Toxicodynetics: A new discipline in clinical toxicology.

OBJECTIVES: Regarding the different disciplines that encompass the pharmacology and the toxicology, none is specifically dedicated to the description and analysis of the time-course of relevant toxic effects both in experimental and clinical studies. The lack of a discipline devoted to this major field in toxicology results in misconception and even in errors by clinicians. MATERIAL AND METHODS: Review of the basic different disciplines that encompass pharmacology toxicology and comparing with the description of the time-course of effects in conditions in which toxicological analysis was not performed or with limited analytical evidence. RESULTS: Review of the literature clearly shows how misleading is the current extrapolation of toxicokinetic data to the description of the time-course of toxic effects. CONCLUSION: A new discipline entitled toxicodynetics should be developed aiming at a more systematic description of the time-course of effects in acute human and experimental poisonings. Toxicodynetics might help emergency physicians in risk assessment when facing a poisoning and contribute to a better assessment of quality control of data collected by poison control centres. Toxicodynetics would also allow a quantitative approach to the clinical effects resulting from drug-drug interaction.

The occupational physician and chemical disasters: old problem, new threats.

Chemical disasters continue to occur, in spite of significant progress in process engineering, industrial hygiene practices, and improved enforcement of health and safety legislation. In addition to the ever-present risk of unintentional incidents, recent geopolitical events have raised the specter of chemical terrorism. Terrorists or even disgruntled employees may exploit lapses in chemical plant security and ready access to large quantities commodity chemicals, capable of causing great harm to the population if suddenly and unexpectedly released. Occupational physicians, who are uniquely equipped to understand the health hazards associated with industrial chemicals should be involved in prevention of planning for, and response to chemical disasters. Measures for improving preparedness include training and collaboration, not only with plant health and safety personnel but also with public safety and health care providers, through drills and assessment of needs and capacities. Occupational physicians should be aware that communications and other systems often fail in disasters, requiring multiple alternatives. Likewise, occupational health specialists should be prepared to deal with mass casualties, including psychological casualties which may be difficult to distinguish from those of organic etiology. Chemical disaster preparedness is an urgent and demanding responsibility for occupational physicians everywhere.

Measurement of carbon monoxide in simulated expired breath.

BACKGROUND: Environmental carbon dioxide (CO) detectors used as an early warning method have been adapted to measure CO concentration in expired breath. This technique has been validated in smokers with relatively low CO concentrations, but its applicability to poisoning has not been demonstrated. OBJECTIVE: To compare the reliability of toxicologically significant CO measurements performed using a portable CO detector with those obtained using infrared spectrometry, the standard method for blood CO concentration determination. DESIGN: Experimental study with a CO detector and infrared spectrometer. A balloon simulated respiratory movements and an expired breath. Balloon gas mixtures contained CO, in one of 21 different concentrations from 100 to 600 parts per million (ppm) in air. CO concentration was measured directly with the portable CO detector and two gas samples obtained at the beginning and end of the simulated expired breath were diluted, with validation, for spectrometric measures. MAIN OUTCOME MEASURES: Portable CO detector concentrations were compared with the mean value of the reference method. Simple linear regression was performed using ANOVA to evaluate the parallel between the model with the reference method. RESULTS: Portable CO detector concentration measurements were perfectly linear (R2=0.989, P<10(-3)) over a concentration range of 46-645 ppm. The difference from the reference plot was significant (P<0.01). CONCLUSION: Given the linearity of the measurements, the underestimation by the portable CO detector at higher concentrations can be corrected mathematically. A portable CO detector should measure CO in expired breath efficiently and reliably.

[Sodium thiosulfate for acute cyanide poisoning: study in a rat model]. / Thiosulfate de sodium et intoxication cyanhydrique aiguë: étude chez le rat.

