The intersecting roles of violence, gender, and substance use in the emergency department: a research agenda
The relationship between gender, violence, and substance use in the emergency department (ED) is complex. This article examines the role of gender in the intersection of substance use and three types of violence: peer violence, intimate partner violence, and firearm violence. Current approaches to treatment of substance abuse and violence are similar across both genders; however, as patterns of violence and substance abuse differ by gender, interventions may be more effective if they are designed with a specific gender focus.
Liver cancers are one of the deadliest known malignancies which are increasingly becoming a major public health problem in both developed and developing countries. Overwhelming evidence suggests a strong role of infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, as well as metabolic diseases such as obesity and diabetes either individually or synergistically to cause or exacerbate the development of liver cancers. Although numerous etiologic mechanisms for liver cancer development have been advanced and well characterized, the lack of definite curative treatments means that gaps in knowledge still exist in identifying key molecular mechanisms and pathways in the pathophysiology of liver cancers. Given the limited success with current therapies and preventive strategies against liver cancer, there is an urgent need to identify new therapeutic options for patients. Targeting HCV and or alcohol-induced signal transduction, or virus-host protein interactions may offer novel therapies for liver cancer. This review summarizes current knowledge on the mechanistic development of liver cancer associated with HCV infection and alcohol abuse as well as highlights potential novel therapeutic strategies.
Effect of transmission intensity and age on subclass antibody responses to Plasmodium falciparum pre-erythrocytic and blood-stage antigens
Cytophilic immunoglobulin (IgG) subclass responses (IgG1 and IgG3) to Plasmodium falciparum antigens have been associated with protection from malaria, yet the relative importance of transmission intensity and age in generation of subclass responses to pre-erythrocytic and blood-stage antigens have not been clearly defined. We analyzed IgG subclass responses to the pre-erythrocytic antigens CSP, LSA-1, and TRAP and the blood-stage antigens AMA-1, EBA-175, and MSP-1 in asymptomatic residents age 2 years or older in stable (n=116) and unstable (n=96) transmission areas in Western Kenya. In the area of stable malaria transmission, a high prevalence of cytophilic (IgG1 and IgG3) antibodies to each antigen was seen in all age groups. Prevalence and levels of cytophilic antibodies to pre-erythrocytic and blood-stage P. falciparum antigens increased with age in the unstable transmission area, yet IgG1 and IgG3 responses to most antigens for all ages in the unstable transmission area were less prevalent and lower in magnitude than even the youngest age group from the stable transmission area. The dominance of cytophilic responses over non-cytophilic (IgG2 and IgG4) was more pronounced in the stable transmission area, and the ratio of IgG3 over IgG1 generally increased with age. In the unstable transmission area, the ratio of cytophilic to non-cytophilic antibodies did not increase with age, and tended to be IgG3-biased for pre-erythrocytic antigens yet IgG1-biased for blood-stage antigens. The differences between areas could not be attributed to active parasitemia status, as there were minimal differences in antibody responses between those positive and negative for Plasmodium infection by microscopy in the stable transmission area. Individuals in areas of unstable transmission have low cytophilic to non-cytophilic IgG subclass ratios and low IgG3:IgG1 ratios to P. falciparum antigens. These imbalances could contribute to the persistent risk of clinical malaria in these areas and serve as population-level, age-specific biomarkers of transmission.
Alcoholic liver disease (ALD) has been among the leading causes of cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation, suggesting a role for gut-derived toxins in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that increasingly is recognized as a major factor in ALD. Bacterial endotoxin, lipopolysaccharide, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4. Recent studies also have shown that alcohol consumption is associated with alterations in the gut microbiome, and the dysbalance of pathogenic and commensal organisms in the intestinal microbiome may contribute to the abnormal gut-liver axis in ALD. Indeed, bacterial decontamination improves ALD both in human and animal models. This short review summarizes recent findings and highlights emerging trends in the gut-liver axis relevant to ALD.
