Read on for highlights and insights from the third day of the Collaborative Clinical Trials in Intensive Care Medicine Conference at the Monash University Prato Centre (#pratoICM15). This post follows on from The Prato ICM Conference 2015, Day 1 and Day 2.
Professor Jeffrey Rosenfeld (Director of Neurosurgery, The Alfred Hospital, Melbourne Australia) entertains conference participants with a recital of The Piano Trio in B-flat major, Op. 97, by Ludwig van Beethoven, finished in 1811. It is commonly referred to as the Archduke Trio, because it was dedicated to Archduke Rudolph of Austria, the youngest of twelve children of Leopold II, Holy Roman Emperor.
Intracranial hypertension – I need rescuing!
Decompressive craniectomy (DC) remains a controversial neurosurgical procedure. The DECRA trial (N Engl J Med 2011; 364:1493-1502) demonstrated that in adults with severe diffuse traumatic brain injury and refractory intracranial hypertension, early bi-frontotemporoparietal DC decreased intracranial pressure and the length of stay in the ICU, but was associated with more unfavorable clinical outcomes. However, it is still unclear whether this procedure has a role in other scenarios, such as later in the ICU course, or where the pattern of injury includes cerebral contusions. Complications of this procedure include herniation of brain tissue through the bone defect, hydrocephalus, hygromas, infection, and seizures. In this context, the RESCUE-ICP study is seeking to determine whether DC performed at any time post traumatic brain injury (whether diffuse or not) for refractory intracranial hypertension (ICP > 25mmHg) is off any benefit compared to ongoing medical management (including barbiturate coma). Enrolment for this study is now complete and results are expected some time in 2015. Of note, a sister study (RESCUE-aSDH) has also commenced. This is a multi-centre, pragmatic, parallel group randomised trial that aims to compare the clinical and cost-effectiveness of DC versus craniotomy for the management of adult head-injured patients undergoing evacuation of an acute subdural haematoma. The proposed sample size is > 900 patients and recruitment is ongoing.
Sepsis – The PROMISE of ARISE-ing to a new PROCESS of care.
Sepsis continues to be a significant contributor to the workload in ICU. The incidence of severe sepsis admissions is increasing, although over the last decade there has been a significant reduction in crude and adjusted mortality (JAMA 2014;311(13):1308-1316). This has important implications for contemporary trial design, where by such secular trends may significantly impact the expected effect size (particularly if a study takes 4-5 years to complete). The current definition of sepsis remains poorly suited to the critically ill. In particular the systemic inflammatory response state (SIRS) lacks adequate specificity. A recent analysis of the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database, demonstrated that the need for greater than two SIRS criteria to define severe sepsis, excluded one in eight otherwise similar patients with infection, organ failure, and substantial mortality, and failed to define a transition point in the risk of death (N Engl J Med 2015; 372:1629-1638). An updated definition of sepsis is being developed (driven by data mining of large hospital level databases), which will hopefully be available later in 2015.
Three large multicenter studies in geographically distinct areas have now been completed exploring the efficacy of early goal directed therapy (EGDT) in the management of severe sepsis / septic shock. PROMISE, ARISE, and PROCESS all demonstrated no benefit from this intervention compared to standard care. An updated systematic review and meta-analysis has been completed by the same investigators (Intensive Care Med. 2015 May 8. [Epub ahead of print]), confirming the lack of efficacy of EDGT, and the association with increased ICU resource utilization. However, the use of aggregate data in these types of analysis may lead to inaccurate conclusions, particularly where inferences about individuals are based solely on the groups to which they belong (Intensive Care Med. 2010 Jan;36(1):11-21). Individual patient data meta-analysis (IPD MA) represents a evolving statistical technique that will hopefully address these issues, and substantially increase the power smaller individual studies to detect clinically meaningful effects. The key to such an endeavor however is in the apriori harmonization of data collection. Such analyses are planned for the EGDT studies, in addition to those concerning intensity of renal replacement therapy, and intensive insulin therapy in the ICU.