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.

Reversal of factor Xa inhibitors associated intracranial haemorrhage at a tertiary medical centre.

Prior to the approval of andexanet, there were no FDA-approved reversal agents indicated for the treatment of factor Xa inhibitor (FXaI) associated major bleed. Four-factor prothrombin complex concentrate (4F-PCC) has been widely used off-label for FXaI-associated bleeding. The purpose of this study was to compare the effectiveness and safety of andexanet and 4F-PCC for the reversal of FXaI-associated intracranial haemorrhage. The primary end point is in-hospital mortality; secondary endpoints include haemostatic efficacy and safety. This study is a singlecentre, retrospective chart review, including patients admitted between 1 January 2016 and 15 August 2019, who received 4F-PCC or andexanet for the management of FXaI-associated intracranial haemorrhage. Of the 45 patients included in this study, 23 patients were in the andexanet group and 22 were in the 4F-PCC group. At index admission, mean age was 76 years and the majority of patients (64%) were on apixaban with 33% presented with Glasgow Coma Scale 24 (GCS) score less than 12. At hospital discharge, 47% of patients in the andexanet group had died or discharged to hospice compared with 45% in the 4F-PCC group. No thromboembolic events were observed in either group within 5 days after administration of the reversal agent. The results of this study suggest that haemostasis and mortality at discharge during the index hospitalization appears to be similar between groups. Prospective randomized control trials comparing safety and efficacy of andexanet and 4F-PCC are needed.

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.

Evaluation of prophylactic antibiotics in penetrating brain injuries at an academic level 1 trauma center.

OBJECTIVE: Infections from penetrating brain injuries (PBI) lead to higher morbidity and mortality rates. The results of this research will be evaluated to develop institutional guideline for antibiotic prophylaxis in this patient population. The objective was to characterize the prophylactic antibiotic usage for patients presenting with PBI. PATIENTS AND METHODS: This retrospective chart review included patients with a PBI identified through the institution's trauma center registry between December 2015 and July 2018. The primary outcome was the proportion of patients that received prophylactic antibiotics. Secondary outcomes included antibiotic administration timing, selection and duration of antibiotic regimens, infection rates and patient outcomes. RESULTS: The study population included 33 patients, with 82 % males and an average age of 32 years. The most common mechanism of injury was a gunshot wound (94 %). Of the 33 patients, 24 (73 %) received at least one dose of prophylactic antibiotics. The median time to antibiotic administration was 52.8 min (IQR, 18-120), while the median duration of prophylaxis was 24 h (IQR, 7-84). The most common antibiotic regimen was a single cefazolin dose, with the next most common regimen included scheduled ceftriaxone and metronidazole. Overall, there were no documented central nervous system or skin and soft tissue infections during the initial admission, while 4 patients (12 %) were treated for pneumonia. Survivors (67 %) had a median hospital length of stay of 5.8 days. CONCLUSION: The median duration of prophylaxis was shorter than the current data suggesting antibiotics for 5 days; however, there were no documented central nervous system infections, which is less than previously reported in the literature.

Pharmacologic Treatment of Neurobehavioral Sequelae Following Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of disability in the United States. With decreasing mortality rates, a higher number of patients are impacted by long-term neuropsychiatric sequelae, such as cognitive deficits, depression, anxiety, and sleep-wake disorders. These sequelae are primarily driven by the disruption of key neurotransmitter homeostasis including dopamine, norepinephrine, serotonin, and acetylcholine. Neurostimulants are centrally acting medications used to assist in restoring these neurotransmitter abnormalities and are pharmacologic options to ameliorate symptoms in post-TBI patients. Examples of neurostimulants include amantadine, selective serotonin reuptake inhibitors, tricyclic antidepressants, central stimulants (ie, methylphenidate), modafinil, and donepezil. Large, well-powered studies have not been performed to validate their use in patients with TBI, leaving uncertainty for these agents' place in therapy. Current practice is driven by consideration of patient-specific factors to select the most appropriate agent. This review provides clinicians with a summary of the available literature on neurostimulants following TBI to guide appropriate usage to help improve patients' symptoms and optimize safety.

Dopac distribution and regulation in striatal dopaminergic varicosities and extracellular space.

DOPAC, the major intermediate metabolite of dopamine, is found in the cytosolic compartment of dopaminergic terminals/varicosities and in the extracellular space. It has been proposed that extracellular DOPAC is derived from newly synthesized dopamine rather than from dopamine in the signaling pool. On the basis of literature data supporting such a concept, we hypothesize a DOPAC synthesis/secretory complex producing extracellular DOPAC and use a computational simulation model of dopaminergic varicosities to estimate the distribution of DOPAC between cytosolic and extracellular compartments, amount of newly synthesized dopamine entering the DOPAC synthesis/secretory complex, and potential regulatory processes in the complex. Results suggest that about two-thirds of DOPAC is in the extracellular space. Approximately one-third of newly synthesized dopamine is immediately processed to DOPAC, which is then secreted into extracellular space. Extracellular DOPAC concentration is approximately 300 times higher than extracellular dopamine, and cytosolic DOPAC is ∼18-fold higher than cytosolic dopamine. We suggest that the high levels of extracellular DOPAC coupled with evidence for its production from newly synthesized dopamine imply the existence of an as yet undiscovered regulatory/signaling role for DOPAC.