A Retrospective Characterization of Dexmedetomidine-Suspected Fever and Its Consequences in Adult Critically Ill Patients.

BACKGROUND: Current evidence for dexmedetomidine-suspected fever (DSF) is limited. Lack of recognition may lead to costly or potentially harmful interventions for critically ill patients. OBJECTIVE: The primary objective was to characterize escalations of care related to DSF. Secondary objectives were to describe the incidence, severity, and consequences associated with DSF. METHODS: A retrospective review was conducted in critically ill adults who developed fever ≥39°C within 12 h from initiation of dexmedetomidine, with resolution of fever to <39°C within 12 h after discontinuation. The primary outcome was percentage of patients who received an escalation of care due to fever. Secondary outcomes included the percentage of patients who developed a multidrug-resistant organism or Clostridium difficile infection. RESULTS: Eighteen of 3943 patients screened in 4099 encounters met criteria for DSF (0.4%). The majority were white (83.3%), male (66.7%), and underwent cardiac surgery (61.1%). Median (interquartile range [IQR]) time to fever onset and resolution were 5.5 (3.6-7.6) and 1.3 (1.0-2.9) h. Nine patients (50%) underwent infectious workup including antimicrobial initiation (n = 1, 5.6%), broadening of antimicrobials (n = 4, 22.2%), or culture collection (n = 9, 50%). Eleven patients (61.1%) underwent attempted temperature reduction. Twelve patients (66.7%) underwent diagnostic imaging. Incidence of multidrug-resistant organism and C. difficile infection were low (11.1 and 16.7% of fever patients, respectively). CONCLUSION AND RELEVANCE: Incidence of DSF was low and more common in cardiac surgery patients. Unrecognized DSF led to an escalation of care in most patients. Dexmedetomidine exposure should be considered as a potential cause of fever in critically ill adults.

Partial Balint's syndrome and left homonymous hemianopsia presenting after resection of a right occipito-parietal glioblastoma.

A 66-year-old left-handed male was admitted to our acute inpatient rehabilitation (AIR) unit following a resection of the right occipito-parietal glioblastoma. He presented with symptoms of horizontal oculomotor apraxia, contralateral optic ataxia and left homonymous hemianopsia. We diagnosed this patient with partial Bálint's syndrome (BS)- oculomotor apraxia, optic ataxia but not simultanagnosia. BS is typically caused by bilateral posterior parietal lesions, but we here describe a unique case due toresection of a right intracranial tumor. A short AIR stay allowed our patient to learn how to compensate for visuomotor and visuospatial deficits, and improved his quality of life significantly.

Adverse events related to total ankle replacement devices: an analysis of reports to the United States Food and Drug Administration.

BACKGROUND: The published outcomes of total ankle replacement (TAR) implants came from limited institutions creating observational bias. For broader perspective, we queried the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) voluntary database to explore complications reported outside published literature. METHODS: The database was reviewed retrospectively between November 2011 and April 2019 using two product codes assigned to six TAR devices. RESULTS: Among 648 relevant reports available in the database, common complications were aseptic loosening (19.3%), infection (18.2%), and alignment/mechanical issues (16.5%). Others included instrument/instrumentation complications, impingement, polyethylene problems, fractures, avascular necrosis of talus (AVN), and packaging issues. CONCLUSION: MAUDE database revealed various patterns of device-related malfunctions that have been under-reported in published data. Despite inconsistency in the available reports, it provided opportunities for improvements in quality control, device design, and ultimately patient safety. Database would be further strengthened by more robust reporting mechanism or mandatory reporting of device-related complications.

Acid-base effects of continuous infusion furosemide in clinically stable surgical ICU patients: an analysis based on the Stewart model.

