Safety and efficacy of fixed versus variable-dose prothrombin complex concentrate for emergent reversal of vitamin K antagonists: A systematic review and meta-analysis.

STUDY OBJECTIVE: Four-factor prothrombin complex concentrate (4F-PCC) is standard of care for emergent vitamin K antagonist (VKA) reversal but optimal dosing is uncertain. This meta-analysis estimated the proportion of patients treated with fixed dose (FD) 4F-PCC who achieved adequate reversal and compared safety and efficacy of FD versus weight-based dose (WB) strategies. METHODS: This review was conducted according to PRISMA guidelines. Medline and Scopus were searched and included studies evaluating FD regimens and comparing FD and WB for emergent VKA reversal. Data was pooled using random effects. Subgroup analyses examined heterogeneity. Risk of bias was assessed with Newcastle-Ottawa Scale and RoB2 score. RESULTS: Twenty-three studies (n = 2055) were included with twelve (n = 1143) comparing FD versus WB. The proportion of patients achieving goal INR with FD varied depending on the INR target, being significantly higher for INR <2 (90.9%, 95% Confidence Interval (CI) 87.2, 94.06) compared to INR <1.6 (70.97%, 95%CI 65.33, 76.31). Compared to WB, FD was less likely to achieve a goal INR <1.6 (Risk Difference (RD) -13%, 95% CI -21, -4) but achieved similar reversal for a goal INR <2.0, (RD -1%, 95%CI -7, 4). There was no difference in hospital mortality (RD 4%, 95%CI -2, 9) or thrombosis (RD 0.0%, 95%CI -3, 3). CONCLUSION: FD VKA reversal was associated with significantly lower attainment of goal INR compared to WB with lower INR targets. This did not translate to differences in hospital mortality, but these results should be interpreted cautiously in light of the observational nature of the included studies.

Inactivated Four-Factor Prothrombin Complex Concentrate Dosing Practices for Reversal of Warfarin-Related Intracranial Hemorrhage.

BACKGROUND/OBJECTIVE: Inactivated four-factor prothrombin complex concentrate (I4F-PCC, Kcentra®) has become an important agent for the urgent or emergent reversal of bleeding associated with vitamin K antagonists such as warfarin. There is recognized inter-institutional variability with the use of I4F-PCC, especially as it relates to dosing practices. We sought to characterize variations in I4F-PCC dosing practices and their impact on patient outcomes and describe overall real-world clinical practice surrounding I4F-PCC utilization in the context of the management of warfarin-related intracranial hemorrhage (ICH). METHODS: This is a multicenter retrospective pragmatic registry study of adult patients admitted at a participating study site between January 1, 2014, and December 31, 2015, who received I4F-PCC for reversal of warfarin-related ICH. Practices around warfarin-related ICH reversal in context of I4F-PCC utilization are described, including repeat I4F-PCC dosing, adjunctive reversal agents, and dose rounding policies (i.e., rounding doses to nearest vial size vs preparing exact/unrounded doses). All research was approved by local human investigation committees at each institution. RESULTS: Seventeen institutions contributed data on 528 patients to this registry. These institutions were primarily urban centers (74%), located in the southeast USA (47%), with Level 1 Trauma designation (79%), and with Comprehensive Stroke Center designation (74%). Most patients included in the study had sustained a non-traumatic ICH (68%), had a median admission GCS of 14 (IQR 7-15), and were receiving warfarin for atrial fibrillation (57.4%). There was substantial time latency between baseline INR and I4F-PCC (median 2.4 h, IQR 1.4-4.5 h). Most patients received adjunctive reversal agents, including vitamin K (89.5%) and fresh frozen plasma (FFP) (31.9%). A smaller proportion (6.0%) of patients received repeat I4F-PCC dosing. The median ICU length of stay (LOS) was 3 days (IQR 2-7 days), median hospital LOS was 6 days (IQR 3-12 days), and overall mortality rate was 28.8%. For institutions rounding doses to the nearest vial size, the first post-I4F-PCC dose INR was statistically but not clinically significantly lower than for institutions without vial size dose rounding, with comparable degrees of INR reduction from baseline. No differences were observed between dose rounding cohorts in adverse effects, ICU or hospital LOS, modified Rankin score at discharge, or mortality rates. CONCLUSIONS: Most patients received single doses of I4F-PCC, with adjunctive reversal agents and rounding doses to vial size. The time difference from baseline INR to factor product administration is a potential opportunity for process improvement in the management of warfarin-related ICH.

