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Objective To study coronary interventions and mortality among patients with ST-elevated myocardial infarction (STEMI) who were admitted with septic shock. Methods Data from the national emergency department sample (NEDS) that constitutes 20% sample of hospital-owned emergency departments in the United States was analyzed for the septic shock related visits from 2016 to 2018. Septic shock was defined by the ICD codes. Results Out of 1 375 507 adult septic shock patients, 521 300 had a primary diagnosis of septic shock (mean age 67.41±15.67 years, 51.1% females) in the national emergency database for the years 2016 to 2018. Of these patients, 2768 (0.53%) had STEMI recorded during the hospitalization. Mortality rates for STEMI patients were higher than patients without STEMI (52.3% vs 23.5%). Mortality rates improved with PCI among STEMI patients (43.8% vs 56.2%). Coronary angiography was performed among 16% of patients of which percutaneous coronary intervention (PCI) rates were 7.7% among patients with STEMI septic shock. PCI numerically improved mortality, however, had no significant difference than patients without PCI on multivariate logistic regression and univariate logistic regression post coarsened exact matching of baseline characteristics among STEMI patients. Among the predictors, STEMI was a significant predictor of mortality in septic shock patients (OR 2.87, 95% CI 2.37-3.49; PConclusion STEMI complicating septic shock worsens mortality. PCI and coronary angiography numerically improved mortality, however, had no significant difference from patients without PCI. More research will be needed to improve mortality in such a critically ill subgroup of patients.

Objective To determine whether surge conditions were associated with increased mortality. Design Multicenter cohort study. Setting U.S. ICUs participating in STOP-COVID. Patients Consecutive adults with COVID-19 admitted to participating ICUs between March 4 and July 1, 2020. Interventions None Measurements and Main Results The main outcome was 28-day in-hospital mortality. To assess the association between admission to an ICU during a surge period and mortality, we used two different strategies: (1) an inverse probability weighted difference-in-differences model limited to appropriately matched surge and non-surge patients and (2) a meta-regression of 50 multivariable difference-in-differences models (each based on sets of randomly matched surge- and non-surge hospitals). In the first analysis, we considered a single surge period for the cohort (March 23 – May 6). In the second, each surge hospital had its own surge period (which was compared to the same time periods in matched non-surge hospitals). Our cohort consisted of 4342 ICU patients (average age 60.8 [sd 14.8], 63.5% men) in 53 U.S. hospitals. Of these, 13 hospitals encountered surge conditions. In analysis 1, the increase in mortality seen during surge was not statistically significant (odds ratio [95% CI]: 1.30 [0.47-3.58], p = .6). In analysis 2, surge was associated with an increased odds of death (odds ratio 1.39 [95% CI, 1.34-1.43], p Conclusions Admission to an ICU with COVID-19 in a hospital that is experiencing surge conditions may be associated with an increased odds of death. Given the high incidence of COVID-19, such increases would translate into substantial excess mortality.

Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. NCT02960854.

Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear.Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability.In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models.A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%).There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival. Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. Primary Funding Source: None.

BackgroundPatients with distributive shock who are unresponsive to traditional vasopressors are commonly considered to have severe distributive shock and are at high mortality risk. Here, we assess the cost-effectiveness of adding angiotensin II to the standard of care (SOC) for severe distributive shock in the US critical care setting from a US payer perspective.MethodsShort-term mortality outcomes were based on 28-day survival rates from the ATHOS-3 study. Long-term outcomes were extrapolated to lifetime survival using individually estimated life expectancies for survivors. Resource use and adverse event costs were drawn from the published literature. Health outcomes evaluated were lives saved, life-years gained, and quality-adjusted life-years (QALYs) gained using utility estimates for the US adult population weighted for sepsis mortality. Deterministic and probabilistic sensitivity analyses assessed uncertainty around results. We analyzed patients with severe distributive shock from the ATHOS-3 clinical trial.ResultsThe addition of angiotensin II to the SOC saved .08 lives at Day 28 compared to SOC alone. The cost per life saved was estimated to be $108,884. The addition of angiotensin II to the SOC was projected to result in a gain of .96 life-years and .66 QALYs. This resulted in an incremental cost-effectiveness ratio of $12,843 per QALY. The probability of angiotensin II being cost-effective at a threshold of $50,000 per QALY was 86 percent.ConclusionsFor treatment of severe distributive shock, angiotensin II is cost-effective at acceptable thresholds.

Background In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. Methods We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes. Results Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30–676.00 pg/mL] vs 42 pg/mL [IQR 30.46–87.34 pg/mL] in controls; P P P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P P P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P P = 0.003). In the placebo group, a baseline ANG I/II ratio P = 0.01) on unadjusted analyses. Conclusions Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction. Trial registration ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Introduction: Rhabdomyolysis and delayed acetaminophen hepatotoxicity may be associated with elevated serum transaminase values. Establishing the cause of elevated transaminases may be especially difficult because of limited or inaccurate histories of acetaminophen ingestion. We hypothesized that the comparative ratios of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) can differentiate acetaminophen hepatotoxicity from rhabdomyolysis. Methods: A retrospective chart review of patients in four hospitals from 2006 to 2011 with a discharge diagnosis of acetaminophen toxicity or rhabdomyolysis was performed. Subjects were classified into three groups: rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose with undetectable serum acetaminophen concentrations [acetaminophen(delayed)]. Ratios of AST, ALT, and CK were compared using non-parametric statistical methods. Results: 1,353 subjects were identified and after applying our exclusion criteria there were 160 in the rhabdomyolysis group, 68 in the acetaminophen overdose (all) group, and 29 in the acetaminophen (delayed) group. The AST/ALT ratio for the rhabdomyolysis group was 1.66 (Interquartile range: 1.18–2.22), for the acetaminophen overdose (all) group was 1.38 (1.08–1.69, statistically lower than the rhabdomyolysis group, p = 0.018), and for the acetaminophen (delayed)group was 1.30 (1.06–1.63, p = 0.037). CK/AST ratios were 21.3 (12.8–42.2), 5.49 (2.52–15.1, p < 0.001), and 3.80 (1.43–13.8, p < 0.001) respectively. CK/ALT ratios were 37.1 (16.1–80.0), 5.77 (2.79–25.2, p < 0.001), and 5.03 (2.20–17.4, p < 0.001) respectively. Increasing CK to transaminase ratio cutoffs resulted in increasing test sensitivity but lower specificity. Conclusion: AST/ALT, CK/AST and CK/ALT ratios are significantly larger in rhabdomyolysis when compared to patients with acetaminophen toxicity. This result suggests that the ratios could be used to identify patients with rhabdomyolysis who otherwise might have been diagnosed as delayed acetaminophen toxicity. Such patients may not require treatment with N-acetylcysteine, resulting in cost savings and improved resource utilization.

Introduction Prolongation of the QT interval is a well-recognized complication associated with many commonly used medications. Emergency Department monitoring of the corrected QT (QTc) both before and after medication administration is typically performed using the 12‑lead electrocardiogram (ECG). The purpose of this study is to compare the QTc reported on the 12‑lead ECG to that reported by single brand of bedside monitor. Methods A convenience sample of emergency department patients over the age of 18 undergoing bedside monitoring and who had an ECG ordered by their treating physician were enrolled. These patients underwent simultaneous ECG and monitor QTc calculation. The primary outcome of interest was the correlation between the monitor and ECG QTc. Secondary outcomes included ability of each method to identify patients with a QTc > 500 ms and the ability of each method to identify patients with a QTc Results A total of 125 patients had simultaneous ECG and monitor QTc measurements recorded. There was moderate correlation between the monitor and ECG QTc (Pearson's correlation coefficient = 0.55). The median difference between the ECG QTc and the monitor QTc (ECG QTc minus monitor QTc) was − 7 ms (IQR − 23 to 11 ms). Conclusion We found that there was moderate correlation between the QTc reported on the 12 lead ECG and that reported by the bedside monitor. This correlation is not strong enough to support the use of the bedside monitor as a substitute for the 12‑lead ECG when evaluating a patient's QTc.

