The etiology and outcome of non-traumatic coma in critical care: a systematic review.

BACKGROUND: Non-traumatic coma (NTC) is a serious condition requiring swift medical or surgical decision making upon arrival at the emergency department. Knowledge of the most frequent etiologies of NTC and associated mortality might improve the management of these patients. Here, we present the results of a systematic literature search on the etiologies and prognosis of NTC. METHODS: Two reviewers independently performed a systematic literature search in the Pubmed, Embase and Cochrane databases with subsequent reference and citation checking. Inclusion criteria were retrospective or prospective observational studies on NTC, which reported on etiologies and prognostic information of patients admitted to the emergency department or intensive care unit. RESULTS: Eventually, 14 studies with enough data on NTC, were selected for this systematic literature review. The most common causes of NTC were stroke (6-54%), post-anoxic coma (3-42%), poisoning (<1-39%) and metabolic causes (1-29%). NTC was also often caused by infections, especially in African studies affecting 10-51% of patients. The NTC mortality rate ranged from 25 to 87% and the mortality rate continued to increase long after the event had occurred. Also, 5-25% of patients remained moderately-severely disabled or in permanent vegetative state. The mortality was highest for stroke (60-95%) and post-anoxic coma (54-89%) and lowest for poisoning (0-39%) and epilepsy (0-10%). CONCLUSION: NTC represents a challenge to the emergency and the critical care physicians with an important mortality and moderate-severe disability rate. Even though, included studies were very heterogeneous, the most common causes of NTC are stroke, post anoxic, poisoning and various metabolic etiologies. The best outcome is achieved for patients with poisoning and epilepsy, while the worst outcome was seen in patients with stroke and post-anoxic coma. Adequate knowledge of the most common causes of NTC and prioritizing the causes by mortality ensures a swift and adequate work-up in diagnosis of NTC and may improve outcome.

In-hospital mortality and long-term survival of patients with acute intoxication admitted to the ICU.

OBJECTIVE: To assess in-hospital and long-term mortality of Dutch ICU patients admitted with an acute intoxication. DESIGN: Cohort of ICU admissions from a national ICU registry linked to records from an insurance claims database. SETTING: Eighty-one ICUs (85% of all Dutch ICUs). PATIENTS: Seven thousand three hundred thirty-one admissions between January 1, 2008, and October 1, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Kaplan-Meier curves were used to compare the unadjusted mortality of the total intoxicated population and for specific intoxication subgroups based on the Acute Physiology and Chronic Health Evaluation IV reasons for admission: 1) alcohol(s), 2) analgesics, 3) antidepressants, 4) street drugs, 5) sedatives, 6) poisoning (carbon monoxide, arsenic, or cyanide), 7) other toxins, and 8) combinations. The case-mix adjusted mortality was assessed by the odds ratio adjusted for age, gender, severity of illness, intubation status, recurrent intoxication, and several comorbidities. The ICU mortality was 1.2%, and the in-hospital mortality was 2.1%. The mortality 1, 3, 6, 12, and 24 months after ICU admission was 2.8%, 4.1%, 5.2%, 6.5%, and 9.3%, respectively. Street drugs had the highest mortality 2 years after ICU admission (12.3%); a combination of different intoxications had the lowest (6.3%). The adjusted observed mortality showed that intoxications with street drugs and "other toxins" have a significant higher mortality 1 month after ICU admission (odds ratioadj = 1.63 and odds ratioadj= 1.73, respectively). Intoxications with alcohol or antidepressants have a significant lower mortality 1 month after ICU admission (odds ratioadj = 0.50 and odds ratioadj = 0.46, respectively). These differences were not found in the adjusted mortality 3 months upward of ICU admission. CONCLUSIONS: Overall, the mortality 2 years after ICU admission is relatively low compared with other ICU admissions. The first 3 months after ICU admission there is a difference in mortality between the subgroups, not thereafter. Still, the difference between the in-hospital mortality and the mortality after 2 years is substantial.

Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.

Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-ß adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.

Differential roles of phase I and phase II enzymes in 3,4-methylendioxymethamphetamine-induced cytotoxicity.

