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President's Message - Research in the ICU: It’s What We (Should) Do

Jerry J. Zimmerman, MD, PhD, FCCM,

Most critical care providers recognize the importance of investigation to improve outcomes of critically ill patients,1–3 but actual evidence identifying best practices remains sparse.4 The intensive care unit (ICU) represents an ideal environment for the conduct of clinical research. In addition to the electronic medical record, detailed physiologic monitoring represents usual practice in the ICU. Similarly, biomarker samples and imaging studies, frequently collected in the ICU for clinical decision-making, are also available for research.

Despite this surfeit of resources, clinical research may be less likely in the ICU setting because the high intensity of clinical work may leave little time to pursue investigation. Research in the ICU is uniquely challenging because the environment, the patients’ conditions, and trial design are typically and simultaneously complex.

Effects of this aggregate complexity were demonstrated in an investigation that quantified challenges of enrolling adult patients into research studies.5 Nearly 60% of occasions for recruiting eligible critically ill patients into various investigations were not realized, primarily because of missed opportunities (lack of research staff, expired enrollment window, decisions not to approach) and inability to consent (difficulty in contacting decision-makers, primary physician refusal, prohibition of co-enrollment). Interestingly, as with pediatric clinical research, 90% of adult consent encounters involve surrogate decision-makers. On the other hand, because critical care is expensive and associated with high morbidity and mortality, clinical research involving critically ill patients should be a healthcare priority.6 In addition, intensive care providers’ personalities may be more inclined to action than to investigation. With the ongoing threats of death and disability, there is a need for urgent decision-making, and critical care practitioners may be reluctant to contemplate a (complex) research protocol, preferring clinical decisionmaking based on clinical experience and pathophysiologic plausibility.7

In contrast to research activities in the ICU, in the hematology/oncology or hematopoietic stem cell transplantation units, virtually every patient is enrolled in one or more research protocols. Probably the most convincing example of iterative randomized controlled trials (RCTs) translating into gradual clinical improvements relates to the amazing success story of long-term outcomes for children with acute lymphocytic leukemia (ALL).8 In 1950, ALL was generally fatal within three months. During the following decades, the first chemotherapy trials were initiated.9,10 As a result of gradual improvements in both chemotherapy and supportive care, complete remission rates in children with ALL now approach 99%.11 In fairness, decreased mortality of the cancer patient population has been attributable in part to interventions received in the ICU.12​

Discussion of research as an aspect of standard of practice in critical care would be incomplete without mentioning the potential harm to patients and families of proceeding with empiric practice not founded on rigorous evidence.13 Use of a new technology or device in the realm of standard practice is associated with unknown safety and efficacy, and such practice is not subject to any review. But within a research protocol, patients have the opportunity to make informed choices. When physicians use innovative therapies outside of research, institutional safeguards are typically lacking. A number of therapies that were innovatively introduced subsequently evolved into standards of practice without adequate testing of safety and efficacy and later were found to cause harm.14 Research subjects are typically protected by multiple layers of oversight, unlike everyday ICU patients, who may be subjected to anecdotal experimentation. Patients receiving innovative or so-called compassionate-use therapy have less protection than patients enrolled in an organized research protocol. Accordingly, innovative use of a drug, device, or biologic agent may be riskier to patients than the same use in the context of an appropriately designed and conducted clinical trial.15 It has been argued that the ethics and regulatory requirements for clinical practice, quality improvement, and clinical research should be identical.13 If the relative safety and efficacy of complex therapies in critically ill patients are unknown (due to lack of research), practitioners have an ethical imperative to investigate and identify such knowledge.

Critical care practitioners face two major problems in terms of including their patients in clinical trials, namely, identification of practical, clinically meaningful primary outcome measures and maintenance of relative equipoise regarding the research question. An outcome measure must be accurately determined, easy to record, and responsive to change. Clearly, outcome measures for RCTs must discriminate between the experimental and control arms of the trial and must be carefully considered.16 An outcome should demonstrate a causal relationship to the disease process under study (biological plausibility) and must be clinically relevant to patients, families, and providers. Surrogate outcomes must have direct, valid relationships with clinically meaningful measures.17​

Relatively few RCTs conducted in the ICU setting that have used mortality as a primary outcome measure have shown a beneficial impact of the experimental intervention. Accordingly, there has been an evolving consensus to identify primary end points other than crude differences in all-cause mortality.18–20 In this regard, various measures of long-term health-related quality of life appear promising.21–23 However, numerous methodologic challenges remain for studies examining long-term outcomes; these include patient heterogeneity, premorbid conditions, subsequent uncharacterized insults, variable home environments, lack of follow-up, competing mortality, and the individuality of coping mechanisms.24

Although it has been argued that the critical aspect of equipoise relates to lack of agreement within a relevant clinical or scientific community,25 sometimes when an unstable patient is spiraling toward death or disability, individual physician uncertainty is more likely to be influenced by bias based on anecdote and personal experience.26 For trials involving a placebo arm, attainment of community clinical equipoise as well as individual physician equipoise is essential but often difficult to achieve.27 Only when both community and individual equipoise exist concurrently can an investigation be legitimately conducted with true equipoise.28

