Geoffrey K Isbister

Publications of Geoffrey K Isbister

• Solving the 'Brown snake paradox': In vitro characterisation of Australasian snake presynaptic neurotoxin activity.

  Authors: Carmel M Barber, Geoffrey K Isbister, Wayne C Hodgson

  Toxicology letters. 02/2012; 210(3):318-23.

  Pseudonaja textilis (Eastern Brown snake) and Oxyuranus scutellatus scutellatus (Coastal taipan) are clinically important Australian elapid snakes, whose potent venoms contain the presynaptic (β)Pseudonaja textilis (Eastern Brown snake) and Oxyuranus scutellatus scutellatus (Coastal taipan) are clinically important Australian elapid snakes, whose potent venoms contain the presynaptic (β) neurotoxins, textilotoxin and taipoxin, respectively, and a number of postsynaptic neurotoxins. However, while taipan envenoming frequently results in neurotoxicity, Brown snake envenoming causes an isolated coagulopathy and neurotoxicity is rare. This phenomenon is called the 'Brown snake paradox'. This study compared the pharmacology of both venoms and their respective presynaptic neurotoxins to investigate this phenomenon. From size-exclusion high performance liquid chromatography (HPLC) analysis textilotoxin represents a significantly smaller proportion (5.7%) of P. textilis venom compared to taipoxin in O. s. scutellatus venom (20.4%). In the chick biventer cervicis nerve-muscle (CBCNM) preparation both venoms caused concentration-dependent neurotoxicity, with P. textilis venom being significantly more potent than O. s. scutellatus venom. Conversely, taipoxin was significantly more potent than textilotoxin when compared at the same concentration. Textilotoxin only partially contributed to the overall neurotoxicity of P. textilis venom, while taipoxin accounted for the majority of the neurotoxicity of O. s. scutellatus venom in the CBCNM preparation. Compared with taipoxin, textilotoxin is less potent and constitutes a smaller proportion of the venom. This is likely to be the reason for the absence of neurotoxicity in envenomed humans thus explaining the 'Brown snake paradox'.

• Restricting cough and cold medicines in children.

  Authors: Geoffrey K Isbister, Felicity Prior, Henry A Kilham

  Journal of paediatrics and child health. 02/2012; 48(2):91-8.

  Aims:  Based on concerns about safety and efficacy, international authorities have either advised against the use of cough and cold medication or considering such action. We aimed to systematicallyAims:  Based on concerns about safety and efficacy, international authorities have either advised against the use of cough and cold medication or considering such action. We aimed to systematically review the evidence for the effectiveness and safety of cough and cold medicines in children. Methods:  We conducted a systematic review to identify studies relating to the use of products to treat symptoms of the common cold, influenza or allergic rhinitis, and relating to poisoning or toxicity from unintentional ingestion or overdose in children (<12 years). Medline, Embase and the Cochrane database were searched. No meta-analysis was undertaken because of the paucity of evidence, multiple medicines available, and the need to consider both effectiveness and safety. Results:  Seventy two relevant studies or clinical reports were identified. There was little support for the effectiveness of these medicines for acute cough or the common cold in children. However, the majority of these medicines do not appear to be highly toxic in children and are not a major cause of severe effects following unintentional poisoning. The common use of these agents does not appear to be responsible for increased deaths in young children. Many cases of toxicity from cough and cold medications in young children are a result of therapeutic error. Particular medications, including diphenhydramine and codeine, appear to be associated with a high frequency of severe adverse effects and toxicity. Conclusion:  Restriction of cough and cold medicines in children is supported by currently available evidence.

• Dexmedetomidine in the emergency department: assessing safety and effectiveness in difficult-to-sedate acute behavioural disturbance.