INTRODUCTION: Antidotes are available to treat some specific poisonings; however, the mainstay of treatment for the poisoned patient remains supportive care. Extracorporeal membrane oxygenation (ECMO) is one of the most aggressive supportive measures available to manage poisoned patients. OBJECTIVE: To characterize the recommendation and use of ECMO in cases reported to the California Poison Control System (CPCS). METHODS: This retrospective chart review queried the CPCS database from 1997 to 2016 for cases containing the American Association of Poison Control Centers (AAPCC) code for ECMO, and “ECMO” and “ECLS” free-text searches. The collected data included year, age, gender, substances involved, route of exposure, clinical effects, treatments, and medical outcome. RESULTS: A total of 94 cases discussed ECMO as a supportive option with 16 cases utilizing ECMO. Cases where ECMO was discussed rose from one case in 1997 to 13 cases in 2016. Of the 94 cases where ECMO was discussed, 38 cases (40%) involved toxicity from a cardiovascular agent(s) and 33 cases (35%) involved exposure to hydrocarbons. Of the 16 cases where ECMO was performed, 13 (81%) involved males. The median age was 17 years (range 1 month–54 years). Ten cases (63%) involve patients under the age of 18. In this series, 13 of 16 ECMO-supported patients survived (81%). CONCLUSIONS: ECMO is being recommended more often for treatment of acute poisoning cases by the CPCS. All caregivers involved in the treatment of poisoning should gain a working knowledge of the potentially lifesaving technology of ECMO, its indications for use, adverse effects, and drug or poison interactions.

Background We sought to determine the effects of alternative resuscitation strategies on microcirculatory perfusion and examine any association between microcirculatory perfusion and mortality in sepsis. Methods This was a prospective, formally designed substudy of participants in the Protocolized Care in Early Septic Shock (ProCESS) trial. We recruited from six sites with the equipment and training to perform these study procedures. All subjects were adults with septic shock, and each was assigned to alternative resuscitation strategies. The two main analyses assessed (1) the impact of resuscitation strategies on microcirculatory perfusion parameters and (2) the association of microcirculatory perfusion with 60-day in-hospital mortality. We measured sublingual microcirculatory perfusion using sidestream dark field in vivo video microscopy at the completion of the 6-h ProCESS resuscitation protocol and then again at 24 and 72 h. Results We enrolled 207 subjects (demographics were similar to the overall ProCESS cohort) and observed 40 (19.3%) deaths. There were no differences in average perfusion characteristics between treatment arms. Analyzing the relationship between microcirculatory perfusion and mortality, we found an association between vascular density parameters and mortality. Total vascular density (beta = 0.006, p

Venlafaxine is commonly used in the United States for approved and non-Food and Drug Administration–approved indications in adults. It is used off-label to treat children for psychiatric diagnoses. The aim of the study was to describe venlafaxine toxicities in children and to identify the venlafaxine dose per weight that correlates with toxicities. An 11-year retrospective study of venlafaxine ingestion in children was performed using the California Poison Control System (CPCS) database. Data was extracted from phone calls received by CPCS clinicians and follow-up phone calls made to assess the patient’s progress in a health-care setting. Inclusion criteria were venlafaxine ingestion cases reported to CPCS between January 2001 and December 2011, children aged 20 years and under, venlafaxine as the only ingested substance, managed in a health-care facility, and followed to a known outcome. Two hundred sixty-two cases met the study criteria. Common presentations included gastrointestinal (14.9%), altered mental status (13.7%), and tachycardia (13.4%). The majority of the cases resulted in no effect (51.5%) or minor effect (19.9%). The average estimated dose per weight was 18.3 mg/kg in all patients and 64.5 mg/kg in those experiencing moderate-to-severe adverse effects. Seizures occurred in only 4 of the 262 cases at doses ranging from 1500 to 7500 mg. Although the estimated dose per weight exceeded 10 mg/kg for the majority of the cases, only 12 cases resulted in moderate or severe outcomes. The majority of venlafaxine ingestion cases in children resulted in either no clinical effects or minor clinical effects.

In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols.Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock.ICUs of Acute Respiratory Distress Syndrome Network participating hospitals.Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite.Fluid management by protocol.Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite).FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

BACKGROUND Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 mu g of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P

Background: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. Trial registration ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Seizures of both immediate and delayed onset after ingestion of bupropion SR and bupropion XL formulations are well documented, but are less well characterized after insufflation. Bupropion is crushed and insufflated to experience a high similar to that from amphetamines and cocaine. We sought to characterize the abuse of bupropion via insufflation in cases reported to the California Poison Control System (CPCS) and the incidence of seizures.An 11-year (2002-2012) retrospective observational case series of insufflated bupropion exposures evaluated in a health care facility (HCF) were reviewed after searching our database for all bupropion insufflation exposures. Patients with coingestants, multiple exposure routes, or age less than 18 were excluded. Data included age, gender, estimated bupropion dose, occurrence of pre-HCF seizures, symptoms and vital signs reported to the CPCS, treatments, and adverse events that occurred until time of discharge.74 cases were identified (1 excluded due to age, 5 excluded due to additional oral ingestion of bupropion, and 1 excluded due to being unable to follow). A total of 67 cases met inclusion criteria. The median age was 36 (range, 18-65) years. The total dose of bupropion insufflated was reported in 52 pts; median dose of 1500 (range, 100-9000) mg. Eighteen cases (27%) involved staggered or chronic exposures. Of the 67 patients, 20 (30%) experienced a seizure prior to arrival at the HCF. Of these, 19 patients (95%) presented with tachycardia. None of these patients had a second seizure in the emergency department. There were no major medical outcomes and no deaths. Of the 67 patients, 9 patients received benzodiazepines and 6 patients received single-dose activated charcoal.The abuse of bupropion by crushing and insufflating through the nose is uncommon (67/2270 or 3.0%) compared with that by oral bupropion exposures reported to CPCS. Seizures are common but are self-limited. Delayed seizures (more than 8 h after exposure) appear to be rare. Tachycardia is present in almost all patients who have seizures.

Objective Characterize clinical presentations and outcomes of dabigatran and rivaroxaban exposures reported to a poison control system. Methods Data for cases of dabigatran and rivaroxaban exposures called into the California Poison Control System from January 2011 to July 2013 were collected. Data collected included patient demographics, type of exposure, medication, dosage, vital signs, laboratory values, interventions, outcomes, and disposition. Exclusion criteria included confirmed nonexposures or miscoded cases. Results A total of 56 cases were identified, with 7 excluded, leaving 37 dabigatran and 12 rivaroxaban cases. Children age 12 years or less accounted for 5 dabigatran and 2 rivaroxaban cases. Bleeding was reported in 15 dabigatran cases. There were 4 cases of acute self-harm overdose with dabigatran ranging from 1800 to 3900 mg. Mild bleeding was reported in only one of these overdose cases. There were 2 fatal hemorrhages in dabigatran cases, both in chronic therapeutic dosing. Bleeding was reported in 5 rivaroxaban cases, all in patients with chronic exposure; no deaths were reported. There were no adverse outcomes in pediatric patients. Coagulation parameters did not correlate well with bleeding. Conclusions In our series, the greatest risk of adverse events was in patients chronically taking these agents, irrespective of excess dosing. Acute self-harm ingestions and accidental pediatric ingestions had few adverse effects, although massive overdose can lead to abnormal coagulation studies. It does not appear that single low-dose ingestions of either medication will lead to clinically significant bleeding. It may be possible to manage some pediatric exposures and most accidental ingestions with observation.