A computational analysis of the structural determinants of APOBEC3's catalytic activity and vulnerability to HIV-1 Vif
APOBEC3s (A3) are Zn(2+) dependent cytidine deaminases with diverse biological functions and implications for cancer and immunity. Four of the seven human A3s restrict HIV by 'hypermutating' the reverse-transcribed viral genomic DNA. HIV Virion Infectivity Factor (Vif) counters this restriction by targeting A3s to proteasomal degradation. However, there is no apparent correlation between catalytic activity, Vif binding, and sequence similarity between A3 domains. Our comparative structural analysis reveals features required for binding Vif and features influencing polynucleotide deaminase activity in A3 proteins. All Vif-binding A3s share a negatively charged surface region that includes residues previously implicated in binding the highly-positively charged Vif. Additionally, catalytically active A3s share a positively charged groove near the Zn(2+) coordinating active site, which may accommodate the negatively charged polynucleotide substrate. Our findings suggest surface electrostatics, as well as the spatial extent of substrate accommodating region, are critical determinants of substrate and Vif binding across A3 proteins with implications for anti-retroviral and anti-cancer therapeutic design.
The flexibility of HIV protease plays a critical role in enabling enzymatic activity and is required for substrate access to the active site. While the importance of flexibility in the flaps that cover the active site is well known, flexibility in other parts of the enzyme is also critical for function. One key region is a loop containing Thr 80 which forms the walls of the active site. Although not situated within the active site, amino acid Thr80 is absolutely conserved. The mutation T80N preserves the structure of the enzyme but catalytic activity is completely lost. To investigate the potential influence of the T80N mutation on HIVp flexibility, wide-angle scattering (WAXS) data was measured for a series of HIV protease variants. Starting with a calculated WAXS pattern from a rigid atomic model, the modulations in the intensity distribution caused by structural fluctuations in the protein were predicted by simple analytic methods and compared to the experimental data. An analysis of T80N WAXS data shows that this variant is significantly more rigid than the WT across all length scales. The effects of this single point mutation extend throughout the protein, so as to alter the mobility of amino acids in the enzymatic core. These results support the contentions that significant protein flexibility extends throughout HIV protease and is critical to catalytic function.
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, and efforts to develop therapeutic vaccine strategies have been limited by immune escape due to HCV variants that are resistant to current vaccines or HCV variants that rapidly acquire new resistance-conferring mutations. Recently, the crystal structure of the viral envelope protein E2 region was resolved as well as how E2 docks to the host CD81 protein; therefore, antibodies that block this interaction should prevent viral entry into host cells. In this issue of the JCI, Bailey and colleagues show that immune escape of HCV can occur by naturally occurring polymorphisms in E2 that are distinct from those at mapped sites of antibody binding. These data reveal alternative mechanisms of resistance that need to be considered in both natural viral escape as well as in rationale vaccine design against HCV.
Implementation of patient-reported outcome measures in U.S. Total joint replacement registries: rationale, status, and plans
BACKGROUND: In the U.S. and abroad, the use of patient-reported outcome measures to evaluate the impact of total joint replacement surgery on patient quality of life is increasingly common. Analyses of patient-reported outcomes have documented substantial pain relief and functional gain among the vast majority of patients managed with total joint replacement. In addition, postoperative patient-reported outcomes are useful to identify persistent pain and suboptimal outcomes in the minority of patients who have them. The leaders of five U.S. total joint replacement registries report the rationale, current status, and vision for the use of patient-reported outcome measures in U.S. total joint replacement registries.
METHODS: Surgeon leaders of the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry, American Joint Replacement Registry, California Joint Replacement Registry, Michigan Arthroplasty Registry Collaborative Quality Initiative, and Virginia Joint Registry report the rationale supporting the adoption of patient-reported outcome measures, factors associated with the selection and successful implementation of patient-reported outcome measures, and barriers to complete and valid data.
RESULTS: U.S. registries are at varied stages of implementation of preoperative surveys and postoperative total joint replacement outcome measures. Surgeon leaders report unified rationales for adopting patient-reported outcome measures: to capture data on pain relief and functional gain following total joint replacement as well as to identify suboptimal implant performance. Key considerations in the selection of a patient-reported outcome measure include its ability to measure both joint pain and physical function while limiting any burden on patients and surgeons related to its use. Complete patient-reported outcomes data will be associated with varied modes of survey completion, including options for home-based completion, to ensure consistent timing and data capture.
CONCLUSIONS: The current stage of implementation of patient-reported outcome measures varies widely among U.S. registries. Nonetheless, evidence from the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry supports the feasibility of successful implementation of patient-reported outcome measures with careful attention to the selection of the outcome measure, mode and timing of postoperative administration, and minimization of any burden on the patient and surgeon.
