Background
Excessive blood loss and increased blood transfusion requirements may have significant impact on the short-term and long-term outcomes after liver transplantation.

Objectives
To compare the potential benefits and harms of different methods of decreasing blood loss and blood transfusion requirements during liver transplantation.

Search methods
We searched The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and metaRegister of Controlled Trials until September 2011.

Selection criteria
We included all randomised clinical trials that were performed to compare various methods of decreasing blood loss and blood transfusion requirements during liver transplantation.

Data collection and analysis
Two authors independently identified the trials and extracted the data. We analysed the data with both the fixed-effect and the random-effects model using RevMan Analysis. For each outcome we calculated the risk ratio (RR), mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CI) based on available data analysis. We also conducted network meta-analysis.

Main results
We included 33 trials involving 1913 patients. The sample size in the trials varied from 8 to 209 participants. The interventions included pharmacological interventions (aprotinin, tranexamic acid, epsilon amino caproic acid, antithrombin 3, recombinant factor (rFvIIa), oestrogen, prostaglandin, epinephrine), blood substitutes (blood components rather than whole blood, hydroxy-ethyl starch, thromboelastography), and cardiovascular interventions (low central venous pressure). All the trials were of high risk of bias. Primary outcomes were reported in at least two trials for the following comparisons: aprotinin versus control, tranexamic acid versus control, recombinant factor VIIa (rFVIIa) versus control, and tranexamic acid versus aprotinin. There were no significant differences in the 60-day mortality (3 trials; 6/161 (3.7%) in the aprotinin group versus 8/119 (6.7%) in the control group; RR 0.52; 95% CI 0.18 to 1.45), primary graft non-function (2 trials; 0/128 (0.0%) in the aprotinin group versus 4/89 (4.5%) in the control group; RR 0.15; 95% CI 0.02 to 1.25), retransplantation (3 trials; 2/256 (0.8%) in the aprotinin group versus 12/178 (6.7%) in the control group; RR 0.21; 95% CI 0.02 to 1.79), or thromboembolic episodes (3 trials; 4/161 (2.5%) in the aprotinin group versus 5/119 (4.2%) in the control group; RR 0.59; 95% CI 0.19 to 1.84) between the aprotinin and control groups. There were no significant differences in the 60-day mortality (3 trials; 4/83 (4.8%) in the tranexamic acid group versus 5/56 (8.9%) in the control group; RR 0.55; 95% CI 0.17 to 1.76), retransplantation (2 trials; 3/41 (7.3%) in the tranexamic acid group versus 3/36 (8.3%) in the control group; RR 0.79; 95% CI 0.18 to 3.48), or thromboembolic episodes (5 trials; 5/103 (4.9%) in the tranexamic acid group versus 1/76 (1.3%) in the control group; RR 2.20; 95% CI 0.38 to 12.64) between the tranexamic acid and control groups. There were no significant differences in the 60-day mortality (3 trials; 8/195 (4.1%) in the recombinant factor VIIa (rFVIIa) group versus 2/91 (2.2%) in the control group; RR 1.51; 95% CI 0.33 to 6.95), thromboembolic episodes (2 trials; 24/185 (13.0%) in the rFVIIa group versus 8/81 (9.9%) in the control group; RR 1.38; 95% CI 0.65 to 2.91), or serious adverse events (2 trials; 90/185 (48.6%) in the rFVIIa group versus 30/81 (37.0%) in the control group; RR 1.30; 95% CI 0.94 to 1.78) between the rFVIIa and control groups. There were no significant differences in the 60-day mortality (2 trials; 6/91 (6.6%) in the tranexamic acid group versus 1/87 (1.1%) in the aprotinin group; RR 4.12; 95% CI 0.71 to 23.76) or thromboembolic episodes (2 trials; 4/91 (4.4%) in the tranexamic acid group versus 2/87 (2.3%) in the aprotinin group; RR 1.97; 95% CI 0.37 to 10.37) between the tranexamic acid and aprotinin groups. The remaining outcomes in the above comparisons and the remaining comparisons included only only trial under the primary outcome or the outcome was not reported at all in the trials. There were no significant differences in the mortality, primary graft non-function, graft failure, retransplantation, thromboembolic episodes, or serious adverse events in any of these comparisons. However, the confidence intervals were wide, and it is not possible to reach any conclusion on the safety of the interventions. None of the trials reported the quality of life in patients.