  Authors: Leonie Calver, Geoffrey K Isbister

  Emergency medicine journal : EMJ. 12/2011;

  ObjectivesTo investigate the safety and effectiveness of dexmedetomidine for sedating patients in whom previous attempts at sedation in the emergency department have failed.MethodsA study was carriedObjectivesTo investigate the safety and effectiveness of dexmedetomidine for sedating patients in whom previous attempts at sedation in the emergency department have failed.MethodsA study was carried out on dexmedetomidine for sedation of patients with acute behavioural disturbance for whom at least two previous attempts at sedation with other drugs had failed. Either a loading dose of dexmedetomidine was administered or a loading dose then an infusion. Administration was titrated to the sedative effect and vital signs. The sedation assessment tool was used to assess effectiveness, and adverse effects were recorded. Effective sedation was defined as a fall in the sedation assessment tool by two levels or more for an hour or more.ResultsA total of 13 patients were given dexmedetomidine. Five of the 13 had a loading dose only. Of these five, successful sedation was achieved in two, and the other three were only briefly sedated during the loading dose. One patient had hypotension. Eight patients received an infusion after the loading dose. Three were successfully sedated, but one developed hypotension. Four patients required a decrease in the infusion rate for hypotension, and in three of these the rate decrease compromised the sedation and one of these required intubation for sedation. The final patient had persistent acute behavioural disturbance, which required intubation for management. Five of the eight patients developed hypotension, and, of the five, one had bradycardia and one went into atrial fibrillation.ConclusionIntravenous dexmedetomidine for difficult-to-sedate patients with acute behavioural disturbance is not safe in the emergency department setting.

• Individual Patient Assessment of Methadone-induced QT Prolongation With Digital Holter Recording.

  Authors: Leonie Calver, Adrian J Dunlop, Geoffrey K Isbister

  Journal of addiction medicine. 12/2011; 6(1):92-3.

  A 27-year-old male who had been on methadone therapy for 6 months was investigated with a 12-lead digital holter because of a prolonged QT on a standard 12-lead electrocardiogram (ECG). The patientA 27-year-old male who had been on methadone therapy for 6 months was investigated with a 12-lead digital holter because of a prolonged QT on a standard 12-lead electrocardiogram (ECG). The patient had 24-hour holter recording on and off methadone therapy and multiple digitized 12-lead ECG data were captured for on-screen measurement of the QT interval. For each 24-hour period QT-HR pairs were plotted on the QT nomogram showing QT prolongation on methadone but not when it was ceased. This provides a highly accurate method for evaluating drug-induced QT prolongation.

• Sedation assessment tool to score acute behavioural disturbance in the emergency department.

  Authors: Leonie A Calver, Barrie Stokes, Geoffrey K Isbister

  Emergency medicine Australasia : EMA. 12/2011; 23(6):732-40.

  The objective of the study was to evaluate the effectiveness of the sedation assessment tool (SAT) in assessing patient response to treatment for acute behavioural disturbance (ABD). The SAT is aThe objective of the study was to evaluate the effectiveness of the sedation assessment tool (SAT) in assessing patient response to treatment for acute behavioural disturbance (ABD). The SAT is a simplified version of the altered mental status score (AMSS) and is a 7-point scale assessing levels of agitation and sedation using only two descriptors. To assess the SAT we firstly compared plots of the SAT and the AMSS versus time in patients with ABD recruited to a clinical trial. AMSS were converted to the SAT for this comparison. Second, the sensitivity and specificity were calculated for an increase in the SAT to +2 or +3 as a predictor of whether additional sedation was required in a prospective cohort of 138 patients. Third, interrater reliability was assessed using two individuals to score the same patient at two different time points and finally the time to record the score was measured. Plots of AMSS and SAT for 91 patients in the clinical trial illustrated similar trends in agitation/sedation. Seventeen of 138 patients in the second cohort had an increase in the SAT. Fifteen of 17 (88%) received additional sedation. The sensitivity and specificity of the SAT for additional sedation was 100% (95% CI 75-100%) and 98% (95% CI 94-100%), respectively. The median time for staff to assign the SAT was 10 s (range 3-15 s). Interrater reliability was high with a kappa of 0.87. The SAT is a simple, rapid and useful measure of the level of agitation/sedation in patients with ABD. Increases in the score reliably indicated the need for further sedation.

• Intravenous paracetamol toxicity in a malnourished child.