Elevated serum glucose levels and survival after acute heart failure: a population-based perspective
BACKGROUND: Limited data are available about the characteristics, treatment and survival in patients without diabetes mellitus (DM), previously diagnosed DM and patients with hyperglycaemia who present with acute decompensated heart failure (ADHF). Our objectives were to examine differences in these endpoints in patients hospitalized with ADHF.
METHODS: Patients hospitalized with ADHF during 1995, 2000, 2002 and 2004 comprised the study population.
RESULTS: A total of 5428 non-diabetic patients were hospitalized with ADHF, 3807 with diagnosed DM and 513 with admission hyperglycaemia. Patients with admission hyperglycaemia experienced the highest in-hospital death rates (9.9%) compared to those with diagnosed DM (6.5%) and non-diabetics (7.5%). Patients with diagnosed DM had the greatest risk of dying after hospital discharge.
CONCLUSIONS: Patients with elevated blood glucose levels at hospital admission are more likely to die acutely. After resolution of the acute illness, patients with previously diagnosed DM need careful monitoring and enhanced treatment.
In-hospital management and outcomes of acute coronary syndromes in relation to prior history of heart failure
INTRODUCTION: The prognostic significance of prior heart failure in acute coronary syndromes has not been well studied. Accordingly, we evaluated the baseline characteristics, management patterns and clinical outcomes in patients with acute coronary syndromes who had prior heart failure.
METHODS AND RESULTS: The study population consisted of acute coronary syndrome patients in the Global Registry of Acute Coronary Events, expanded Global Registry of Acute Coronary Events and Canadian Registry of Acute Coronary Events between 1999 and 2008. Of the 13,937 eligible patients (mean age 66±13 years, 33% female and 28.3% with ST-elevation myocardial infarction), 1498 (10.7%) patients had a history of heart failure. Those with prior heart failure tended to be older, female and had lower systolic blood pressure, higher Killip class and creatinine on presentation. Prior heart failure was also associated with significantly worse left ventricular systolic function and lower rates of cardiac catheterization and coronary revascularization. The group with previous heart failure had significantly higher rates of acute decompensated heart failure, cardiogenic shock, myocardial (re)infarction and mortality in hospital. In multivariable analysis, prior heart failure remained an independent predictor of in-hospital mortality (odds ratio 1.48, 95% confidence interval 1.08-2.03, p=0.015).
CONCLUSIONS: Prior heart failure was associated with high risk features on presentation and adverse outcomes including higher adjusted in-hospital mortality in acute coronary syndrome patients. However, acute coronary syndrome patients with prior heart failure were less likely to receive evidence-based therapies, suggesting potential opportunities to target more intensive treatment to improve their outcome.
GLOW is an observational, longitudinal, practice-based cohort study of osteoporosis in 60,393 women aged ≥ 55 years in 10 countries on three continents. In this Review, we present insights from the first 3 years of the study. Despite cost analyses being frequently based on spine and hip fractures, we found that nonvertebral, nonhip fractures were around five times more common and doubled the use of health-care resources compared with hip and spine fractures combined. Fractures not at the four so-called major sites in FRAX(®) (upper arm, forearm, hip and clinical vertebral fractures) account for > 40% of all fractures. The risk of fracture is increased by various comorbidities, such as Parkinson disease, multiple sclerosis and lung and heart disease. Obesity, although thought to be protective against all fractures, substantially increased the risk of fractures in the ankle or lower leg. Simple assessment by age plus fracture history has good predictive value for all fractures, but risk profiles differ for first and subsequent fractures. Fractures diminish quality of life as much or more than diabetes mellitus, arthritis and lung disease, yet women substantially underestimate their own fracture risk. Treatment rates in patients at high risk of fracture are below those recommended but might be too frequent in women at low risk. Comorbidities and the limits of current therapeutic regimens jeopardize the efficacy of drugs; new regimens should be explored for severe cases.
Frailty index of deficit accumulation and falls: data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton cohort
BACKGROUND: To investigate the association between frailty index (FI) of deficit accumulation and risk of falls, fractures, death and overnight hospitalizations in women aged 55 years and older.
METHODS: The data were from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton Cohort. In this 3-year longitudinal, observational cohort study, women (N=3,985) aged ≥ 55 years were enrolled between May 2008 and March 2009 in Hamilton, Canada. A FI including co-morbidities, activities of daily living, symptoms and signs, and healthcare utilization was constructed using 34 health deficits at baseline. Relationship between the FI and falls, fractures, death and overnight hospitalizations was examined.
