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.

Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate.

BACKGROUND: Controversy exists regarding first-line use of the recently approved reversal agent andexanet alfa due to limitations of the ANEXXA-4 study, thrombotic risks, and high medication acquisition cost. The purpose of this study was to evaluate the safety and effectiveness of 4F-PCC for the reversal of emergent oral fXa inhibitor-related bleeding. Furthermore, we aimed to evaluate a subgroup using strict ANNEXA-4 patient selection criteria. METHODS: This was a retrospective study conducted utilizing chart review of adult patients that received 4F-PCC for oral fXa inhibitor-related bleeding. The primary endpoint was the rate of clinical success defined as achieving excellent or good hemostatic effectiveness following the administration of 4F-PCC. Secondary endpoints included in-hospital mortality and arterial/venous thromboembolism, and cost compared with andexanet alfa. RESULTS: A total of 119 patients were included, with 83 patients in the ANNEXA-4 criteria subgroup. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. Clinical success was achieved in 106 of 119 patients (89%) and 74 of 83 patients (90%) in the strict criteria subgroup. Three of 119 patients (2.5%) had a thrombotic event during hospital stay and the overall mortality rate was 13%. The average cost increase of andexanet alfa compared to 4F-PCC would have been $29,500 per patient. CONCLUSIONS: Administration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. Further direct prospective comparison of 4F-PCC to andexanet alfa is warranted.

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.

Therapeutic augmentation of ketogenic diet with a sodium-glucose cotransporter 2 inhibitor in a super-refractory status epilepticus patient.

BACKGROUND: A ketogenic diet (KD) may have a role in treating patients in super-refractory status epilepticus (SRSE). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have a risk of ketoacidosis that could facilitate induction of KD. CASE SUMMARY: A 42-year-old with a history of drug resistant epilepsy developed SRSE requiring several pharmacological interventions during her hospital course including the initiation of KD that failed. SGLT2 inhibitor therapy was initiated in a successful attempt to augment ketone production. CONCLUSION: SGLT2 inhibitors may have a therapeutic value in SRSE patients who cannot achieve ketosis with KD alone.

Fosphenytoin-induced purple glove syndrome: A case report.

BACKGROUND: Purple glove syndrome (PGS) is a poorly understood severe adverse drug reaction that is typically associated with intravenous phenytoin administration. Although fosphenytoin is thought to circumvent this risk of PGS, we reveal a rare case of PGS in a patient treated with fosphenytoin therapy. CASE SUMMARY: A 71-year-old male with history of epilepsy was admitted for seizures and traumatic brain injury and intravenous fosphenytoin and levetiracetam were initiated. The patient continued to have seizure activity on continuous electroencephalography for which fosphenytoin dosing was increased with subsequent seizure control. Serum phenytoin levels became elevated with a total level reaching as high as 25.8ug/mL. Three days into fosphenytoin therapy he developed PGS in both hands. Causation was assessed with the Naranjo adverse drug reaction algorithm that suggested fosphenytoin was probably the cause of PGS. Ten days after discontinuing the fosphenytoin and administering a 7-day course of methylprednisolone, the purple glove syndrome completely resolved. CONCLUSION: Early recognition and emergent management of PGS are key for optimal recovery. Although fosphenytoin has a significantly reduced risk of associated PGS compared to phenyotin, increased awareness for fosphenytoin-induce PGS can accelerate intervention and minimize morbidity of this rare yet detrimental adverse reaction.