Unlike practices in the United States where it is associated with other antidotes, sodium thiosulfate is not used for emergency therapy for cyanide poisoning in France. The purpose of this study was to develop a rat model using intraperitoneal injections of sodium thiosulfate at a dose of 225 mg/kg to test its therapeutic efficacy for acute cyanide poisoning. Efficacy was assessed directly by quantifying arterial blood cyanide and indirectly using markers of hypoxia: serum lactate and arteriolization of venous blood gases. Cyanide poisoning induced intense biological anomalies which were persistent (serum lactate) or transient (blood gases). Sodium thiosulfate was found to be an effective antidote in the rat enabling rapid normalization of hypoxia markers and clearing of cyanide from arterial blood.

Lingual angioedema after perindopril use.

We report a case of severe lingual edema and airway compromise associated with angiotensin-converting enzyme inhibitor use. Although angiotensin-converting enzyme inhibitors are generally considered as safe drugs, angioedema may induce severe respiratory distress and death.

Value of C-reactive protein in the detection of bacterial contamination at the time of presentation in drug-induced aspiration pneumonia.

STUDY OBJECTIVES: To compare the plasma concentration of C-reactive protein (CRP) with traditional markers for diagnosis of bacterial pneumonia in patients with suspected aspiration. DESIGN: Prospective, nonrandomized, controlled study of consecutive hospital admissions. SETTING: Toxicology ICU in a university hospital. PATIENTS OR PARTICIPANTS: Acutely poisoned comatose patients admitted to the hospital with suspicion of aspiration pneumonia. INTERVENTIONS: Distal protected catheter sampling per fiberoptic bronchoscopy and bacteriologic culture were employed as a standard to detect the bacterial component of suspected aspiration pneumonia. Plasma CRP concentrations, temperature, and WBC count were measured on hospital day 1. MEASUREMENTS AND RESULTS: Sixty-six patients were evaluated. Thirty-two had bacterial contamination by positive culture (> or =10(3) cfu/mL). Multiple receiver-operating characteristic (ROC) curves were used to compare each parameter for detection of infection secondary to aspiration. The ROC curve of CRP concentrations showed that a CRP >75 mg/L is associated with bacterial contamination with a sensitivity of 87%, specificity of 76%, positive predictive value of 78%, and negative predictive value of 87%. ROC curves of temperature and WBC count demonstrated poor diagnostic value of these markers in indicating the bacterial component of suspected aspiration pneumonia. CONCLUSIONS: Early measurement of CRP is useful for the diagnosis of aerobic bacterial content of aspiration pneumonia and perhaps in determining the need for invasive bacteriologic sampling. Temperature and WBC count are poor indicators of bacterial infection of aspiration pneumonia in poisoned patients.

Prolonged severe hypercapnia complicating near fatal asthma in a 35-year-old woman.

OBJECTIVE: We describe a patient with a prolonged and severe hypercapnia occurring during an episode of status asthmaticus induced by ophthalmic instillation of carteolol. SETTING: Prehospital Emergency Medical Service and Pulmonary Intensive Care Unit in a university hospital. PATIENT: A 35-year-old female developed an acute asthma attack while at home, which required advanced life support. INTERVENTION: On hospital admission, arterial blood gases revealed a PaCO2 of 208 mmHg. Hypercapnia persisted with a PaCO2 of more than 190 mmHg for 10 h, with pH always less than 7.00. The patient was finally discharged after 26 days without sequelae. CONCLUSION: This case illustrates the cerebral and cardiovascular tolerance of severe and prolonged hypercapnia associated with major acidosis.

Complication profiles of adult asthmatics requiring paralysis during mechanical ventilation.