  Authors: Ingrid Berling, Michael Anscombe, Geoffrey K Isbister

  Clinical toxicology (Philadelphia, Pa.). 11/2011; 50(1):74-6.

  We present a case of intravenous (IV) paracetamol overdose in a nutritionally malnourished child during hospital admission. A ten-fold IV paracetamol dosing error ocurred, with delayed recognitionWe present a case of intravenous (IV) paracetamol overdose in a nutritionally malnourished child during hospital admission. A ten-fold IV paracetamol dosing error ocurred, with delayed recognition and treatment resulting in transient hepatotoxicity, with a peak alanine transaminase (ALT) of 1378 IU/L in a 3-year-old child. Our case suggests that hepatotoxicity may occur for lower doses of IV paracetamol compared to oral ingestion, especially in the malnourished, and that a dose less than 150 mg/kg of IV paracetamol should be used to define treatment following overdose in a child with potential nutritional deficiencies.

• Methanol and ethylene glycol acute poisonings - predictors of mortality.

  Authors: Carolyn V Coulter, Sarah E Farquhar, Claire M McSherry, Geoffrey K Isbister, Stephen B Duffull

  Clinical toxicology (Philadelphia, Pa.). 11/2011; 49(10):900-6.

  Methanol and ethylene glycol cause significant mortality post-ingestion. Predicting prognosis based on the biomarkers osmolal gap, anion gap and pH is beneficial. To evaluate the relationship betweenMethanol and ethylene glycol cause significant mortality post-ingestion. Predicting prognosis based on the biomarkers osmolal gap, anion gap and pH is beneficial. To evaluate the relationship between biomarkers, measured post-methanol and ethylene glycol exposure, and clinical outcomes. A review of the literature identified cases where methanol or ethylene glycol had been ingested and clinical outcomes were recorded. Biomarkers were extracted including osmolal gap, anion gap and pH, with clinical outcomes categorised as recovered, recovered with adverse sequelae and death. Biomarkers were analysed using the Mann-Whitney test for two samples; sensitivity and specificity were evaluated using receiver operating characteristic (ROC) curves. In total, 119 cases of methanol and 88 of ethylene glycol poisoning were identified; 21 methanol and 19 ethylene glycol patients died. For methanol ingestion the mean values, for survival compared to death, were 48 (range: 6-138) and 90 (range: 49-159) mOsm/kg water for osmolal gap (p=0.0052), 31 (range: 11-50) and 41 (range: 30-53) mmol/L for anion gap (p=0.0065) and 7.21 (range: 6.60-7.50) and 6.70 (range: 6.34-7.22) for arterial pH (p<0.0001). The area under the ROC curve was highest for arterial pH, 0.94 (95% CI: 0.89-0.99). For ethylene glycol, these were 49 (range: 0-189) and 79 (range: 25-184) mOsm/kg water for osmolal gap (p=0.050), 28 (range: 6-48) and 38 (range: 20-66) mmol/L for anion gap (p=0.0037) and 7.08 (range: 6.46-7.39) and 6.98 (range: 6.50-7.16) for pH (p=0.072), for survival compared to death. The area under the ROC curve was highest for anion gap, 0.73 (95% CI: 0.60-0.87). Post-methanol ingestion a large osmolal gap, anion gap and low pH (<7.22) were associated with increased mortality; and pH has the highest predictive value. Post-ethylene glycol ingestion, both osmolal gap and anion gap were associated with increased mortality.

• Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal.

  Authors: Freek van Gorp, Stephen Duffull, L Peter Hackett, Geoffrey K Isbister

  British journal of clinical pharmacology. 08/2011; 73(3):402-10.

  WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Escitalopram is a selective serotonin re-uptake inhibitor and the S-enantiomer of racemic citalopram. Previous studies have shown that the most clinicallyWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Escitalopram is a selective serotonin re-uptake inhibitor and the S-enantiomer of racemic citalopram. Previous studies have shown that the most clinically important effect of escitalopram overdose is QT prolongation with the associated risk of torsade de pointes. It remains unclear at what dose the risk of QT prolongation is important and whether decontamination will reduce this risk. WHAT THIS STUDY ADDS • Escitalopram overdose causes a dose-related increase in the QT interval that lags the increase in drug concentration. In escitalopram overdose, single dose activated charcoal reduces the fraction absorbed and reduces the risk of QT interval prolongation. AIMS To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC). METHODS The data set included 78 escitalopram overdose events (median dose, 140 mg [10-560 mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes. RESULTS A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUC(i) /dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α= 0.35). The heart rate corrected QT interval (QT(c) ) was linearly dependent on predicted escitalopram concentration [slope = 87 ms/(mg l(-1) )], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200 mg. CONCLUSIONS There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal.

• A dosing regimen for immediate N-acetylcysteine treatment for acute paracetamol overdose.

  Authors: Finna Shen, Carolyn V Coulter, Geoffrey K Isbister, Stephen B Duffull

  Clinical toxicology (Philadelphia, Pa.). 08/2011; 49(7):643-7.

  Current treatment of paracetamol (acetaminophen) poisoning involves initiating a 3-phase N-acetylcysteine (NAC) infusion after comparing a plasma concentration, taken ≥ 4 h post-overdose, to aCurrent treatment of paracetamol (acetaminophen) poisoning involves initiating a 3-phase N-acetylcysteine (NAC) infusion after comparing a plasma concentration, taken ≥ 4 h post-overdose, to a nomogram. This may result in dosing errors, a delay in treatment, or possibly more adverse effects - due to the use of a high dose rate for the first infusion when treatment is initiated. Our aim was to investigate a novel dosing regimen for the immediate administration of NAC on admission at a lower infusion rate. We used a published population pharmacokinetic model of NAC to simulate a scenario where a patient presents to the hospital 2 h post-overdose. The conventional regimen is commenced 6 h post-overdose when the 4-h plasma paracetamol concentration is available. We investigated an NAC infusion using a lower dosing rate initiated immediately on presentation. We determined a dosing rate that gave an area under the curve (AUC) of the concentration-time curve that was the same or greater than that from the conventional regimen on 90% of occasions. Lower dosing rates of NAC initiated immediately resulted in a similar exposure to NAC. An infusion of 110 mg/kg over the first 5 h (22 mg/kg/h) followed by the last two phases of the conventional regimen, or 200 mg/kg over 9 h (22.6 mg/kg/h) followed by the last phase of the conventional regimen could be used. The novel dosing regimen allowed immediate treatment of a patient using a lower dosing rate. This greatly simplifies the current dosing regimen and may reduce NAC adverse effects while ensuring the same amount of NAC is delivered.

• Digital Holter measurement of QT prolongation in ziprasidone overdose.

  Authors: Ingrid Berling, Geoffrey K Isbister, Leonie Calver, Sally Clunas

  Clinical toxicology (Philadelphia, Pa.). 08/2011; 49(7):694-6.

  QT prolongation is an important complication in drug overdose, particularly with some antidepressants and antipsychotics. There are problems with the accurate measurement of the QT interval andQT prolongation is an important complication in drug overdose, particularly with some antidepressants and antipsychotics. There are problems with the accurate measurement of the QT interval and determining for what QT interval patients should be monitored, because of the risk of torsades des pointes (TdP). We report a case of ziprasidone overdose with QT prolongation, demonstrating different methods of measuring the QT interval. A 47-year-old female presented after taking 1.2 g of ziprasidone and 250 mg of diazepam. She was taking propranolol and venlafaxine therapeutically. She developed bradycardia and QT prolongation (540 msec). She was transferred to a telemetry bed and observed for 48 h until her QT interval returned to normal (460 msec). QT intervals were extracted from (1) 12-lead digital Holter recordings (gold standard); (2) automated measurements on standard electrocardiograms (ECGs); and (3) manual measurements on standard ECGs, and compared on a QT versus time plot. An abnormal QT was determined based on the QT nomogram. Manual QT measurements showed a clear temporal association between ziprasidone overdose and a long QT, consistent with accurate QT measurements using continuous 12-lead Holter recordings with automatic QT measurements. However, standard automated measurements did not indicate an abnormal QT. Manual measurement of the QT interval appeared to be similar to the more accurate measurement of the QT by automated digital Holter recordings and better than standard automated measurements. Manual QT measurements would be more appropriate in clinical assessment of patients.

