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.

Safety of Modified Nimodipine Dosing in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Nimodipine improves outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the impact of alternative dosing strategies on outcome remains unclear. METHODS: We performed a retrospective cohort study of consecutive patients admitted with aSAH to an academic referral center from 2016 to 2019. Patients with a confirmed aneurysm cause who received nimodipine were included; patients who died or had withdrawal of life-sustaining treatment within 24 hours of admission were excluded. Univariable and multivariable modified Poisson regression models were used to identify predictors of using modified nimodipine dosing (30 mg every 2 hours) versus standard dosing (60 mg every 4 hours). Inverse probability weighted and modified Poisson regression models were used to estimate adjusted risk ratios (RRs) for outcome measures, with poor outcome defined as modified Rankin Scale score 4-6 at 3 months. RESULTS: We identified 175 patients with aSAH who met eligibility criteria (mean [SD] age = 57 [13.2] years, 62% female, 73% White); 49% (n = 86) received modified nimodipine dosing. A modified dose was used more frequently in women (RR 2.08, 95% confidence interval [CI] 1.11-3.89, P = 0.02), patients with vasospasm (RR 3.47, 95% CI 1.84-6.51, P < 0.001), and patients who required vasopressors (RR 1.73, 95% CI 1.3-2.32, P < 0.001). Modified dosing was not associated with poor functional outcome (inverse probability weighted RR 1.1, 95% CI 0.8-1.4, P = 0.65). CONCLUSIONS: Modified dosing of nimodipine is well tolerated and may not be associated with worse functional outcome. Prospective studies are needed to better assess the relationship between nimodipine dosing and outcomes in patients with aSAH.

Risk Factors for Opioid Utilization in Patients with Intracerebral Hemorrhage.

BACKGROUND: Headache is a common presenting symptom of intracerebral hemorrhage (ICH) and often necessitates treatment with opioid medications. However, opioid prescribing patterns in patients with ICH are not well described. We aimed to characterize the prevalence and risk factors for short and longer-term opioid use in patients with ICH. METHODS: We conducted a retrospective cohort study using data from a single-center registry of patients with nontraumatic ICH. This registry included data on demographics, ICH-related characteristics, and premorbid, inpatient, and postdischarge medications. After excluding patients who died or received end-of-life care, we used multivariable regression models adjusted for premorbid opioid use to determine demographic and ICH-related risk factors for inpatient and postdischarge opioid use. RESULTS: Of 468 patients with ICH in our cohort, 15% (n = 70) had premorbid opioid use, 53% (n = 248) received opioids during hospitalization, and 12% (n = 53) were prescribed opioids at discharge. The most commonly used opioids during hospitalization were fentanyl (38%), oxycodone (30%), morphine (26%), and hydromorphone (7%). Patients who received opioids during hospitalization were younger (univariate: median [interquartile range] 64 [53.5-74] vs. 76 [67-83] years, p < 0.001; multivariable: odds ratio [OR] 0.96 per year, 95% confidence interval [CI] 0.94-0.98) and had larger ICH volumes (univariate: median [interquartile range] 10.1 [2.1-28.6] vs. 2.7 [0.8-9.9] cm3, p < 0.001; multivariable: OR 1.05 per cm3, 95% CI 1.03-1.08) than those who did not receive opioids. All patients who had external ventricular drain placement and craniotomy/craniectomy received inpatient opioids. Additional risk factors for increased inpatient opioid use included infratentorial ICH location (OR 4.8, 95% CI 2.3-10.0), presence of intraventricular hemorrhage (OR 3.9, 95% CI 2.2-7.0), underlying vascular lesions (OR 3.0, 95% CI 1.1-8.1), and other secondary ICH etiologies (OR 7.5, 95% CI 1.7-32.8). Vascular lesions (OR 4.0, 95% CI 1.3-12.5), malignancy (OR 5.0, 95% CI 1.5-16.4), vasculopathy (OR 10.0, 95% CI 1.8-54.2), and other secondary etiologies (OR 7.2, 95% CI 1.8-29.9) were also risk factors for increased opioid prescriptions at discharge. Among patients who received opioid prescriptions at discharge, 43% (23 of 53) continued to refill their prescriptions at 3 months post discharge. CONCLUSIONS: Inpatient opioid use in patients with ICH is common, with some risk factors that may be mechanistically connected to primary headache pathophysiology. However, the lower frequency of opioid prescriptions at discharge suggests that inpatient opioid use does not necessarily lead to a high rate of long-term opioid dependence in patients with ICH.

Eastern Equine Encephalitis: Case Series in Southern New England and Review of the Literature.

