Chest
Critical Care ReviewsThe Design of Randomized Clinical Trials in Critically Ill Patients
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.
References (62)
- et al.
Rules of evidence and clinical recommendations on the use of antithrombotic agents
Chest
(1992) - et al.
Surgeon-related variables and the clinical trial
Lancet
(1978) - et al.
Should morbidity replace mortality as an endpoint for clinical trials in intensive care?
Lancet
(1995) - et al.
Effect of bronchodilators on lung mechanisms in the acute respiratory distress syndrome (ARDS)
Chest
(1994) - et al.
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis
Chest
(1992) - et al.
Blood transfusion and constituent transfusion
Curr Opin Immunol
(1989) - et al.
Research design and analysis: the many faces of validity
J Crit Care
(1991) - et al.
A methodological framework for assessing health indices
J Chronic Dis
(1985) - et al.
Changes in study design, gender issues, and other characteristics of clinical research published in three major medical journals from 1971 to 1991
J Gen Intern Med
(1995) - et al.
Clinical epidemiology: a basic science for clinical medicine
(1991)
Users' guides to the medical literature. II: How to use an article about therapy or prevention; A. Are the results of the study valid?
JAMA
Fundamentals of clinical trials
The clinical trial
Br Med Bull
The clinical trial
N Engl J Med
Statistical methods of clinical and preventive medicine
Pitfalls in randomized surgical trials
Surgery
The competing objectives of randomized trials
N Engl J Med
Controversy in counting and attributing events in clinical trials
N Engl J Med
Large trials with simple protocols: indications and contraindications
Control Clin Trials
Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome
Am J Respir Crit Care Med
Transfusion requirements in critical care: a pilot study
JAMA
A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care
N Engl J Med
A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58, 050 patients with suspected acute myocardial infarction: ISIS-4
Lancet
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2
Lancet
Treatment of septic shock with human monoclonal antibody HA-1A: a randomized, double-blind, placebo-controlled trial
Ann Intern Med
Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial
N Engl J Med
Recombinant human interleukin-1 receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized double-blind, placebo-controlled trial
JAMA
Sepsis therapy trials: continued disappointment or reason for hope?
JAMA
Efficacy and safety of recombinant human activated protein C for severe sepsis
N Engl J Med
Aspirin, heparin, or both to treat acute unstable angina
N Engl J Med
Sequential experimentation
Cited by (49)
Lantibiotics: the way forward for clinical trials and clinical approval process
2023, Lantibiotics as Alternative TherapeuticsSelection Bias in Observational Studies of Palliative Care: Lessons Learned
2021, Journal of Pain and Symptom ManagementCitation Excerpt :Palliative care (PC) is consistently associated with improved patient and caregiver outcomes, but evaluations of cost savings are inconclusive.5–10 Although randomized controlled trials (RCTs) are the gold standard for causal inference, achieving this standard poses financial, ethical, and logistical challenges for seriously ill patients.11 PC programs are typically evaluated using observational data, raising concerns about selection bias and the appropriate definition of comparison groups.
Clinical trials in critical care
2013, Oh's Intensive Care Manual, Seventh EditionBias reduction in repeated-measures observational studies by the use of propensity score: The case of enteral sedation for critically ill patients
2012, Journal of Critical CareCitation Excerpt :This is because of some intrinsic and structural problems: lack of reliable nosography, concomitant use of different therapies, problems in the definition of end points besides mortality, ethical issues arising with randomization to potentially life-saving treatments, or even the admission to intensive care unit (ICU) itself [4]. Moreover, a unique aspect of critical care research is that patients' eligibility is frequently defined by ICU admission rather than by the presence of a specific disease [5,6]. Further challenges are represented by the lack of tradition of large ICU networks, difficulties in linking or integrating physiologic and therapeutic objectives in designing clinical protocols, and scarcity of independent or nonprofit funds.
Vasopressors and the search for the optimal trial design
2011, Contemporary Clinical TrialsCitation Excerpt :One of the earliest randomised control trials (RCTs) was performed in 1948 [1].
Drs. Hébert and Cook are Career Scientists of the Ontario Ministry of Health.