Asian Cardiovasc Thorac Ann 2007;15:449-452
© 2007 Asia Publishing EXchange Ltd
Evaluating the Quality of Trials of Hypothermic Circulatory Arrest Aortic Surgery
Jeffrey H Shuhaiber, MD
Department of Surgery, University of Illinois, Chicago, USA
For reprint information contact: Jeffrey H Shuhaiber, MD, Tel: 1 312 996 6765, Fax: 1 312 996 1214, Email: jeffrey01{at}mac.com, 614-G, Laflin, Chicago, IL 60607, USA.
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ABSTRACT
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The quality of level 1 evidence in reports on deep hypothermic circulatory arrest was assessed, and the confounding factors in surgical management and study design that can prevent meta-analysis formulation were determined. A systematic search of the literature was conducted using categorized nomenclature for randomized controlled trials in adult patients undergoing deep hypothermic circulatory arrest in the last 40 years. Twelve randomized controlled trials (2.3%) were found among 504 publications on deep hypothermic circulatory arrest listed on Medline from 1960; only 4 of them related to adults. One adequately powered study demonstrated reduced blood loss in deep hypothermic circulatory arrest using aprotinin. Three studies comparing retrograde and antegrade perfusion were underpowered. The median CONSORT score was 14 (range, 13–15). There were no consistent measures of similar outcomes (neuropsychometric, neurocognitive). No explanation was provided for the difference in reported ranges of neurological deficits in nonrandomized (5%–70%) and randomized (3%–9%) studies. Existing studies of deep hypothermic circulatory arrest are insufficient and inconsistent in the outcome measured, which explains the lack of a meta-analysis. Neurological injury remains high, and an appropriately powered study of interventions that can optimize cerebral perfusion is necessary.
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INTRODUCTION
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Since the inception of deep hypothermic circulatory arrest (DHCA), sufficient evidence from retrospective data has demonstrated its importance in cardiovascular surgery.1 However, the call for evidence-based medicine is increasing.2 The demand that all customs and rituals of surgery be subjected to scrutiny will begin to generate doubt about the efficacy of most medical interventions.3 The current thinking is that government agencies regard evidence-based surgery as the great purgative of contemporary surgical practice. In recent years, there have been two main driving forces to utilize randomized controlled trials (RCTs) in cardiac surgery: evolving technology and techniques, and demand from official governmental agencies for evidence. Clinical decision-making, application of new or modified interventions in surgical practice, and reimbursement issues demand meta-analyses of RCTs.
Meta-analyses of RCTs include studies of variable methodological quality.4 The quality of such trials ranges across a spectrum of least to best designed and executed.5 Meta-analysts need to take this information into consideration to reduce or avoid bias whenever possible. Uncertainty continues to surround the benefits and drawbacks of different cerebral protection methods in DHCA.1 No meta-analysis in DHCA currently exists. Possible reasons are that high-quality studies have enrolled a limited number of patients and have not comprehensively examined relevant patient outcomes. In this study, the application of level 1 evidence in the field of DHCA was revisited. The quality of the RCTs in cardiothoracic surgery was evaluated with a view to continued evolving technology application. This demand challenges current practice and calls for better designed and conducted RCTs. An additional aim was to determine whether a meta-analysis was feasible.
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METHODS
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Systematic searches of PubMed and Embase to identify RCTs in the field of hypothermic circulatory arrest (HCA) or DHCA were performed. The search strategies employed a number of free-text keywords as well as controlled vocabulary terms, including (but not limited to) the following: HCA; adult HCA; deep HCA; retrograde cerebral perfusion and HCA; antegrade cerebral perfusion and HCA. Article bibliographies were hand-searched to ensure that no studies were missed. The inclusion dates were from 1960 until the end of December 2005. Inclusion criteria were adult patients undergoing DHCA, and evaluation of one of the following outcomes of interest: estimated blood loss, neurological deficit sustained, and post-arrest cerebral recovery. The articles and their respective biographies were further searched to identify those with an adult population and the specified inclusion criteria. Each RCT was evaluated against the benchmark criteria offered by the Consolidated Statement for Randomized Controlled Trials (CONSORT) based on a 22-point scale assessing whether the investigators had adequately reported and conducted the RCT according to the CONSORT criteria.5 Trials were scored from 0 (worst) to 22 (best) based on the number of CONSORT criteria fulfilled. Each trial was scrutinized with respect to the title and abstract, introduction, methods (participants, interventions, objectives, outcomes, sample size, randomization, blinding, statistical methods), results (participant flow, recruitment, baseline data, numbers analyzed, outcomes and estimation, ancillary analyses, adverse events), and discussion (interpretation, generalization, overall evidence in the context of current evidence). A database of papers that did not meet the inclusion criteria (Table 1
) and those that did (Table 2) was generated. Each study was carefully reviewed with particular attention directed to the size of each treatment arm, trial quality (CONSORT-guided), potential patient or surgical management confounding variables, and statement of current practice and recommendations for practice change.