Accuracy of Valproic Acid Concentration Correction Based on Serum Albumin.

BACKGROUND: Patient-specific factors can alter the pharmacokinetic disposition of valproic acid. Specifically, the free fraction of valproic acid can increase substantially in patients with hypoalbuminemia or as serum drug concentrations rise due to saturable protein binding. Direct measurement of free serum drug concentrations allows for accurate assessment of drug levels, but the assay may not be readily available in all institutions. The effect of hypoalbuminemia on free fraction has been quantified and serves as the basis of an equation used to "correct" measured total valproic acid concentrations. The aim of this study was to evaluate the accuracy of the equation. METHODS: This retrospective study included adult patients with measurable free and total valproic acid concentrations between July 2014 and June 2017. The primary aim was to assess the relationship between measured and predicted free valproic acid concentrations. Free levels were categorized as subtherapeutic, therapeutic, or supratherapeutic based on the reference range of 7-23 mg/L. Concordance was defined as measured and predicted concentrations falling within the same category. RESULTS: The analysis included 174 patients with a median age of 58 years and a median albumin of 3 g/dL. The majority of patients were hospitalized (88.5%). Concordance occurred in 56.9% of samples. A Spearman's correlation coefficient of 0.60 (p < 0.001) was found between the measured and predicted free valproic acid concentrations. Concordance of concentrations was 42% for ICU patients, 63% for floor patients, and 65% for outpatients. Of those with discordant concentrations, 97% of the predicted concentrations underestimated the measured concentrations. CONCLUSIONS: There is discordance between predicted and measured free serum valproic acid concentrations when using the proposed equation. Because of the potential impact of underestimation and variability of free valproic acid concentrations, a measured free level is the ideal option for therapeutic drug monitoring of valproic acid.

Current Practices of Intraventricular Antibiotic Therapy in the Treatment of Meningitis and Ventriculitis: Results from a Multicenter Retrospective Cohort Study.

BACKGROUND: Central nervous system (CNS) infections are particularly prevalent in the adult neurocritical care patient population and are associated with significant morbidity and mortality. Factors relevant to the nature of CNS infections pose significant challenges to clinicians treating afflicted patients. Intraventricular (IVT) administration of antibiotics may offer several benefits over systemic therapy; however, the outcomes and current practices of such treatments are poorly described in the literature. OBJECTIVE: To describe current practices and outcomes of patients receiving intraventricular antibiotic treatment for CNS infections in neurological intensive care units of academic medical centers nationwide. METHODS: A retrospective cohort study was conducted on patients admitted to intensive care units who received IVT antibiotic treatment at participating centers in the USA between January 01, 2003, and December 31, 2013. Clinical and laboratory parameters, microbiology, surgical and antimicrobial management, and treatment outcomes were collected and described. RESULTS: Of the 105 patients included, all received systemic antimicrobial therapy along with at least one dose of IVT antimicrobial agents. Intraventricular vancomycin was used in 52.4% of patients. The average dose was 12.2 mg/day for a median duration of 5 days. Intraventricular aminoglycosides were used in 47.5% of the patients, either alone or in combination with IVT vancomycin. The average dose of gentamicin/tobramycin was 6.7 mg/day with a median duration of 6 days. Overall mortality was 18.1%. Cerebrospinal fluid (CSF) culture sterilization occurred in 88.4% of the patients with a rate of recurrence or persistence of positive cultures of 9.5%. CONCLUSION: Intraventricular antimicrobial agents resulted in a high CSF sterilization rate. Contemporary use of this route typically results in a treatment duration of less than a week. Prospective studies are needed to establish the optimal patient population, as well as the efficacy and safety of this route of administration.