Metabolism plays an important role in the toxic effects caused by 3,4-methylenedioxymethamphetamine (MDMA). Most research has focused on the involvement of CYP2D6 enzyme in MDMA bioactivation, and less is known about the contribution of other cytochrome P450 (P450) and phase II metabolism. In this study, we researched the differential roles of phase I P450 enzymes CYP1A2, CYP3A4, and CYP2D6 and phase II enzymes glutathione S-transferase (GST) and catechol-O-methyltransferase (COMT) on the toxic potential of MDMA. MDMA acts as inhibitor of its own metabolism with a relative potency of inhibition of CYP2D>CYP3A>> CYP1A in rat liver microsomes and in human liver [immortalized human liver epithelial cells (THLE)] cells transfected with individual CYP1A2, CYP3A4, or CYP2D6. Cytotoxicity measurements [by 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] in THLE cells showed that the inhibition of phase I enzymes CYP1A2 by alpha-naphthoflavone and CYP3A4 by troleandomycin does not affect MDMA-induced cytotoxicity. MDMA metabolism by CYP2D6 significantly increased cytotoxicity, which was counteracted by CYP2D6 inhibition by quinidine. Inhibition of COMT by 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone (Ro-41-0960) and GST by buthionine sulfoximine showed that COMT is mainly involved in detoxification of CYP2D6-formed MDMA metabolites, whereas glutathione (GSH) is mainly involved in detoxification of CYP3A4-formed MDMA metabolites. Liquid chromatography/tandem mass spectrometry analyses of MDMA-metabolites in the THLE cell culture media confirmed formation of the specific MDMA metabolites and corroborated the observed cytotoxicity. Our data suggest that CYP2D6 as well as CYP3A4 play an important role in MDMA bioactivation. In addition, further studies are needed to address the differential roles of CYP3A4 and GSH/GST in MDMA bioactivation and detoxification.

Disposition of smoked cannabis with high Δ(9)-tetrahydrocannabinol content: a kinetic model.

INTRODUCTION: No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC). METHODS: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0-8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. RESULTS: Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax=175ng/mL, Tmax=14min, and AUC0-8h=8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose=2.8×10(-6)/mL and AUC0-8h/Dose=136×10(-6)min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose=3.4, 2.6 and 2.5×10(-6)/mL and AUC0-8h/Dose=157, 133 and 117×10(-6)min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. CONCLUSION: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%).

Amphetamine reduces vesicular dopamine content in dexamethasone-differentiated PC12 cells only following L-DOPA exposure.

Amphetamine (AMPH) increases brain dopamine (DA) levels via reversal of the membrane DA transporter. Additional mechanisms have been suggested, including inhibition of vesicular monoamine transporters and vesicular leakage of DA and Ca(2+). According to the widely-accepted weak base theory, AMPH disrupts the proton gradient required for filling vesicles with DA. As a result, DA and Ca(2+) will leak from vesicles, giving rise to exocytosis of less-filled vesicles. As several contradictions have been described, the aim of the present study was to re-examine this theory using amperometry and Fura-2 imaging to measure AMPH-induced changes in exocytosis and intracellular Ca(2+) levels, respectively, in PC12 and chromaffin cells. Unexpectedly, 15 min exposure to AMPH (20-200 microM) does not affect the amount of DA released per vesicle, the frequency of exocytosis or intracellular Ca(2+) levels in PC12 cells or chromaffin cells. Comparable results were found following prolonged exposure to AMPH (45 min) or at 37 degrees C. When cells were pre-treated with the DA precursor L-DOPA, vesicle content increased to approximately 150%. When these pre-treated cells are exposed to AMPH, vesicle content is strongly reduced. These results indicate that in dexamethasone-differentiated PC12 cells AMPH-induced vesicle leakage occurs only under specific conditions, therefore arguing for re-evaluation of the theory of AMPH-induced vesicular DA leakage.

Evaluation of available treatment guidelines for the management of lithium intoxication.

Intoxications with lithium carry considerable risk for long-term morbidity and even mortality. Consequently, any patient suspected of lithium intoxication requires immediate and appropriate care. The objectives of this study were to assess the completeness and the applicability of generally available treatment guidelines for the management of patients with a lithium intoxication and, hence, to provide general recommendations for improvement of existing treatment guidelines. Nineteen treatment guidelines originating from 7 different countries were gathered by searching the Internet, online databases, and textbooks and by contacting different poison information centers and university medical centers. A list of items was composed from the retrieved treatment guidelines and a further literature search. Most relevant items were present in the various guidelines. However, in some guidelines, essential information was missing or potentially hazardous information was provided. Clarity, presentation, and applicability of the guidelines, as assessed using parts of the Appraisal of Guidelines Research and Evaluation instrument, were relatively poor. Regular updates of treatment guidelines should be performed to incorporate new essential information. To improve applicability of guidelines, unambiguous key recommendations, alternative treatments, and special care requirements should be provided and authors are recommended to test treatment guidelines using a panel of less experienced caregivers in a hypothetical case scenario.

Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC.

RATIONALE: Delta9-Tetrahydrocannabinol (THC) is the main active constituent of cannabis. In recent years, the average THC content of some cannabis cigarettes has increased up to approximately 60 mg per cigarette (20% THC cigarettes). The pharmacokinetics of THC after smoking cannabis cigarettes containing more than approximately 35 mg THC (3.55% THC cigarettes) is unknown. To be able to perform suitable exposure risk analysis, it is important to know if there is a linear relation at higher doses. OBJECTIVES: The present study aimed to characterise the pharmacokinetics of THC, the active metabolite 11-OH-THC and the inactive metabolite THC-COOH after smoking a combination of tobacco and cannabis containing high THC doses. MATERIALS AND METHODS: This double-blind, placebo-controlled, four-way, cross-over study included 24 male non-daily cannabis users (two to nine joints per month). Participants were randomly assigned to smoke cannabis cigarettes containing 29.3, 49.1 and 69.4 mg THC and a placebo. Serial serum samples collected over a period of 0-8 h were analysed by liquid chromatography electrospray tandem mass spectrometry. Effects on heart rate, blood pressure and 'high' feeling were also measured. RESULTS: Mean maximal concentrations (Cmax) were 135.1, 202.9 and 231.0 microg/L for THC and 9.2, 16.4 and 15.8 microg/L for 11-OH-THC after smoking a 29.3-, 49.1- and 69.4-mg THC cigarette, respectively. A large inter-individual variability in Cmax was observed. Heart rate and 'high' feeling significantly increased with increasing THC dose. CONCLUSIONS: This study demonstrates that the known linear association between THC dose and THC serum concentration also applies for high THC doses.

The oral bioavailability of nitrate from nitrate-rich vegetables in humans.

High dietary nitrate intake may pose a risk to human health. Since up to 80-85% of dietary nitrate intake comes from vegetables, the aim of this study was to determine the absolute bioavailability of nitrate from three nitrate-rich vegetables. In an open, four-way cross-over, single dose study, 12 human subjects underwent the following treatments: (1) intravenous infusion of 500mg sodium nitrate, (2) oral administration of 300g cooked spinach, (3) oral administration of 300g raw lettuce, and (4) oral administration of 300g cooked beetroot. The wash-out period between treatments was at least 6 days. Plasma samples were analysed to assess the nitrate and nitrite concentrations, and pharmacokinetic parameters were calculated. The bioavailability of nitrate was 98+/-12% from cooked spinach, 114+/-14% from raw lettuce and 106+/-15% from cooked beetroot. There was no significant increase in plasma nitrite concentrations. This study shows that nitrate from vegetables, whether cooked or uncooked, is absorbed very effectively, resulting in an absolute nitrate bioavailability of around 100%. Thus, reducing the amount of nitrate in vegetables can be an effective measure to lower the systemic nitrate exposure of the general population. However, other aspects, such as the costs to produce vegetables with a low nitrate content and the possible beneficial effects of nitrate in vegetables, need to be considered when evaluating the usefulness of such a measure.

A case series of xylometazoline overdose in children.

INTRODUCTION: Serious intoxications associated with low doses of imidazolines have been reported. Therefore, the treatment advice for children with xylometazoline overdose is usually to observe the child in the hospital, even after exposure to very low doses. Our aim was to determine the frequency of severe symptoms after xylometazoline exposure, and the systemic dose of xylometazoline below which asymptomatic children do not need to be hospitalized for observation. METHODS: From May 2002 until December 2004, we prospectively collected data on all consecutive cases of xylometazoline exposure in children <6 years old reported to our poisons centre. Follow-up information was collected. The systemic dose was calculated and the frequency of severe symptoms was observed. RESULTS: During 32 months, we included 101 cases of xylometazoline exposure in children. For 63 out of these 101 cases, follow-up information could be collected. No severe symptoms were observed after exposure to xylometazoline doses reported to be below 0.4 mg/kg (95% confidence interval: 0-6%). CONCLUSION: We conclude that less than 6% of children exposed to xylometazoline, at doses reported to be less than 0.4 mg/kg body weight, may develop symptoms that require hospitalization.