PURPOSE OF REVIEW: To describe the clinical presentation, diagnosis, management, and outcomes of 4 confirmed Eastern equine encephalitis (EEE) cases and a review of the literature. RECENT FINDINGS: There was a sharp rise in the number of EEE cases in the United States in 2019, with 38 confirmed cases and 15 deaths. Our institution cared for 10% of patients with neuroinvasive EEE nationwide. These were the first cases seen locally since 2010. SUMMARY: EEE virus causes one of the most lethal types of arboviral encephalitis in the United States with a mortality of 30%-40%. Manifestations of EEE infections can range from mild encephalopathy to coma. Common findings include CSF pleocytosis and involvement of the basal ganglia on MRI. Given the rarity of this disease and nonspecific findings, diagnosis can be challenging, and a high clinical suspicion is important. Management is mainly supportive, and the use of IV immunoglobulin remains controversial. Two of our 4 patients died; these patients had coma within 48 hours, hyponatremia, involvement of bilateral thalami and brainstem, status epilepticus, and severe brain dysfunction in EEG.

Modeling the Clinical Implications of Andexanet Alfa in Factor Xa Inhibitor-Associated Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: Andexanet alfa was recently approved as a reversal agent for the factor Xa inhibitors (FXais) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. We aimed to explore potential clinical implications of andexanet alfa in FXai-associated ICH in this simulation study. METHODS: We simulated potential downstream implications of andexanet alfa across a range of possible hemostatic effects using data from a single center that treats FXai-associated ICH with prothrombin complex concentrate (PCC). We determined baseline probabilities of inadequate hemostasis across patients taking FXai and those not taking FXai via multivariable regression models and then determined the probabilities of unfavorable 3-month outcome (modified Rankin Scale score 4-6) using models comprising established predictors and each patient's calculated probability of inadequate hemostasis. We applied bootstrapping with model parameters from this derivation cohort to simulate a range of hemostatic improvements and corresponding outcomes and then calculated absolute risk reduction (relative to PCC) and projected number needed to treat (NNT) to prevent 1 unfavorable outcome. RESULTS: Training models using real-world patients (n = 603 total, 55 on FXai) had good accuracy in predicting inadequate hemostasis (area under the curve [AUC] 0.78) and unfavorable outcome (AUC 0.78). Inadequate hemostasis was strongly associated with unfavorable outcome (odds ratio 4.5, 95% confidence interval [CI] 2.0-9.9) and occurred in 11.4% of patients taking FXai. Across simulated patients taking FXai comparable to those in A Study in Participants With Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study, predicted absolute risk reduction of unfavorable outcome was 4.9% (95% CI 1.3%-7.8%) when the probability of inadequate hemostasis was reduced by 33% and 7.4% (95% CI 2.0%-11.9%) at 50% reduction, translating to projected NNT of 21 (cumulative cost $519,750) and 14 ($346,500), respectively. DISCUSSION: Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered. Placebo-controlled randomized trials are needed before its use can definitively be recommended.

Short- and long-term opioid use in survivors of subarachnoid hemorrhage.

OBJECTIVES: Opioids are frequently used for analgesia in patients with acute subarachnoid hemorrhage (SAH) due to a high prevalence of headache and neck pain. However, it is unclear if this practice may pose a risk for opioid dependence, as long-term opioid use in this population remains unknown. We sought to determine the prevalence of opioid use in SAH survivors, and to identify potential risk factors for opioid utilization. METHODS: We analyzed a cohort of consecutive patients admitted with non-traumatic and suspected aneurysmal SAH to an academic referral center. We included patients who survived hospitalization and excluded those who were not opioid-naïve. Potential risk factors for opioid prescription at discharge, 3 and 12 months post-discharge were assessed. RESULTS: Of 240 SAH patients who met our inclusion criteria (mean age 58.4 years [SD 14.8], 58% women), 233 (97%) received opioids during hospitalization and 152 (63%) received opioid prescription at discharge. Twenty-eight patients (12%) still continued to use opioids at 3 months post-discharge, and 13 patients (6%) at 12-month follow up. Although patients with poor Hunt and Hess grades (odds ratio 0.19, 95% CI 0.06-0.57) and those with intraventricular hemorrhage (odds ratio 0.38, 95% CI 0.18-0.87) were less likely to receive opioid prescriptions at discharge, we did not find significant differences between patients who had long-term opioid use and those who did not. CONCLUSION: Opioids are regularly used in both the acute SAH setting and immediately after discharge. A considerable number of patients also continue to use opioids in the long-term. Opioid-sparing pain control strategies should be explored in the future.

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.

Serum alpha-1 antitrypsin in acute ischemic stroke: A prospective pilot study.

BACKGROUND: Alpha-1 antitrypsin (AAT) is a potent anti-protease enzyme which may play a role in arterial wall stability. A variant of its encoding gene has been recently linked to ischemic stroke due to large artery atherosclerosis (LAA). We sought to explore potential relationships between ischemic stroke mechanisms, atherosclerosis burden and serum AAT levels. METHODS: We performed a prospective observational study of consecutive patients with acute ischemic stroke who were admitted to an academic comprehensive stroke center over a three-month period. Blood samples were collected within 24 h of hospital admission, and stroke subtype classification was determined based on modified TOAST criteria. Modified Woodcock scoring system was used to quantify calcification of major cervico-cranial arteries as a surrogate for atherosclerosis burden. Linear regression analysis was used to assess the association between serum AAT levels and calcification scores, both as continuous variables. RESULTS: Among eighteen patients met our inclusion criteria and were enrolled in our study, 10 patients (56%) were men; mean age was 66 (SD 12.5); median NIH stroke scale was 4 (IQR 9.5); 8 patients (44%) had stroke due to LAA. The median serum level of AAT was 140 mg/dl (IQR 41.7) for patients with LAA-related stroke, and 148.5 mg/dl (IQR 37.7) for patients with other stroke mechanisms (p = 0.26). Higher serum AAT levels was associated with lower modified Woodcock calcification scores. (p-value = 0.038) CONCLUSIONS: Measurement of AAT levels in patients with acute stroke is feasible, and there may be associations between AAT levels and stroke mechanism that warrant further study in larger samples.