• Development and evaluation of a prototype of a novel clotting time test to monitor enoxaparin.

  Authors: Abhishek Gulati, James M Faed, Geoffrey K Isbister, Stephen B Duffull

  Pharmaceutical research. 08/2011; 29(1):225-35.

  Dosing of the anticoagulant enoxaparin may result in bleeding following excessive doses or thrombosis if dose is too low. Rarely, anti-Xa activity is used to assess the dose for enoxaparin, but itsDosing of the anticoagulant enoxaparin may result in bleeding following excessive doses or thrombosis if dose is too low. Rarely, anti-Xa activity is used to assess the dose for enoxaparin, but its utility to predict clotting or bleeding remains uncertain. We aimed to develop a clotting time test to monitor enoxaparin therapy. A previously developed mathematical model of the coagulation network was used to identify suitable targets for monitoring enoxaparin therapy. In vitro experiments were then carried out to demonstrate proof of mechanism of the clotting time test activated by the new target activator. Using the mathematical model, we identified Xa as a plausible activating agent for a clotting time test for enoxaparin. In vitro experiments showed a prolongation of the Xa clotting time of 4.6-fold in the presence of enoxaparin (0.5 IU/ml) where 10 nM Xa was used to activate clotting. Using both simulations and in vitro experiments, we provide a proof of mechanism for the Xa clotting time (XaCT) test, which can be considered for further development to provide a biomarker of the effect of enoxaparin on the clotting system.

• Early endoscopy or CT in caustic injuries: a re-evaluation of clinical practice.

  Authors: Geoffrey K Isbister, Colin B Page

  Clinical toxicology (Philadelphia, Pa.). 08/2011; 49(7):641-2.

• Spider bite.

  Authors: Geoffrey K Isbister, Hui Wen Fan

  Lancet. 07/2011; 378(9808):2039-47.

  Spiders are a source of intrigue and fear, and several myths exist about their medical effects. Many people believe that bites from various spider species cause necrotic ulceration, despite evidenceSpiders are a source of intrigue and fear, and several myths exist about their medical effects. Many people believe that bites from various spider species cause necrotic ulceration, despite evidence that most suspected cases of necrotic arachnidism are caused by something other than a spider bite. Latrodectism and loxoscelism are the most important clinical syndromes resulting from spider bite. Latrodectism results from bites by widow spiders (Latrodectus spp) and causes local, regional, or generalised pain associated with non-specific symptoms and autonomic effects. Loxoscelism is caused by Loxosceles spp, and the cutaneous form manifests as pain and erythema that can develop into a necrotic ulcer. Systemic loxoscelism is characterised by intravascular haemolysis and renal failure on occasion. Other important spiders include the Australian funnel-web spider (Atrax spp and Hadronyche spp) and the armed spider (Phoneutria spp) from Brazil. Antivenoms are an important treatment for spider envenomation but have been less successful than have those for snake envenomation, with concerns about their effectiveness for both latrodectism and loxoscelism.

• Indications for single-dose activated charcoal administration in acute overdose.

  Authors: Geoffrey K Isbister, Venkata V Pavan Kumar

  Current opinion in critical care. 06/2011; 17(4):351-7.