Methamphetamine (METH) has been associated with a dilated cardiomyopathy. The first and rate-limiting step of metabolism is dependent on the polymorphic enzyme CYP2D6.To evaluate if polymorphisms in CYP2D6 can be associated with the development of a methamphetamine-induced cardiomyopathy.We performed a prospective case-control pilot study. Cases were defined by a urinary drug screen positive for amphetamine and evidence of heart failure by beta natriuretic peptide (BNP) greater than 300 pg/ml and symptoms of heart failure. Controls were defined with urinary drug screens positive for amphetamines but without evidence of heart failure defined by a BNP lesser than 300 pg/ml or symptoms of heart failure. Exclusion criteria were less than 18 years or greater than 60 years of age, urinary toxicology screen positive for additional stimulants, known coronary artery disease (CAD) defined by greater than 50% stenosis on catheterization or previous myocardial infarction, known cardiomyopathy of alternative etiology or inability to provide consent. Patients underwent gas chromatography confirmation-mass spectroscopy for methamphetamine, genotyping of CYP2D6, limited echocardiography, and participated in a modified 2007 National Survey of Drug Use and Health Stimulant Survey. Genotype results were analyzed with traditional classifications and "Activity Scores".Fifty-six patients completed the study with 19 cases and 37 controls. There was no statistically significant difference in days of use in a month, age, gender, or ethnicity between cases and controls. While not statistically significant, age and days of use did trend higher in cases. CYP2D6 genotype demonstrated that the lower the activity score/poor metabolizer group had less heart failure than extensive metabolizers/higher activity score. However, it did not reach statistical significance. When adjusting for higher days of use, extensive metabolizers had the highest odds of developing a dilated cardiomyopathy. (OR: 2.33, 95% CI: 0.54-10.13). Echo findings in all cases showed reduced ejection fractions with a mean of 18.6% (range: 10-35%) and 70% had a dilated cardiomyopathy. No cardiomyopathies were seen in the controls. Mean ejection fraction was 56.75% (range: 45-70%). The odds ratio of having a dilated cardiomyopathy in extensive metabolizers was 1.62 (95% CI: 0.47-5.5).Our study demonstrates a trend that individuals with decreased metabolic activity were less likely to develop heart failure. While not statistically significant, a signal is present that extensive metabolizers may be at increased risk for the development of a cardiomyopathy.

Contrast media used today is considered "low-osmolality." No study has evaluated the effect of intravenous contrast media on the measurement of the osmolal gap in adult patients.To determine if "low-osmolality" intravenous contrast media administered to adult patients undergoing computed tomography (CT) of the abdomen and pelvis affects the osmolal gap.We performed a prospective pilot study in the Emergency Department of a university-affiliated tertiary care center. Patients were enrolled if they were age ≥18 years and60 years and the treatment team had ordered an abdomen and pelvis CT with intravenous (i.v.) contrast procedure and a serum basic metabolic panel (BMP) that included serum glucose, blood urea nitrogen, and sodium. Once enrolled, a serum osmolality and serum ethanol level was ordered and obtained on the same blood draw as the BMP before the CT. Patients were excluded if they had detectable ethanol on laboratory screen, if they were suspected to have ingested methanol, ethylene glycol, isopropanol, mannitol, or underwent CT with i.v. contrast within the prior 24 h. Paired samples were compared using the Wilcoxon signed-rank test.Of the 100 patients screened, 18 patients were lost due to withdrawal of consent or missing data. The median of the osmolal gap pre-CT was 8.18 with an interquartile range of 4.76-11.15. The median of the osmolal gap post-CT was 11.23 with an interquartile range of 7.29-14.83. The difference in the osmolal gap was a median of 2.34 (p = 0.0003) with an interquartile range of -1.32-5.97.Although the effect in our study was small, clinicians should be aware of the ability of contrast media to increase the osmolal gap.

OBJECTIVE The current national opioid epidemic is a public health emergency. We have identified an outbreak of exaggerated opioid toxicity caused by fentanyl adulterated tablets purchased on the street as hydrocodone/acetaminophen. METHODS Over an 8-day period in late March 2016, a total of 18 patients presented to our institution with exaggerated opioid toxicity. The patients provided a similar history: ingesting their "normal dose" of hydrocodone/acetaminophen tablets but with more pronounced symptoms. Toxicology testing and analysis was performed on serum, urine, and surrendered pills. RESULTS One of the 18 patients died in hospital. Five patients underwent cardiopulmonary resuscitation, one required extracorporeal life support, three required intubation, and two received bag-valve-mask ventilation. One patient had recurrence of toxicity after 8 hours after naloxone discontinuation. Seventeen of 18 patients required boluses of naloxone, and four required prolonged naloxone infusions (26-39 hours). All 18 patients tested positive for fentanyl in the serum. Quantitative assays conducted in 13 of the sera revealed fentanyl concentrations of 7.9 to 162 ng/mL (mean = 52.9 ng/mL). Pill analysis revealed fentanyl amounts of 600-6,900 μg/pill. The pills are virtually indistinguishable from authentic hydrocodone/acetaminophen tablets and are similar in weight. To date, our county has reported 56 cases of fentanyl opioid toxicity, with 15 fatalities. In our institution, the outbreak has stressed the capabilities and resources of the emergency department and intensive care units. CONCLUSIONS A serious outbreak of exaggerated opioid toxicity caused by fentanyl-adulterated tablets purchased on the street as hydrocodone/acetaminophen is under way in California. These patients required higher dosing and prolonged infusions of naloxone. Additionally, observation periods off naloxone were extended due to delayed, recurrent toxicity. The outbreak has serious ramifications for public health and safety, law enforcement, and healthcare facilities and resources.

Asthma is a highly prevalent disease that presents commonly to the emergency department (ED) in acute exacerbation. Recent asthma treatment guidelines have added content dedicated to the management of acute exacerbations. Effective management of an exacerbation requires rapid assessment of severity through physical examination, measurement of peak expiratory flow rate, and response to initial treatment. Most therapies are directed at alleviating bronchospasm and decreasing airway inflammation. While inhaled short-acting beta-agonists, systemic corticosteroids, and supplemental oxygen are the initial and often only therapies required for patients with mild moderate exacerbations, high-dose beta agonists and inhaled anti-cholinergics should also be given to patients with severe exacerbations. Adjunctive therapy with intravenous magnesium and Heliox-driven nebulization of bronchodilators should be considered for patients presenting with severe and very severe exacerbations. Early recognition and appropriate management of respiratory failure are required to mitigate the risk of complications including death. Disposition should be determined based on serial assessments of the response to therapy over the first 4 h in the ED. Patients stable for discharge should receive medications, asthma education including a written asthma action plan, and should have follow-up scheduled for them by ED staff. Rapid implementation of evidence-based, multi-disciplinary care is required to ensure the best possible outcomes for this potentially treatable disease.

To test a multiplex real-time polymerase chain reaction (PCR) method for simultaneous detection of multiple organisms in bloodstream infections.Prospective observational study at the University of California Davis Medical Center (Sacramento, CA). Two hundred adult (18 yrs) patients from the emergency room, intensive care units, and general medicine wards at risk of a bloodstream infection and who manifested signs of systemic inflammatory response syndrome (SIRS). Whole blood samples for PCR testing were collected at the same time as blood culture (BC). PCR results were compared to blood and other culture results.PCR detected potentially significant bacteria and fungi in 45 cases compared to 37 by BC. PCR detected the methicillin resistance (mecA) gene in all three culture-confirmed methicillin-resistant Staphylococcus aureus cases. More than 68% of PCR results were confirmed by blood, urine, and catheter culture. Independent clinical arbitrators could not rule out the potential clinical significance of organism(s) detected by PCR, but not by BC. PCR did not detect Enterococcus faecalis in five BC-confirmed cases. On average, seven patient samples could be tested simultaneously with the PCR method in 6.54 +/- .27 hrs.Multiplex PCR detected potentially significant bacteria and fungi that were not found by BC. BC found organisms that were not detected by PCR. Despite limitations of both BC and PCR methods, PCR could serve as an adjunct to current culture methods to facilitate early detection of bloodstream infections. Early detection of microorganisms has the potential to facilitate evidence-based treatment decisions, antimicrobial selection, and adequacy of antimicrobial therapy.