Outcomes of protocolised analgesia and sedation in a neurocritical care unit.

OBJECTIVES: Providing analgesia and sedation while allowing for neurological assessment is important in the neurocritical care unit (NCCU), yet data are limited about the effects of protocolised analgesia and sedation. We developed an analgesia-based sedation protocol and evaluated its effect on medication utilisation and costs in the NCCU. METHODS: We conducted a retrospective cohort study of patients who are mechanically ventilated and admitted to a 12-bed NCCU over four years. To compare outcomes, we used gamma and negative binomial regression models, and interrupted time-series sensitivity analyses. RESULTS: The study cohort consisted of 1197 patients: 576 pre-protocol and 621 post-protocol. The protocol resulted in an increase in fentanyl use [incidence rate ratio (IRR) = 2.8, (95% confidence limits (CLs) 1.9, 4.2)] and a decrease in propofol use (IRR = 0.8, CLs 0.6, 1.0). There was a decrease in fentanyl (cost ratio = 0.8, CLs 0.5, 1.1) and propofol costs (cost ratio = 0.6, CLs 0.5, 0.8). The sensitivity analyses results were similar. There was no effect on healthcare utilisation, healthcare costs, and in-hospital mortality. CONCLUSION: Protocolised analgesia and sedation increased analgesia use, decreased sedative use, and reduced medication-associated costs in the NCCU. Our results suggest that similar NCCUs should consider use of population-specific protocols to manage analgesia and sedation.

Concordance between Activated Partial Thromboplastin Time and Antifactor Xa Assay for Monitoring Unfractionated Heparin in Hospitalized Hyperbilirubinemic Patients.

BACKGROUND: Activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) monitoring methods for unfractionated heparin (UFH) often disagree. The extent of discordance for those with elevated bilirubin remains unclear. Our objective was to evaluate concordance between activated aPTT and anti-Xa methods for hyperbilirubinemic patients on UFH. METHODS: This was a retrospective cohort study of 26 patients hospitalized at Rhode Island Hospital between August 2014 and September 2014. Patients had at least one bilirubin measurement >5 mg/dL. After categorizing lab values, percent agreement and kappa were used to examine concordance between aPTT and anti-Xa. RESULTS: Overall percent agreement between aPTT and anti-Xa was 50%. A nontherapeutic aPTT and therapeutic anti-Xa accounted for 98% of all disagreement. Specifically, 76.7% of disagreement was due to a subtherapeutic aPTT and a therapeutic anti-Xa. Unweighted kappa was 0.141 (95%CI: 0.048-0.235). CONCLUSION: Concordance between aPTT and anti-Xa values was poor in hyperbilirubinemic patients.

Effect of Probiotics on the Incidence of Healthcare-Associated Infections in Mechanically Ventilated Neurocritical Care Patients.

BACKGROUND: Healthcare-associated infections (HAIs) are seen in 17% of critically ill patients. Probiotics, live nonpathogenic microorganisms, may aid in reducing the incidence of infection in critically ill patients. We hypothesized that administration of probiotics would be safe and reduce the incidence of HAIs among mechanically ventilated neurocritical care patients. METHODS: We assembled 2 retrospective cohorts of mechanically ventilated neurocritical care patients. In the preintervention cohort from July 1, 2011, to December 31, 2011, probiotics were not used. In the postintervention group from July 1, 2012, to December 31, 2012, 1 g of a combination of Lactobacillus acidophilus and Lactobacillus helveticus was administered twice daily to all patients who were mechanically ventilated for more than 24 hours. RESULTS: There were a total of 167 patients included, 80 patients in the preintervention group and 87 patients in the postintervention group. No patients in the preintervention group received probiotics. Eighty-five (98%) patients in the postintervention group received probiotics for a median of 10 days (interquartile range, 4-20 days). There were 14 (18%) HAIs in the preintervention group and 8 (9%) HAIs in the postintervention group (P = .17). Ventilator days, lengths of stay, in-hospital mortality, and discharge disposition were similar between the pre- and postintervention groups. There were no cases of Lactobacillus bacteremia or other adverse events associated with probiotics use. CONCLUSION: Probiotics are safe to administer in neurocritical care patients; however, this study failed to demonstrate a significant decrease in HAIs or secondary outcomes associated with probiotics.