Ketamine in seizure management and future pharmacogenomic considerations.

Ketamine is a noncompetitive N-methyl-D-aspartate antagonist with emerging evidence for use in medically refractory epilepsy. We describe the novel use of low-dose intravenous (IV) ketamine transitioning to enteral formulation in a patient with drug-resistant localization-related refractory epilepsy. We performed a National Library of Medicine (NLM) literature review using search terms "ketamine", "low dose", and "seizure" for similar cases, followed by an illustrative clinical case. Our NLM search engine methodology yielded 24 hits, none of which described use of low-dose ketamine for seizures. Anesthetic doses are used for status epilepticus, but we show that in a patient with postoperative worsening of his chronic seizure burden, low-dose IV ketamine can be used to avoid oversedation and intubation. We demonstrate that IV ketamine can be transitioned to oral regimen to shorten length of stay in the intensive care unit and hospital and has future CYP2B6 pharmacogenomic considerations for further dose individualization.

Safety and efficacy of repeated doses of 14.6 or 23.4 % hypertonic saline for refractory intracranial hypertension.

BACKGROUND: The efficacy of administering single bolus doses of 14.6 or 23.4 % hypertonic saline (HTS) to treat refractory intracranial hypertension has been demonstrated in the literature and has emerged as an important therapeutic option in treating these patients. However, many institutions lack experience with this therapy and there are few published studies evaluating the safety of repeated bolus dosing of HTS. METHODS: A retrospective review of patients admitted between January 2008 and July 2012 was conducted to evaluate the use of repeated dosing of HTS in patients with refractory intracranial hypertension. The primary objective was to evaluate the safety of repeated dosing of HTS assessed by documented adverse effects such as central pontine myelinolysis (CPM) and severe fluctuations in serum sodium concentrations. Secondary objectives were to evaluate the efficacy of repeated dosing HTS in reducing intracranial pressure (ICP) and to compare the dose-response relationship of 14.6 and 23.4 % doses. RESULTS: Fifty-five patients were included for evaluation, each receiving an average of 8.9 (range 2-61) doses of HTS. A statistically significant increase in mean serum sodium concentration occurred with the administration of HTS (p < 0.0001). No cases of CPM were identified. The use of HTS was found to be effective based on decreases in ICP after administration (p < 0.0001, mean ICP reduction: 10.1 mmHg, range 3-23.6 mmHg). The efficacy of 23.4 % saline in decreasing ICP was not found to be significantly different than 14.6 % saline (p = 0.23). CONCLUSIONS: Repeat bolus dosing of 14.6 or 23.4 % HTS appears to be relatively safe and effective for treating refractory intracranial hypertension assuming there is frequent electrolyte monitoring and concomitant fluid management.

Safety of intraventricular hemorrhage (IVH) thrombolysis based on CT localization of external ventricular drain (EVD) fenestrations and analysis of EVD tract hemorrhage.

BACKGROUND: The purpose of the study is to review the CT findings associated with ventriculostomy placement in regards to the safety of an EVD plus recombinant tissue plasminogen activator (rt-PA) for IVH. METHODS: A retrospective review was conducted for patients receiving intraventricular rt-PA for IVH from January 2004 to September 2009. Safety was assessed by the presence of EVD tract hemorrhage by CT at baseline after EVD placement, worsening hemorrhage after rt-PA, and CSF infection. IVH volumetrics were assessed by the Le Roux score and outcomes by Glasgow Outcome Scale and modified Rankin Scale. RESULTS: Twenty-seven patients received rt-PA for IVH. Median dose was 2 mg (range 0.3-8) and a median of two doses (range 1-17) were given. Worsening EVD catheter tract hemorrhage after rt-PA was 46.7 %, with a significantly higher incidence of worsening tract hemorrhage seen with incorrectly placed EVDs (p = 0.04). IVH hematoma burden decreased by a median Le Roux score of 10 (range 3-16) prior to rt-PA to 4 (range 0-16) after rt-PA. There were no central nervous system bacterial infections. CONCLUSION: Intraventricular rt-PA appears to be relatively safe especially when all EVD fenestrations are within the ventricle and reduces IVH burden similar to other studies. We describe a CT-based EVD tract hemorrhage grading scale to evaluate EVD tract hemorrhage before and after thrombolysis, and a bone-window technique to evaluate EVD fenestrations prior to IVH thrombolysis. Further research is needed evaluating these imaging techniques in regard to intraventricular thrombolytic safety and EVD tract hemorrhage.

