What’s New in Critical Illness and Injury Science? Weighing the evidence for dexmedetomidine dosing in critically ill patients with obesity

Obesity continues to remain a global epidemic demonstrating a significant barrier to therapeutic management. Recent findings from the Centers for Disease Control and Prevention, derived from the National Health and Nutrition Examination Survey conducted between 2017 and 2020, indicate that approximately 42.4% of adults in the United States are affected.[1] The implications of obesity are profound, as it substantially heightens the risk of developing various acute and chronic medical conditions, often resulting in the need for intensive care unit (ICU) admissions. In addition, the critically ill population affected by obesity presents challenging intricacies due to alterations in the pharmacokinetic (relationship between drug dose and body concentration) and pharmacodynamic (the pharmacologic effect of the drug concentration) processes, which are not only affected by patients’ weight but also by various factors, including patient age, the nature of the critical illness, rapid physiological changes, as well as ICU interventions and therapies.[2] Thus, adjustment of medication dosing regimens is expected based on the physiochemistry (hydrophilic or lipophilic) of the used medication.

Obesity is typically defined by a body mass index (BMI) surpassing 30 kg/m². It is subdivided into three classes: Class 1: BMI of 30 to <35, Class 2: BMI of 35 to <40, and Class 3: BMI of 40 or higher, which is sometimes categorized as “severe” obesity.[1] Medication dosing is primarily determined by the patient’s weight and not BMI. However, it is important to note that much of the scientific evidence available on medication dosing focus on the cohorts composed of individuals with normal weight, raising concerns about its applicability to obese patients in general and the severely obese in particular. Thus, the need to address the choice of weight metric to utilize, whether it be actual, ideal, lean, or adjusted weight, to optimize treatment efficacy is essential for appropriate ICU practice.[3]

Within all ICUs, sedation and analgesia or analgosedation are routinely employed to enhance patient care, safety, and comfort. The approach to sedation has evolved over time, with the Society of Critical Care Medicine 2018 guidelines advocating for light sedation levels, incorporating daily awakening trials, and favoring the use of propofol or dexmedetomidine (DEX) over benzodiazepines to yield improved short-term outcomes.[4] Indeed, the utilization of DEX has gained popularity across all critically ill populations, including those with neurologic critical illnesses, albeit a medication that has now been in use for almost 24 years. As an alpha-2 adrenergic agonist, with a unique pharmacological profile, characterized by sedation, hypnosis with preserved degree of arousability simulating natural sleep and anxiolysis, coupled with minimal respiratory depression makes DEX an attractive choice for various clinical scenarios.[5] The use of DEX in ICUs has been associated with a shorter time to liberation from mechanical ventilation,[6] reduced incidence of agitated delirium,[7] and even prevention of delirium.[8] In a recently published systematic review and meta-analysis of 77 randomized clinical trials that included 11,997 critically ill patients, the use of DEX compared to other sedation regimens was associated with a decreased risk of delirium, more time at target sedation, and a modest reduction in the duration of mechanical ventilation and ICU length of stay.[9] However, DEX is more expensive than its benzodiazepine and gamma-aminobutyric acid (GABA) inhibition competitors, thus beckoning the question of how one optimizes effective sedation with this medication without overuse.

In this issue of IJCIIS, He et al. describe a single-center study evaluating DEX use in a neurocritical care unit comparing dosing by actual body weight (ABW) versus adjusted body weight (AdjBW).[10] Undeniably, the data regarding the pharmacokinetics of DEX in neurocritical care are limited, let alone devoid in patients with obesity. In a qualitative systemic review investigating the role of DEX for sedation in critically ill neurologically injured patients, only eight trials, including three randomized controlled trials and five observational studies, enrolling 650 patients, were selected and showed that DEX may provide better sedation and reduced analgesic requirements when compared to sedation with propofol or midazolam.[11] Unfortunately, none of the included studies focused or commented on the obese neurologically injured patient.

