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.

Emergent external ventricular drain placement in patients with factor Xa inhibitor-associated intracerebral hemorrhage after reversal with andexanet alfa.

BACKGROUND: Andexanet alfa (AA), a factor Xa-inhibitor (FXi) reversal agent, is given as a bolus followed by a 2-hour infusion. This long administration time can delay EVD placement in intracerebral hemorrhage (ICH) patients. We sought to evaluate the safety of EVD placement immediately post-AA bolus compared to post-AA infusion. METHODS: We conducted a retrospective study that included adult patients admitted with FXi-associated ICH who received AA and underwent EVD placement The primary outcome was the occurrence of a new hemorrhage (tract, extra-axial, or intraventricular hemorrhage). Secondary outcomes included mortality, intensive care unit and hospital length of stay, and discharge modified Rankin Score. The primary safety outcome was documented thrombotic events. RESULTS: Twelve patients with FXi related ICH were included (EVD placement post-AA bolus, N = 8; EVD placement post-AA infusion, N = 4). Each arm included one patient with bilateral EVD placed. There was no difference in the incidence of new hemorrhages, with one post-AA bolus patient had small, focal, nonoperative extra-axial hemorrhage. Morbidity and mortality were higher in post-AA infusion patients (mRS, post-AA bolus, 4 [4-6] vs. post-AA infusion 6 [5,6], p = 0.24 and post-AA bolus, 3 (37.5 %) vs. post-AA infusion, 3 (75 %), p = 0.54, respectively). One patient in the post-AA bolus group had thrombotic event. There was no difference in hospital LOS (post-AA bolus, 19 days [12-26] vs. post-AA infusion, 14 days [9-22], p = 0.55) and ICU LOS (post-AA bolus, 10 days [6-13] vs. post-AA infusion, 11 days [5-21], p = 0.86). CONCLUSION: We report no differences in the incidence of tract hemorrhage, extra-axial hemorrhage, or intraventricular hemorrhage post-AA bolus versus post-AA infusion. Larger prospective studies to validate these results are warranted.

Timing of vasoactive agents and corticosteroid initiation in septic shock.

Septic shock remains a health care concern associated with significant morbidity and mortality. The Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock recommend early fluid resuscitation and antimicrobials. Beyond initial management, the guidelines do not provide clear recommendations on appropriate time to initiate vasoactive therapies and corticosteroids in patients who develop shock. This review summarizes the literature regarding time of initiation of these interventions. Clinical data regarding time of initiation of these therapies in relation to shock onset, sequence of treatments with regard to each other, and clinical markers evaluated to guide initiation are summarized. Early-high vasopressor initiation within first 6 h of shock onset is associated with lower mortality. Following norepinephrine initiation, the exact dose and timing of escalation to adjunctive vasopressor agents are not well elucidated in the literature. However, recent data indicate that timing may be an important factor in initiating vasopressors and adjunctive therapies, such as corticosteroids. Norepinephrine-equivalent dose and lactate concentration can aid in determining when to initiate vasopressin and angiotensin II in patients with septic shock. Future guidelines with clear recommendations on the time of initiation of septic shock therapies are warranted.

Relationship Between Glucose Time in Range in Diabetic and Non-Diabetic Patients and Mortality in Critically Ill Patients.

Background: Shorter time spent in specific blood glucose ranges is associated with mortality benefit in critically ill patients. However, various time in range values are reported, each based on a specific blood glucose range. Objective: To evaluate relationship between percentage of time spent at various blood glucose ranges (TIR) and mortality in critically ill patients. Methods: Single-center, retrospective, cohort study that included adult patients admitted to ICU for at least one day. We evaluated the relationship between TIR at prespecified blood glucose ranges and hospital mortality in diabetic and non-diabetic patients Results: Of the 5287 patients included, 3705 (70.0%) were non-diabetic and 1582 were diabetic (29.9%). Diabetic patients had higher in-hospital mortality rate (15.8%) compared to non-diabetic patients (11.3%), p < 0.0001, and with higher incidence of hyperglycemia (77.8% vs. 39.4%) and hypoglycemia (14.3% vs. 10%) compared to non-diabetic patients, p < 0.0001. The highest median TIR for both diabetic [76% (49.1 - 97.8%)] and non-diabetic patients [100% (92.3--100%)] was at blood glucose range of 70-180 mg/dL. In non-diabetic cohort, the only optimal TIR of 40% at blood glucose range of 70-120 mg/dL was identified. Non-diabetic patients stratified into TIR 70-120 mg/dL > 40% reported significantly lower mortality (7.0%) rate compared to patients with TIR 70-120 mg/dL < 40% (15.7%), OR 0.52, 95% CI 0.27-0.97, adjusted-p = 0.03. In diabetic patients, no relationship was detected between TIR at all predefined glucose ranges and hospital mortality. Conclusion: Critically ill non-diabetic patients who spent at least 40% of time in blood glucose range of 70-120 mg/dL had improved survival. This association was not observed in diabetic patients.