Safety and Tolerability of Concentrated Intraventricular Nicardipine for Poor-Grade Aneurysmal Subarachnoid Hemorrhage-Related Vasospasm.

Objective: To report the preliminary safety, tolerability, and cerebral spinal fluid (CSF) sampling utility of serial injections of concentrated intraventricular nicardipine (IVN) in the treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods: We report the clinical, radiographic, and laboratory safety and tolerability data of a retrospective case series from a single academic medical center. All patients with aSAH developed vasospasm despite enteral nimodipine and received serial injections of concentrated IVN (2.5 mg/mL). CSF injection safety, tolerability, and utility are defined and reported. Results: A total of 59 doses of concentrated IVN were administered to three patients with poor-grade SAH. In Case 1, a 33-year-old man with modified Fisher scale (mFS) grade 4 and Hunt-Hess scale (HH) score 4 received 26 doses; in Case 2, a 36-year-old woman with mFS grade 4 and HH score 5 received 13 doses; and in Case 3, a 70-year-old woman with mFS grade 3 and HH score 4 received 20 doses. No major safety or tolerability events occurred. Two patients were discharged to a rehabilitation facility, and one died after discharge from the hospital. Conclusions: A concentrated 4 mg IVN dose (2.5 mg/mL) in a 1.6 mL injection appears relatively safe and tolerable and potentially offers a second-line strategy for treating refractory vasospasm in poor-grade SAH without compromising intracranial pressure or cerebral perfusion pressure.

Effectiveness of an electronic health system-based best-practice advisory to enhance the time to de-escalation of vancomycin for respiratory indications.

Objective: Methicillin-resistant Staphylococcus aureus (MRSA) infection is highly unlikely when nasal-swab results are negative. We evaluated the impact of an electronic prompt regarding MRSA nasal screening on the length of vancomycin therapy for respiratory indications. Design: Retrospective, single-center cohort study. Setting: Tertiary-care academic medical center (Mayo Clinic) in Jacksonville, Florida. Patients: Eligible patients received empiric treatment with vancomycin for suspected or confirmed respiratory infections from January through April 2019 (preimplementation cohort) and from October 2019 through January 2020 (postimplementation cohort). Intervention: The electronic health system software was modified to provide a best-practice advisory (BPA) prompt to the pharmacist upon order verification of vancomycin for patients with suspected or confirmed respiratory indications. Pharmacists were prompted to order a MRSA nasal swab if it was not already ordered by the provider. Methods: We reviewed patient records to determine the time from vancomycin prescription to de-escalation. The secondary end point was incidence of acute kidney injury. Results: The study included 120 patients (preimplementation, n = 61; postimplementation, n = 59). Median time to de-escalation was significantly shorter for the postimplementation cohort: 76 hours (interquartile range [IQR], 52-109) versus 42 hours (IQR, 37-61; P = .002). Acute kidney injury occurred in 11 patients (18%) in the preimplementation cohort and in 3 patients (5%) in the postimplementation cohort (P = .01; number needed to treat, 8). Conclusions: Implementation of a BPA notification for MRSA nasal screening helped decrease the time to de-escalation of vancomycin.

Colistin neurotoxicity mimicking Guillain-Barré syndrome in a patient with cystic fibrosis: case report and review.

Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy, which is characterized by areflexia and ascending paresthesia which can progress to a respiratory failure. Certain conditions, such as vasculitis and heavy metal and drug toxicity, may have misleadingly similar clinical presentation to GBS. We describe a case of a patient with cystic fibrosis and intravenous colistin-induced neurotoxicity mimicking GBS. The patient had used inhaled colistin on five occasions with no adverse effects, however, developed symptoms on the second day of intravenous treatment. Overlapping findings between immune-mediated polyneuropathy and drug-induced neurotoxicity include limb paresthesia and decreased reflexes. Perioral tingling, however, is a common presentation of colistin-induced neurotoxicity, and therefore, is an important differentiating factor. Early diagnosis prevents further neurologic decline, extensive unnecessary workup and potentially harmful incorrect management.

Eosinophils infiltrate thyroids, but have no apparent role in induction or resolution of experimental autoimmune thyroiditis in interferon-gamma(-/-) mice.