Thus, this study by He et al. is not only timely but also builds on known pharmacokinetics and dynamics from the literature.[10] We know that DEX exhibits rapid systemic distribution, is highly protein-bound with estimates of up to 94% binding to albumin and α1-glycoprotein, and is lipophilic in nature, which makes its volume of distribution much higher in the obese population that further contributes to its multifaceted pharmacokinetic profile.[5] Yet, our studies do not reflect all populations in safety and efficacy clinical trials, especially for DEX as the volume of distribution exhibits considerable variability, particularly in critically ill patients, ranging from 109 to 233 L.[12-14] This wide range of distribution, influenced by factors such as vasopressor use and hypoalbuminemia, complicates the determination of optimal dosing regimens in critically ill patients, particularly in the context of obesity. In addition, DEX is affected by blood flow since it undergoes primary hepatic transformation, followed by renal excretion, which in turn impacts the clearance of the drug.[15] Notably, in a study involving morbidly obese patients undergoing elective laparoscopy, pharmacokinetic parameters were found to be significantly altered when compared to patients with normal weight. Peak plasma concentration, elimination half-life, and apparent volume of distribution were all higher in obese patients, while drug clearance, when normalized to ABW, was significantly lower.[15] These findings highlight the importance of considering obesity-related alterations in pharmacokinetics when dosing DEX for critically ill obese patients. It is worth noting that the elevated serum concentrations of DEX can induce hemodynamic disturbances, particularly bradycardia and hypotension, as commonly observed side effects,[5] thus the need to use the smallest possible dose to achieve the desired level of sedation.

Understanding the pharmacokinetic intricacies of DEX in obese patients is crucial for optimizing sedation management. In the study by He et al.,[10] the authors investigated the effectiveness of DEX as a single agent in achieving a predetermined sedation goal (Richmond Agitation-Sedation Scale (RASS) −1 to +1 range) using ABW compared to AdjBW in patients whose weight exceeds 120% of their ideal body weight (IBW). The group’s main findings were that there was no difference between the two cohorts, one that is neither unexpected nor surprising. First, the patients in both groups were <100 Kg meaning that dosing for both groups was similar. To illustrate, for a 100 Kg person (IBW 70 Kg) in the ABW versus AdjBW groups, initial dosing would roughly equate to 20 versus 16.4 μg/h. This difference in dosing is not tremendously significant between the two groups, although it does beckon if the patients had a higher BMI (ABW > 100) and perhaps lead to changes in goal RASS acquisition. Another key consideration in this study is the significant variability in the number of RASS measurements obtained, suggestive of variability in dose titration required for each individual patient. Last, although there was no difference in the safety outcomes reported, DEX was more frequently discontinued in the ABW cohort due to either bradycardia or hypotension. This latter finding is even more surprising given the minuscule difference in dose between the groups.

There are some interesting hypotheses-generating findings in this small study, including preliminary evidence that DEX dosing based on AdjBW is apparently at least as effective as ABW. Whether this finding is verified in larger, multicenter trials of neurocritical care patients with higher BMIs remains to be seen. Undeniably, the potential to use fewer drugs to attain the same desired clinical effect, especially in larger patients, could potentially translate into financial savings for hospitals. As a descriptive study and at a minimum, the importance of this report by He et al.,[10] challenges weight-based dosing strategies in obesity. Nonetheless, this is a single-center report and should be evaluated in this context only.

As the population ages and increases in physical size, the optimal dosing titrated to the effect is paramount to successful therapeutic efficacy and safety. Given the significant alterations in drug distribution, metabolism, and elimination, the standard weight-based dosing guidelines may be insufficient. Precision dosing strategies using lean or IBW should be considered to account for the unique physiological characteristics of obesity as well as derangements of critical illnesses. We should weigh the benefits and harms of each of these approaches and design phase 2–4 clinical trials to reflect these unique differences in populations. With these appropriately designed studies, we will be invariably providing a common ICU population with the best equitable and proper therapeutic intervention. Improved research and targeted quality improvement measures are warranted to elucidate the precise pharmacokinetic changes associated with DEX in obesity, enabling clinicians to provide safer and more effective sedation regimens for this growing patient population.

Research quality and ethics statement

This report was exempt from the requirement of approval from the Institutional Review Board/Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines; however, no specific guideline is available for editorials.