Use of droxidopa for blood pressure augmentation after acute spinal cord injury: case reports.

Hypotension secondary to autonomic dysfunction is a common complication of acute spinal cord injury (SCI) that may worsen neurologic outcomes. Midodrine, an enteral α-1 agonist, is often used to facilitate weaning intravenous (IV) vasopressors, but its use can be limited by reflex bradycardia. Alternative enteral agents to facilitate this wean in the acute post-SCI setting have not been described. We aim to describe novel application of droxidopa, an enteral precursor of norepinephrine that is approved to treat neurogenic orthostatic hypotension, in the acute post-SCI setting. Droxidopa may be an alternative enteral therapy for those intolerant of midodrine due to reflex bradycardia. We describe two patients suffering traumatic cervical SCI who were successfully weaned off IV vasopressors with droxidopa after failing with midodrine. The first patient was a 64-year-old male who underwent C3-6 laminectomies and fusion after a ten-foot fall resulting in quadriparesis. Post-operatively, the addition of midodrine in an attempt to wean off IV vasopressors resulted in significant reflexive bradycardia. Treatment with droxidopa facilitated rapidly weaning IV vasopressors and transfer to a lower level of care within 72 hours of treatment initiation. The second patient was a 73-year-old male who underwent C3-5 laminectomies and fusion for a traumatic hyperflexion injury causing paraplegia. The addition of midodrine resulted in severe bradycardia, prompting consideration of pacemaker placement. However, with the addition of droxidopa, this was avoided, and the patient was weaned off IV vasopressors on dual oral therapy with midodrine and droxidopa. Droxidopa may be a viable enteral therapy to treat hypotension in patients after acute SCI who are otherwise not tolerating midodrine in order to wean off IV vasopressors. This strategy may avoid pacemaker placement and facilitate shorter stays in the intensive care unit, particularly for patients who are stable but require continued intensive care unit admission for IV vasopressors, which can be cost ineffective and human resource depleting.

Vitamin C for Sepsis and Septic Shock.

BACKGROUND: Sepsis remains a leading cause of death in the critically ill. The combination of thiamine, vitamin C, and hydrocortisone has recently emerged as a potential adjunctive therapy and supportive care for patients with sepsis and septic shock. AREAS OF UNCERTAINTY: Several randomized and observational controlled trials evaluated the role of vitamin C in sepsis and septic shock. However, there are variabilities in the findings of these studies that led to a substantial global debate on incorporating vitamin C therapy in clinical practice. DATA SOURCES: A PubMed and Embase English language literature search through April 2021 was performed using the following terms: ascorbic acid, vitamin C, corticosteroid, hydrocortisone, thiamine, HAT, sepsis, and shock. Citations, including controlled trials, observational studies, review articles, guidelines, and consensus statements, were reviewed. The risk of bias for each clinical study was systematically evaluated. Relevant clinical data focusing on efficacy, safety, and special considerations regarding the use of vitamin C with and without thiamine and hydrocortisone in sepsis and septic shock were narratively summarized. RESULTS: The most commonly used vitamin C dosing in sepsis and septic shock is 1.5 g every 6 hours with and without thiamine and hydrocortisone. Current literature is limited because of heterogeneity in vitamin C regimen used, initiation time, and duration of treatment. This limitation led to variability in outcomes evaluated. Vitamin C decreases proinflammatory mediators and slows the progression of endothelial injury in severe sepsis. There is an inconsistency between randomized controlled trials and observational controlled trials regarding mortality, resolution in organ failure, hospital and intensive care unit length of stay findings with the use of vitamin C in septic shock. Vitamin C seems to be safe in comparison with placebo. CONCLUSIONS: Future studies with consistent end points, initiation time with an emphasis on early initiation, and standard vitamin C dosing regimen are needed to determine the overall benefit of vitamin C in sepsis.

Pharmacists leadership in a medication shortage response: Illustrative examples from a health system response to the COVID-19 crisis.

As medication experts, clinical pharmacists play an active and dynamic role in a medication shortage response. Supplementing existing guidelines with an actionable framework of discrete activities to support effective medication shortage responses can expand the scope of pharmacy practice and improve patient care. Dissemination of best practices and illustrative, networked examples from health systems can support the adoption of innovative solutions. In this descriptive report, we document the translation of published shortage mitigation guidelines into system success through broad pharmacist engagement and the adaption and implementation of targeted strategies. The profound, wide-reaching medication shortages that accompanied the coronavirus disease 2019 (COVID-19) pandemic are used to highlight coordinated but distinct practices and how they have been combined to expand the influence of the pharmacy enterprise.

Evaluation and Management of Seizures and Status Epilepticus.