Secondary outcomes were reported in at least two trials for the following comparisons - aprotinin versus control, tranexamic acid versus control, rFVIIa versus control, thromboelastography versus control, and tranexamic acid versus aprotinin. There was significantly lower allogeneic blood transfusion requirements in the aprotinin group than the control group (8 trials; 185 patients in aprotinin group and 190 patients in control group; SMD -0.61; 95% CI -0.82 to -0.40). There were no significant differences in the allogeneic blood transfusion requirements between the tranexamic acid and control groups (4 trials; 93 patients in tranexamic acid group and 66 patients in control group; SMD -0.27; 95% CI -0.59 to 0.06); rFVIIa and control groups (2 trials; 141 patients in rFVIIa group and 80 patients in control group; SMD -0.05; 95% CI -0.32 to 0.23); thromboelastography and control groups (2 trials; 31 patients in thromboelastography group and 31 patients in control group; SMD -0.73; 95% CI -1.69 to 0.24); or between the tranexamic acid and aprotinin groups (3 trials; 101 patients in tranexamic acid group and 97 patients in aprotinin group; SMD -0.09; 95% CI -0.36 to 0.19). The remaining outcomes in the above comparisons and the remaining comparisons included only only trial under the primary outcome or the outcome was not reported at all in the trials. There were no significant differences in the blood loss, transfusion requirements, hospital stay, or intensive care unit stay in most of the comparisons.

Authors' conclusions
Aprotinin, recombinant factor VIIa, and thromboelastography groups may potentially reduce blood loss and transfusion requirements. However, risks of systematic errors (bias) and risks of random errors (play of chance) hamper the confidence in this conclusion. We need further well-designed randomised trials with low risk of systematic error and low risk of random errors before these interventions can be supported or refuted.

Methods to decrease blood loss and transfusion requirements for liver transplantation

Background
Critical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ill patients are unknown. This review was published in 2008 and updated in 2015.

Objectives
To examine:

1. The effect of AT III on mortality in critically ill participants.

2. The benefits and harms of AT III.

We investigated complications specific and not specific to the trial intervention, bleeding events, the effect on sepsis and disseminated intravascular coagulation (DIC) and the length of stay in the intensive care unit (ICU) and in hospital in general.

Search methods
We searched the following databases from inception to 27 August 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid SP), EMBASE (Ovid SP,), CAB, BIOSIS and CINAHL. We contacted the main authors of trials to ask for any missed, unreported or ongoing trials.

Selection criteria
We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published, or language. We contacted the investigators and the trial authors in order to retrieve missing data. In this updated review we include trials only published as abstracts.

Data collection and analysis
Our primary outcome measure was mortality. Two authors each independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI). We performed subgroup analyses to assess risk of bias, the effect of AT III in different populations (sepsis, trauma, obstetrics, and paediatrics), and the effect of AT III in patients with or without the use of concomitant heparin. We assessed the adequacy of the available number of participants and performed trial sequential analysis (TSA) to establish the implications for further research.

Main results
We included 30 RCTs with a total of 3933 participants (3882 in the primary outcome analyses).

Combining all trials, regardless of bias, showed no statistically significant effect of AT III on mortality with a RR of 0.95 (95% CI 0.88 to 1.03), I² statistic = 0%, fixed-effect model, 29 trials, 3882 participants, moderate quality of evidence). For trials with low risk of bias the RR was 0.96 (95% Cl 0.88 to 1.04, I² statistic = 0%, fixed-effect model, 9 trials, 2915 participants) and for high risk of bias RR 0.94 (95% Cl 0.77 to 1.14, I² statistic = 0%, fixed-effect model, 20 trials, 967 participants).

For participants with severe sepsis and DIC the RR for mortality was non-significant, 0.95 (95% Cl 0.88 to 1.03, I² statistic = 0%, fixed-effect model, 12 trials, 2858 participants, moderate quality of evidence).

We conducted 14 subgroup and sensitivity analyses with respect to the different domains of risk of bias, but detected no statistically significant benefit in any subgroup analyses.