Critical Care Management of Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVES: Anti-N-methyl-D-aspartate receptor encephalitis is considered an immune-mediated form of encephalitis with paraneoplastic and nonparaneoplastic forms. Delay in recognition is common and patients typically present to the ICU without a diagnosis or with complications following a delayed diagnosis. The aim of this review is to provide a focused overview for the ICU clinician regarding presentation, diagnosis, and critical care management. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: PubMed database search with manual review of articles involving anti-N-methyl-D-aspartate receptor encephalitis. DATA SYNTHESIS: Anti-N-methyl-D-aspartate receptor encephalitis is increasingly encountered in the ICU. The cascade of events initiating anti-N-methyl-D-aspartate receptor antibody formation may involve an infectious trigger particularly in the setting of teratoma. Following a prodrome, most patients develop psychiatric symptoms followed by movement disorder. Classical, psychiatric, and catatonic phenotypes may be distinguished based on the presence and severity of symptoms. Early immunotherapy and low initial cerebrospinal fluid inflammation are independent predictors of positive outcomes in ICU patients. Concomitant organ failure, status epilepticus, and the identification of a tumor did not influence outcome in critically ill patients. Supportive care in the ICU includes management of various manifestations of dyskinesia, status epilepticus, autonomic disorders, and the need for general sedation. Common treatment strategies and limitations are discussed including the emerging role of bortezomib. CONCLUSIONS: Intensivists should be familiar with the presentation and management of anti-N-methyl-D-aspartate receptor encephalitis. Early diagnosis and immediate implementation of steroids, immunoglobulins, and/or plasmapheresis and immune therapy are associated with a good neurologic outcome although response may be delayed. The selection and timing of second-line immune therapy requires further study.

Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG(®)) to guide decision-making.

Novel oral anticoagulants present challenges and uncertainties in the management of hemorrhagic emergencies. An 84-year-old man taking dabigatran presented with a subdural hematoma requiring neurosurgical intervention. Routine coagulation assays were prolonged at admission and following administration of Factor VIII Inhibitor Bypassing Activity (FEIBA). Thromboelastography (TEG(®)) was utilized to assess clot dynamics prior to placement of a subdural drain, which was safely inserted despite a prolonged thrombin time (TT). Exclusive reliance on the TT may delay necessary interventions. TEG(®) may be a valuable tool to investigate hemostasis in patients on dabigatran requiring emergent procedures.

Pain Assessment Following Opioid Administration in Aneurysmal Subarachnoid Hemorrhage Associated Headache.

Background: Headache is a debilitating complication following an aneurysmal subarachnoid hemorrhage (aSAH). Despite its impact on morbidity and quality of life, limited evidence characterizes the effectiveness of opioids. Objective: The aim of this study was to evaluate opioid associated reduction in pain scores in patients with aSAH-associated headache. Methods: This is a retrospective study of adult patients with an aSAH, Hunt and Hess grades I - III, admitted to a neurosciences intensive care unit. Descriptive and inferential statistics were used to characterize headache treatment strategies and opioid associated reduction in pain scores. Results: Opioids were used in up to 97.6% of patients for the management of aSAH-associated headache. Median reduction in pain after opioid administration was -1 (IQR: -3-0). Correlation between opioid dose and change in pain scores was negligible (rs = .01). Overall, 68.8% of patients were discharged on an opioid analgesic with predictive factors being severe headache (OR 2.52; 1.04 - 6.14) and oral morphine milligram equivalents ≥60 mg per day during the hospital stay (OR 3.02; 1.22 - 7.47). Conclusions: Opioids were associated with a small reduction in pain when assessed via the NRS. An increased opioid dose did not correlate with a greater reduction in assessed pain scores. A high percentage of patients remained on opioids throughout hospitalization and were eventually discharged on an opioid. The impact of discharge opioid prescriptions and risk of opioid persistence creates a cause for concern. It is imperative that we seek improved pain management strategies for aSAH-associated headache.