The need for ICU admission in intoxicated patients: a prediction model.

CONTEXT: Intoxicated patients are frequently admitted from the emergency room to the ICU for observational reasons. The question is whether these admissions are indeed necessary. OBJECTIVE: The aim of this study was to develop a model that predicts the need of ICU treatment (receiving mechanical ventilation and/or vasopressors <24 h of the ICU admission and/or in-hospital mortality). MATERIALS AND METHODS: We performed a retrospective cohort study from a national ICU-registry, including 86 Dutch ICUs. We aimed to include only observational admissions and therefore excluded admissions with treatment, at the start of the admission that can only be applied on the ICU (mechanical ventilation or CPR before admission). First, a generalized linear mixed-effects model with binominal link function and a random intercept per hospital was developed, based on covariates available in the first hour of ICU admission. Second, the selected covariates were used to develop a prediction model based on a practical point system. To determine the performance of the prediction model, the sensitivity, specificity, positive, and negative predictive value of several cut-off points based on the assigned number of points were assessed. RESULTS: 9679 admissions between January 2010 until January 2015 were included for analysis. In total, 632 (6.5%) of the patients admitted to the ICU eventually turned out to actually need ICU treatment. The strongest predictors for ICU treatment were respiratory insufficiency, age >55 and a GCS <6. Alcohol and "other poisonings" (e.g., carbonmonoxide, arsenic, cyanide) as intoxication type and a systolic blood pressure ≥130 mmHg were indicators that ICU treatment was likely unnecessary. The prediction model had high sensitivity (93.4%) and a high negative predictive value (98.7%). DISCUSSION AND CONCLUSION: Clinical use of the prediction model, with a high negative predictive value (98.7%), would result in 34.3% less observational admissions.

Modeling the effect of succimer (DMSA; dimercaptosuccinic acid) chelation therapy in patients poisoned by lead.

CONTEXT: Kinetic models could assist clinicians potentially in managing cases of lead poisoning. Several models exist that can simulate lead kinetics but none of them can predict the effect of chelation in lead poisoning. Our aim was to devise a model to predict the effect of succimer (dimercaptosuccinic acid; DMSA) chelation therapy on blood lead concentrations. MATERIALS AND METHODS: We integrated a two-compartment kinetic succimer model into an existing PBPK lead model and produced a Chelation Lead Therapy (CLT) model. The accuracy of the model's predictions was assessed by simulating clinical observations in patients poisoned by lead and treated with succimer. The CLT model calculates blood lead concentrations as the sum of the background exposure and the acute or chronic lead poisoning. The latter was due either to ingestion of traditional remedies or occupational exposure to lead-polluted ambient air. The exposure duration was known. The blood lead concentrations predicted by the CLT model were compared to the measured blood lead concentrations. RESULTS: Pre-chelation blood lead concentrations ranged between 99 and 150 µg/dL. The model was able to simulate accurately the blood lead concentrations during and after succimer treatment. The pattern of urine lead excretion was successfully predicted in some patients, while poorly predicted in others. CONCLUSIONS: Our model is able to predict blood lead concentrations after succimer therapy, at least, in situations where the duration of lead exposure is known.

Intoxication following minor stabs from the spines of a porcupine fish.

We report an unusual intoxication by tetrodotoxin (TTX). A curator of an aquarium sustained minor punctures in his finger from the spines of a porcupine fish during an autopsy of a dead porcupine fish. He developed paresthesias, numbness, paresis, dizziness and headache. The death of the fish might have caused some autolysis, leading to increased availability of TTX. In combination with direct contact with the organ fluids, this probably led to TTX exposure via minor wounds.

Clinical presentation and management of an Aruban rattlesnake bite in the Netherlands.