RESULTS: The FI was significantly associated with age, with a mean rate of deficit accumulation across baseline age of 0.004 or 0.021 (on a log scale) per year. During the third year of follow-up, 1,068 (31.89%) women reported at least one fall. Each increment of 0.01 on the FI was associated with a significantly increased risk of falls during the third year of follow-up (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.02-1.03). The area under the curve (AUC) of the predictive model was 0.69 (95% CI: 0.67-0.71). Results of subgroup and sensitivity analyses indicated the relationship between the FI and risk of falls was robust, while bootstrap analysis judged its internal validation. The FI was significantly related to fractures (hazard ratio [HR]: 1.02, 95% CI: 1.01-1.03), death (OR: 1.05, 95% CI: 1.03-1.06) during the 3-year follow-up period and overnight hospitalizations (incidence rate ratio [IRR]: 1.02, 95% CI: 1.02-1.03) for an increase of 0.01 on the FI during the third year of follow-up. Measured by per standard deviation (SD) increment of the FI, the ORs were 1.21 and 1.40 for falls and death respectively, while the HR was 1.17 for fractures and the IRR was 1.18 for overnight hospitalizations respectively.
CONCLUSION: The FI of deficit accumulation increased with chronological age significantly. The FI was associated with and predicted increased risk of falls, fractures, death and overnight hospitalizations significantly.
Concern and risk perception of osteoporosis and fracture among post-menopausal Australian women: results from the Global Longitudinal Study of Osteoporosis in Women (GLOW) cohort
PURPOSE: The purpose of this study is to identify factors associated with concern and perception of risks of osteoporosis and osteoporotic fractures and determine whether bone mineral density (BMD) testing influenced concern and risk perception.
METHODS: Study subjects (n = 1,082, age 55-94 years) were female Australian participants of the Global Longitudinal Study of Osteoporosis in Women (GLOW). Self-administered questionnaires were sent annually from 2007 to 2010. Study outcomes included 'concern about osteoporosis', 'perception of getting osteoporosis' and 'perception of fracture risk' compared to similar aged women. The closest post-BMD testing or baseline questionnaires were used for women with and without BMD testing, respectively. Multinomial logistic regression was used for the analysis.
RESULTS: BMD testing, prior fracture after age 45, younger age and lower self-reported general health were significantly associated with being 'very' or 'somewhat concerned' about osteoporosis and having a 'much higher' or 'little higher' risk perception of osteoporosis and fractures. A poorer BMD result was associated with higher concern and higher risk perceptions. The presence of comorbidities, having >/=2 falls in the preceding year and maternal osteoporosis were associated with higher concern. Maternal osteoporosis, presence of comorbidities, weight loss of >/=5 kg in the preceding year and low body mass index were associated with higher perceptions of osteoporosis risk.
CONCLUSION: Women's concern and risk perception of osteoporosis and osteoporotic fractures were reasonably well founded. However, increasing age, height loss, smoking and drinking were not associated with concern and perception despite being known osteoporosis risk factors. These factors should be considered in planning for education and awareness raising programmes.
Comparison between Frailty Index of Deficit Accumulation and Phenotypic Model to Predict Risk of Falls: Data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton Cohort
OBJECTIVES: To compare the predictive accuracy of the frailty index (FI) of deficit accumulation and the phenotypic frailty (PF) model in predicting risks of future falls, fractures and death in women aged > /=55 years.
METHODS: Based on the data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 3-year Hamilton cohort (n = 3,985), we compared the predictive accuracy of the FI and PF in risks of falls, fractures and death using three strategies: (1) investigated the relationship with adverse health outcomes by increasing per one-fifth (i.e., 20%) of the FI and PF; (2) trichotomized the FI based on the overlap in the density distribution of the FI by the three groups (robust, pre-frail and frail) which were defined by the PF; (3) categorized the women according to a predicted probability function of falls during the third year of follow-up predicted by the FI. Logistic regression models were used for falls and death, while survival analyses were conducted for fractures.