High-osmolarity saline in neurocritical care: systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Intracranial hypertension and cerebral edema are known contributors to secondary brain injury and to poor neurologic outcomes. Small volume solutions of exceedingly high osmolarity, such as 23.4% saline, have been used for the management of intracranial hypertension crises and as a measure to prevent or reverse acute brain tissue shifts. We conducted a systematic literature review on the use of 23.4% saline in neurocritically ill patients and a meta-analysis of the effect of 23.4% saline on intracranial pressure reduction. DESIGN: We searched computerized databases, reference lists, and personal files to identify all clinical studies in which 23.4% saline has been used for the treatment of neurocritical care patients. Studies that did not directly involve either effects on cerebral hemodynamics or the treatment of patients with clinical or radiographic evidence of intracranial hypertension and/or cerebral swelling were eliminated. MEASUREMENTS AND MAIN RESULTS: We identified 11 clinical studies meeting eligibility criteria. A meta-analysis was performed to evaluate the percent decrease in intracranial pressure and the 95% confidence intervals, from baseline to 60 minutes or nadir from the six studies from which this information could be extracted. A fixed effects meta-analysis estimated that the percent decrease in intracranial pressure from baseline to either 60 minutes or nadir after administration of 23.4% saline was 55.6% (se 5.90; 95% confidence interval, 43.99-67.12; p < 0.0001). CONCLUSIONS: Highly concentrated hypertonic saline such as 23.4% provides a small volume solution with low cost and an over 50% reduction effect on raised intracranial pressure. Side effects reported are minor overall in view of the potentially catastrophic event that is being treated. High quality data are still needed to define the most appropriate osmotherapeutic agent, the optimal dose, the safest and most effective mode of administration and to further elucidate the mechanism of action of 23.4% saline and of osmotherapy in general.

Failed mechanical thrombectomy: prevalence, etiology, and predictors.

OBJECTIVE: Despite advances in endovascular techniques, mechanical thrombectomy (MT) fails to achieve successful reperfusion in approximately 20% of patients. This study aimed to identify common etiologies and predictors of failed thrombectomy in a contemporary series. METHODS: A prospectively maintained database of MT patients between January 2013 and August 2021 was interrogated. Failed MT was defined as a final modified Thrombolysis in Cerebral Infarction score < 2b. Demographic data, procedural details, stroke etiology, and anatomical data in patients who underwent MT with subsequent failed reperfusion were collected. RESULTS: Of a total 1010 MT procedures, 120 (11.9%) were unsuccessful. The mean patient age was 66.8 years; 51.5% of patients were male, and 61.1% were White. The most common failure location was intracranial (93.3%) followed by failure at the arch (3.3%) and neck (3.3%). Among patients with intracranial failure, underlying intracranial atherosclerosis (ICAS) was the cause of failure in 84 patients (70%). Compared with patients with successful MT, patients with failed MT had a longer onset to puncture time (p = 0.012) and onset to groin time (p = 0.04). Rescue stenting was performed in 45 cases: 39 patients (4.4%) with successful MT and 6 (5.0%) with MT failure (p = 0.765). Multivariate analysis demonstrated that diabetes mellitus (p = 0.009) was independently associated with unsuccessful reperfusion. CONCLUSIONS: Failed MT was encountered in approximately 12% of MT procedures. The most common cause of failed MT was underlying ICAS. Further studies to evaluate better ways of early identification and treatment of ICAS-related large-vessel occlusion are warranted.

Characterization of Opioid Use in the Intensive Care Unit and Its Impact Across Care Transitions: A Prospective Study.

PURPOSE: The objective of this study is to characterize opioid intensity in the intensive care unit (ICU) and its association with opioid utilization across care transitions. METHODS: This is a prospective cohort study. Medically ill ICU patients with complete medication histories who survived to discharge were included. Opioid intensity was characterized based on IV morphine milligram equivalents (IV MME). Primary outcomes were opioid prescribing upon ICU and hospital discharge. RESULTS: Opioids were prescribed to 34.1% and 31.1% of patients upon ICU and hospital discharge. Within the ≥50 mean IV MME/ICU day cohort, 64.7% of patients received opioids after ICU discharge compared to 45.8% and 13.6% in the 1-49 mean IV MME/ICU day and no opioid groups (P < .05). Within the ≥50 mean IV MME/ICU day cohort, 70.6% of patients were prescribed opioids after hospitalization compared to 37.3% and 13.6% of patients who received less or no opioids. (P < .05). Within the ≥50 mean IV MME/ICU day cohort, 29.4% of patients were opioid naïve and discharged with an opioid, which is over double compared to patients with lower opioid requirements (P < .05). CONCLUSION: Patients with higher mean daily ICU opioid requirements had increased opioid prescribing across care transitions despite preadmission opioid use.

Manganese encephalopathy: an under-recognized condition in the intensive care unit.

BACKGROUND: Manganese encephalopathy is a potential complication of parenteral nutrition. Lack of early recognition leads to unnecessary testing and to continued exposure to manganese. METHODS: Case report and review of the literature. RESULTS: We describe the clinical and imaging findings of a patient with manganese encephalopathy in whom the diagnosis was delayed due to lack of recognition of the characteristic imaging findings. CONCLUSION: Manganese encephalopathy has protean clinical and imaging findings that can easily be overlooked.

