In this issue of Critical Care Medicine, Merck et al (1) report the results of a preplanned sub-analysis of a prospectively collected database from the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) III clinical trial of progesterone versus placebo for moderate and severe traumatic brain injury (TBI). The ProTECT III trial, although a negative study, was a landmark clinical trial in terms of study design. The investigators wisely chose to standardize the critical care management and physiologic goals of all enrolled patients in order to reduce the variability of medical and surgical management other than the treatment group assignments. The trial design included a standardized critical care protocol with physiologic targets and recommended interventions, on-site training of frontline staff, regular review of protocol compliance, and timely feedback to sites with regard to protocol “transgressions.”
These “Clinical Standardization Guidelines” were published with the article as a 13-page appendix (1). They were largely derived from the third edition of the Brain Trauma Foundation guidelines (2), which were released in 2007, supplemented with expert opinion from a clinical standardization team composed of 13 neurologists, neurosurgeons, trauma surgeons, and emergency physicians. The ProTECT III Clinical Standardization Guidelines were finalized in 2010 so they do not reflect more recent changes in the fourth edition of the Brain Trauma Foundation guidelines (3) or the results of recent clinical trials such as Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST:TRIP) (4), European Study of Therapeutic Hypothermia (32–35°C) for Intracranial Pressure Reduction after Traumatic Brain Injury (Eurotherm3235), or Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) (6).
The guidelines included avoidance of hypotension defined by systolic blood pressure less than 100 mm Hg, blood transfusion for hemoglobin less than 8 g/dL, correction of international normalized ratio (INR) greater than 1.4, and maintenance of glucose between 80 and 180 mg/dL, among others. The guidelines also included maintenance of intracranial pressure (ICP) less than 20 mm Hg and brain tissue oxygen tension (PbtO2) greater than 15 mm Hg. One weakness of the study is that, because ProTECT III enrolled patients with moderate as well as severe TBI, only half of patients underwent ICP monitoring and only 18% underwent PbtO2 monitoring.
Study investigators prospectively planned to collect data on an hourly basis for physiologic variables and at least daily for laboratory values, such as platelet count, hemoglobin, and INR using a standard case report form for the study. These data were reported throughout the hospitalization and included duration of time spent in transgression and interventions to address the transgression. The authors evaluated transgressions from the recommended protocol in real-time and provided regular feedback to sites in order to correct these protocol deviations on an ongoing basis. Collection and analysis of this large volume of hourly physiologic data surely required significant labor on the part of the study investigators. Despite these efforts, as described in the article, patients in both treatment groups experienced deviations from the critical care protocol about one-quarter of the time.
The study by Merck et al (1) analyzed the association of transgression frequency and duration of transgression on mortality and functional outcomes using the Glasgow Outcomes Scale-extended. The authors reported strong associations between single transgressions and duration of transgression with higher chance of mortality and worse functional outcomes at 6 months. In multivariable models, the strongest associations with poor outcomes occurred with coagulopathy based on elevated INR, hyperglycemia, anemia, elevated ICP, and systemic hypotension. In the absence of level I or II evidence, the results of the present study lend support for many of the physiologic goals recommended by current guidelines, including the fourth edition of the Brain Trauma Foundation guidelines (3), which form the basis of most contemporary critical care management of severe TBI.
It is important to emphasize, however, that—despite the title of the article—the present study is not a clinical trial of “goal-directed therapy (GDT)” for TBI patients. It is the result of a well-designed observational study of a single cohort that lacked a control group of “usual care” patients or a comparison group managed with a different clinical protocol. Despite the a priori design and planned analysis, the ProTECT III clinical trial was designed to answer a different question related to the effect of progesterone on outcomes after TBI.
Although the present study supplies proof-of-concept data in support of many standard variables for management of TBI patients by showing that deviation from these variables is associated with higher chances of death or disability, it does not prove causation or demonstrate that interventions to correct these “transgressions” improve outcomes. Purpose-designed clinical trials will be necessary to define the optimal clinical protocol for TBI patients by comparing outcomes of patients randomized to undergo one standard protocol compared with those who are randomized to either “usual care” or a different standard protocol.
Given the checkered history of the term “GDT,” the authors showed some bravery in using this term to describe the present study. The term “early GDT” gained popularity based on the impressive results a single-center clinical trial of a “bundle” of interventions based on a standard clinical protocol for early management of sepsis in the Emergency Department (7). Initial enthusiasm for this approach led to the adoption of many of these physiologic goals in clinical guidelines, including the Society of Critical Care Medicine’s “Surviving Sepsis” campaign. Three subsequent clinical trials comparing the “early GDT” protocol with “usual care” (8–10) and a planned meta-analysis of the trials (11) were unable to demonstrate a survival benefit despite a higher number of interventions in the treatment groups.
As other authors have suggested, the major challenge in interpreting the results of the three landmark clinical trials of “early GDT” for sepsis—Protocolized Care for Early Septic Shock (PRoCESS), Australasian Resuscitation in Sepsis Evaluation (ARISE), and Protocolised Management in Sepsis (PRoMISe)—is the potential contamination of the “usual care” group (11). These trials may have been unsuccessful in demonstrating a benefit to the sepsis bundle, in part, because the standard of care had shifted in the usual treatment group based on the Surviving Sepsis campaign itself. For sepsis, in many ways, “early GDT” may have been a victim of its own success.
The results of these trials of GDT in sepsis may hold important lessons for the design of upcoming clinical trials of GDT for TBI. In particular, clinical trials that compare a standard clinical protocol against some nebulous “usual care” group are at high risk to yield negative results, especially when usual care may have been significantly influenced by clinical guidelines and international campaigns like the Brain Trauma Foundation guidelines. Clinical trials that compare groups that are randomized between two separate but equally prescriptive clinical protocols—such as the acute respiratory distress syndrome network clinical trial of lung volume targets (12)—may have a higher chance of yielding interpretable results.
Fortunately, for TBI research, several clinical trials are either underway or recently completed that compare different clinical management protocols using study designs that have yielded readily interpretable clinical information. These have included the aforementioned BEST:TRIP (4), Eurotherm3235 (5), and RESCUEicp trials (6) as well as the Brain Oxygen Optimization in Severe TBI (BOOST) clinical trials of brain tissue oximetry-based treatment protocols. The BOOST phase II clinical trial (13) compared clinical protocols for management of severe TBI based on a combination of ICP and PbtO2 monitoring versus ICP monitoring alone using algorithm-based interventions for each protocol. Based on the promising results of the phase II study, BOOST phase III is scheduled to begin enrollment of patients in spring of 2019.
One significant limitation of the present study is the paucity of data on brain tissue oximetry or multimodality monitoring which could have been used to individualize some aspects of the physiologic goals for these patients. A strength of multi-modality monitoring is that it may provide evidence that some physiologic goals should be either more stringent or more relaxed based on individual patient variables such as intracranial compliance, responsiveness of cerebral oxygen to ICP or body temperature, and/or responsiveness of metabolic markers to serum glucose, for example (14). There is reason to be optimistic that the BOOST phase III clinical trial will provide more guidance to help individualize some of these physiologic goals.
In reviewing clinical trials of “GDT,” other authors have commented on the tension between care that is purely driven by standardized protocols—sometimes denigrated as “cookie cutter” or “one-size-fits-all”—and care pathways that are individualized or customizable based on a patient’s specific characteristics (15). As the authors of the present study state in the Discussion section of the article, “it is likely that a combination of precision based medicine and GDT is the best approach for optimizing individualized care” (1).
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