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RESULTS
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Twelve RCTs (2.3%) evaluating DHCA were found among 504 relevant publications listed on Medline from 1960 (Tables 1
and 2).6–17 Of the 4 RCTs on adults, only one was able to demonstrate with sufficient power the effect of aprotinin in reducing blood loss. Three RCTs comparing retrograde and antegrade perfusion in DHCA were underpowered, which was stated by the respective authors. Regarding the outcomes of interest and interventions utilized, no consistency was evident in the population sample, surgical practice, and methods of cerebral perfusion, protection, and monitoring. This lack of consistency prevented us from conducting a meta-analysis.
The median CONSORT score of the 4 trials that met the inclusion criteria was 14; range, 13–15 (Table 2). Two important pieces of information were lacking throughout the DHCA trials. First, the studies did not report the number of patients receiving the intended treatments or completing the study protocol. No statement was made about whether any deviation from the study protocol occurred. Second, no trial addressed multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those pre-specified and those exploratory. Only one trial described the flow of each participant through each stage. Specifically, none of the RCTs were consistent with outcome measured; neuropsychometric vs neurocognitive vs nasopharyngeal temperature. No explanation was provided for the difference in the range of neurological deficits in non-RCTs (5%–70%) and RCTs (3%–9%). A closer look was taken at the cannulation techniques, neurological monitoring during hypothermia, and degree variation in hypothermia. It is clear that these 3 factors can have a confounding effect, resulting in further heterogeneity among the RCTs. Two of the trials did not control for these factors.
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DISCUSSION
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Randomized controlled trials provide the best clinical evidence for a particular action and or intervention, but extrapolation to clinical practice is less useful if the RCT conduct and analysis is questionable. It is clear to the surgical society that to perform surgical interventions, strong and solid objective evidence has to be available. This is in contrast to the medical field where the evidence is easier to obtain for less invasive procedures. In light of evidence-based medicine, the severity of the surgical intervention has to be matched proportionally with the most credible investigational assessment conduct of the research. In this study, the 4 RCTs presented had small treatment arms and lacked at least 25% of the CONSORT criteria, particularly blinding, allocation concealment, and intention to treat.
There has been ongoing controversy over the last decade as to whether the optimal cerebral perfusion is retrograde or antegrade. The answer cannot be determined from the available RCTs, given the constraints and limitations of these studies. Well-designed CONSORT-oriented RCTs will provide different outcomes for which a meta-analysis will provide the evidence to justify either cerebral perfusion technique. Extrapolation to general surgical practice cannot be made satisfactorily at this time. These types of calculations are fraught with unreliability and lack of direct clinical interpretation. With regard to statistical methodology, 75% of the studies performed a priori power calculations (post-hoc) as planned.
There is no doubt that variations in surgical technique and subjective bias have proved to be obstacles to large-scale multicenter trials in surgery. It is understandable that inability to apply blinding, problems in concealment, and non-standardization of the techniques will plague any RCT in surgery. Our quest for evidence-based surgery should at least eliminate rituals and old habits that have long been practiced.
Although the assessment of neurological function was made using surrogate markers, there remains a large deficit of object imaging data to determine whether function is related to structure. None of the 4 included trials reported any imaging of the brain despite a poor neuropsychometric score, or during brain ischemic time while on HCA.
Difficulties will remain with the application of evidence-based surgery. The main driving force is that surgery is an art that utilizes science, and rarely the other way round. However, continued attempts can be fruitful and may meet the consumer and governmental demands. More and more often, healthcare providers and policy decision makers consult systematic reviews containing meta-analyses of clinical trials to make evidence-based decisions. Such reports strive to minimize bias by the systematic identification, commentary, synthesis, and exclusion of heterogeneity of all relevant studies on a unique topic. Such reports are not without flaws; however, they are the best we have so far. Given that the systematic review of RCTs in HCA or DHCA is currently riddled with inherent problems, it remains to be seen in the next decade whether our specialty will be empowered by at least one.
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TOP
ABSTRACT
INTRODUCTION