Osmotherapy: use among neurointensivists.

BACKGROUND: Cerebral edema and raised intracranial pressure are common problems in neurological intensive care. Osmotherapy, typically using mannitol or hypertonic saline (HTS), has become one of the first-line interventions. However, the literature on the use of these agents is heterogeneous and lacking in class I studies. The authors hypothesized that clinical practice would reflect this heterogeneity with respect to choice of agent, dosing strategy, and methods for monitoring therapy. METHODS: An on-line survey was administered by e-mail to members of the Neurocritical Care Society. Multiple-choice questions regarding use of mannitol and HTS were employed to gain insight into clinician practices. RESULTS: A total of 295 responses were received, 79.7% of which were from physicians. The majority (89.9%) reported using osmotherapy as needed for intracranial hypertension, though a minority reported initiating treatment prophylactically. Practitioners were fairly evenly split between those who preferred HTS (54.9%) and those who preferred mannitol (45.1%), with some respondents reserving HTS for patients with refractory intracranial hypertension. Respondents who preferred HTS were more likely to endorse prophylactic administration. Preferred dosing regimens for both agents varied considerably, as did monitoring parameters. CONCLUSIONS: Treatment of cerebral edema using osmotically active substances varies considerably between practitioners. This variation could hamper efforts to design and implement multicenter trials in neurocritical care.

The Effect of Sample Handling on Free Valproic Acid Levels.

BACKGROUND: Valproic acid (VPA) is a broad-spectrum anticonvulsant drug. Under normal conditions, this drug is highly protein bound. However, in patients with hypoalbuminemia, the free fraction can increase substantially while the total VPA levels remain in therapeutic range. The neurologic activity and toxicity of the drug are directly related to free drug levels. METHODS: Our in-house free VPA assay was validated using 20 patient samples obtained from a reference laboratory (RL1). It was further evaluated by parallel testing with RL1 using samples collected from our patients. Subsequently, sample handling effects were investigated by comparing free VPA levels measured in our laboratory to 3 selected RLs with different sample transportation conditions. RESULTS: No significant bias was observed between the in-house assay (y) and RL1 (x) assay in free VPA measurement (y = 1.12x + 0.072, r = 0.994). However, patient samples collected in our institution and sent to RL1 revealed significant negative bias (y = 0.776x - 3.861, r = 0.954). A large discrepancy in free VPA levels was further observed from identical aliquots of the same samples transported to 3 RLs in different conditions. CONCLUSIONS: Our study demonstrated that sample handling has significant impact on free VPA levels. The observed magnitude of variation exceeds a clinically acceptable limit and could alter clinical decisions.

Cefoxitin-Serum Creatinine Interference in a Patient With Nontuberculous Mycobacteria Ventriculomeningitis.

Cefoxitin is a second-generation cephamycin antibiotic, which at concentrations ≥100 µg/mL is known to modestly interfere, for up to 2 hours post-infusion, with serum creatinine measurement via the traditional Jaffe-based assay. We report a case of a severe serum creatinine elevation while utilizing cefoxitin as a component of an antimicrobial regimen in a critically ill patient with Mycobacterium abscessus ventriculomeningitis. Our results, both via patient serum analysis and a cefoxitin spiking experiment, demonstrate interference despite the utilization of improved modern Jaffe-based assays. In fact, the cefoxitin-creatinine interference may be clinically relevant at concentrations 3 times lower than that listed in the package insert and may display more than a modest interference at typical therapeutic concentrations.

Platelet Function Testing with a VerifyNow-Directed Personalized Antiplatelet Strategy and Associated Rates of Thromboembolic Complications After Pipeline Embolization for Complex Cerebral Aneurysms.