Our secondary objective was to assess the benefits and harms of AT III. For complications specific to the trial intervention the RR was 1.26 (95% Cl 0.83 to 1.92, I² statistic = 0%, random-effect model, 3 trials, 2454 participants, very low quality of evidence). For complications not specific to the trial intervention, the RR was 0.71 (95% Cl 0.08 to 6.11, I² statistic = 28%, random-effects model, 2 trials, 65 participants, very low quality of evidence). For complications other than bleeding, the RR was 0.72 ( 95% Cl 0.42 to 1.25, I² statistic = 0%, fixed-effect model, 3 trials, 187 participants, very low quality of evidence). Eleven trials investigated bleeding events and we found a statistically significant increase, RR 1.58 (95% CI 1.35 to 1.84, I² statistic = 0%, fixed-effect model, 11 trials, 3019 participants, moderate quality of evidence) in the AT III group. The amount of red blood cells administered had a mean difference (MD) of 138.49 (95% Cl -391.35 to 668.34, I² statistic = 84%, random-effect model, 4 trials, 137 participants, very low quality of evidence). The effect of AT III in patients with multiple organ failure (MOF) was a MD of -1.24 (95% Cl -2.18 to -0.29, I² statistic = 48%, random-effects model, 3 trials, 156 participants, very low quality of evidence) and for patients with an Acute Physiology and Chronic Health Evaluation score (APACHE) at II and III the MD was -2.18 (95% Cl -4.36 to -0.00, I² statistic = 0%, fixed-effect model, 3 trials, 102 participants, very low quality of evidence). The incidence of respiratory failure had a RR of 0.93 (95% Cl 0.76 to 1.14, I² statistic = 32%, random-effects model, 6 trials, 2591 participants, moderate quality of evidence). AT III had no statistically significant impact on the duration of mechanical ventilation (MD 2.20 days, 95% Cl -1.21 to 5.60, I² statistic = 0%, fixed-effect model, 3 trials, 190 participants, very low quality of evidence); on the length of stay in the ICU (MD 0.24, 95% Cl -1.34 to 1.83, I² statistic = 0%, fixed-effect model, 7 trials, 376 participants, very low quality of evidence) or on the length of stay in hospital in general (MD 1.10, 95% Cl -7.16 to 9.36), I² statistic = 74%, 4 trials, 202 participants, very low quality of evidence).

Authors' conclusions
There is insufficient evidence to support AT III substitution in any category of critically ill participants including the subset of patients with sepsis and DIC. We did not find a statistically significant effect of AT III on mortality, but AT III increased the risk of bleeding events. Subgroup analyses performed according to duration of intervention, length of follow-up, different patient groups, and use of adjuvant heparin did not show differences in the estimates of intervention effects. The majority of included trials were at high risk of bias (GRADE; very low quality of evidence for most of the analyses). Hence a large RCT of AT III is needed, without adjuvant heparin among critically ill patients such as those with severe sepsis and DIC, with prespecified inclusion criteria and good bias protection.

/pdf/antithrombin-iii-for-critically-ill-patients-35uiewcch4.pdf

Antithrombin III for critically ill patients.

Antithrombin III in critically ill patients

Blood banking and transfusion medicine , Blood banking and transfusion medicine , کتابخانه دیجیتال جندی شاپور اهواز

Blood Banking and Transfusion Medicine

Treatment with AT III concentrates is a good example for the discrepancy between the optimistic expectations based on theoretical considerations or animal experiments and the result of clinical studies. 15 years after the introduction into clinical practice, a benefit for patients treated with AT III concentrates has not been proven. In hereditary antithrombin III deficiency, randomized clinical trials are completely lacking and only few and small sized randomized studies were performed in patients with acquired AT III deficiency. In none of these trials, a significant clinical benefit with regard to reduction of morbidity or mortality was detectable. Based on the published data, one can state that AT III concentrates may be beneficial in some special clinical situations in patients with hereditary antithrombin III deficiency (such as delivery, acute serious thromboembolic complications and postoperative thromboprophylaxis). In acquired AT III deficiency, there is no proven indication for the use of AT III concentrates.

Antithrombin III concentrates--are they clinically useful?

Antithrombin III supplementation during orthotopic liver transplantation in cirrhotic patients: a randomized trial.

The multimeric analysis was carried out on the plasma of 18 patients with severe von Willebrand's disease (vWD) using two different types of agarose: Seakem HGT(P) and Seaplaque LGT. No pattern was found in any of the patients using Seakem HGT(P). On the contrary, by Seaplaque LGT, a multimeric pattern was found in four patients belonging to three different families, indicating that it is possible to identify and characterize variable multimeric patterns also in type III vWD.

The multimeric pattern of von Willebrand's factor (vWF) can be demonstrated also in the severe form of the disease.

[Substitution therapy with antithrombin III in orthotopic liver transplantation: possible effect on hemorrhage reduction].

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Antithrombin III supplementation during orthotopic liver transplantation in cirrhotic patients: a randomized trial.

The multimeric pattern of von Willebrand's factor (vWF) can be demonstrated also in the severe form of the disease.

[Substitution therapy with antithrombin III in orthotopic liver transplantation: possible effect on hemorrhage reduction].