Altered Pharmacokinetics and Pharmacodynamics of Drugs in the Intensive Care Unit
Creators: Hefny, Fatma
Publisher: name: University of Alberta Library
Year: 2023

<p>Critical illness is unique for its complex nature which very often requires a range of professional expertise to provide the most comprehensive care possible, hence the need for a multidisciplinary approach. One of the most important aspects to accurate drug dosing and dose individualization in critically ill patients is their renal function. Especially considering its dynamic changes during treatment warranting multiple dose adjustments. However, hyper-functioning kidneys, known as augmented renal clearance (ARC), which could contribute to therapeutic failures in the intensive care unit (ICU) is often overlooked. Therefore, our research aimed to conduct a systematic review and meta-analysis of prevalence and risk factors of ARC in the critically ill, offering a step towards early identification of those at risk, allowing timely medication optimization. Moreover, ARC alters the disposition of renally eliminated medications currently used in the intensive care unit, resulting in underdosing and potential therapy failure. Our research addresses the rising concern of inadequate dosing in patients with ARC by summarizing the currently available evidence in a narrative review. Our research addressed an example of a life threatening neurocritical care condition, namely aneurysmal subarachnoid hemorrhage (aSAH). Subarachnoid hemorrhage (SAH) results from bleeding in the subarachnoid space often caused by head trauma or more commonly, a ruptured brain aneurysm resulting in aSAH. Delayed cerebral ischemia (DCI)is one of the main complications contributing to unfavorable outcomes in patients with aSAH. Nimodipine is the only drug shown to decrease the incidence of DCI and improve patient outcomes. Various administration techniques are used to facilitate administration through an enteral feeding tube (FT) for patients unable to swallow tablets or capsules. It is not clear whether these techniques of administration are equivalent. Hence, our research aimed to examine if different nimodipine formulations and administration techniques via FT were associated with the safety and effectiveness of nimodipine. <br>
In the first project of our research, we generated a random-effects meta-analytic model and forest plots for a total of 70 studies resulting in a pooled ARC prevalence (95% CI) of 39 % (34.9-43.3). Prevalence for neuro, trauma, mixed and sepsis ICUs were 74 (55-87), 58 (48-67), 36 (31-41) and 33 (21-48), respectively. Age, male sex and trauma were associated with ARC with pooled OR (95% CI) of 0.95 (0.93-0.96), 2.36 (1.28-4.36), 2.60 (1.21-5.58), respectively. This supports our hypothesis that certain critically ill populations will have higher risk of developing ARC more than other cohorts. The results of the second project of our research summarized the extent to which ARC influences the probability of target attainment in several medications requiring dosing changes to mitigate the risk of therapeutic failure. The results demonstrated the need for higher than standard doses and reduced dosing intervals in patients with ARC. These results provide clinicians with a guide to navigate drug dosing requirements for patients with ARC and to anticipate aspects of treatment where deviation from standard dosing regimens could be prudent. With regards to the third project of our research, results from 727 patient records showed that administration of nimodipine oral liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (OR 2.31[1.46 - 3.66] and 3.22[1.61-6.41], for old and new commercially available formulations, respectively). It also showed that bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to blood pressure reduction (OR 2.82[1.57-5.06]). Moreover, tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of DCI (OR 6.66[3.48-12.74] and 3.92[2.05-7.52], respectively). Our findings suggest that different enteral nimodipine formulation and administration techniques are associated with variable propensity for diarrhea, hypotension and DCI and highlights the need to determine the optimal formulation/technique for enteral nimodipine administration. In summary, ARC is a prevalent phenomenon in critically ill adults that alters drug disposition and affects target attainment and the risk of adverse drug reactions. Moreover, neurocritical care and trauma patients are at a higher risk of developing ARC and special attention is prudent when it comes to drug dosing in these subpopulations. Additionally, we concluded that the tolerability and efficacy of nimodipine treatment in aSAH patients is significantly dependent on the method of delivery.</p>