RESULTS: The FI and PF agreed with each other at a good level of consensus (correlation coefficients > /= 0.56) in all the three strategies. Both the FI and PF approaches predicted adverse health outcomes significantly. The FI quantified the risks of future falls, fractures and death more precisely than the PF. Both the FI and PF discriminated risks of adverse outcomes in multivariable models with acceptable and comparable area under the curve (AUCs) for falls (AUCs > /= 0.68) and death (AUCs > /= 0.79), and c-indices for fractures (c-indices > /= 0.69) respectively.
CONCLUSIONS: The FI is comparable with the PF in predicting risks of adverse health outcomes. These findings may indicate the flexibility in the choice of frailty model for the elderly in the population-based settings.
Empirically based composite fracture prediction model from the Global Longitudinal Study of Osteoporosis in Postmenopausal Women (GLOW)
CONTEXT: Several fracture prediction models that combine fractures at different sites into a composite outcome are in current use. However, to the extent individual fracture sites have differing risk factor profiles, model discrimination is impaired.
OBJECTIVE: The objective of the study was to improve model discrimination by developing a 5-year composite fracture prediction model for fracture sites that display similar risk profiles.
DESIGN: This was a prospective, observational cohort study.
SETTING: The study was conducted at primary care practices in 10 countries.
PATIENTS: Women aged 55 years or older participated in the study.
INTERVENTION: Self-administered questionnaires collected data on patient characteristics, fracture risk factors, and previous fractures.
MAIN OUTCOME MEASURE: The main outcome is time to first clinical fracture of hip, pelvis, upper leg, clavicle, or spine, each of which exhibits a strong association with advanced age.
RESULTS: Of four composite fracture models considered, model discrimination (c index) is highest for an age-related fracture model (c index of 0.75, 47 066 women), and lowest for Fracture Risk Assessment Tool (FRAX) major fracture and a 10-site model (c indices of 0.67 and 0.65). The unadjusted increase in fracture risk for an additional 10 years of age ranges from 80% to 180% for the individual bones in the age-associated model. Five other fracture sites not considered for the age-associated model (upper arm/shoulder, rib, wrist, lower leg, and ankle) have age associations for an additional 10 years of age from a 10% decrease to a 60% increase.
CONCLUSIONS: After examining results for 10 different bone fracture sites, advanced age appeared the single best possibility for uniting several different sites, resulting in an empirically based composite fracture risk model.
PURPOSE: The purpose of this exploratory focus group study was to describe the perspectives of teens and their parents about self-management knowledge, behaviors (including division of labor associated with T1D management), and resources used to manage T1D. The overall goal is to use this information to develop a teen-family transition clinic.
METHODS: The self and family management behaviors framework undergirded the separate teen-parent focus groups that were conducted concurrently. Note-based qualitative content analysis was used, resulting in several important messages. RESULTS: From the teens' perspective there was variation in interest in learning more about T1D and management. Those teens who had been diagnosed at a very young age reported not knowing anything else but diabetes, while those diagnosed later developmentally embraced the active learning process. Diabetes camp and peer group support were not seen as beneficial. All the teens were interested in "helping others" with diabetes. Parents shared the common struggle with transition of self-management, with variation in parenting styles. A small group of parents reported their "job" as a parent was to make sure their child was self-sufficient in self-management, but felt pressure from the health care providers (HCPs) to physically do the care, defeating the purpose. Parents and teens reported wanting HCPs to be less focused on "numbers" (blood glucose levels) and more on the whole person. Scheduling appointment changes and long waiting times were reported as problematic by all participants.
CONCLUSIONS: Teen and parent perspectives are critical in designing future well-received adolescent-family transition clinics. Development from the ground up with family recommendations may contribute to high-quality health outcomes.
