Supplementation therapy with Antithrombin Drugs in the Combined Treatment of Sepsis

Purpose — to assess the efficacy of supplementation therapy for antithrombin deficiency in the combined treatment of sepsis.Materials and methods. A prospective-retrospective study of the efficacy of supplementation therapy for antithrombin deficiency during sepsis was carried out; 90 patients were examined. The patients were split into two groups whether antithrombin deficiency correction was or was not undertaken. The composite outcome — the incidence of cardiovascular complications as of day 28 from the therapy commencement — was chosen as the primary endpoint of the study. The secondary endpoints of the study were prevalence of adverse events as of day 28 from the therapy commencement and 180-day mortality.Results. There was no difference between the groups either in respect of 28-day mortality or composite outcome. Analysis of secondary endpoints revealed that in the group of patients who received antithrombin supplementation therapy, the risk of development of an acute renal injury was significantly lower on day 28 and 180 from therapy commencement: OR 3.5 [95% CI 1.05–11.66] at P=0.04 and OR 2.92 [95% CI 1.02–8.31] at P=0.045, respectively.Conclusion. Correction of antithrombin level to activity level ‘over 61%’ is associated with decreased incidence degree III acute kidney failure (KDIGO).


Introduction
SEPSIS-3 (Surviving Sepsis Campaign 3) suggests considering sepsis as a life-threatening dysfunction of organs that is caused by dysregulation of the body's response to infection [1]. Mortality of sepsis patients amounts to 25-30% and might reach 35-40% and more in septic shock patients [2].
In most cases, the immediate cause of death during sepsis is multiple organ failure. Most frequently affected are cardiovascular system (up to 80% of cases), kidneys (up to 70%) and respiratory system (60-65%); nervous system (up to 50%) and liver (35% of cases) are affected rarer [3][4][5]. Blood coagulation system suffers in more than half of patients (up to 55-60%), thus, being somewhere «in the middle of the list».
Coagulation disorders often manifest as disseminated intravascular coagulation (DIC) syndrome (DIC) [6]. In this instance, decrease of plasma physiological anticoagulants including antithrombin (AT), which are markers of system coagulation activation, is observed [7,8]. In particular, reduced AT activity is a consequence of excessive formation of thrombin [9], increased permeability of vessels [10], and accelerated degradation of AT, which develop as part of DIC [11] and largely affect mortality during sepsis [12].
The efficacy of antithrombin supplementation therapy as part of combined treatment of sepsis was studied at least in six randomized controlled studies [13][14][15][16][17][18]. Contradictory results were received. For example, the KyberSept study (2001) did not find any positive effect from administration of high doses of AT [18]. However, analysis in subgroups showed better survivability of patients with sepsis-associated DIC [17].  demonstrated that AT therapy at low doses (1500 IU/day for 3 days) improves the treatment outcome; mortality of patients in the 'very low antithrombin activity' group was noticeably lower in patients who received antithrombin therapy [19].
Nevertheless, the latest version of SEPSIS-3 does not include a recommendation to include AT into combined treatment of sepsis due to unproven efficacy [22].
If this is the reason for reserved attitude to antithrombin therapy during sepsis, this study has been undertaken to obtain additional data in this field. Its purpose was to assess the efficacy of supplementation therapy for antithrombin deficiency in combined treatment of sepsis.
The study and control groups were comparable as regards gender and age, antithrombin activity, and past history of: cardiac rhythm disorders, ischemic heart disease, cardiac insufficiency, and chronic kidney disease (table 1).
Thus, the comparison between groups revealed no differences in parameters shown ( Sepsis diagnosis and therapy followed SEPSIS III guidelines [22]. The starting antibacterial therapy included drugs of a wide range of action; after pathogen verification and establishment of sensitivity, if necessary, the prescribed therapy was adjusted. The infusion therapy was also carried out pursuant to SEPSIS III guidelines [22].
The intensive care strategy and tactics was the same for all patients. Daily monitoring was carried out in compliance with the Harvard Standard requirements [23].
The only difference of the study group consisted in antithrombin correction by intravenous administration of the drug ANTITHROMBIN III human (BAXTER, USA). Taking into account the results of earlier study [24], patients whose antithrombin on day 5 was less than 61% of activity, received supplementation AT therapy until the target value of 'over 61% of activity' was reached. The said level of AT activity was maintained during the whole period of patient's stay in ICU, as necessary, by repeated transfusions.
The dose and regularity of administration was always set based on clinical efficacy and laboratory findings individually in each particular case.
The starting dose was calculated according to product's instructions for use:

Dd = Mt ((Lt-Li)/2)
where Lt is the target AT activity (%); Li is the initial AT activity (%); Mt is the body weight (kg); Dd is the required dose of the drug (IU).
Homeostasis was examined using analyzer ACL TOP 700 (Instrumentation Laboratory, USA).
Endpoints of the study. The primary endpoint of the study was the composite outcome: the prevalence of cardiovascular complications on day 28 from treatment commencement. The secondary endpoints were the incidence of adverse events as of day 28 from treatment commencement and 180 day mortality.
• NCA (non-fatal cardiac arrest) -absence of hearth rhythm or presence of a chaotic rhythm, which requires any component of basic or extended cardiopulmonary resuscitation [29].
• FDA (first detected or first occurred arrhythmia): ECG signs of flutter, atrial fibrillation, or atrioventricular block of the second or third degree.
• Composite outcome of treatment -was calculated as a sum of the above complications [31].
Data were acquired at two timepoints determined in the study: day 28 in ICU and day 180 from the treatment commencement.
Statistical analysis. Data obtained in the course of the study were processed using software for statistical analysis: Statistica 10 (Stat Soft, Inc. 2011) and MedCalc 12.5.0. (MedCalc Software, USA) [32].
All variables received in the course of the study were subjected to standardization and analysis for normality of distribution using the Shapiro-Wilk test [33].
Variables featuring normal distribution were presented as arithmetic means (M) and root-mean-square deviation values. To determine the significance of differences of normally distributed variable, paired Student ttest was used.
Variables that did not follow normal distribution were presented as a median and interquartile interval (Me [25; 75]), the confidence interval was regarded equal to 95% (CI 95%). Significance of differences was assessed with the help of the following non-parametric criteria: Mann-Whitney U-test for independent groups; frequencies of qualitative variables were compared using twotailed Fisher's exact test and odds ratio.
Differences were considered significant at P 0.05.
В результате проведенного исследования было установлено, что коррекция недостаточ-come between the study group and control group: The antithrombin supplementation therapy did not lower the risk of development of adverse events in patients on therapy day 28 ( However, significant decrease of the risk of development of degree III ARF III was found in the study group: OR -0.29 [95% CI 0.09-0.95] at P=0.04.
Half a year after discharge from the hospital, the revealed trends were not changed.
The 180-day mortality was equal in the study group to 47.5% and in the control group -52% (P=0.83). The results demonstrates that the AT does not rise the chances of favorable outcome during sepsis( OR 1.20 (95% CI 0.52-2.75), P=0.67).
The number of patients who continued treatment for stage III ARF half a year after discharge from hospital amounted to 15% in the study and 36% in the control groups (P=0.03); hence, AT therapy prevented the risk of developing chronic renal insufficiency (OR = 2.92 (95% CI 1.02-8.31), P=0.045).
Thereby, antithrombin deficiency correction is associated with reduced risk of developing renal insufficiency both on therapy day 28 and on day 180 after discharge from the hospital.
There are experimental data that demonstrate AT efficacy in terms of prophylaxis and treatment of acute renal injury. Early in the 2000s, investigations were performed to show that a therapy with AT drugs employed using the model of experimental sepsis in primates resulted in lessening of pulmonary and renal insufficiency. The authors suggested that AT inhibited deposition of fibrin, decreased inflammation and multiple organ dysfunction syndrome [34]. In another study, using a rabbit model of Masugi nephritis the AT-enriched plasma administered into the renal artery inhibited production of prothrombinase and participated in fibrinolysis [35].
Discussing the results, we hypothesize that increasing the antithrombin activity level interrupts the pathological process that includes systemic inflammation, endothelial dysfunction, hemodynamic changes, as well as renal microcirculation alteration that promotes injury of nephrons, localized blood congestion in the renal microcirculatory pathway, release of inflammatory cytokines, and coagulation system activation [36,37]. Restoration of antithrombin activity affected the process that initiated cell apoptosis in different tissues associated with the multiple organ dysfunction [38][39][40].
In our study, the antithrombin therapy did not reduce mortality presumably due to lowtherapeutic effect or insufficient numbers of patients in a study cohort. In any case, however, our data confirm the findings of earlier studies that have demonstrated no influence of AT therapy on survival of sepsis patients [13][14][15]. Multi-center randomized controlled clinical study is needed to clarify whether the supplementation antithrombin therapy would be therapeutically effective in sepsis patients.

Conclusion
Therapy for antithrombin deficiency by exogenously administrated drug prevents development of stage II acute renal failure in patients with sepsis.