Study Objective. To assess the effectiveness of using low-dose recombinant activated factor VII (rFVIIa) to reverse the effects of warfarin in critically ill patients with major bleeding events. Design. Prospective observational study. Setting. Intensive care unit of a 500-bed university-affiliated hospital. Patients. Sixteen nonhemophiliac patients who had been receiving warfarin and had an acute major bleeding event. Intervention. Patients received rFVIIa 1.2 mg for reversal of anticoagulation. Measurements and Main Results. Patients were identified from clinical pharmacology consult service electronic tracking records, and their data were cross-checked with the pharmacy information system. Information collected for each patient included extent of bleeding and magnitude of elevation in international normalized ratio (INR). A mean ± SD dose of rFVIIa 16.3 ± 4.1 μg/kg (range 11–25 μg/kg) reduced the mean INR from 2.8 ± 1.6 (range 1.44–6.34) to 1.07 ± 0.27 (range 0.86–1.92, p

Magnesium (Mg) may be a significant factor in asthma management. There is debate about how to best assess Mg status. We evaluated multiple indices of Mg status and lung function in 52 people with mild to moderate asthma and 47 controls. Mg measures included serum total, ionized and erythrocyte Mg, intravenous Mg load retention and dietary recall. Methacholine challenge and pulmonary function tests were used to assess diagnosis and severity of asthma. Mg status was similar in asthma and controls, and was not correlated to lung function. Total serum Mg closely reflected ionized Mg and offers a useful clinical diagnostic monitor.

Background/purpose Mono-L-aspartyl chlorin e6 (NPe6) is a photosensitizer that exhibits chemical purity, absorption at 664 nm wavelength and may be useful in photodynamic therapy (PDT). Methods This open label phase I clinical trial at the University of California, Davis Medical Center examined the pharmacokinetic properties of Npe6 and clinical response to PDT with this photosensitizer. A single intravenous dose of Npe6 was administered to 14 cancer patients with superficial malignancies (basal cell carcinoma = 22 lesions, squamous cell cancer = 13 lesions, papillary carcinoma = 14 lesions). Patients received one of five ascending doses (0.5 mg/kg (n = 4), 1.0 mg/kg (n = 3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n = 1)) 4-8 h prior to light activation. The total light dose (range 25-200 J/cm2) depended on the tumor shape and size. Light was delivered using an argon-pumped tunable dye laser. Serum NPe6 concentrations were measured over a 28-day period. The toxicity and cutaneous clinical efficacy of NPe6 were observed. Results Four weeks post-PDT, 20 of 22 basal cell carcinoma tumors (91%) showed a complete response. Eighteen of 27 other malignant cutaneous tumors showed a complete (n = 15/27, 56%) or partial (n = 3/27, 11%) response. Fewer non-responders were seen at an Npe6 dose level of 1.65 mg/kg or higher. Only 2 of 14 patients experienced an adverse event that was definitely related to NPe6 administration. Photosensitivity resolved within 1 week of NPe6 dosing in 12 of 14 patients. Analysis of serum levels of 11 individual patients indicated that a two-compartment model with a residual phase best fits the data. The mean alpha, beta, and terminal half-lives were 8.63+/-2.92, 105.90+/-37.59 and 168.11+/-53.40 h (+/-1 SD), respectively. The observed mean volume of distribution was 5.94+/-2.55 l, and the mean clearance was 0.0394+/-0.0132 l/h. These values were independent of the dose administered. Conclusion The photosensitizer, NPe6, was well tolerated with minimal phototoxic side effects, and demonstrated preliminary efficacy against cutaneous malignancies.

Objective: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. Design: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. Setting: One hundred fifty-seven intensive care units in the United States and Canada. Patients: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Interventions: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. Measurements and Main Results: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. Conclusions: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels. (Crit Care Med 2004; 32:2173‐2182)

Amphetamine-derived medications are being prescribed with increasing frequency to younger pediatric patients to treat attention deficit hyperactivity disorder. Although choreiform movements were reported in adults with amphetamine abuse and in those under therapeutic treatment for attention deficit hyperactivity disorder, previous literature concerning the pediatric population is spare. We describe two children who developed chorea after ingesting amphetamine-derived medications prescribed to treat attention deficit hyperactivity disorder. Patient 1, a 10-year-old boy, accidently received an extra dose of lisdexamfetamine dimesylate the night before the onset of acute chorea involving his arms, legs, and trunk. Patient 2, an 8-month-old boy, accidentally ingested his stepbrother's mixed amphetamine salts (Adderall XR) and developed acute chorea. Benzodiazepines, diphenhydramine, benztropine, and opioids did not suppress the chorea in either case. The 10-year-old received haloperidol, which significantly improved his abnormal findings, and he returned to baseline in approximately 48 hours. The 8-month-old was observed in the pediatric intensive care unit, and his signs resolved by 72 hours. Our cases demonstrate that choreiform movements of sustained duration can occur in children with acute supratherapeutic ingestions of amphetamine-derived medications.

Study objective: We determine the incidence of clinically important bleeding in children with superwarfarin rodenticide ingestions not treated with gastrointestinal decontamination or prophylactic vitamin K. Methods: We prospectively studied patients younger than 6 years of age who reported to our poison center with acute unintentional superwarfarin ingestions. Patients who received gastrointestinal decontamination or prophylactic vitamin K were excluded. Forty-eight– to 96-hour prothrombin time or international normalized ratio (INR) blood tests were recommended, and telephone contact was attempted at least 3 days after ingestion. Results: A total of 595 consecutive patients were enrolled during the 16-month study period. Fifty patients were excluded: 8 who were known to have ingested 1 pellet or less; 25 who received activated charcoal; 15 who were treated with induced emesis; and 2 who received prophylactic vitamin K. The resulting study group contained 545 patients. Eighty-two patients were lost to follow-up. Follow-up was obtained for 463 patients, including 222 by telephone contact alone, 62 by 48- to 96-hour INR, and 179 by both methods. None of the patients had clinically important coagulopathy. Two patients had an INR of 1.5 or greater (1.5 and 1.8) without symptoms. Single nosebleeds were reported in another 2 patients with normal 48-hour INRs. Another child had a small amount of blood crusted in the nose with no other symptoms and no laboratory work available. One child with a normal 48-hour INR had blood-streaked stools that were thought to be caused by an anal fissure. Conclusion: Children with acute unintentional superwarfarin ingestions of less than 1 box may be managed without gastric decontamination or prophylactic vitamin K. Laboratory testing for coagulopathy should be reserved for cases involving clinically evident bleeding abnormalities. [Ingels M, Lai C, Tai W, Manning BH, Rangan C, Williams SR, Manoguerra AS, Albertson T, Clark RF. A prospective study of acute, unintentional, pediatric superwarfarin ingestions managed without decontamination. Ann Emerg Med. July 2002;40:73-78.]