The National Institutes of Health’s Roadmap for Medical Research emphasized the need to translate basic research more expeditiously into human studies and to identify appropriate tests and treatments.29 Clinical trials are generally classified into one of two categories: 1) those that test variations of current practices, where the primary hypothesis is based on clinical experience; and 2) those that test fundamentally new concepts, where the primary hypothesis is based on pathophysiology and preliminary investigations.30​

Before conducting a formal RCT, pre-RCT investigations are almost always beneficial for refining various aspects of the research design. This approach typically involves descriptive, epidemiologic, and observational studies. Systematic reviews and meta-analyses may also inform design of large RCTs,31,32 and may be considered the ethical and scientific foundation for all clinical trials.32

Single-center trials predominate because they are logistically easier to conduct, less expensive, do not typically require prolonged negotiation for study design or funding, utilize simplified data collection tools, enroll a less heterogeneous population, permit better planning for definitive trials, and are useful for hypothesis generation.33 Problems with single-center trials frequently include limited external validity, implausible hypothesized effect size, unequal allocation of resources, possible lack of blinding, loss of equipoise for definitive trials, and unwarranted evolution into “standard of care.”33,34 However, launching large, multicenter RCTs without performing pilot, single-center trials would be foolish and wasteful.

Traditionally, the double-blind, placebo-controlled RCT has represented the gold standard of clinical trial design.33 Some have advocated that evidence-based practice should continue to rely on RCTs.30 Given the history of critical care evidence-based medicine, it has been argued that at least two beneficial RCTs are necessary, with at least one of them being a confirmatory trial.35 If results of the clinical trial are destined for dissemination into clinical practice, both the entire intervention as well as the methodologic and clinical contexts of the intervention need to be understood.

There are numerous difficulties in conducting RCTs in critically ill patients.16 If some clinicians view assignment of their patients to a placebo arm as a potential threat, individual physician equipoise will need to be ascertained to ensure a trial’s success; this may require a potential culture shift toward intellectual honesty.

Critically ill patients, even those who have specific syndromes such as severe sepsis or acute respiratory distress syndrome, frequently represent heterogeneous populations. For this reason, a signal from a specific intervention may be more difficult to detect. Critically ill patients commonly receive a variety of concurrent interventions. Typically, these are accounted for by randomization, assuming the sample size is large enough. If not, a post hoc regression analysis may be required to cull out influences of various noncontrolled concurrent interventions. Criticisms of the RCT in this context include homogeneous patient populations, measuring study outcomes that are not important to patients, using protocols that are overly complex and conducted in specialized centers, and using study treatments that are inconsistent with usual care. Although RCTs emphasizing strict protocol adherence are essential for demonstrating the efficacy of a particular approach, they might not address effectiveness in more generalized practice settings.

Comparative effectiveness research involves “generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care.”36 Such observational studies in general are recognized as being inherently limited by indication bias and effects of unmeasured confounding variables.37,38 “Observational research methods cannot escape a key limitation: characteristics of the patient that drive real-life clinical decisions may also influence clinical outcomes leading to uncertainty about whether they or the intervention itself causes the outcomes.”36

The key role of individual clinical research performance sites has been relatively underappreciated. Competing agendas including conflict of commitment, financial pressure, regulatory burdens, risk aversion, and multiple research priorities stress the local research mission and infrastructure.39 Suggestions to address these real impediments to clinical research include instituting a process of clinical research improvement methodology, responding to the actual needs of site-based research, identifying clinical research as a key mission of the institution, establishing a clear process for reviewing and assigning research priorities, and improving local public understanding of the role of clinical research. Meaningful research collaborations between physician-scientist and clinician-educator faculty represents an important mechanism to facilitate clinical/ translational research.40

Increasingly the pharmaceutical and device industries fund the large, expensive, definitive assessment, phase 3 efficacy trials. However, because of commercial motives— actual or potential—bias represents a significant risk to the integrity of such studies.41 Site investigators can maximize the benefit of industry collaboration in clinical research by insisting on the key principles summarized in Table 1. Table 1. Key Principles of Industry Collaboration.42

Improving clinically meaningful patient-centered outcomes should be a goal of all ICU clinical research. Ultimately research must be focused on interventions that both lower costs and improve quality43 in order to increase the value of care provided in the ICU. Critical care practitioners should support the goals of evidence-based medicine and maintain equipoise on important research quests. Unfortunately only a trivial number of critically ill patients are enrolled in clinical trials, while new technologies, drugs, interventions, and treatment plans are constantly implemented.44 To identify and promote optimal care for critically ill patients, researchers need to increase both the number of clinical trials and the number of patients enrolled in such trials.44 In this regard everyone in the ICU can promote the concept of a learning healthcare environment, where clinical care, traditional clinical research, and quality improvement are so integrated and intercalated that they are basically inseparable. Each activity informs and benefits the others, ultimately generating an evidence basis for critical care practice.


References

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