OBJECTIVES: We sought to test the strength of correlation between predicted and observed systemic acid-base status based on the Stewart model equations during continuous infusion (CI) furosemide therapy. DESIGN, SETTING AND PARTICIPANTS: This was a prospective, single-center, observational study conducted in the Surgical ICU of a large academic medical center. Ten critically ill patients who received CI furosemide were included. MAIN OUTCOMES AND MEASURES: The primary purpose was to characterize the relationship between changes in serum electrolyte and acid-base status and the excretion of electrolytes in the urine during infusion of CI furosemide in critically ill patients. As a secondary endpoint, we sought to evaluate the predictive application of the Stewart model. Over 72-h, intake and output volumes, electrolyte content of fluids administered, plasma and urine electrolytes, urine pH, and venous blood gases were collected. Predicted and observed changes in acid-based status were compared for each day of diuretic therapy using Spearman's correlation coefficient. RESULTS: The mean (SD) strong ion difference (SID) increased from 45.2 (3.2) at baseline to 49.6 (4.0) after 72 h of continuous infusion furosemide. At Day 1, the mean SID (observed) (SD) was 47.5 (3.5) and the predicted SID was 49.5 (5.8). Day 1 observed plasma SID was positively correlated with the predicted SID (rs = 0.80, p = 0.01). By Days 2 and 3, the correlations of observed and predicted SID were no longer statistically significant. CONCLUSIONS AND RELEVANCE: Using the Stewart model, increases in SID as an indicator of metabolic alkalosis due to the chloruretic effects of furosemide were observed. Predicted and observed SID correlated well over the first 24 h of treatment.

Continuous electroencephalography predicts delayed cerebral ischemia after subarachnoid hemorrhage: A prospective study of diagnostic accuracy.

OBJECTIVE: Delayed cerebral ischemia (DCI) is a common, disabling complication of subarachnoid hemorrhage (SAH). Preventing DCI is a key focus of neurocritical care, but interventions carry risk and cannot be applied indiscriminately. Although retrospective studies have identified continuous electroencephalographic (cEEG) measures associated with DCI, no study has characterized the accuracy of cEEG with sufficient rigor to justify using it to triage patients to interventions or clinical trials. We therefore prospectively assessed the accuracy of cEEG for predicting DCI, following the Standards for Reporting Diagnostic Accuracy Studies. METHODS: We prospectively performed cEEG in nontraumatic, high-grade SAH patients at a single institution. The index test consisted of clinical neurophysiologists prospectively reporting prespecified EEG alarms: (1) decreasing relative alpha variability, (2) decreasing alpha-delta ratio, (3) worsening focal slowing, or (4) late appearing epileptiform abnormalities. The diagnostic reference standard was DCI determined by blinded, adjudicated review. Primary outcome measures were sensitivity and specificity of cEEG for subsequent DCI, determined by multistate survival analysis, adjusted for baseline risk. RESULTS: One hundred three of 227 consecutive patients were eligible and underwent cEEG monitoring (7.7-day mean duration). EEG alarms occurred in 96.2% of patients with and 19.6% without subsequent DCI (1.9-day median latency, interquartile range = 0.9-4.1). Among alarm subtypes, late onset epileptiform abnormalities had the highest predictive value. Prespecified EEG findings predicted DCI among patients with low (91% sensitivity, 83% specificity) and high (95% sensitivity, 77% specificity) baseline risk. INTERPRETATION: cEEG accurately predicts DCI following SAH and may help target therapies to patients at highest risk of secondary brain injury. Ann Neurol 2018;83:958-969.

Hydrochloric Acid Infusion for the Treatment of Metabolic Alkalosis in Surgical Intensive Care Unit Patients.

BACKGROUND: Older reports of use of hydrochloric acid (HCl) infusions for treatment of metabolic alkalosis document variable dosing strategies and risk. OBJECTIVES: This study sought to characterize use of HCl infusions in surgical intensive care unit patients for the treatment of metabolic alkalosis. METHODS: This retrospective review included patients who received a HCl infusion for >8 hours. The primary end point was to evaluate the utility of common acid-base equations for predicting HCl dose requirements. Secondary end points evaluated adverse effects, efficacy, duration of therapy, and total HCl dose needed to correct metabolic alkalosis. Data on demographics, potential causes of metabolic alkalosis, fluid volume, and duration of diuretics as well as laboratory data were collected. RESULTS: A total of 30 patients were included, and the average HCl infusion rate was 10.5 ± 3.7 mEq/h for an average of 29 ± 14.6 hours. Metabolic alkalosis was primarily diuretic-induced (n = 26). Efficacy was characterized by reduction in the median total serum CO2 from 34 to 27 mM/L ( P < 0.001). The change in chloride ion deficit and change in apparent strong ion difference (SIDa) were not correlated with total HCl administered. There were no documented serious adverse effects related to HCl infusions. CONCLUSION: HCl was effective for treating metabolic alkalosis, and no serious adverse events were seen. In this clinical setting, the baseline chloride ion deficit and SIDa were not useful for prediction of total HCl dose requirement, and serial monitoring of response is recommended.