Bites by Aruban Rattlesnake (Crotalus durissus unicolor) are rare and not known to induce severe envenomations. Here, we present a case of a 57 year-old man bitten by his pet Aruban Rattlesnake (Crotalus durissus unicolor). He was admitted to hospital within 15 min. Three and a half hours later his fibrinogen concentration decreased to 0.6 g/L (normal: 2.0-4.0). Nine hours post-bite, he was treated with polyvalent snake antivenom covering Crotalus durissus. Three hours later his fibrinogen became undetectable while at that time clotting times were prolonged (PT 38.7 s (normal: 12.5-14.5) and aPTT 40 s (normal: 25-35)). His platelet count remained within normal limits. Creatine kinase (CK) concentrations reached a maximum of 1868 U/L (normal: <200) 16 h post-bite. After a second antivenom dose, 10.5 h after the first antivenom administration, clotting times returned to normal. Fibrinogen was restored to normal within three days. He was discharged from hospital on day five. In conclusion, administration of polyvalent snake antivenom covering Crotalus durissus snakebites shows cross-neutralization and is effective in the treatment of patients bitten by Crotalus durissus unicolor.

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans.

CONTEXT: No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning. OBJECTIVE: Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model. MATERIAL AND METHODS: This was a kinetic modelling study. We used a two-compartment model, with a non-systemic gastrointestinal compartment (gut lumen) and the whole body as one systemic compartment. The only data available from the literature were used to calibrate the unknown model parameters. The calibrated model was then validated by comparing its predictions with measured data from three different experimental human studies. RESULTS: The model predicted total DMSA plasma and urine concentrations measured in three healthy volunteers after ingestion of DMSA 10 mg/kg. The model was then validated by using data from three other published studies; it predicted concentrations within a factor of two, representing inter-human variability. CONCLUSIONS: A simple kinetic model simulating the kinetics of DMSA in humans has been developed and validated. The interest of this model lies in the future potential to use it to predict blood lead concentrations in lead-poisoned patients treated with DMSA.

Rhabdomyolysis in Clozapine Overdose.

CONTEXT: Clozapine is used for decennia for the treatment of schizophrenia. Agranulocytosis, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis are well-known adverse effects of clozapine, which are sometimes life threatening. Here we report a case of rhabdomyolysis upon an acute overdose of clozapine. CASE: A male patient, 36 years, with elevated creatinine kinase levels (9899 U/l), developed rhabdomyolysis afterafter admission to the emergency department. Approximately 2-4 h earlier he had intoxicated himself with his maintenance oral medication clozapine 125 mg, temazepam 20 mg and lorazepam 1.5 mg. Co-medications, and physical and laboratory examinations did not reveal other risk factors for rhabdomyolysis. According to the Naranjo probability scale there was a probable relation between clozapine dose and symptoms, that developed approximately 2-4 h after the auto-intoxication of 125 mg tablets. At day 5 of hospitalization, clozapine and creatinine kinase levels returned to normal and the patient was discharged with no somatic sequelae. CONCLUSIONS: Elevated creatinine kinase levels in acute clozapine intoxication may be an indicator that rhabdomyolysis may be involved.

Evaluation of semi-generic PBTK modeling for emergency risk assessment after acute inhalation exposure to volatile hazardous chemicals.

BACKGROUND: Physiologically Based Toxicokinetic Models (PBTK) may facilitate emergency risk assessment after chemical incidents with inhalation exposure, but they are rarely used due to their relative complexity and skill requirements. We aimed to tackle this problem by evaluating a semi-generic PBTK model built in MS Excel for nine chemicals that are widely-used and often released in a chemical incident. MATERIAL & METHODS: The semi-generic PBTK model was used to predict blood concentration-time curves using inhalation exposure scenarios from human volunteer studies, case reports and hypothetical exposures at Emergency Response Planning Guideline, Level 3 (ERPG-3) levels.(2) Predictions using this model were compared with measured blood concentrations from volunteer studies or case reports, as well as blood concentrations predicted by chemical-specific models. The performances of the semi-generic model were evaluated on biological rationale, accuracy, and ease of use and range of application. RESULTS: Our results indicate that the semi-generic model can be easily used to predict blood levels for eight out of nine parent chemicals (dichloromethane, benzene, xylene, styrene, toluene, isopropanol trichloroethylene and tetrachloroethylene). However, for methanol, 2-propanol and dichloromethane the semi-generic model could not cope with the endogenous production of methanol and of acetone (being a metabolite of 2-propanol) nor could it simulate the formation of HbCO, which is one of the toxic end-points of dichloromethane. The model is easy and intuitive to use by people who are not so familiar with toxicokinetic models. CONCLUSION: A semi-generic PBTK modeling approach can be used as a 'quick-and-dirty' method to get a crude estimate of the exposure dose.