Title:
Evidence based evaluation of immuno-coagulatory interventions in critical care.

Abstract:
Cochrane systematic reviews with meta-analyses of randomised trials provide guidance for clinical practice and health-care decision-making. In case of disagreements between research evidence and clinical practice, high quality systematic reviews can facilitate implementation or deimplementation of medical interventions into clinical practice. This applies especially to treatment of critically ill patients where interventions are most often costly and the clinical conditions are associated with high mortality.
To assess the potential benefits or harms of 1) antithrombin III (AT III) for critically ill patients; 2) inhaled nitric oxide (INO) for acute respiratory distress syndrome (ARDS) and acute lung injury (ALI); 3) aerosolized prostacyclin for ARDS and ALI; 4) thrombelastography (TEG) or thromboelastometry (ROTEM) to monitor haemotherapy versus usual care in patients with massive transfusion.
We performed four systematic reviews of relevant randomised clinical trials. To quantify the estimated effect of various interventions, we conducted meta-analyses, where appropriate, to determine intervention effects using the Cochrane Collaboration methodology, trial sequential analyses (TSA), the GRADE, and the PRISMA-guidelines when conducting our systematic reviews. All reviews were performed according to published protocols following the recommendations of the Cochrane Handbook for systematic reviews of interventions. We performed multiple subgroup and sensitivity analyses with regard to methodological quality and various clinical outcomes. Trials were identified through Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE Science Citation Index-Expanded, The Chinese Biomedical Database and LILACS. We included all randomized clinical trials. We hand-searched reference lists, reviews, and contacted authors and experts for additional trials. We searched ClinicalTrials.gov, Centre Watch Clinical Trials Listing Service and ControlledTrials.com for missed, unreported, or ongoing trials. We screened bibliographies of relevant articles and conference proceedings and wrote to trialists and pharmaceutical companies producing the drugs in question.
Four systematic reviews included a total of 44 trials with 5,551 patients. Only 15 of the trials were classified as trials with low risk of bias (high methodological quality) regarding generation of the allocation sequence, allocation concealment, blinding, follow-up and other types of bias. 1) Compared with placebo or no intervention, AT III did not significantly affect overall mortality (relative risk (RR) 0.96, 95% confidence interval (CI) 0.89 to 1.03). No subgroup analyses on risk of bias, populations of patients, or with and without adjuvant heparin yielded significant results. AT III significantly increased the risk of bleeding events (RR 1.52, 95% CI 1.30 to 1.78). 2) INO showed no statistically significant effect on overall mortality (RR 1.06, 95% CI 0.93 to 1.22) and in several subgroup and sensitivity analyses, indicating robust results. Limited data demonstrated no effect of INO on duration of ventilation, ventilator-free days, and length of stay in the intensive care unit and hospital. We found a statistically significant, but transient improvement in oxygenation in the first 24 hours, expressed as the ratio of PO2 to fraction of inspired oxygen (mean difference (MD) 15.91, 95% CI 8.25 to 23.56). However, INO appears to significantly increase the risk of renal impairment among adults (RR 1.59, 95% CI 1.17 to 2.16) but did not significantly affect the risk of bleeding or methaemoglobin or nitrogen dioxide formation. 3) We found only one small low risk of bias paediatric trial examining the role of aerosolized prostacyclin in ALI or ARDS. Based on this limited amount of data, we were unable to support or refute the routine use of this intervention in ALI or ARDS. 4) Compared with standard treatment, TEG or ROTEM showed no statistically significant effect on overall mortality (RR 0.77, 95% CI 0.35 to 1.72) but only five trials provided data on mortality. Our analyses demonstrated a statistically significant effect of TEG or ROTEM on the amount of bleeding (MD -85.05 ml, 95% CI -140.68 to -29.42) but failed to show any statistically significant effect on other predefined outcomes. However, whether this reduction has implication for the patient's clinical condition is still uncertain.
We did not find reliable evidence to support the clinical use of the assessed immuno-coagulatory interventions for general use in critical care based on the available evidence. A large proportion of the trials had serious methodological shortcomings, small number of patients, and short trial duration. The sparse data provided in the included trials may be or may not be promising but is not necessarily evidence of absence of a beneficial or harmful effect, because many of the outcome measures have not been adequately addressed so far. There is an urgent need for several randomised clinical trials with low risk of bias and low risk of random error to evaluate the use of the assessed interventions.