Chest
Volume 121, Issue 4, April 2002, Pages 1290-1300
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Critical Care Reviews
The Design of Randomized Clinical Trials in Critically Ill Patients

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There are a number of difficulties in the conduct of randomized trials in the critically ill. These include difficulties in the definition of diseases and syndromes, a heterogenous population of patients undergoing a variety of therapeutic interventions, and outcomes that may not be able to discriminate between beneficial and risky therapies. Following a brief description of different randomized clinical trials (RCTs) and design philosophies, we outline the effects of different design choices in the complex critical care environment. Once the study topic has been determined to be relevant and important, then the potential investigator must establish whether efficacy or effectiveness will be the focus of the RCT. If an effectiveness design philosophy is chosen, then broad representation of study sites, liberal eligibility criteria, easily implemented intervention study protocols, and patient-centered outcomes should be chosen. The potential investigator wishing to establish efficacy will conduct the study in the centers of excellence and adopt stringent eligibility criteria, rigorous study protocols, and opt for outcomes that will be sensitive to change. In conclusion, we describe some of the major challenges and possible solutions to help a potential investigator through the myriad of difficulties in initiating an RCT in a complex environment.

Section snippets

What Is Unique About Critical Care RCTs?

A unique aspect of critical care research is that patients' eligibility is primarily defined by location of care in the ICU rather than by the presence of a specific disease. Additionally, many clinical entities in the ICU are often nonspecific constellations of physiologic and biological abnormalities forming syndromes, rather than well-defined disease entities such as breast or lung cancer. Finally, the pathologic processes affecting critically ill patients, resulting in homeostatic

Overall Design Approaches

The ideal RCT establishes whether therapeutic interventions work, and determines the overall benefits and risks of each alternative in predefined patient populations. This is accomplished by minimizing the influence of chance, bias, and confounding through appropriate methodology. In addition, the ideal RCT should attempt to fulfill its objectives with the fewest patients possible (often termed statistical efficiency).12 Unfortunately, these objectives are frequently in direct conflict rather

RCT Design Alternative

Once investigators have chosen whether an efficacy, effectiveness, or a hybrid approach will best answer the research question, there are several design options that may be considered (Table 2).4 A two-group, parallel design is the most common of RCT design choices. In this design, often the simplest to plan, implement, analyze, and interpret, patients are randomly allocated to one of two therapeutic interventions and followed forward in time. Parallel group designs may also be used to

The Patient Population in Critical Care RCTs

One of the difficulties faced by investigators is that potential study participants must usually be admitted to an ICU in order to be considered critically ill. Eligibility or selection of patients based on a location creates difficulties in precisely defining the entry point into the clinical trial. For example, let us assume that an investigator states that patients will remain eligible only for the first 24 h following ICU admission. By adopting a broad definition for the term ICU, the clock

Study Interventions

The complexity and multiplicity of interventions used in the care of critically ill patients present unique challenges for the clinical investigator planning an RCT. In general, as the number of potential interventions increase, available options for the pursuit of optimal patient care exponentially rises. A major consequence of complex care is increased biological variation and practice variation that ultimately increases experimental noise, and thereby makes it more difficult to detect

Outcome Measures

In most clinical trials, a number of potential outcomes, both fatal and nonfatal, are considered by the clinical investigative team. An outcome is defined as a measurement (ie, arterial BP) or an event (ie, death) potentially modified following the implementation of an intervention. If all are given equal consideration, concerns arise about multiple comparisons and interpretation of a study with heterogeneous findings. Thus, it is important to choose a primary outcome that will determine the

Conclusion

In this article on RCTs in the critical care setting, several major RCT design characteristics were discussed. We outlined issues of special interest to critical care investigators related to RCT design approaches, disease definitions, patient selection, study interventions, and outcome measures. Although RCTs provide the most unbiased and accurate assessment of the efficacy and effectiveness of therapeutic and preventive interventions, they remain challenging and expensive to conduct. As more

ACKNOWLEDGMENT

We thank our students, teachers, and colleagues who contributed many of the ideas outlined in this article. We also thank Drs. Peter Tugwell, Andreas Laupacis, and Arthur Slutsky for reviewing this article, and Christine Piché for secretarial support. We also thank our collaborators, without whom many of the studies used as examples in this series would not have been possible.

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