  Gastrointestinal decontamination in overdose patients remains a controversial problem in emergency medicine. There has been a significant decrease in the use of single-dose activated charcoal (SDAC)Gastrointestinal decontamination in overdose patients remains a controversial problem in emergency medicine. There has been a significant decrease in the use of single-dose activated charcoal (SDAC) in recent years based on little new evidence and possibly because the overall mortality in overdose patients is low. Human volunteer studies suggest SDAC is effective and this effect occurs for up to 4 h after ingestion, but the magnitude of the reduction in area under the curve (AUC) decreases over time. Two randomized controlled trials including one recent large study did not find SDAC to be beneficial. Pharmacokinetic and pharmacodynamic studies of specific drugs in overdose suggest that for most drugs SDAC decreases drug exposure, but this does not translate to clinical benefit in all cases. The administration of SDAC is a low-risk intervention. Although SDAC is unlikely to be beneficial in many overdose patients, for some subgroups with severe poisoning, the benefits will outweigh the low risk of administration. The use of SDAC should be based on the potential toxicity of the drug ingested and the potential benefit of SDAC balanced against the willingness of the patient to take SDAC and the low risk of administration.

• A pharmacological approach to first aid treatment for snakebite.

  Authors: Megan E Saul, Paul A Thomas, Peter J Dosen, Geoffrey K Isbister, Margaret A O'Leary, Ian M Whyte, Sally A McFadden, Dirk F van Helden

  Nature medicine. 06/2011; 17(7):809-11.

  Snake venom toxins first transit the lymphatic system before entering the bloodstream. Ointment containing a nitric oxide donor, which impedes the intrinsic lymphatic pump, prolonged lymph transitSnake venom toxins first transit the lymphatic system before entering the bloodstream. Ointment containing a nitric oxide donor, which impedes the intrinsic lymphatic pump, prolonged lymph transit time in rats and humans and also increased rat survival time after injection of venom. This pharmacological approach should give snakebite victims more time to obtain medical care and antivenom treatment.

• Life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis.

  Authors: Colin B Page, Paul A Wilson, Aidan Foy, Michael A Downes, Ian M Whyte, Geoffrey K Isbister

  The Medical journal of Australia. 06/2011; 194(11):614.

• Erratum to: The in vitro toxicity of venoms from South Asian Hump-nosed pit vipers (Viperidae: Hypnale).

  Authors: Kalana Maduwage, Wayne C Hodgson, Nicki Konstantakopoulos, Margaret A O'Leary, Indika Gawarammana, Geoffrey K Isbister

  Journal of venom research. 01/2011; 2:E17.

  [This corrects the article on p. 17 in vol. 2, PMID: 21677795.].

• The pharmacokinetics of methanol in the presence of ethanol: a case study.

  Authors: Carolyn V Coulter, Geoffrey K Isbister, Stephen B Duffull

  Clinical pharmacokinetics. 01/2011; 50(4):245-51.

  Methanol is a toxic alcohol that can cause significant morbidity and mortality in overdose, while ethanol is a readily available and effective antidote. Little is known about the pharmacokinetics ofMethanol is a toxic alcohol that can cause significant morbidity and mortality in overdose, while ethanol is a readily available and effective antidote. Little is known about the pharmacokinetics of methanol in the presence of ethanol and vice versa. This paper explores the influence of methanol and ethanol on the pharmacokinetics of each other along with the effect of continuous venovenous haemodiafiltration (CVVHD) on alcohol removal. Multiple plasma, urine and dialysate samples were collected from a 42-year-old male who ingested 166 g of methanol. Methanol and ethanol concentrations in both plasma and urine were assayed and the concentration-time data were modelled using nonlinear mixed-effects modelling software NONMEM® VI. Simulations were performed using the final model parameters in MATLAB® software where a variety of initial doses and ethanol infusions were assessed. The final model included a competitive metabolic interaction between methanol and ethanol as well as first-order elimination due to renal, CVVHD and an additional non-renal non-CVVHD mechanism. Simulations from the model show a loading dose of 28.4 g/70 kg of ethanol results in a target plasma concentration of 1 g/L. Due to the competitive interaction between methanol and ethanol, higher amounts of methanol require lower maintenance doses of ethanol but for longer. CVVHD was shown to increase the dose rate of ethanol required but to decrease the duration of the maintenance phase. A detailed understanding of the pharmacokinetics of methanol and ethanol in the presence of each other is required to accurately determine the doses of ethanol required to treat different methanol poisonings.

• The in vitro toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Hypnale).