OBJECTIVE: To assess the characteristics and the incidence of morbidity of intubated asthmatic patients who received long-term paralysis. DESIGN: Retrospective cohort study. SETTING: Five intensive care units (ICUs) in Paris and the surrounding suburbs. PATIENTS AND PARTICIPANTS: The NMB group consisted of patients who received neuromuscular blocking agents for more than 12 h (NMB group) versus sedation alone (SED). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The incidence of post-extubation muscle weakness and/or myopathy was 18% in the NMB group compared to 2% in the SED group ( p=0.01). The occurrence of ventilator-associated pneumonia was higher in the NMB group (42% versus 4%; p<0.0001). The duration of ICU stay and of mechanical ventilation were significantly greater in the NMB group. Multiple logistic regression analysis showed that inclusion in the NMB group was the only independent predictor of the presence of the overall morbidity [odds ratio 6.4 (2.09; 19.64)]. CONCLUSION: While greater initial severity of respiratory compromise in the NMB group may explain part of the difference, use of NMB agents appears to be strongly related to the presence of significant complications among mechanically-ventilated asthmatic patients.

Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity.

OBJECTIVE: Acute chloroquine intoxication is responsible for a membrane-stabilising effect which results in electrocardiographic (ECG) and hemodynamic disturbances. Diazepam is used in acute chloroquine intoxication on the basis of clinical and experimental observations, but its utility alone, in man, remains unproven. The goal of this study was to verify whether diazepam alone has an effect on the membrane-stabilising effect observed in moderately severe chloroquine intoxications. DESIGN: Prospective, multi-center, double-blind, placebo-controlled study. SETTING: Prehospital mobile intensive care units (Paris) and hospital intensive care units (paris and Dakar). PATIENTS AND PARTICIPANTS: Adults with moderately severe intoxication defined as: a suspected ingested dose of 2 or more but less than 4 g, systolic blood pressure (SBP) higher than 80 mmHg, QRS duration less than 0.12 s and the absence of dysrhythmia at inclusion. INTERVENTIONS: Patients received either a loading dose of 0.5 mg/kg diazepam followed by an infusion of 1 mg/kg over 24 h or an equivalent volume of placebo. MEASUREMENTS AND RESULTS: Outcome was measured by serial assessments of SBP, ECG (QRS and QT segments) and clinical deterioration. There were no significant differences observed in the initial or serial ECG or SBP measurements. There were no deaths and no patient had to be removed from the study due to clinical deterioration. CONCLUSIONS: Diazepam, at the dose studied, does not appear to reverse the chloroquine-induced membrane-stabilising effect in acute moderately severe chloroquine intoxication. Supportive intensive care of these intoxications appears to be all that is necessary.

Treatment of acute methanol poisoning with fomepizole.

OBJECTIVE: To assess the efficacy and safety of fomepizole, a competitive alcohol dehydrogenase inhibitor, in methanol poisoning and to test the hypothesis that fomepizole obviates the need for hemodialysis in selected patients. DESIGN AND SETTING: Retrospective clinical study in three intensive care units in university-affiliated teaching hospitals. PATIENTS: All methanol-poisoned patients admitted to these ICUs and treated with fomepizole from 1987-1999 (n=14). MEASUREMENTS AND RESULTS: The median plasma methanol concentration was 50 mg/dl (range 4-146), anion gap 22.1 mmol/l (11.8-42.2), arterial pH 7.34 (7.11-7.51), and bicarbonate 17.5 mmol/l (3.0-25.0). Patients received oral or intravenous fomepizole until blood methanol was undetectable. The median cumulative dose was 1250 mg (500-6000); the median number of twice daily doses was 2 (1-16). Four patients underwent hemodialysis for visual impairment present on admission. Four patients with plasma methanol concentrations of 50 mg/dl or higher and treated without hemodialysis recovered fully. Patients without pretreatment visual disturbances recovered, with no sequelae in any case. There were no deaths. Fomepizole was safe and well tolerated, even in the case of prolonged treatment. Analysis of methanol toxicokinetics in five patients demonstrated that fomepizole was effective in blocking methanol's toxic metabolism. CONCLUSIONS: Fomepizole appears safe and effective in the treatment of methanol-poisoned patients. If our results are confirmed in prospective analyses, hemodialysis may prove unnecessary in patients presenting without visual impairment or severe acidosis.