Association between chlorinated pesticides in the serum of prepubertal Russian boys and longitudinal biomarkers of metabolic function
Organochlorine pesticides (OCPs) have been linked to adult metabolic disorders; however, few studies have examined these associations in childhood. We prospectively evaluated the associations of baseline serum OCPs (hexachlorobenzene, beta-hexachlorocyclohexane, and p,p'-dichlorodiphenyldichloroethylene) in Russian boys with subsequent repeated measurements of serum glucose, insulin, lipids, leptin, and calculated homeostatic model assessment of insulin resistance (IR). During 2003-2005, we enrolled 499 boys aged 8-9 years in a prospective cohort; 318 had baseline serum OCPs and serum biomarkers measured at ages 10-13 years. Multivariable generalized estimating equation and mediation regression models were used to examine associations and direct and indirect (via body mass index (BMI) (weight (kg)/height (m)(2))) effects of prepubertal OCP tertiles and quintiles with biomarkers. In multivariable models, higher p,p'-dichlorodiphenyldichloroethylene (quintile 5 vs. quintile 1) was associated with lower leptin, with relative mean decreases of 61.8% (95% confidence interval: 48.4%, 71.7%) in models unadjusted for BMI and 22.2% (95% confidence interval: 7.1%, 34.9%) in models adjusted for BMI; the direct effect of p,p'-dichlorodiphenyldichloroethylene on leptin accounted for 27% of the total effect. IR prevalence was 6.6% at ages 12-13 years. Higher hexachlorobenzene (tertile 3 vs. tertile 1) was associated with higher odds of IR in models adjusted for BMI (odds ratio = 4.37, 95% confidence interval: 1.44, 13.28). These results suggest that childhood OCPs may be associated with IR and lower leptin.
BACKGROUND: In animal studies, organochlorine pesticide (OCP) exposure alters pubertal development; however, epidemiological data are limited and inconsistent.
OBJECTIVE: To evaluate the associations of serum OCP concentrations [hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE)] with male pubertal onset.
METHODS: In Chapaevsk, Russia, a town environmentally contaminated with OCPs, 350 8-9 year old boys with measured OCPs were enrolled during 2003-2005 and were followed annually for eight years. We evaluated three measures of pubertal onset: testicular volume (TV) > 3 mL in either testis, or stage 2 or greater for genitalia (G2+), or pubic hair (P2+). We used multivariable interval-censored models to evaluate associations of OCPs (quartiles) with physician-assessed pubertal onset. RESULTS: In adjusted models, boys with higher HCB concentrations had later mean ages of TV > 3 mL and P2+ (but not G2+). Mean age at attaining TV > 3 mL was delayed 3.6 (95% CI: -2.6, 9.7), 7.9 (95% CI: 1.7, 14.0), and 4.7 months (95% CI: -1.4, 10.9) for HCB Q2, Q3, and Q4, respectively, compared to Q1 (trend p: 0.06). Boys with higher HCB concentrations reached P2+ 0.1 months earlier (95% CI: -5.8, 5.6) for Q2, 4.7 months later (95% CI: -1.0, 10.3) for Q3 and 4.6 months later (95% CI: -1.1, 10.3) for Q4 compared to Q1 (trend p: 0.04). There were no associations of serum beta-HCH and p,p'-DDE concentrations with age of pubertal onset.
CONCLUSION: Higher prepubertal serum HCB concentrations were associated with later age of gonadarche and pubarche.
Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial
BACKGROUND: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in human aneurysmal subarachnoid haemorrhage (aSAH). We evaluated safety, feasibility and tolerability of intravenous dantrolene (IV-D) in patients with aSAH.
METHODS: In this single-centre, randomised, double blind, placebo-controlled trial, 31 patients with aSAH were randomised to IV-D 1.25 mg every 6 h for 7 days (n=16) or equiosmolar free water/5% mannitol (placebo; n=15). Primary safety end points were incidence of hyponatraemia (sNa≤132 mmol/L) and liver toxicity (proportion of patients alanine transaminase, aspartate aminotransferase and AlkPhos >5× upper-limit-of-normal). Secondary end points included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored for clinical/radiological cVSP, delayed cerebral ischaemia (DCI), and 3-month functional outcomes. Quantitative analyses of angiograms and daily transcranial Doppler (TCD) were performed.
RESULTS: Between IV-D versus placebo, no differences were observed in the primary outcomes (hyponatremia 44% vs 67% (p=0.29); liver toxicity 6% vs 0% (p=1.0)). Three patients in the IV-D versus two in the placebo group had severe adverse events possibly attributable to infusion and reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain oedema requiring osmotherapy. The majority of adverse events were not related to infusion (17 vs 5 (RR 2.2; 95% CI 0.7 to 6.7; p=0.16) in IV-D vs placebo). No differences in any categorical cVSP outcomes, DCI, 3-month outcomes or quantitative angiogram and TCD analyses were seen in this small safety trial not powered to detect efficacy.
CONCLUSIONS: In this small trial, IV-D after aSAH was feasible, tolerable and safe.
TRIAL REGISTRATION NUMBER: http://clinicaltrials.gov NCT01024972.