Seizures are frequently triggered by an inciting event and result from uninhibited excitation and/or decreased inhibition of a pool of neurons. If physiologic seizure abortive mechanisms fail, the ensuing unrestrained synchronization of neurons-status epilepticus-can be life-threatening and is associated with the potential for marked morbidity in survivors and high medical care costs. Prognosis is intimately related to etiology and its response to therapeutic measures. Timely implementation of pharmacologic therapy while concurrently performing a stepwise workup for etiology are paramount. Neurodiagnostic testing should guide titration of pharmacologic therapies, and help determine if there is a role for immune modulation.

Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage.

BACKGROUND/OBJECTIVE: There are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH. METHODS: We conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidence of thrombotic events after AA or 4F-PCC adminstration, during hospitalization. RESULTS: A total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79 years [72-86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6 h (21 [78%] vs 10 [71%], p = 0.71) and 24 h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6 h (9.3 mL [6.9-26.4] vs 10 mL [9.4-22.1], adjusted p = 0. 997) and 24-h (9.2 mL [6.1-18.8] vs 9.9 [9.4-21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53). CONCLUSION: In this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

Phenobarbital Monotherapy for the Management of Alcohol Withdrawal Syndrome in Surgical-Trauma Patients.

BACKGROUND: Benzodiazepine is first-line therapy for alcohol withdrawal syndrome (AWS), and phenobarbital is an alternative therapy. However, its use has not been well validated in the surgical-trauma patient population. OBJECTIVE: To describe the use of fixed-dose phenobarbital monotherapy for the management of patients at risk for AWS in the surgical-trauma intensive care unit. METHODS: Surgical-trauma critically ill patients who received phenobarbital monotherapy, loading dose followed by a taper regimen, for the management of AWS were included in this evaluation. The effectiveness of phenobarbital monotherapy to treat AWS and prevent development of AWS-related complications were evaluated. Safety end points assessed included significant hypotension, bradycardia, respiratory depression, and need for invasive mechanical ventilation. RESULTS: A total of 31 patients received phenobarbital monotherapy; the majority of patients were at moderate risk for developing AWS (n = 20; 65%) versus high risk (n = 11; 35%). None of the patients developed AWS-related complications; all patients were successfully managed for their AWS. Nine patients (29%) received nonbenzodiazepine adjunct therapy for agitation post-phenobarbital initiation. Three patients (10%) experienced hypotension, and 3 (10%) were intubated. None of the patients had clinically significant bradycardia or respiratory depression. CONCLUSION AND RELEVANCE: Fixed-dose phenobarbital monotherapy appears to be well tolerated and effective in the management of AWS. Further evaluation is needed to determine the extent of benefit with the use of phenobarbital monotherapy for management of AWS.

Sedation, Analgesia, and Paralysis in COVID-19 Patients in the Setting of Drug Shortages.

The rapid spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global pandemic. The 2019 coronavirus disease (COVID-19) presents with a spectrum of symptoms ranging from mild to critical illness requiring intensive care unit (ICU) admission. Acute respiratory distress syndrome is a major complication in patients with severe COVID-19 disease. Currently, there are no recognized pharmacological therapies for COVID-19. However, a large number of COVID-19 patients require respiratory support, with a high percentage requiring invasive ventilation. The rapid spread of the infection has led to a surge in the rate of hospitalizations and ICU admissions, which created a challenge to public health, research, and medical communities. The high demand for several therapies, including sedatives, analgesics, and paralytics, that are often utilized in the care of COVID-19 patients requiring mechanical ventilation, has created pressure on the supply chain resulting in shortages in these critical medications. This has led clinicians to develop conservation strategies and explore alternative therapies for sedation, analgesia, and paralysis in COVID-19 patients. Several of these alternative approaches have demonstrated acceptable levels of sedation, analgesia, and paralysis in different settings but they are not commonly used in the ICU. Additionally, they have unique pharmaceutical properties, limitations, and adverse effects. This narrative review summarizes the literature on alternative drug therapies for the management of sedation, analgesia, and paralysis in COVID-19 patients. Also, this document serves as a resource for clinicians in current and future respiratory illness pandemics in the setting of drug shortages.

Intravenous brivaracetam for the management of refractory focal non-convulsive status epilepticus.

Diagnosis and management of status epilepticus (SE), including non-convulsive status epilepticus (NCSE), is challenging, with a reported 30%-50% of epilepticus patients not responding to available antiseizure medications (ASMs). Injectable benzodiazepines, fosphenytoin, valproate, levetiracetam, lacosamide and phenobarbital are commonly used for treating SE. Brivaracetam, a new ASM, with higher affinity and greater selectivity for the synaptic vesicle glycoprotein 2A than levetiracetam, has been approved as monotherapy or adjunct for treatment of focal onset seizures. Brivaracetam may have a role in the management of SE. However, limited data exist on brivaracetam's efficacy in SE. We describe a patient case with focal NCSE refractory to levetiracetam, fosphenytoin, lacosamide and valproate who demonstrated clinical and electrographic improvement on continuous electroencephalography monitoring after brivaracetam administration.