Effects of respiratory acidosis and alkalosis on the distribution of cyanide into the rat brain.

The aim of this study was to determine whether respiratory acidosis favors the cerebral distribution of cyanide, and conversely, if respiratory alkalosis limits its distribution. The pharmacokinetics of a nontoxic dose of cyanide were first studied in a group of 7 rats in order to determine the distribution phase. The pharmacokinetics were found to best fit a 3-compartment model with very rapid distribution (whole blood T(1/2)alpha = 21.6 +/- 3.3 s). Then the effects of the modulation of arterial pH on the distribution of a nontoxic dose of intravenously administered cyanide into the brains of rats were studied by means of the determination of the permeability-area product (PA). The modulation of arterial blood pH was performed by variation of arterial carbon dioxide tension (PaCO2) in 3 groups of 8 anesthetized mechanically ventilated rats. The mean arterial pH measured 20 min after the start of mechanical ventilation in the acidotic, physiologic, and alkalotic groups were 7.07 +/- 0.03, 7.41 +/- 0.01, and 7.58 +/- 0.01, respectively. The mean PAs in the acidotic, physiologic, and alkalotic groups, determined 30 s after the intravenous administration of cyanide, were 0.015 +/- 0.002, 0.011 +/- 0.001, and 0.008 +/- 0.001 s(-1), respectively (one-way ANOVA; p < 0.0087). At alkalotic pH the mean permeability-area product was 43% of that measured at acidotic pH. This effect of pH on the rapidity of cyanide distribution does not appear to be limited to specific areas of the brain. We conclude that modulation of arterial pH by altering PaCO2 may induce significant effects on the brain uptake of cyanide.

Lack of effect of single high doses of buprenorphine on arterial blood gases in the rat.

High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD(50)) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD(50) using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD(50) determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6-176.5). The mean dose received by surviving animals was 96.9 +/- 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD(50), is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.

A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths.

AIMS: To assess the trends in the number, mortality and the nature of forensic cases involving toxicological detection of buprenorphine or methadone among toxicological investigations performed in Paris from June 1997 to June 2002. DESIGN: Retrospective, 5 year study with review of premortem data, autopsy, police reports, hospital data, and post-mortem toxicological analyses. SETTING AND PARTICIPANTS: 34 forensic cases of buprenorphine and 35 forensic cases of methadone detection among 1600 toxicological investigations performed at the Laboratory of Toxicology in the Medical Examiner's Office in Paris. MEASUREMENTS AND RESULTS: Therapeutic, toxic or lethal drug concentrations were defined based upon the results of blood analyses and the published literature. Drug concentrations were cross-referenced with other available ante- and post-mortem data. Subsequently, we classified a 'clear responsibility', 'possible responsibility' or 'not causative' role for buprenorphine or methadone in the death process, or 'no explanation of death'. Buprenorphine and methadone can be regarded as being directly implicated in, respectively, four of 34 death cases (12%) and three of 35 death cases (9%), and their participation in the lethal process is strongly plausible in eight (buprenorphine) and 11 (methadone) additional deaths. CONCLUSIONS: Analysis of causes of death reveals the difficulties in determining the role of substitution drugs in the death process, as many other factors may be involved, including circumstances surrounding death, past history, differential selection of subjects into either substitution modality and concomitant intake of other drugs (especially benzodiazepines and neuroleptics). The potential for synergistic or additive actions by other isolated molecules-particularly opioids, benzodiazepines, other psychotropes and alcohol-must be also considered.

Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 1995-99.