Early detection of consciousness in patients with acute severe traumatic brain injury.

See Schiff (doi:10.1093/awx209) for a scientific commentary on this article. Patients with acute severe traumatic brain injury may recover consciousness before self-expression. Without behavioural evidence of consciousness at the bedside, clinicians may render an inaccurate prognosis, increasing the likelihood of withholding life-sustaining therapies or denying rehabilitative services. Task-based functional magnetic resonance imaging and electroencephalography techniques have revealed covert consciousness in the chronic setting, but these techniques have not been tested in the intensive care unit. We prospectively enrolled 16 patients admitted to the intensive care unit for acute severe traumatic brain injury to test two hypotheses: (i) in patients who lack behavioural evidence of language expression and comprehension, functional magnetic resonance imaging and electroencephalography detect command-following during a motor imagery task (i.e. cognitive motor dissociation) and association cortex responses during language and music stimuli (i.e. higher-order cortex motor dissociation); and (ii) early responses to these paradigms are associated with better 6-month outcomes on the Glasgow Outcome Scale-Extended. Patients underwent functional magnetic resonance imaging on post-injury Day 9.2 ± 5.0 and electroencephalography on Day 9.8 ± 4.6. At the time of imaging, behavioural evaluation with the Coma Recovery Scale-Revised indicated coma (n = 2), vegetative state (n = 3), minimally conscious state without language (n = 3), minimally conscious state with language (n = 4) or post-traumatic confusional state (n = 4). Cognitive motor dissociation was identified in four patients, including three whose behavioural diagnosis suggested a vegetative state. Higher-order cortex motor dissociation was identified in two additional patients. Complete absence of responses to language, music and motor imagery was only observed in coma patients. In patients with behavioural evidence of language function, responses to language and music were more frequently observed than responses to motor imagery (62.5-80% versus 33.3-42.9%). Similarly, in 16 matched healthy subjects, responses to language and music were more frequently observed than responses to motor imagery (87.5-100% versus 68.8-75.0%). Except for one patient who died in the intensive care unit, all patients with cognitive motor dissociation and higher-order cortex motor dissociation recovered beyond a confusional state by 6 months. However, 6-month outcomes were not associated with early functional magnetic resonance imaging and electroencephalography responses for the entire cohort. These observations suggest that functional magnetic resonance imaging and electroencephalography can detect command-following and higher-order cortical function in patients with acute severe traumatic brain injury. Early detection of covert consciousness and cortical responses in the intensive care unit could alter time-sensitive decisions about withholding life-sustaining therapies.

Electronic Health Data Predict Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUD: Using electronic health data, we sought to identify clinical and physiological parameters that in combination predict neurologic outcomes after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a single-center retrospective cohort study of patients admitted with aSAH between 2011 and 2016. A set of 473 predictor variables was evaluated. Our outcome measure was discharge Glasgow Outcome Scale (GOS). For laboratory and physiological data, we computed the minimum, maximum, median, and variance for the first three admission days. We created a penalized logistic regression model to determine predictors of outcome and a multivariate multilevel prediction model to predict poor (GOS 1-2), intermediate (GOS 3), or good (GOS 4-5) outcomes. RESULTS: One hundred and fifty-three patients met inclusion criteria; most were discharged with a GOS of 3. Multivariate analysis predictors of mortality (AUC 0.9198) included APACHE II score, Glasgow Come Scale (GCS), white blood cell (WBC) count, mean arterial pressure, variance of serum glucose, intracranial pressure (ICP), and serum sodium. Predictors of death/dependence versus independence (GOS 4-5)(AUC 0.9456) were levetiracetam, mechanical ventilation, WBC count, heart rate, ICP variance, GCS, APACHE II, and epileptiform discharges. The multiclass prediction model selected GCS, admission APACHE II, periodic discharges, lacosamide, and rebleeding as significant predictors; model performance exceeded 80% accuracy in predicting poor or good outcome and exceeded 70% accuracy for predicting intermediate outcome. CONCLUSIONS: Variance in early physiologic data can impact patient outcomes and may serve as targets for early goal-directed therapy. Electronically retrievable features such as ICP, glucose levels, and electroencephalography patterns should be considered in disease severity and risk stratification scores.

Phase II Proof-of-Concept Trial of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Major Depressive Disorder.