© 2014Sriratanaviriyakul et al.; licensee BioMed Central Ltd. Introduction. Drug reaction with eosinophilia and systemic symptoms syndrome is a potentially life-threatening cutaneous hypersensitivity reaction characterized by extensive mucocutaneous eruption, fever, hematologic abnormalities including eosinophilia and/or atypical lymphocytosis, and extensive organ involvement. The drugs most often responsible for causing drug reaction with eosinophilia and systemic symptoms syndrome are anticonvulsants, antimicrobial agents and antipyretic or anti-inflammatory analgesics. Although azithromycin is widely prescribed in clinical practice, serious cutaneous reactions from this agent have been rarely described. We report the first adult case of drug reaction with eosinophilia and systemic symptoms syndrome associated with azithromycin.Case presentation. A 44-year-old previously healthy Caucasian man with history of tobacco use presented to his primary care physician with fever and productive cough. He was prescribed azithromycin, promethazine hydrochloride and dextromethorphan hydrobromide syrup. One week later, he developed a blistering erythematous rash over both hands, which over the next two weeks spread to involve nearly his entire body surface, sparing only his face. He was admitted to an outside hospital with signs of systemic inflammatory response syndrome and severe sepsis, presumably from a skin infection. Despite aggressive therapy he deteriorated, with worsening diffuse erythema, and was transferred to our institution. He developed multiple organ failure requiring ventilatory and hemodynamic support. Pertinent laboratory studies included a leukocytosis with a white blood cell count of 17.6×109/L and 47% eosinophils. A skin biopsy showed evidence of spongiotic lichenoid dermatitis with eosinophils and neutrophils, compatible with a systemic drug-induced hypersensitivity reaction. Our patient was started on high-dose steroids and showed dramatic improvement within 48 hours.Conclusions: We report the first adult case of drug reaction with eosinophilia and systemic symptoms syndrome associated with azithromycin exposure. Clinicians should be aware of this potentially devastating complication from this commonly prescribed medication.

Levetiracetam is a new anticonvulsant, which works to block high-voltage-activated Ca(++) channels in children, for partial-onset seizures. Reports of clinical experience with pediatric ingestions are minimal. The purpose of this study was to characterize the toxicity of accidental levetiracetam exposures in children less than 6 years of age.This was an 11-year retrospective observational case series of pediatric (6 years old) levetiracetam ingestions reported to a Poison Control System from 2002 to 2013. Case narratives were individually reviewed to collect desired information on exposure and clinical course. Inclusion criteria were levetiracetam as a single ingested medication, age less than 6 years, treatment in a health care facility, and followed to a known outcome.Eighty-two cases met inclusion criteria with 55% female patients and overall median age of 2.0 years (range: 1-60 months). The levetiracetam dose ingested was reported in 69 (84.1%) cases, with exact dose (median dose, 45.0 mg/kg; range, 10.5-1429 mg/kg) reported in 33 cases (40.2%). Of these, twenty-nine cases (88%) involved the oral solution formulation and 28 cases (85%) had unintentional therapeutic error as the cause of the exposure. No dose-response relationship was demonstrated; however, the odds of a levetiracetam-naive patient, (median dose, 26.9 mg/kg; N = 15) with an unintentional exposure, developing drowsiness or ataxia was 6 times that of a patient who was not naïve to levetiracetam (median dose, 70.1 mg/kg; N = 20) (Odds ratio [OR], 6.0; 95% confidence interval [CI], 1.03-35.91).Of the 82 cases, 17 (20.7%) developed untoward clinical effects of drowsiness and/or ataxia. Eighty patients (97.6%) were treated and discharged from the emergency department, and two patients (2.4%) were admitted. The two patients admitted included a two-month old who was accidentally given a dose 10 times that of her usual dose and a 3-year old who was lethargic on arrival to the hospital after ingestion of an unknown dose. Of all patients, 66 patients (80.5%) had no effect from the drug exposure. The medical outcome was considered to be minor in 15 cases (18.3%), and moderate in 1 case (1.2%). There were no cases with major outcomes and no deaths.Pediatric levetiracetam exposures were associated with few transient clinical effects. Poison Control Centers may wish to consider acuity of ingestion when developing send-in protocols.

IntroductionOver the past decade, there has been a sharp increase in the number of newly identified synthetic drugs. These new drugs are often derivatives of previously abused substances but have unpredictable toxicity. One of these drugs is gacyclidine, a derivative of phencyclidine (PCP). Gacyclidine has been studied as a neuroprotective agent in trauma and as a therapy of soman toxicity. There are no previous reports of its use as a drug of abuse.Case reportsDuring a two-month period in the summer of 2013, a series of patients with severe agitation and end-organ injury were identified in an urban academic Emergency Department (ED). A urine drug of abuse screen was performed on all patients, and serum samples were sent for comprehensive toxicology analysis. A total of five patients were identified as having agitation, rhabdomyolysis, and elevated troponin (Table 1). Three of the five patients reported use of methamphetamine, and all five patients had urine drug screens positive for amphetamine. Comprehensive serum analysis identified methamphetamine in three cases, cocaine metabolites in one case, and a potential untargeted match for gacyclidine in all five cases. No other drugs of abuse were identified.DiscussionThis is the first series of cases describing possible gacyclidine intoxication. The possible source of the gacyclidine is unknown but it may have been an adulterant in methamphetamine as all patients who were questioned reported methamphetamine use. These cases highlight the importance of screening for new drugs of abuse when patients present with atypical or severe symptoms. Gacyclidine has the potential to become a drug of abuse both by itself and in conjunction with other agents and toxicity from gacyclidine can be severe. It is the role of the medical toxicology field to identify new agents such as gacyclidine early and to attempt to educate the community on the dangers of these new drugs of abuse.

Background In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. Methods We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a doubleblind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure–free days to day 14. Results The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P = 0 .21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P = 0 .96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was assoc iated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P = 0 .01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P = 0 .003). Rosuvas tatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. Conclusions Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis a ssociated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.)

The transportation of critically ill patients requiring mechanical ventilation is recognized as a high-risk and expensive procedure. Approaches have included using manual bag-type valve resuscitators and expensive portable transport ventilators. This study evaluated the effectiveness of the inexpensive portable RespirTech PRO (RTP) gas-powered automatic resuscitator during intrahospital transport of critically ill mechanically ventilated patients. Twenty medical intensive care patients on stable mechanical ventilator settings had arterial blood gas and vital sign determination before routine transport out of the intensive care unit (ICU). Repeat measurements were made during transport approximately 30 minutes after being placed on the RTP portable pressure-cycled automatic resuscitator using an FiO2 of 100%. During use of the RTP for transport, there were no statistically significant variations observed in mean arterial blood pressure [82 +/- 11 SD (range 65 to 112) mm Hg before transport versus 85 +/- 14 SD (range 59 to 110) mm Hg during transport], heart rate [94 +/- 16 SD (range 74 to 127) beats/min) before versus 96 +/- 17 SD (range 69 to 132) beats/min during], arterial pH [7.41 +/- 0.07 SD (range 7.31 to 7.58) before versus 7.42 +/- 0.05 SD (range 7.37 to 7.52) during], and PaCO2 [43 +/- 10 SD (range 26 to 65) mm Hg before versus 43 +/- 10 SD (range 27 to 61 mm Hg) during]. Because the FiO2 before transport was 63 +/- 26 SD (range 30% to 100%) versus 100% during transport using the RTP, the mean PaO2 was significantly increased from 124 +/- 86 SD (range 57 to 367) mm Hg before transport to 297 +/- 168 SD (range 65 to 537) mm Hg during (P< .001). No transportation associated clinical adverse events were noted. Several previous investigations have shown that portable ventilators are safe and effective in intrahospital transport of mechanically ventilated patients. This study showed that the portable pressure-cycled RTP also allows safe transportation of mechanically ventilated ICU patients. By analogy, the RTP is potentially useful as an automatic resuscitator for emergency medical care. This RTP is a disposable resuscitator/ventilator device that provides an inexpensive alternative for transporting ventilator-dependent patients.