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin (MTg)-sensitized splenocytes activated with MTg and interleukin (IL)-12. Our previous studies showed that, when used as donors and recipients, interferon (IFN)-gamma(-/-) and wild-type (WT) DBA/1 mice both develop severe G-EAT. Thyroid lesions in IFN-gamma(-/-) mice have many eosinophils and few neutrophils, while those in WT mice have extensive neutrophil infiltration and few eosinophils. Thyroid lesions in IFN-gamma(-/-) mice consistently resolve by day 40-50, whereas those in WT mice have ongoing inflammation and fibrosis persisting for more than 60 days. To determine if the extensive infiltration of eosinophils in thyroids of IFN-gamma(-/-) mice contributes to thyroid damage and/or early resolution of G-EAT, anti-IL-5 was used to inhibit migration of eosinophils to thyroids. G-EAT severity was compared at day 20 and day 40-50 in IFN-gamma(-/-) recipients given anti-IL-5 or control immunoglobulin G (IgG). Thyroids of anti-IL-5-treated IFN-gamma(-/-) mice had few eosinophils and more neutrophils at day 20, but G-EAT severity scores were comparable to those of control IgG-treated mice at both day 20 and day 40-50. Expression of chemokine (C-X-C motif) ligand 1 (CXCL1) mRNA was higher and that of chemokine (C-C motif) ligand 11 (CCL11) mRNA was lower in thyroids of anti-IL-5-treated IFN-gamma(-/-) mice. IL-5 neutralization did not influence mRNA expression of most cytokines in IFN-gamma(-/-) mice. Thus, inhibiting eosinophil migration to thyroids did not affect G-EAT severity or resolution in IFN-gamma(-/-) mice, suggesting that eosinophil infiltration of thyroids occurs as a consequence of IFN-gamma deficiency, but these cells have no apparent pathogenic role in G-EAT.

Safety, Tolerability, and Efficacy of Pain Reduction by Gabapentin for Acute Headache and Meningismus After Aneurysmal Subarachnoid Hemorrhage: A Pilot Study.

Introduction: Severe, often sudden-onset headache is the principal presenting symptoms of aneurysmal subarachnoid hemorrhage (aSAH). We hypothesized that gabapentin would be safe and tolerable for aSAH-induced headaches and would reduce concurrent opioid use. Methods: We performed a single-center, double-blind, randomized, placebo-controlled trial (registered at ClinicalTrials.gov; NCT02330094) from November 24, 2014, to June 24, 2017, where aSAH patients received either dose-escalating gabapentin or oral placebo, both alongside a standard of care pain regimen. After 7 days, patients had the option to continue in an open-label period until 14 days after enrollment or until discharge from the intensive care unit. Our primary endpoint was the efficacy of gabapentin in reducing headache numeric pain scores and opioid usage in patients with aSAH compared to the placebo group. We identified 63 potential patients with aSAH for the study. After applying stringent exclusion criteria, 16 eligible patients were enrolled into one of two arms. Results: The study ended prematurely after reaching a pre-specified funding period and an unexpected drop in aSAH cases. There was a trend toward lower headache numeric pain scores and opioid use in the gabapentin treated arm; however this was not significantly different. Gabapentin was well tolerated by participants and no adverse effects were reported. Conclusions: While there was a trend toward lower pain scores and opioid requirement in the gabapentin group, the study was underpowered to detect a difference. Larger multicenter trials are required to evaluate the efficacy of gabapentin to reduce opioid requirements after aSAH.

Transition from intravenous to enteral ketamine for treatment of nonconvulsive status epilepticus.

BACKGROUND: Nonconvulsive status epilepticus (NCSE) is a diagnosis that is often challenging and one that may progress to refractory NCSE. Ketamine is a noncompetitive N-methyl-d-aspartate antagonist that increasingly has been used to treat refractory status epilepticus. Current Neurocritical Care Society guidelines recommend intravenous (IV) ketamine infusion as an alternative treatment for refractory status epilepticus in adults. On the other hand, enteral ketamine use in NCSE has been reported in only 6 cases (1 adult and 5 pediatric) in the literature to date. CASE PRESENTATION: A 33-year-old woman with a history of poorly controlled epilepsy presented with generalized tonic-clonic seizures, followed by recurrent focal seizures that evolved into NCSE. This immediately recurred within 24 h of a prior episode of NCSE that was treated with IV ketamine. Considering her previous response, she was started again on an IV ketamine infusion, which successfully terminated NCSE. This time, enteral ketamine was gradually introduced while weaning off the IV formulation. Treatment with enteral ketamine was continued for 6 months and then tapered off. There was no recurrence of NCSE or seizures and no adverse events noted during the course of treatment. CONCLUSION: This case supports the use of enteral ketamine as a potential adjunct to IV ketamine in the treatment of NCSE, especially in cases without coma. Introduction of enteral ketamine may reduce seizure recurrence, duration of stay in ICU, and morbidity associated with intubation.