Commentary and concepts“Resuscitation time bias”—A unique challenge for observational cardiac arrest research☆
Introduction
Observational studies play an important role in cardiac arrest research. They are particularly important in this setting as randomized clinical trials might not be feasible for answering questions about cardiac arrest. This can be due to the complexity of consent and randomization during acute events, the relative rarity of cardiac arrests, and/or requirements for very large sample sizes due to patient heterogeneity and relatively modest treatment effects. Unfortunately, observational studies suffer from a number of potential biases. In addition to the well-known bias introduced by confounding, selection bias and information bias may also be present [1].
Multiple methods have been developed to address the potential bias introduced by confounding (e.g. stratification, regression models, matching) and these are often used in observational studies. Other biases are less often explicitly addressed in observational studies. One potential bias that is often overlooked is “immortal time bias” [2]. This bias occurs when the outcome (most often mortality) cannot occur because exposure is defined in a way which implicitly assumes, but often does not acknowledge, that patients are essentially “immortal” until they receive the exposure [2].
A less well-known and described bias pertains to observational studies of exposures (e.g. drugs, airway management) during cardiac arrest. In this situation, an exposure is more likely to occur the longer the cardiac arrest continues. Since length of resuscitation is strongly associated with worse outcome [[3], [4], [5]], this will tend to bias the results toward a harmful effect. This bias can be considered the reverse of immortal time bias and will be termed “resuscitation time bias” in the current manuscript.
The aim of this manuscript is to provide a brief overview of immortal time bias with respect to cardiac arrest research and a comprehensive discussion related to resuscitation time bias. This includes a brief overview of the theoretical framework, real-word examples, and potential methods to deal with this type of bias. We hope this manuscript will provide a better understanding of these types of biases and provide a framework for future observational studies assessing intra- and post-cardiac arrest interventions.
Section snippets
Immortal time bias
Immortal time bias occurs because exposure in observational studies is not defined at a discrete time point but rather occurs at some point over a period of time. As such, those who receive the exposure are, by definition, alive for the period of time until they receive the exposure. In contrast, those patients who die early will have a much lower likelihood of receiving the exposure. This biases the results towards a beneficial effect of the exposure [2].
Immortal time bias is pertinent to many
Resuscitation time bias
While immortal time bias is an issue when analyzing post-cardiac arrest interventions in observational studies, a related problem arises when assessing intra-cardiac arrest interventions. This problem, which we term “resuscitation time bias” occurs because interventions during cardiac arrest (e.g. drug administration, endotracheal intubation) are related to time in three ways. First, interventions are more likely to be implemented the longer the duration of the cardiac arrest, i.e. the length
Methods to deal with immortal and resuscitation time bias
There are various methods to deal with the potential biases discussed above. A common and simple method for partly addressing immortal time bias in post-cardiac arrest studies is to restrict the population to those surviving to a certain timepoint after ROSC (e.g. 24 h after ROSC as in the TTM study discussed above [10]). As shown above, this somewhat deals with the problem but is not always an ideal solution since patients who could have potentially benefitted from the intervention might have
Conclusion
This manuscript has discussed immortal time bias and a related bias which we have termed resuscitation time bias. Both are relevant for cardiac arrest research although the latter represents a challenge that is unique to this patient population. Future observational research should aim to address these biases analytically or acknowledge these issues in the limitations when not possible. Hopefully, addressing these biases will provide for a more valid interpretation of observational research and
Conflict of interest statement
None of the authors have any conflicts of interest.
References (30)
- et al.
Intubation is not a marker for coma after in-hospital cardiac arrest: a retrospective study
Resuscitation
(2017) - et al.
Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study
Lancet
(2012) - et al.
European Resuscitation Council guidelines for resuscitation 2015: section 11. The ethics of resuscitation and end-of-life decisions
Resuscitation
(2015) - et al.
Outcome when adrenaline (epinephrine) was actually given vs: not given–post hoc analysis of a randomized clinical trial
Resuscitation
(2012) - et al.
Modern epidemiology
(2008) Immortal time bias in pharmaco-epidemiology
Am J Epidemiol
(2008)- et al.
A validated prediction tool for initial survivors of in-hospital cardiac arrest
Arch Intern Med
(2012) - et al.
Duration of prehospital resuscitation efforts after out-of-Hospital cardiac arrest
Circulation
(2016) - et al.
The association between duration of resuscitation and favorable outcome after out-of-hospital cardiac arrest: implications for prolonging or terminating resuscitation
Circulation
(2016) - et al.
Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes
BMJ
(2010)
Examining bias in studies of statin treatment and survival in patients with cancer
JAMA Oncol
Immortal time bias in critical care research: application of time-varying Cox regression for observational cohort studies
Crit Care Med
Understanding immortal time bias in observational cohort studies
Anaesthesia
American Heart Association’s get with the guidelines-resuscitation I. Association between therapeutic hypothermia and survival after in-hospital cardiac arrest
JAMA
Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry
Circ Cardiovasc Interv
Cited by (0)
- ☆
A Spanish translated version of the abstract of this article appears as Appendix in the final online version at https://doi.org/10.1016/j.resuscitation.2018.02.006.