The intensive care unit (ICU) patient is particularly predisposed to the development of complications resulting from medication use, including drug interactions (DIs). Because of the multiple medications that these patients are usually prescribed, the likelihood of DIs occurring in the ICU is more frequent than with most acute care patients. Other factors including severity of illness, multisystem organ failure, and age can put the ICU patient at higher risk for DIs. In a review of 9900 patients, 83,200 drug exposures occurred with 3600 adverse drug effects noted. Of those adverse drug effects, 234 (6.5%) were caused by drug interactions. 25 The incidence of potential DIs has been estimated to be approximately 17% of surgical patients, 22% of medicine patients, 19% of skilled nursing home patients, and 23% of outpatient clinic patients. 25 In one small study conducted over a 5-month period in a six-bed ICU, 102 potential DIs were identified in 44.3% of patients. 22 Factors associated with increased potential for interactions included advanced age, number of concomitant drugs, severity of illness, and length of ICU stay. Today's critical care practitioners must familiarize themselves with the variety of possible mechanisms for DIs and various important factors including time course, dosage, routes, and individual patient risk factors that can lead to significant interactions. By enhancing knowledge in the prediction of interactions, the practitioner can minimize the negative impact and even take advantage, on occasion, of these sometimes unavoidable combinations, to provide the safest and optimal medication therapy for the ICU patient.

Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure.BackgroundPatients with acute renal failure (ARF) have high morbidity and mortality rates, particularly if they have serious comorbid conditions. Several studies indicate that in rats with ARF caused by ischemia or certain nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal function and suppresses protein catabolism.MethodsOur objective was to determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance the recovery of renal function and is safe in patients with ARF. The study was designed as a randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals. Seventy-two patients with ARF were randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of patients). At baseline, the mean (± sd) APACHE II scores in the rhIGF-I and placebo-treated groups were 24 ± 5 and 25 ± 8, respectively. In the rhIGF-I and placebo groups, the mean (median) urine volume and urinary iothalamate clearances (glomerular filtration rate) were 1116 ± 1037 (887) and 1402 ± 1183 (1430)ml/24hr and 6.4 ± 5.9 (4.3) and 8.7 ± 7.2 (4.4)ml/min and did not differ between the two groups. Patients were injected subcutaneously every 12hours with rhIGF-I, 100 μg/kg desirable body weight, or placebo for up to 14days. Injections were started within six days of the onset of ARF. The primary end-point was a change in glomerular filtration rate from baseline. Other end points included changes from baseline in urine volume, creatinine clearance and serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or ultrafiltration, and mortality rate.ResultsDuring the treatment period, which averaged 10.7 ± 4.1 and 10.6 ± 4.5days in the rhIGF-I and placebo groups, there were no differences in the changes from baseline values of the glomerular filtration rate, creatinine clearance, daily urine volume, or serum urea nitrogen, creatinine, albumin or transferrin. In patients who did not receive renal replacement therapy, there was also no significant difference in serum creatinine and urea between the two groups. Twenty patients in the rhIGF-I group and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve rhIGF-I–treated patients and 12 placebo-treated patients died during the 28days after the onset of treatment.ConclusionsrhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity.

An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of propofol on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. Hippocampal slices 400 um thick were perfused with oxygenated artificial cerebrospinal fluid, and electrodes were placed in the CA1 region to record extracellular field population spike (PS) or excitatory postsynaptic potential (EPSP) responses to stimulation of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid (GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. The major effect of propofol (7–28 μM) was a dose and time dependent increase in the intensity and duration of GABA-mediated inhibition. This propofol effect could be rapidly and completely reversed by exposure to known GABA A antagonists, including picrotoxin, bicuculline and pentylenetetrazol. It was also reversed by the chloride channel antagonist, 4,4′-diisothiocyanostilbene-2,2′-disulfonicacid (DIDS). It was not antagonized by central (flumazenil) or peripheral (PK11195) benzodiazepire antagonists. Reversal of endogenous inhibition was also noted with the antagonists picrotoxin and pentylenetetrazol. Input/output curves constructed using stimulus propofol caused only a small enhancement of EPSPs at higher stimulus intensities but had no effect on PS amplitudes. These studies are consistent with propofol having a GABA A -chloride channel mechanism causing its effect on recurrent collateral evoked inhibition in the rat hippocampal slice.

Objectives: Although rare, massive hemoptysis and major bronchial disruptions are associated with high mortality. Selective ventilation of the uninvolved lung can increase the likelihood of survival. Specialized devices used for single lung ventilation are often not readily available and can be difficult to place in the emergency department. The authors evaluated a blind rotational technique for selective mainstem intubation using either a standard endotracheal tube (ET) or a directional-tip endotracheal tube (DTET). Methods: This was a prospective, randomized trial on 25 human cadavers. The desired side of mainstem intubation was determined by randomization. Each cadaver was used for four ET, four DTET, and four control intubations. In the ET group, the trachea was intubated. The tube was then rotated 90° in the direction of the desired placement and advanced until resistance was met. In the DTET group, the technique was identical, except the trigger was activated to flex the tip during advancement. In the control group, an ET was advanced in neutral alignment until resistance was met. A bronchoscopist blinded to the desired placement determined tube position. Comparison testing was performed using Pearson's chi-square test. Results: When attempting to intubate the left mainstem, use of the ET with the rotational technique was successful 72.3% of the time (95% confidence interval [95% CI] = 57% to 84%). Intubation of the left mainstem using the DTET was successful 68.5% of the time (95% CI = 54% to 81%; p = 0.67). Attempts to selectively intubate the right mainstem using the rotational technique were highly successful in both groups: 94% for the ET (95% CI = 84% to 99%) versus 97.8% for the DTET (95% CI = 89% to 100%). Among controls, the right mainstem was intubated 93% of the time (95% CI = 86% to 97%). Conclusions: In a cadaveric model, the left mainstem bronchus can be selectively intubated with moderate reliability using this rotational technique. Use of a DTET confers no significant advantage. The ability to generalize these findings to living subjects is unknown.

Background. The availability of cadaveric organs is the major problem in transplantation today. Methods. A retrospective review of donors in a single organ procurement organization (OPO) was performed. Donors were divided into three eras: before, during, and after the presence of a local lung transplant program. Lung procurement rates by OPO in the United States in 1999 and 2000 were also retrospectively reviewed. Results. Lung transplant rates were higher in the presence of a local lung program: 4.9% at baseline, 19.1% with a local program, and 7.1% after closure of the local lung program (P

Study hypothesis: Administration of the benzodiazepine antagonist flumazenil may unmask seizures in mixed cocainebenzodiazepine intoxication. Design: Male Sprague-Dawley rats received 100 mg/kg cocaine IP alone, 5 mg/kg diazepam alone, or a combination of diazepam and cocaine. Three minutes later, groups were challenged with vehicle or flumazenil 5 or 10 mg/kg IP. Animal behavior, seizures (time to and incidence), death (time to and incidence), and cortical EEG tracings were recorded. Interventions: Administration of flumazenil to animals after they had received a combination dose of cocaine and diazepam. Results: In group 1, animals received cocaine followed by vehicle. This resulted in 100% developing seizures and death. Group 2 received diazepam alone followed by vehicle. Animals became somnolent and none died. Group 3 received diazepam followed by 5 mg/kg flumazenil. Animals became somnolent after diazepam and then active after flumazenil administration. In group 4, a combination of cocaine and diazepam was administered simultaneously. This resulted in no overt or EEG-detectable seizures and a 50% incidence of death. Group 5 received a similar combination of cocaine and diazepam, followed later by 5 mg/kg flumazenil. This resulted in an increased incidence of seizures, 90% ( P P ≤.01), compared with group 4. Group 6 received cocaine and diazepam followed by 10 mg/kg flumazenil. This also resulted in an increased incidence of seizures, 90% ( P ≤.01), and death, 90% ( P ≤.05), compared with group 4. Conclusion: Flumazenil can unmask seizures and increase the incidence of death in a model of combined cocaine-diazepam intoxications.

