Bioavailability or just availability? How the national propofol shortage example may transform tenets of critical care management.

F or generations, clinical pharmacology in critical care centered on the idea that drugs were chosen for a certain condition or indication relative to their efficacy, pharmacodynamics, pharmacokinetics, bioavailability, or actions on distinct receptors. Most critical care physicians likely have vivid recollections of their formative years when learned mentors would insist, in painstaking detail, that a specific vasoactive agent was better at generating a desired effect because of a certain pharmacologic principle or property. However, in this decade, the ostensible epidemic of shortages of various drugs that are fundamental in our profession are forcing 21st-century clinicians to choose a particular medicament simply because it is the only one available. In just this year alone, critical care practitioners have seen shortages in the vital life-sustaining pharmacologic vasoactives (e.g., norepinephrine, phenylephrine, vasopressin, nitroglycerin), intravenous phosphate electrolyte replacements as well as sedatives, analgesics, and neuromuscular blockers (1). Drug shortages on this nonexhaustive list occur for a multitude of reasons, including manufacturing difficulties, quality control issues, and the realities of marketplace de-emphasis of off-patent pharmaceuticals (2, 3). Interestingly, despite traditional cogitation, discussion, and dogmatic pedantics about whether one medication is better than another for a clinical situation, it may end up that in many cases it does not really make that big of a difference after all. In this issue of Critical Care Medicine, Roberts et al (4) report their findings on whether the recent national shortage of propofol had any impact on the duration of mechanical ventilation. In a single-academic-center retrospective analysis of 281 intensive care unit patients mechanically ventilated for 48 hrs and receiving continuously infused sedatives for intensive care unit care 24 hrs, a cohort of 153 patients before the national propofol shortage were compared with 128 patients after the shortage relative to sedative choices and ventilation strategies (4). The number of patients receiving 24 hrs of propofol in the after-group was 84% less than in the before-group. Although in an unadjusted analysis there was a statistical prolongation of mechanical ventilation in the after-group, when subjected to a multivariable linear regression, only admission to a medical service, severity of illness as measured by Acute Physiology and Chronic Health Evaluation II score (5), and use of pressure-controlled ventilation achieved a statistical difference between groups (4). Propofol has been available as a sedative for intensive care unit patients since the mid-1990s. Although there are rare side effects (6), for the most part, propofol has achieved arguably a canonical status in critical care for its titratability, short half-life, and overall efficacy. Thus, when the drug suddenly becomes unavailable, there are concerns that substantial detriments in patient care may result. As the study by Cooper et al (4) demonstrated, not only was there a statistically significant increase in infusions of longer-acting sedatives (e.g., lorazepam, midazolam), but also a significantly higher use of neuromuscular-blocking infusions (4). That the use of these alternative agents did not result in statistical lengthening of mechanical ventilation is a testament to the importance of flexibility and adaptability in the overall care process, clearly clinical behaviors adjusted at a multidisciplinary level to otherwise offset the expected effect. Will the findings in the current study, coupled with continued ongoing shortages of other drugs, lead to further experimental reassessments of long-held tenets that currently guide clinical decisionmaking? Historically, dogmatic beliefs are hard to change, even with evidence-based substantiation to the contrary. Consider the example of a study published over 20 yrs ago by Cooper et al (7), which demonstrated in a prospective, randomized, blinded, crossover trial that correction of acidemia using bicarbonate vs. saline in vasopressordependent critically ill patients with lactic acidosis did not improve hemodynamics. Although the study categorically shattered the long-held notion that acidemic conditions must be attenuated to achieve vasopressor efficacy, it is very likely that most clinicians either remain unaware or still hold to and teach others this long-held belief. The difference now, as compared with 20 yrs ago, is that physicians finding themselves in perceived untenable situations as a result of the inaccessibility of heretofore ubiquitous drugs may in fact be forced into reappraisals of clinical tenets. Indeed, such changes in pharmacologic considerations may well lead to other alterations in critical care along the “less is more” style that has befallen treatment strategies for mechanical ventilation (8), invasive monitoring (9), and gastrointestinal prophylaxis (10). On the other hand, it may be a stretch to draw transformative conclusions about patient care practices and clinical decisionmaking based on one single-center, retrospective study. The authors readily acknowledge that they cannot exclude the possibility that there were some unrecognized or unverifiable effects on mechanical ventilation duration as a result of the limitations of their investigation. In addition, the lack of standardized *See also p. 406.