Background: We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder. Methods: We conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo. Results: Due to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation. Conclusions: The interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176).

Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials.

OBJECTIVE: Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly. METHODS: Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials. In each trial, elderly (≥65 years) patients with insomnia were randomized to suvorexant 30 mg, suvorexant 15 mg, and placebo. By design, fewer patients were randomized to 15 mg. Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints were measured. RESULTS: Suvorexant 30 mg (N = 319) was effective compared with placebo (N = 318) on patient-reported and polysomnographic sleep maintenance, and onset endpoints at Night 1 (polysomnographic endpoints)/Week 1 (patient-reported endpoints), Month 1, and Month 3. Suvorexant 15 mg (N = 202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing because of adverse events over 3 months were 6.4% for 30 mg (N = 627 treated), 3.5% for 15 mg (N = 202 treated), and 5.5% for placebo (N = 469 treated). Somnolence was the most common adverse event (8.8% for 30 mg, 5.4% for 15 mg, 3.2% for placebo). CONCLUSION: Suvorexant generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated in elderly patients with insomnia (clinicaltrials.gov; NCT01097616, NCT01097629, NCT01021813).

A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia.

BACKGROUND: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults. METHODS: A double-blind, placebo-controlled, randomized, two 4-week-period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep. RESULTS: A total of 324 patients received study treatment, 315 received ≥1 dose of placebo, and 318 ≥1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated. CONCLUSIONS: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant.

Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis.

BACKGROUND: This study explored whether antagonism of orexin receptors might be an effective mechanism for migraine prevention. METHODS: We conducted a randomized, double-blind, placebo-controlled, pilot trial. Patients experiencing four to 14 days with migraine during a one-month baseline period were randomized to the orexin receptor antagonist filorexant 10 mg nightly or placebo for three months. Efficacy was assessed by mean monthly migraine days (headache plus at least one associated migraine symptom) and headache days. Safety and tolerability were assessed by adverse event reports and laboratory tests. RESULTS: Of 120 patients treated with filorexant and 115 treated with placebo, 97 (81%) and 101 (88%), respectively, completed the trial. There was no statistically significant difference between treatments for change from baseline in mean monthly migraine days (filorexant = -1.7, placebo = -1.3, difference = -0.4 (95% CI: -1.3, 0.4)) or headache days (filorexant = -1.7, placebo = -1.2, difference = -0.5 (95% CI: -1.4, 0.4)). Filorexant was generally well tolerated but was associated with a higher proportion of patients who reported adverse events than placebo (47% vs 37%), particularly somnolence (13% vs 4%). CONCLUSIONS: These data fail to provide evidence that antagonism of orexin receptors with filorexant, when administered at night, is effective for migraine prophylaxis.

High risk for seizures following subarachnoid hemorrhage regardless of referral bias.

BACKGROUND: To investigate the frequency, predictors, and clinical impact of electrographic seizures in patients with high clinical or radiologic grade non-traumatic subarachnoid hemorrhage (SAH), independent of referral bias. METHODS: We compared rates of electrographic seizures and associated clinical variables and outcomes in patients with high clinical or radiologic grade non-traumatic SAH. Rates of electrographic seizure detection before and after institution of a guideline which made continuous EEG monitoring routine in this population were compared. RESULTS: Electrographic seizures occurred in 17.6 % of patients monitored expressly because of clinically suspected subclinical seizures. In unselected patients, seizures still occurred in 9.6 % of all cases, and in 8.6 % of cases in which there was no a priori suspicion of seizures. The first seizure detected occurred 5.4 (IQR 2.9-7.3) days after onset of subarachnoid hemorrhage with three of eight patients (37.5 %) having the first recorded seizure more than 48 h following EEG initiation, and 2/8 (25 %) at more than 72 h following EEG initiation. High clinical grade was associated with poor outcome at time of hospital discharge; electrographic seizures were not associated with poor outcome. CONCLUSIONS: Electrographic seizures occur at a relatively high rate in patients with non-traumatic SAH even after accounting for referral bias. The prolonged time to the first detected seizure in this cohort may reflect dynamic clinical features unique to the SAH population.

Long-term open-label safety study of rizatriptan acute treatment in pediatric migraineurs.