Application of Cannabinoids in Neurosciences: Considerations and Implications.

Medicinal cannabinoid use continues to evolve across the United States, although legitimate federal recognition for medicinal purpose is lacking. Variability exists across states within the United States with respect to legislation, and health care institutions encounter challenges when patients present with a history of medicinal cannabinoid use. Emerging evidence in the field of neurosciences suggests a role of cannabinoids for neurologic medical conditions such as Parkinson disease, multiple sclerosis, and epilepsy. We aim to provide an overview of cannabinoids including a historical perspective, pharmacology, applications in neurosciences, and challenges in health care and academia. Knowledge of the appropriate role of cannabinoids in the clinical setting is essential for all health care practitioners including nursing.

Optimal norepinephrine-equivalent dose to initiate epinephrine in patients with septic shock.

PURPOSE: The specific norepinephrine dose at which epinephrine should be added in septic shock is unclear. This study sought to determine the norepinephrine-equivalent dose at epinephrine initiation that correlated with hemodynamic stability. METHODS: Septic shock patients receiving both norepinephrine and epinephrine were included in this study. Classification and regression tree analysis was conducted to determine breakpoints in norepinephrine-equivalent dose predicting hemodynamic stability, with two cohorts identified. The primary outcome was hemodynamic stability, and secondary outcomes were shock-free survival, time to achieve hemodynamic stability, and change in SOFA score. RESULTS: Optimal dose group was identified as initiating epinephrine when norepinephrine-equivalent dose was between 37 and 133 µg/min. A total of 138 and 61 patients were classified in optimal and non-optimal dose groups, respectively. Baseline characteristics were similar between groups except vasopressin use was more frequent in the optimal dose group. More patients in optimal dose group versus non-optimal dose group achieved hemodynamic stability (40 [29%] vs. 9 [14.8%]), absolute risk difference 14.2% [95% CI 2.5-25.9%]; p = .03). On multivariable analysis, initiating epinephrine within the optimal norepinephrine-equivalent dose range was independently associated with higher odds of hemodynamic response (OR 3.06 [95% CI 1.2-7.6]; p = .02). No differences were observed in other secondary outcomes. CONCLUSIONS: Initiation of epinephrine when patients were receiving norepinephrine-equivalent doses of 37-133 µg/min was associated with a higher rate of hemodynamic stability.

Compliance with Procalcitonin Algorithm Antibiotic Recommendations for Patients in Medical Intensive Care Unit.

STUDY OBJECTIVES: To describe compliance with antibiotic recommendations based on a previously published procalcitonin (PCT)-guided algorithm in clinical practice, to compare PCT algorithm compliance rates between PCT assays ordered in the antibiotic initiation setting (PCT concentration measured less than 24 hours after antibiotic initiation or before antibiotic initiation) with those in the antibiotic continuation setting (PCT concentration measured 24 hours or more after antibiotic initiation), and to evaluate patient- and PCT-related factors independently associated with algorithm compliance in patients in the medical intensive care unit (MICU). DESIGN: Single-center retrospective cohort study. SETTING: Large MICU in a tertiary care academic medical center. PATIENTS: A total of 527 adults admitted to the MICU unit over a 2-year period (November 1, 2011-October 31, 2013) who had a total of 957 PCT assays performed. PCT assays whose results were determined in the MICU were allocated retrospectively to either the initiation setting cohort or the continuation setting cohort based on timing of the PCT assay. MEASUREMENTS AND MAIN RESULTS: Each PCT assay was treated as a separate episode. Antibiotic regimens were compared between the 24-hour periods before and after the results of each PCT assay and evaluated against an algorithm to determine compliance. Clinical, laboratory, PCT-related, and microbiologic variables were assessed during the 24-hour period after the PCT assay results to determine their influence on PCT algorithm compliance. A larger proportion of PCT episodes occurred in the initiation setting (540 [56.4%]) than in the continuation setting (417 [43.5%]). Overall, compliance with PCT algorithm recommendations was low (48.5%) and not significantly different between the initiation setting and the continuation setting (49.1% vs 47.7%, p=0.678). No patient-related or PCT-related factors were independently associated with PCT algorithm compliance on multivariable logistic regression. CONCLUSION: Compliance with PCT algorithm antibiotic recommendations in both the initiation and continuation settings was lower than that reported in published randomized studies. No factors were independently associated with PCT algorithm compliance. Institutions using PCT assays to guide antibiotic use should assess compliance with algorithm antibiotic recommendations. Inclusion of a formalized antimicrobial stewardship program along with a PCT-guided algorithm is highly recommended.