  Authors: Kalana Maduwage, Wayne C Hodgson, Nicki Konstantakopoulos, Margaret A O'Leary, Indika Gawarammana, Geoffrey K Isbister

  Journal of venom research. 01/2011; 2:17-23.

  Hump-nosed pit vipers (Genus Hypnale) are venomous snakes from South India and Sri Lanka. Envenoming by Hypnale species may cause significant morbidity and is characterized by local envenoming andHump-nosed pit vipers (Genus Hypnale) are venomous snakes from South India and Sri Lanka. Envenoming by Hypnale species may cause significant morbidity and is characterized by local envenoming and less commonly coagulopathy and acute renal failure. Currently there are three nominal species of this genus: H. hypnale, H. zara and H. nepa. This study investigates the biochemical and pharmacological properties of the venoms from the three Hypnale species in Sri Lanka. The three Hypnale venoms had similar chromatographic profiles using reverse phase high performance liquid chromatography and fractions with procoagulant activity were identified. Hypnale venoms had potent cytotoxicity in cultured rat aorta smooth muscle cells with similar IC(50) values. The venoms had weak neurotoxic and myotoxic activity in the isolated chick biventer muscle preparation. They had mild procoagulant activity with close MCC(5) values and also phospholipase activity. Locally available polyvalent antivenom did not neutralise any venom effects. The study demonstrates that the three Hypnale venoms are similar and cytotoxicity appears to be the most potent effect, although they have mild procoagulant activity. These findings are consistent with clinical reports.

• Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study.

  Authors: Geoffrey K Isbister, Leonie A Calver, Colin B Page, Barrie Stokes, Jenni L Bryant, Michael A Downes

  Annals of emergency medicine. 10/2010; 56(4):392-401.e1.

  We determine whether droperidol, midazolam, or the combination is more effective for intramuscular sedation in violent and acute behavioral disturbance in the emergency department (ED). We conductedWe determine whether droperidol, midazolam, or the combination is more effective for intramuscular sedation in violent and acute behavioral disturbance in the emergency department (ED). We conducted a blinded randomized controlled trial of intramuscular sedation for violent and acute behavioral disturbance, comparing droperidol (10 mg), midazolam (10 mg), and droperidol (5 mg)/midazolam (5 mg). Inclusion criteria were patients requiring physical restraint and parenteral sedation. The primary outcome was the duration of the violent and acute behavioral disturbance, defined as the time security staff were required. Secondary outcomes included time until additional sedation was administered, staff and patient injuries, further episodes of violent and acute behavioral disturbance, and drug-related adverse effects. From 223 ED patients with violent and acute behavioral disturbance, 91 patients were included; 33 received droperidol, 29 received midazolam, and 29 received the combination. There was no difference in the median duration of the violent and acute behavioral disturbance: 20 minutes (interquartile range [IQR] 11 to 37 min) for droperidol, 24 minutes (IQR 13 to 35 minutes) for midazolam, and 25 minutes (IQR 15 to 38 minutes) for the combination. Additional sedation was required in 11 (33%; 95% confidence interval [CI] 19% to 52%) droperidol patients, 18 (62%; 95% CI 42% to 79%) midazolam patients, and 12 (41%; 95% CI 24% to 61%) in the combination group. The hazard ratio for additional sedation in the midazolam versus droperidol group was 2.31 (95% credible interval 1.01 to 4.71); for the combination versus droperidol, 1.18 (95% credible interval 0.46 to 2.50). Patient and staff injuries and number of further episodes of violent and acute behavioral disturbance did not differ between groups. There were two adverse effects for droperidol (6%; 95% CI 1% to 22%), 8 for midazolam (28%; 95% CI 13% to 47%), and 2 for the combination (7%; 95% CI 1% to 24%). An abnormal QT occurred in 2 of 31 (6%; 95% CI 1% to 23%) droperidol patients, which was not different from the other groups. Intramuscular droperidol and midazolam resulted in a similar duration of violent and acute behavioral disturbance, but more additional sedation was required with midazolam. Midazolam caused more adverse effects because of oversedation, and there was no evidence of QT prolongation associated with droperidol compared with midazolam.