Attenuating the systemic inflammatory response to adult cardiopulmonary bypass: A critical review of the evidence base

1 Chronic Disease Research Centre, Tropical Medicine Research Institute, The University of the West Indies, Bridgetown, Barbados
2 The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
3 INOVA Heart & Vascular Institute, INOVA Fairfax Hospital for Children, Falls Church, VA , USA
4 Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, USA
5 Department of Anesthesiology, Hofstra Northshore‐LIJ Medical School, New Hyde Park, NY, USA
6 Cardiac Surgery Research and Perfusion, Flinders University and Flinders Medical Centre Adelaide, South Australia
7 Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Winston‐Salem, NC, USA

Start Date:

Jan 2011

End Date:

Dec 2014

Rationale:

A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically‐based review exists to cover the scope of anti‐inflammatory interventions deployed. To address this shortcoming, Professor Landis was invited in 2011 to head the Inflammation Section of the STS/SCA Perfusion Guidelines Writing Group. The Writing Group was tasked to produce an evidence based review of anti‐inflammatory interventions to underpin clinical practice guidelines endorsed by the Society of Thoracic Surgeons (STS), the Society for Cardiovascular Anesthetists (SCA) and the American Society for ExtraCorporeal Technology (AMSECT). The Inflammation group included the Presidents of SCA and AMSECT.

Methods:

The literature search was designed to capture clinical trials reporting on the inflammatory response to adult CPB, together with clinical outcomes or surrogate markers for organ injury to five index organs: heart, lung, brain, kidney and gut. This recovered > 1600 articles in PubMed that were entered into the Guideliner™ reviewing software (www.Guideliner.org/default.aspx). A title review narrowed the search to 608 Abstracts of which 236 were selected for full paper review. In order to be included, trials had to measure at least one inflammatory mediator and one pre‐specified clinical outcome (defined by “Outcomes 2010” Consensus Statement). The rules for deciding on inclusion/exclusion of papers and assignment of Level of Evidence were based on the Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guideline (http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Co...).

Main Results:

Ninety‐eight papers satisfied inclusion criteria and formed the evidence base. Thirty three different interventions and approaches to attenuate the systemic inflammatory response were identified. Only a minority of papers (35/98=35.7%) were able to demonstrate any clinical improvement to one or more of the pre‐defined outcome measures, (most frequently myocardial protection or length of ICU stay). No single intervention was supported by h4 level A evidence (multiple RCTs or meta‐analysis). Interventions with Level A evidence to support reducing inflammation included off‐pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions with level B evidence (single RCT) for minimizing inflammation, included nitric‐oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl‐L‐carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These results are consistent with a "multiple hit" hypothesis, whereby clinically effective suppression of inflammation requires hitting multiple inflammatory targets.

Expected impact:

This critical review endorsed by STS, SCA and AMSECT concluded that no single intervention used on its own demonstrated h4 evidence for limiting adverse outcomes due to the systemic inflammatory response. The societies further concluded that the variability of the evidence base and small sample sizes precluded drafting of clinical practice guidelines, the original purpose of the exercise. The secondary analysis showing that suppression of a single inflammatory biomarker was required but not sufficient to confer a clinical benefit implied that further research is warranted to evaluate combinations of interventions capable of achieving synergy by targeting the many pathways that are activated.

Next Steps / Future Plans:

The variability in the evidence base is caused by a complete disregard by researchers in the field for measuring the four criteria used in the systemic inflammatory response syndrome (SIRS) definition (temperature, heart rate, respiration rate, leukocytes). The SIRS definition, however, was borrowed from the sepsis field and is widely considered too nonspecific and irrelevant for the systemic inflammatory response to heart surgery. Further steps will need to be taken to seek consensus in order to redefine the systemic inflammatory response, with a first step to formally abandon the use of SIRS.