Two dihydropyridine type calcium channel blockers (CCBs) were studied for any protective or therapeutic effect upon cocaine-induced toxicity and death in rats. To test for the protective effects, rats were pretreated with vehicle (control), nifedipine or nimodipine, intraperitoneally (IP) 30 minutes prior to an LD85 of cocaine, or intravenously (IV) 10 minutes prior to cocaine administration. Animals receiving IP control vehicle developed seizures in 5.6 +/- 1.0 minutes and respiratory arrest in 9.8 +/- 1.4 minutes. Animals pretreated IP with nifedipine or nimodipine developed seizures and respiratory arrest significantly sooner than the controls, although the overall incidences of seizures and respiratory arrest were not significantly different. Pretreatment with IV CCBs resulted in similar findings. To test the therapeutic effect of CCBs given following cocaine overdose, rats were administered cocaine IP and then treated with IV nifedipine or nimodipine once seizures occurred. In these animals, there was no significant difference in the incidence or time to respiratory arrest compared to vehicle controls. This study demonstrates that neither pretreatment nor posttreatment with the CCBs nifedipine or nimodipine reduces cocaine toxicity in this rodent model.

Status asthmaticus (SA) is defined as an acute, severe asthma exacerbation that does not respond readily to initial intensive therapy, while near-fatal asthma (NFA) refers loosely to a status asthmaticus attack that progresses to respiratory failure. The in-hospital mortality rate for all asthmatics is between 1% to 5%, but for critically ill asthmatics that require intubation the mortality rate is between 10% to 25% primarily from anoxia and cardiopulmonary arrest. Timely evaluation and treatment in the clinic, emergency room, or ultimately the intensive care unit (ICU) can prevent the morbidity and mortality associated with respiratory failure. Fatal asthma occurs from cardiopulmonary arrest, cerebral anoxia, or a complication of treatments, e.g., barotraumas, and ventilator-associated pneumonia. Mortality is highest in African-Americans, Puerto Rican-Americans, Cuban-Americans, women, and persons aged ≥ 65 years. Critical care physicians or intensivists must be skilled in managing the critically ill asthmatics with respiratory failure and knowledgeable about the few but potentially serious complications associated with mechanical ventilation. Bronchodilator and anti-inflammatory medications remain the standard therapies for managing SA and NFA patients in the ICU. NFA patients on mechanical ventilation require modes that allow for prolonged expiratory time and reverse the dynamic hyperinflation associated with the attack. Several adjuncts to mechanical ventilation, including heliox, general anesthesia, and extra-corporeal carbon dioxide removal, can be used as life-saving measures in extreme cases. Coordination of discharge and follow-up care can safely reduce the length of hospital stay and prevent future attacks of status asthmaticus.

Background Early diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH. Methods This study retrospectively reviewed 101 acutely hospitalized inpatients with heterogeneous diagnoses, who consecutively underwent CT chest and RHC during the same admission. Two separate teams, each consisting of a radiologist and pulmonologist, blinded to clinical and RHC data, individually reviewed the chest CT's. Results Multiple regression analyses controlling for age, sex, ascending aortic diameter, body surface area, thoracic diameter and pulmonary wedge pressure showed that a main pulmonary artery (PA) diameter ≥29 mm (odds ratio (OR) = 4.8), right descending PA diameter ≥19 mm (OR = 7.0), true right descending PA diameter ≥ 16 mm (OR = 4.1), true left descending PA diameter ≥ 21 mm (OR = 15.5), right ventricular (RV) free wall ≥ 6 mm (OR = 30.5), RV wall/left ventricular (LV) wall ratio ≥0.32 (OR = 8.8), RV/LV lumen ratio ≥1.28 (OR = 28.8), main PA/ascending aorta ratio ≥0.84 (OR = 6.0) and main PA/descending aorta ratio ≥ 1.29 (OR = 5.7) were significant predictors of PH in this population of hospitalized patients. Conclusion This combination of easily measured CT-based metrics may, upon confirmatory studies, aid in the non-invasive detection of PH and hence in the determination of RHC candidacy in acutely hospitalized patients.

Background The goal of this study is to determine the clinical value of multiplex polymerase chain reaction (PCR) study for enhancing pathogen detection in patients with suspected septicemia after trauma, emergency, and burn surgery. PCR-based pathogen detection quickly reveals occult bloodstream infections in these high-risk patients and may accelerate the initiation of targeted antimicrobial therapy. Methods We conducted a prospective observational study comparing results for 30 trauma and emergency surgery patients to 20 burn patients. Whole-blood samples collected with routine blood cultures (BCs) were tested using a new multiplex, PCR-based, pathogen detection system. PCR results were compared to culture data. Results PCR detected rapidly more pathogens than culture methods. Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Multiple Organ Dysfunction (MODS) scores were greater in PCR-positive versus PCR-negative trauma and emergency surgery patients (P ≤ .033). Negative PCR results (odds ratio, 0.194; 95% confidence interval, 0.045–0.840; P = .028) acted as an independent predictor of survival for the combined surgical patient population. Conclusion PCR detected the presence of pathogens more frequently than blood culture. These PCR results were reported faster than blood culture results. Severity scores were significantly greater in PCR-positive trauma and emergency surgery patients. The lack of pathogen DNA as determined by PCR served as a significant predictor of survival in the combined patient population. PCR testing independent of traditional prompts for culturing may have clinical value in burn patients. These results warrant further investigation through interventional trials.

Death from cocaine intoxication results from one or more of the multiple mechanisms including seizures, cardiovascular collapse, or apnea. In the free-moving rat model, continuous seizures are a major cause of death. To study other mechanisms of death unrelated to seizures in this model, we suppressed lethal seizures with diazepam (DZP) and investigated the effect of several pharmacological agents. Rats were pretreated with vehicle alone, diazepam 5 mg/kg alone, or a combination of DZP plus either nifedipine (NIFD) 2 mg/kg, propranolol (PROP) 10 mg/kg, or prazosin (PRAZ) 5 mg/kg. Five minutes after pretreatment, all animals received cocaine 100 mg/kg. Each test group consisted of 15 animals and all agents were given IP. Two animals in each group had cortical electrodes implanted. Animals that received vehicle followed by cocaine had 100% incidence of seizures and death. Those rats that received DZP alone followed by cocaine had no seizures and 53% death. Rats that received DZP plus NIFD or DZP plus PROP had suppression of seizures but no significant change in the incidence of death. The group that received DZP and PRAZ followed by cocaine had no seizures and 13% incidence of death (p0.001). Electroencephalogram recordings showed cortical electrical spike activity or spike-and-wave afterdischarges in all animals clinically observed to have seizures. In the absence of clinical seizure activity, no significant cortical spike activity was noted. It is concluded that animals protected from seizures with diazepam can still have nonseizure deaths after high-dose cocaine. The incidence of death in these animals is not reduced with nifedipine or propranolol pretreatment but is reduced with prazosin pretreatment.