BACKGROUND: VerifyNow-directed personalized antiplatelet therapy for aneurysm embolization with a Pipeline Embolization Device (PED) remains controversial. Evaluate thrombotic complications between patients who received VerifyNow-directed personalized antiplatelet therapy versus those who did not after PED flow diversion of complex cerebral aneurysms. METHODS: This was a retrospective cohort of consecutive patients undergoing flow diversion with PED at the Medical University of South Carolina between January 2012 and May 2018. Patients who received VerifyNow-directed personalized antiplatelet therapy were compared with those who received antiplatelet therapy without platelet function testing. Patients with a P2Y12 reaction unit (PRU) ≥194 were deemed to be clopidogrel hyporesponsive. The primary outcome is the rate of thrombotic complications, and the secondary outcomes are the rate of hemorrhagic and thrombotic complications stratified by PRU and high-risk clinical and procedure-related candidate predictors. RESULTS: Thrombotic complications were not different between patients managed with (n = 159) versus without (n = 110) VerifyNow (6.9% vs. 7.3%; P = 0.911). Hemorrhagic complications were also no different (3.1% vs. 4.5%; P = 0.550). PRU stratification revealed no difference in thrombotic or hemorrhagic complications (P = 0.488 and P = 0.136, respectively). The only significant predictors for thrombotic complications were the presence of diabetes (OR 2.9; P = 0.034), obesity (OR 5.1; P ≤ 0.001), fusiform aneurysm (OR 3.3; P = 0.023), posterior circulation implantation (OR 3.4; P = 0.016), and >1 PED implanted (OR 2.4; P = 0.046). CONCLUSIONS: The role of VerifyNow and personalized antiplatelet therapy in patients undergoing flow diversion with PED to treat complex aneurysms did not demonstrate a benefit in reducing thrombotic complications.

Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week.

Millions of individuals in the United States require long-term treatment with an oral anticoagulant. For decades, vitamin K antagonists were the only oral option available; however, they have a number of well-known limitations. Introduction of the direct oral anticoagulants (DOACs) has long been considered a major therapeutic advance, largely because they lack the need for therapeutic monitoring. Despite this, DOACs, like vitamin K antagonists, can still cause major and clinically relevant nonmajor bleeding, even when used appropriately. Drug-drug interactions (DDIs) involving the DOACs represent an important contributor to increased bleeding risk. Awareness of these DDIs and how best to address them is of critical importance in optimizing management while mitigating bleeding risk. This review provides an overview of DOAC metabolism, the most common drugs likely to contribute to DOAC DDIs, their underlying mechanisms, and how best to address them.

Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus.

Methylnaltrexone and alvimopan are two new and potentially useful agents in the management of opioid-induced bowel dysfunction and prevention of postoperative ileus. Both agents have promising prokinetic properties and appear to be capable of reversing the effects of opioids on delayed gastrointestinal transit. This article reviews currently available published literature to provide an overview of the clinical trials and to provide insight for the potential use of these agents for patients requiring opioid based analgesia. These compounds represent a new class of compounds that may impact the therapeutics for opioid induced bowel dysfunction as well as postoperative ileus.

Aminoglycoside pharmacokinetic parameters in neurocritical care patients undergoing induced hypothermia.

STUDY OBJECTIVE: To determine the effects of mild-to-moderate induced hypothermia-a neuroprotectant and/or therapeutic strategy for the management of intracranial hypertension in neurologically injured patients-on the pharmacokinetics of aminoglycoside therapy. DESIGN: Pharmacokinetic analysis. SETTING: Critical care unit at a university-affiliated hospital. PATIENTS: Three patients, aged 22, 24, and 47 years, who received tobramycin and had documented tobramycin levels while undergoing induced hypothermia for more than 24 hours for intracranial hypertension. MEASUREMENTS AND MAIN RESULTS: For each of the three patients, predicted pharmacokinetic parameters (volume of distribution, first-order elimination rate constant, half-life, and renal drug clearance) based on population data were compared with their actual pharmacokinetic parameters that were calculated based on observed tobramycin serum levels. All three patients had a normal creatinine clearance, estimated according to established methods. When pharmacokinetic parameters were calculated after the first tobramycin dose using a one-compartment method, all patients had a slower first-order elimination rate and a larger volume of distribution compared with predicted population estimates. CONCLUSION: These findings suggest that induced hypothermia may result in impaired elimination of aminoglycosides. Caution should be exercised when attempting to use predicted pharmacokinetic parameters to dose aminoglycosides in this patient population, and first-dose pharmacokinetics should be considered to optimize the dose and dosing interval early in the course of therapy. Further investigation of this phenomenon with greater numbers of patients are needed to confirm these findings and to determine optimal dosing strategies of aminoglycosides in patients undergoing induced hypothermia.