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.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

BACKGROUND/OBJECTIVE: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. METHODS: This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48 h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21 days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. RESULTS: A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60 ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). CONCLUSIONS: Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48 h), creatinine clearance < 60 ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

Droperidol for the treatment of acute migraine headaches.

OBJECTIVE: To evaluate the safety and efficacy of droperidol for the relief of acute migraine headaches. DATA SOURCES: A MEDLINE search (1946 to August 2014) was performed using the following keywords and associated medical subject headings: droperidol, inapsine, headache, migraine, and migraine disorder. STUDY SELECTION AND DATA EXTRACTION: The search was conducted to identify randomized controlled trials comparing droperidol with placebo or an active control in adult patients with acute migraine headaches that were published in English. Primary end points included acute headache improvement after the intervention. Safety end points included the frequency of extrapyramidal symptoms, somnolence, and cardiac adverse effects. DATA SYNTHESIS: In all, 5 manuscripts are included in this review. Patients presenting to the emergency department with acute headache desire rapid pain relief, which was the primary objective in each of the evaluated studies. Droperidol was better than placebo and at least as effective as comparator drugs such as prochlorperazine, meperidine, or olanzapine using droperidol doses of 2.5 to 5 mg, given either intramuscularly (IM) or intravenously (IV). The most commonly reported adverse effects were extrapyramidal symptoms and sedation. Cardiac adverse effects were not reported in any of the studies; however, only 2 articles described using cardiac monitoring. CONCLUSIONS: Parenteral droperidol is an effective option for the treatment of acute migraine. The minimum effective dose is 2.5 mg given IM or IV. Clinicians must be aware of the risk for adverse events, select appropriate patients, perform EKG monitoring for patients at risk of QTc prolongation, and institute treatment if necessary.

Fludrocortisone evaluation in aneurysmal subarachnoid hemorrhage patients with cerebral salt wasting (Flush Salt).

OBJECTIVE: Cerebral salt wasting is a condition that can occur in patients with aneurysmal subarachnoid hemorrhage and is characterized by excessive natriuresis, resulting in hyponatremia and hypovolemia. Fludrocortisone is a mineralocorticoid that facilitates retention of sodium and water. Guideline recommendations are weak regarding fludrocortisone use in this patient population due to mixed clinical effectiveness in prior studies. The purpose of this study was to evaluate the clinical effectiveness of fludrocortisone for cerebral salt wasting in patients with aneurysmal subarachnoid hemorrhage. METHODS: This single-site, retrospective study evaluated data from March 29th, 2014 through August 31st, 2021. Patients were included if they were admitted for aneurysmal subarachnoid hemorrhage and received fludrocortisone. Patients were excluded if they were less than 18 years old, pregnant, or received fludrocortisone for less than 48 h. Patients served as their own control and endpoints compared baseline data (24 h prior to fludrocortisone) to a run-in period (0-24-hour post fludrocortisone) and a steady-state period (24-48-hour post fludrocortisone). The primary endpoint was fluid balance, determined by urine output and net daily intake. Secondary endpoints included 3 % hypertonic saline (or equivalent) intake and median serum sodium. RESULTS: There were 110 patients included in this study. Daily doses of fludrocortisone over the 48-hour period varied from 100 mcg to 500 mcg, with 48 % of patients receiving between 200 mcg and 300 mcg daily. Median 24-hour urine output was reduced over the course of the study period (8232 mL at baseline, 8464 mL during 24-hour run-in, and 7080 mL during steady-state timeframe); p = 0.014. There was a 18 % reduction in net volume intake (p = 0.001), including a 38 % reduction in 3 % hypertonic saline (or equivalent) required during the study period; p = 0.025). CONCLUSION: Fludrocortisone was associated with decreased urine output and subsequently, decreased volume intake, to maintain euvolemia in patients with aneurysmal subarachnoid hemorrhage and cerebral salt wasting.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.