The anticonvulsant properties of F-721(3-diethylamino-2,2-dimethylpropyl 5[p-trifluoromethylphenyl]-2furoate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N- methyl- d -aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures (ED50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhibited only partial activity against clonic seizures induced in the subcutaneous Metrazol and subcutaneous bicuculline test in mice and was inactive in this species against tonic seizures induced in the subcutaneous strychnine test. F-721 was effective against MES seizures following oral administration to mice (ED50: 31.3 mg/kg) and only partially effective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal electroshock model following oral administration (ED50: 9.9 mg/kg). F-721 was also effective against corneal-kindled and amygdaloid-kindled seizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kindled rats at doses that did not cause sedation or ataxia. At 40 mg/kg, F-721 reduced afterdischarge duration by 83.2% and reduced the seizure severity score to 1.7. The ED50 for 50% reduction of afterdischarge duration was 16.3 mg/kg, ip. In cultured mouse spinal cord neurons, F-721 suppressed sustained repetitive firing in response to a depolarizing current with a median inhibitory concentration (IC50) of 1.9 μM. F-721 had no effect on adenosine uptake γ-aminobutyric acid or NMDA receptor binding. Comparative data from previous studies with clinically established antiepileptic agents reveal that F-721's profile of activity most closely resembles that of phenytoin and carbamazepine. However, F-721 was notably more efficacious in suppressing amygdaloid-kindled seizures in rats and was a more potent antagonist of icv NMDA clonic seizures. Our studies indicate that F-721 is a potent, orally active anticonvulsant with a favorable margin of safety. The profile of anticonvulsant activity of F-721 suggests potential utility in the management of generalized tonic-clonic, simple and complex partial seizures.

Paired-pulse facilitation was studied at the perforant path-granule cell synapses in the dentate gyrus of urethane-anesthetized rats. Extracellular field potentials comprising excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) were used to compare facilitation of both responses at interpulse intervals between 10 and 1000 ms. In this model system EPSPs, produced at stimulus intensities well below the PS threshold, exhibited paired-pulse facilitation (PPF) at intervals less than 40 ms. Between 40 and 100 ms both responses were of equal size and from 200 to 1000 ms the second response exhibited paired-pulse depression (PPD). With higher stimulus intensities, PSs exhibited early (10–30 ms) and late (400–1000 ms) PPD and intermediate interval (40–200 ms) PPF. The enhanced PS amplitude during facilitation was accompanied by a modest decrease in EPSP slope and increase in PS latencies to onset and to peak. If PS amplitude was increased to the same extent by simply increasing stimulus intensity, an increase in EPSP slope and decrease in PS latencies to onset and peak were observed. Current source-density analysis revealed that the current sink generated by synaptic activation of granule cell dendrites was indistinguishable between control and facilitated responses up to the onset of the PS. However, the facilitated response exhibited a marked increase in the duration and amplitude of current flowing into the dendrites during the late phase of the EPSP. PPF of the PS was attenuated or blocked by the administration of the known NMDA receptor-ion channel blockers, MK-801, dextromethorphan and ketamine. The depressant effects of these pharmacological agents on facilitation shared the same time course as facilitation itself, peaking at 60 ms and lasting approximately 200 ms. These data suggest that facilitation in this situation is due to postsynaptic rather than presynaptic modulations, and is based upon an increase in the NMDA-mediated component of the evoked response. No increase in transmitter release, per se, could be demonstrated.

The rate of sudden unexpected death in epilepsy (SUDEP) approaches 9 per 1,000 patient-years in patients with refractory epilepsy. Respiratory causes are implicated in SUDEP. We reported that ictal hypoxemia occurs in one-third of seizures in localization-related epilepsy. We now report on respiratory changes in the ictal/postictal period including changes in end-tidal CO₂ (ETCO₂) that correlate directly with alveolar CO(2) , allowing a precise evaluation of seizure-related respiratory disturbances.One hundred eighty-seven seizures were recorded in 33 patients with localization-related epilepsy, with or without secondarily generalized convulsions, undergoing video-electroencephalography (EEG) telemetry with recording of respiratory data.The ictal/postictal ETCO₂ increase from baseline was 14 ± 11 mm Hg (11, -1 to 50) [mean ± standard deviation (SD) (median, range)]. ETCO₂ peak was at or above 50 mm Hg with 35 of 94 seizures, 60 mm Hg with 15, and 70 mm Hg with five seizures. Eleven of the 33 patients had seizures with ETCO₂ elevation above 50 mm Hg. The duration of ictal/postictal ETCO(2) increase above baseline was 424 ± 807 s (154, 4 to 6225). The duration of ictal apnea was 49 ± 46 s (31, 6-222); most ictal apneic events were central. Oxygen desaturation to 60% or less occurred with 10 seizures, including five that did not progress to generalized convulsions. Respiratory rate and amplitude increased postictally. The peak ictal ETCO₂ change and duration of change were not associated with apnea duration or seizure duration. Peak ETCO₂ change was significantly associated with contralateral seizure spread.Severe and prolonged increases in ETCO₂ occur with seizures. Postictally, respiratory effort is not impaired. Ictally triggered ventilation-perfusion inequality from pulmonary shunting or transient neurogenic pulmonary edema may account for these findings.

Epidemiological data shows low dietary magnesium(Mg) may be related to incidence and progression of asthma.To determine if long term(6.5 month) treatment with oral Mg would improve asthma control and increase serum measures of Mg status in men and women with mild-to-moderate asthma.55 males and females aged 21 to 55 years with mild to moderate asthma according to the 2002 National Heart, Lung, and Blood Institute(NHLBI) and Asthma Education and Prevention Program(NAEPP) guidelines and who used only beta-agonists or inhaled corticosteroids(ICS) as asthma medications were enrolled.Subjects were randomly assigned to consume 340 mg(170 mg twice a day) of Mg or a placebo for 6.5 months.Multiple measures of Mg status including serum, erythrocyte, urine, dietary, ionized and IV Mg were measured.markers of asthma control were: methacholine challenge test(MCCT) and pulmonary function test(PFT) results. Subjective validated questionnaires on asthma quality of life(AQLQ) and control(ACQ) were completed by participants. Markers of inflammation, including c-reactive protein(CRP) and exhaled nitric oxide(eNO) were determined.The concentration of methacholine required to cause a 20% drop in forced expiratory volume in in minute(FEV(1)) increased significantly from baseline to month 6 within the Mg group. Peak expiratory flow rate(PEFR) showed a 5.8% predicted improvement over time(P = 0.03) in those consuming the Mg. There was significant improvement in AQLQ mean score units(P0.01) and in overall ACQ score only in the Mg group(P = 0.05) after 6.5 months of supplementation. Despite these improvements, there were no significant changes in any of the markers of Mg status.Adults who received oral Mg supplements showed improvement in objective measures of bronchial reactivity to methacholine and PEFR and in subjective measures of asthma control and quality of life.

Increasing doses of the injectable anesthetics etomidate, Saffan, thiopental, ketamine, and xylazine and the vehicles saline and propylene glycol were administered to urethane-anesthetized rats. Their effects in vivo on perforant pathway-evoked field excitatory post-synaptic potentials and population spikes in the hippocampal dentate gyrus were determined. The primary purpose was to ascertain whether these compounds affect hippocampal excitability in a manner consistent with their proposed mechanisms of action. Compared with their respective vehicles, thiopental, etomidate, and xylazine reduced the amplitude of population spikes to single perforant pathway stimulation by 20-30% at the highest doses tested. Xylazine also increased the latency to onset of the population spike. No other effects were observed. Using paired pulse paradigms, it was determined that etomidate produced a dramatic, prolonged reduction in granule cell excitability at interpulse intervals of 10-100 ms. The magnitude of the effect was dose related and was reversible with the discontinuance of administration of the drug. Similar changes occurred with Saffan (althesin) and thiopental. Ketamine produced a small but significant depression in granule cell excitability during intervals of 10-200 ms. Xylazine had no effect. These data corroborate the importance of a prolongation of gamma-aminobutyric acid A-mediated inhibition to the mechanism of actions of etomidate, thiopental, and Saffan at relevant exposure concentrations in vivo.