Clinical paperBrain biomarkers and management of uncertainty in predicting outcome of cardiopulmonary resuscitation: A nomogram paints a thousand words☆
Introduction
The realization that medical care must be tailored to prognosis has led to an increasing role for prediction models in patient management. Cardiologists were the first to combine clinical presentation, electrocardiography and cardiac biomarker data to direct physician care within the context of myocardial infarction.1, 2, 3 Although it is clear that neither creatine kinases nor troponins constitute “ideal” biomarkers,4, 5, 6, 7, 8, 9 use of standardized definitions and predefined biomarker laboratory measurements have led to significant advances in the treatment of ischemic heart disease by enabling more precise disease stratification and creation of tools for directing and measuring treatment.
Within the context of cardiopulmonary resuscitation (CPR) it is increasingly clear that patient treatment after ROSC (return of spontaneous circulation) should be directed by the likelihood of neurologically intact survival as eventual outcome is determined primarily by the extent of ischemic brain damage.10, 11 The reluctance of clinicians to use biomarkers as prognostic tools within this context has been limited by two main problems: research on brain biomarkers has been performed with an almost “ascetic” attitude in that it has concentrated solely on the discriminative ability of the isolated biomarker tested without integration of the clinical picture. This has led to a (justifiable) clinician vote of no confidence because clearly there is no perfect single predictor of a poor outcome, be it severe neurological injury or death. Secondly, despite studies performed on human subjects, there remains a clear gap between “bench” research and “bedside” implementation of biomarkers; in other words, we have had little idea of how to use the biomarker data when we actually need to discuss the likelihood of death/survival with the patient's family. Under these circumstances, post-ROSC treatment decisions mostly remain based upon complex tests, incidental clinical findings and expert opinion.10, 12
Nomograms serve as a simple visual tool which can be intuitively understood even by non-professionals yet they integrate several variables to produce individual risk assessment. Nomograms can be used to calculate the relative risk of death or severe morbidity13 and nomographic prediction has been demonstrated to be superior to expert opinion in several clinical situations.14, 15 In a previous paper we demonstrated that brain biomarkers add to the predictive strength of conventional clinical variables.16 In this paper we suggest how to apply this information in practical terms; i.e. how biomarker data can be translated into a decision support tool despite cultural diversity regarding acceptable levels of misclassification of a potential survivor. We demonstrate how a nomogram or computer program which includes both biomarker and clinical data could be used to reduce the likelihood of a premature/mistaken diagnosis of death in patients who may survive.
Section snippets
Methods
All out-of-hospital cardiopulmonary arrests (OHCAs) in Israel are treated by the National EMS in accordance with ILCOR guidelines. The Shaare Zedek Medical Center (SZMC), a 850-bed university-affiliated acute care hospital in the Jerusalem district, has since 2003 become the dominant district resuscitation referral center because of its central location and its early implementation of therapeutic hypothermia protocols. Current protocols include cooling of all patients with witnessed VT/VF
Results
Among the 158 patients, 34 (21.5%) died in the ED and an additional 92 (58.2%) died later during admission. Hypothermia was induced in 21 patients. Thirty-two patients (20%) survived to hospital discharge. Survivors were younger, more likely to be men, and included a far higher proportion of patients presenting with VT/VF (Table 1). Median S100B levels at hospital arrival were 2.48 (IQR 0.79–6.75) for survivors and 7.80 (IQR 3.85–16.0) for non-survivors. Median NSE levels were 25.8 (IQR
Discussion
Within the uncertain art of medicine, clinicians, patients and families seek security in the certainty of science. This contrast is most bleak in our dealings with death, where science often fails to provide appropriate tools for prediction of the outcome. Failure in this context is, however, not only related to precision. In fact, it is often associated more with the failure of science to accommodate the diversity of cultural attitudes and beliefs. Thus, use of brain biomarkers for predicting
Conclusions
Predictive models are subject to interpretation and therefore can assist, not replace, clinical decision making. In real life the dilemma lies in the balance between sanctity and quality of life and economic constraints. Decision-assisting tools should enable clinicians and families to jointly select the degree of emphasis they place on either. In this paper we illustrate an approach to develop such a tool for patients after CPR. Using clinical and biomarker data, we created a dynamic nomogram
Authors’ contributions
SE and JDK conceived and designed the study, NK and NA contributed to data acquisition. Data were analyzed by NSL and SE with input from JDK. Interpretation of the data was undertaken by SE and JDK. SE drafted and JDK performed critical revision of the manuscript.
Funding
This study was supported by grant no. 3-00000-3160 from the Chief Scientist Office of the Ministry of Health, Israel. Study design, analyses and interpretation as well as writing of the manuscript and submission for publication were all performed by the authors.
Conflict of interest statement
The authors have no relevant financial information or potential conflicts of interest to disclose.
Acknowledgments
Our deepest thanks to Dr. Heftziba Ivgi who performed the laboratory work and to Hana Amsalem for her valuable assistance in the logistic aspects of this work. We are also indebted to the director of the department of Emergency Medicine, Dr. Todd Zalut, and his staff and to the director of the Cardiac Intensive Care Unit, Dr. Jonathan Balkin, and his staff for their ongoing personal support and willing collaboration throughout the study period.
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A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2013.01.031.