OBJECTIVE: To evaluate the safety/tolerability of rizatriptan in the long-term acute treatment of migraine in pediatric patients. BACKGROUND: Acute migraine treatment options for children are limited. A recent single-attack trial demonstrated that rizatriptan is effective in eliminating migraine headache pain in this population. We evaluated the long-term safety and efficacy of rizatriptan when used for intermittent acute treatment. METHODS: Open-label study in pediatric migraineurs ages 12-17 years. Patients weighing <40 kg received rizatriptan (orally disintegrating tablet) 5 mg, and those weighing ≥40 kg received 10 mg. Patients could treat up to 8 mild/moderate/severe migraine attacks per month for up to 12 months. One dose of study medication was allowed in a 24-hour period. RESULTS: A total of 674 patients were enrolled, and 606 patients were treated with study medication (N = 583 for 10 mg, N = 23 for 5 mg). The mean duration in the study was 292 days, and the mean number of doses of study medication taken was 20. Over the course of the study within 14 days post-any-dose, 66.0% (400) of the 606 treated patients had any adverse event, 2.3% (14) discontinued due to an adverse event, 2.6% (16) had a serious adverse event, and 23.4% (142) had a triptan-related adverse event. Of the 16 patients with serious adverse events within 14 days post-any-dose, the adverse events in 3 were considered drug-related; all 3 patient's adverse events were classified as serious only because they were associated with an overdose (use of >1 dose of study medication in a 24-hour period). The mean percentage of patient's attacks with pain freedom at 2-hours post-dose was 46.3%; this was relatively consistent over time (Months 1-3 = 43.7%, Months 4-6 = 51.9%, Months 7-9 = 49.9%, Months 10-12 = 49.5%). CONCLUSION: Rizatriptan was generally safe and well tolerated in the long-term acute treatment of migraine in pediatric patients aged 12-17 years and demonstrated a consistent treatment effect over time.

Changes in Care Associated With Integrating Medicare and Medicaid for Dual-Eligible Individuals.

Importance: There is growing interest in expanding integrated models, in which 1 insurer manages Medicare and Medicaid spending for dually eligible individuals. Fully integrated dual-eligible special needs plans (FIDE-SNPs) are one of the largest integrated models, but evidence about their performance is limited. Objective: To evaluate changes in care associated with integrating Medicare and Medicaid coverage in a FIDE-SNP in Pennsylvania. Design, Setting, and Participants: This cohort study using a difference-in-differences analysis compared changes in care between 2 cohorts of dual-eligible individuals: (1) an integration cohort composed of Medicare Dual Eligible Special Needs Plan enrollees who joined a companion Medicaid plan following a 2018 state reform mandating Medicaid managed care (leading to integration), and (2) a comparison cohort with nonintegrated coverage before and after the start of Medicaid managed care. Analyses were conducted between February 2022 and June 2023. Main Outcomes and Measures: Analyses examined outcomes in 4 domains: use of home- and community-based services (HCBS), care management and coordination, hospital stays and postacute care, and long-term nursing home stays. Results: The study included 7967 individuals in the integration cohort and 3832 individuals in the comparison cohort. In the integration cohort, the mean (SD) age at baseline was 63.3 (14.7) years, and 5268 individuals (66.1%) were female and 2699 (33.9%) were male. In the comparison cohort, the mean (SD) age at baseline was 64.8 (18.6) years, and 2341 individuals (61.1%) were female and 1491 (38.9%) were male. At baseline, integration cohort members received a mean (SD) of 2.83 (8.70) days of HCBS per month and 3.34 (3.56) medications for chronic conditions per month, and the proportion with a follow-up outpatient visit after a hospital stay was 0.47. From baseline through 3 years after integration, HCBS use increased differentially in the integration vs comparison cohorts by 0.61 days/person-month (95% CI, 0.28-0.94; P < .001). However, integration was not associated with changes in care management and coordination, including medication use for chronic conditions (-0.02 fills/person-month; 95% CI, -0.10 to 0.06; P = .65) or follow-up outpatient care after a hospital stay (-0.01 visits/hospital stay; 95% CI, -0.04 to 0.03; P = .61). Hospital stays did not change differentially between the cohorts. Unmeasured factors contributing to differential mortality limited the ability to identify changes in long-term nursing home stays associated with integration. Conclusions and Relevance: In this cohort study with a difference-in-differences analysis of 2 cohorts of individuals dually eligible for Medicare and Medicaid, integration was associated with greater HCBS use but not with other changes in care patterns. The findings highlight opportunities to strengthen how integrated programs manage care and a need to further evaluate their performance.

Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design.

BACKGROUND: Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6-17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for < 40 kg, 10 mg for ≥ 40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12-17-year-olds. RESULTS: A higher proportion of 12-17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12-17-year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6-17-year-olds. CONCLUSION: Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12-17 and 6-17 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001234.

Rizatriptan for treatment of acute migraine in patients taking topiramate for migraine prophylaxis.

OBJECTIVE: To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis. BACKGROUND: There are limited data from prospective controlled trials demonstrating the benefit of triptans in patients who experience migraine attacks while taking prophylactic medication. METHODS: This was a worldwide, randomized, placebo-controlled, double-blind, multiple-attack study in adults with a >1-year history of migraine taking a stable dose of topiramate for migraine prophylaxis and experiencing ≥2 moderate/severe attacks per month. Participants treated 3 moderate/severe attacks in crossover fashion (2 with rizatriptan 10-mg ODT, 1 with placebo) following random assignment to 1 of 3 treatment sequences. The primary end point was 2-hour pain relief. RESULTS: Two-hour pain relief was significantly greater with rizatriptan compared with placebo (55.0% vs 17.4%, P < .001). Response rates also favored rizatriptan for sustained pain relief from 2-24 hours (32.6% vs 11.1%, P < .001), 2-hour pain freedom (36.0% vs 6.5%, P < .001), normal functional ability at 2 hours (42.2% vs 12.7%, P < .001), and overall treatment satisfaction at 24 hours (60.8% vs 33.6%, P < .001). Few participants reported adverse experiences (16 [15.8%] with rizatriptan, 3 [3.2%] with placebo); none were serious. CONCLUSION: Rizatriptan 10-mg ODT was superior to placebo at all pain end points for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Rizatriptan was generally well tolerated in this population. These results are comparable with those from clinical trials in patients not using prophylaxis, suggesting that the use of topiramate does not affect the efficacy or tolerability of rizatriptan for acute migraine treatment.

Negative Outcome Following Systemic Alteplase Administration Prior to Extracorporeal Membrane Oxygenation in a Kidney Transplant Patient With Cardiac Arrest: A Case Report.

A case of a negative outcome following systemic alteplase administration prior to extracorporeal membrane oxygenation (ECMO) in a kidney transplant patient with cardiac arrest is reported. A patient status-post kidney transplantation was admitted to the surgical intensive care unit (ICU) and experienced cardiac arrest after developing sudden-onset chest pain and shortness of breath. During cardiopulmonary resuscitation, alteplase 50 mg was administered intravenous push for suspected pulmonary embolism (PE) before the patient was evaluated for and started on veno-arterial ECMO. Within several hours, cardiopulmonary resuscitation needed to be reinitiated. Ultimately, the decision was made to cede further resuscitation efforts due to futility. A post-mortem examination included an immediate cause of death of acute myocardial infarction with extensive retroperitoneal hemorrhage. The role of ECMO is emerging in cardiac arrest, and should be considered as a management option before the administration of systemic thrombolysis in patients with increased bleeding risk.

Adverse Events Related to Cartiva Hemiarthroplasty of First Metatarsal: An Analysis of Reports to the United States Food and Drug Administration.

Background: The results supporting Cartiva, a synthetic cartilage implant (Wright Medical) in hallux rigidus have come from limited institutions creating observational bias. Complications experienced in community centers are not routinely included in the published literature. To look at a broader range of potential complications, we reviewed the United States Food and Drug Administration's (FDA) voluntary device database and compared that data with published literature. Methods: The Manufacturer and User Facility Device Experience (MAUDE) database of the FDA was retrospectively reviewed between July 2016 and October 2019 using the product code: PNW, assigned for Cartiva. Results: A total of 49 events have been reported and implant subsidence was the most common with 16 reports. Others include fragmentation (9), infection (4), bone erosion (3), foreign body reaction (1) and unspecified (16). Thirty-five events mentioned further surgeries at a mean interval of 4.75 months. Conclusions: The analysis of the MAUDE database disclosed certain device-related dysfunctions that have been underreported in the published literature. Because of the voluntary nature of reporting, the true incidence of each complication is unknown with this data representing a baseline. The MAUDE database could be further strengthened by a more robust reporting mechanism or mandatory reporting of device-related complications.Levels of Evidence: Level IV: Case series from large database analysis.