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.

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.

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.

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.

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.

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.

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.