AIMS: (1). To assess the trends in the number, mortality and the nature of severe opiate/opioid poisonings from 1995 to 1999 in north-east Paris and adjacent suburbs and (2). to examine the effects of the introduction of high-dose buprenorphine on these parameters. DESIGN: Retrospective, 5-year study with review of pre-hospital, hospital and post-mortem data. SETTING AND PARTICIPANTS: Eighty patients from the toxicological intensive care unit (TICU) in north-east Paris, 421 patients from the pre-hospital emergency medical service in a north-east suburb of Paris (SAMU 93) and 40 deaths from the coroner's office in Paris. MEASUREMENTS AND RESULTS: We found that the number of pre-hospital opiate/opioid poisonings and deaths decreased over 5 years. During the same time frame, opiate/opioid poisoning admissions to our TICU remained steady, but the number of deaths declined. From 1995 to 1999, the detection of buprenorphine among opiate/opioid-poisoned TICU patients increased from two to eight occurrences per year while detection of opiates diminished from 17 to 10 occurrences per year. Increased buprenorphine detection correlated directly with increasing sales over this time period. In spite of the increased use of buprenorphine, the mortality associated with opiate/opioid poisonings has diminished in the pre-hospital environment from 9% in 1995 to 0% in 1999, and in the TICU from 12% in 1995 to 0% in 1997 and thereafter. We found a high frequency of multiple opiate/opioid use in severe poisonings, as well as the frequent association of other psychoactive drugs including ethanol. CONCLUSIONS: The number and the mortality of opiate/opioid poisonings appear to be stable or decreasing in our region. The association of multiple opiates/ opioids appears nearly as common as the association with other psychoactive drugs. The introduction of high-dose buprenorphine coincides with a decrease in opiate/opioid poisoning mortality. Further study will be necessary to clarify this observation.

Advances in the management of digoxin toxicity in the older patient.

Digoxin intoxication is a common problem in the elderly. In its mildest forms it may go undiagnosed, but in severe cases it is often fatal. Altered digoxin pharmacokinetics, attributable to the physiological changes associated with aging, underlying illness, and drug-drug interactions all contribute to the occurrence of digoxin toxicity. Advanced age, male gender, initial hyperkalaemia, underlying heart disease, and advanced atrioventricular block at the time of admission are poor prognostic factors. Supportive care alone is often insufficient. Digoxin-specific Fab therapy may result in dramatic recovery from digoxin intoxication, but it must be administered early and in a an adequate dosage if reductions in mortality are to be achieved.

Modifying toxicokinetics with antidotes.

Five approaches may be described through which antidotes can modify toxicokinetics: (1) Decreased bioavailability of the toxins; (2) Cellular redistribution of the toxin in the organism; (3) Promotion of elimination in an unchanged form; (4) Slowing of metabolic activation pathways; (5) Acceleration of metabolic deactivation pathways. However, the ability to modify toxicokinetics with a new treatment, while demonstrating an understanding of the mechanism of action, must never be construed to be, in and of itself, the goal of therapy. The ultimate evaluation of an antidote modifying toxicokinetics is strictly clinical.

Intubation difficulty in poisoned patients: association with initial Glasgow Coma Scale score.

OBJECTIVE: To determine whether the initial Glasgow Coma Scale (GCS) score is predictive of intubation difficulty in out-of-hospital airway management of poisoned patients. METHODS: A prospective, observational study was performed in a toxicological intensive care unit of a university hospital and in a physician-based out-of-hospital care system. Subjects included consecutive poisoned patients intubated during their airway management by out-of-hospital medical teams before hospitalization. The intubating operator (emergency physician or nurse anesthetist) completed a 1-page checklist concerning the clinical parameters and circumstances (nature of sedation and difficulty) of endotracheal intubation upon hospital arrival. RESULTS: Forms were completed for all 394 consecutive out-of-hospital intubations. The patients ranged from 15 to 95 years of age (median age 38 years). Most (96%) of the intubations were via the oral route. Intubation difficulty was related to GCS values. Intubation difficulty was seen more often in patients with 7 < or = GCS < or = 9 (36%) than in patients with GCS < 7 (15%) or > 9 (10%). Not surprisingly, perceived intubation difficulty was least for those patients undergoing rapid-sequence intubation rather than administration of sedation alone. CONCLUSION: Maximum difficulty of intubation is encountered in poisoned patients with 7 < or = GCS < or = 9. Intubation of such patients appears to be facilitated by appropriate sedation and/or neuromuscular blockade.

Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat.

Opiates and substitution products are frequently abused, alone and in association with benzodiazepines. While this combination may result in severe respiratory depression and death, the quantitative relationship remains uncertain. We performed randomized, blinded intravenous median lethal dose (MLD) studies in Sprague-Dawley rats of morphine, buprenorphine, and methadone, alone and in combination with intraperitoneal flunitrazepam pretreatment. We employed the up-and-down method, performed in quadruplicate, comparing time to death following opioid injection. Results are expressed as median of four series (extremes). The MLDs of morphine, buprenorphine, and methadone alone were 64.0 (33.6:79.5), 234.6 (168.6:284.4), and 22.5 (19.3:24.1) mg/kg, respectively, and 60.6 (35.2:88.2), 38.4 (30.6:54.0), and 13.0 (9.7:13.8) mg/kg, respectively, after pretreatment with 40 mg/kg flunitrazepam. Times to death for morphine, buprenorphine, and methadone alone were 2.5 (0.8:24), 0.02 (0.0:24), and 2.0 (0.0:24) hours, respectively, and 13.5 (0.0:144), 24.0 (0.0:120), and 0.0 (0.0:24) hours, respectively, after pretreatment with flunitrazepam 40 mg/kg, ip. Flunitrazepam significantly altered methadone (P=0.02) and buprenorphine (P=0.02) but not morphine lethality (P=0.77). Flunitrazepam significantly prolonged time to death only for buprenorphine (P<0.01). Flunitrazepam-opioid drug-drug interactions are more complex than is generally believed. Mechanistic studies of flunitrazepam-opioid lethal interactions are needed.

Markedly altered colchicine kinetics in a fatal intoxication: examination of contributing factors.

1. Colchicine poisoning, which is relatively rare, is associated with significant morbidity and mortality. Whilst a new treatment modality, in the form of colchicine-specific Fab fragments is on the horizon, currently available therapy is largely supportive. 2. The elimination of colchicine occurs primarily by hepatic metabolism, following a first-order process, with significant enterohepatic circulation. Renal extraction is responsible for approximately 20% of colchicine elimination. 3. We report a case of colchicine intoxication, complicated by the presence of co-ingestants, in which serum colchicine concentrations remained quasi-constant over the 3 days of the patient's survival, consistent with marked alterations both in metabolism and excretion. The initial presentation was relatively benign but the subsequent course was one of severe colchicine poisoning, resulting in death. 4. Severe colchicine toxicity appears to have resulted in a vicious cycle of progressive organ dysfunction and impaired elimination. 5. Josamycin, one of the co-ingestants and an inhibitor of P-glycoprotein, the membrane pump responsible for multidrug resistance, may have played a significant role in impeding the cellular and biliary elimination of colchicine. Co-ingested opioid and anticholinergic compounds may have altered colchicine absorption and gastrointestinal transit. 6. This case serves as a reminder of the need for attention to co-ingested drugs, to early aggressive therapy, and if available, to consideration of immunotherapy.

Delayed transient loss of consciousness in acute carbon monoxide intoxication.

In acute carbon monoxide intoxication the presence of altered consciousness, ranging from transient loss of consciousness to coma, represents a poor prognostic factor and modifies the approach to therapy. Transient loss of consciousness is, as a rule, contemporaneous to the exposure, generally occurring at the scene of the intoxication. We report an unusual case of delayed transient loss of consciousness, occurring in the absence of any other evident aetiology, in one member of an orchestra composed of 110 members after a mass carbon monoxide poisoning.