beginning and ending supportive therapy for the kidney (B.E.S.T. kidney) investigators. IntensiveCareMed. 2007: 33 (9): 1563-1570.

5. “Karl-Georg Fischer / Essentials of anticoagulation in hemodialysis / Hemodialysis International 2007; 11: 178-189.

6. SA Spinier et al. Anticoagulation Monitoring Part 2: Unfractionated Heparin and Low-Molecular-Weight Heparin. AnnPharmacother 2005; 39: 1275-85.

7. European recommendations for best practice for hemodialysis (part 1). Nephrology and Dialysis 2005; (adj): 65-74.

FIG. 1. An example of the control of anticoagulation of UFH in acute HD using CTA No. 1.

FIG. 2. An example of the control of anticoagulation of UFH in acute HD using CTA No. 2.

Claims (1)

A method for assessing the level of anticoagulation with unfractionated heparin during hemodialysis in patients with acute kidney damage, by examining the patient’s blood, characterized in that in periods of time: before administration of unfractionated heparin, then 10, 30, 60 minutes after the first bolus, then after 10 minutes after a second bolus and 5 minutes before the end of hemodialysis, low-frequency piezotromboelastography is performed and the viscosity characteristics of the blood are measured: t1 is an indicator reflecting the time to reach A1 (min); t2 is an indicator reflecting the time during which the amplitude A increases by 100 units (min); KTA is the constant of thrombin activity, which is defined as the time elapsed from the end of the reaction period to an increase in the amplitude by 100 relative units from the level of the minimum amplitude for the reaction period (rel. Units) and is calculated by the formula:
KTA = 100 / (t2-t1)
and with a CTA value after administration of a bolus of UFH, 2-3 times less than the initial one, the level of anticoagulation is considered optimal.

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