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.

Tracheal intubation in routine practice with and without muscular relaxation: an observational study.

BACKGROUND AND OBJECTIVE: The ease of endotracheal intubation has been recently shown to affect the incidence of laryngeal injury. There remains controversy as to whether or not a muscle relaxant is routinely required for tracheal intubation. This study examined conditions of intubation in our routine practice, which employs a relaxant-sparing approach. METHODS: All adult patients scheduled for surgery with general anaesthesia were prospectively included. A muscle relaxant was used to facilitate intubation when it was required for the surgical procedure and/or otherwise regarded as necessary by the anaesthesiologist. In the remaining patients, a relaxant-free intubation was performed. Intubating conditions were evaluated in all the patients as well as the post-intubation laryngeal symptoms. RESULTS: Between March and July 2003, 612 patients were consecutively included. A muscle relaxant was used in 32% of patients and no relaxant in the remaining patients (68%). Clinically acceptable intubating scores were observed in 98.4% overall with no significant difference between the two groups. Excellent conditions occurred more frequently in the relaxant group as compared to the relaxant-free group, 87% vs. 72%, P = 0.005. Laryngeal symptoms occurred in 184 (33%) patients with no difference between the two groups. CONCLUSIONS: Our relaxant-sparing approach did not increase the incidence of poor conditions of intubation nor laryngeal symptoms. However, excellent conditions occurred more frequently in the relaxant group. A more flexible approach to the issue of the need for neuromuscular blockade prior to intubation is proposed.

[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.

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.

[Victims of fall from height. Study of 287 patients and determination of clinical prognostic factors]. / Patients victimes de chutes de grande hauteur. Etude d'une cohorte de 287 patients et détermination des facteurs pronostiques cliniques.

INTRODUCTION: Fall from height is a common cause of severe blunt urban trauma but this mechanism of trauma is poorly documented. OBJECTIVE: To describe initial clinical parameters, injuries and outcome in patients victims of falls from height and to determinate clinical prognostic factors. STUDY DESIGN: Retrospective study from January 1998 to May 1999 and prospective study from June 1999 to September 2000. Inclusions: patients older than 12 year-old victims of falls with height of more than 3 m. PATIENTS AND METHODS: Studied parameters: demographic data, fall circumstances, prehospital clinical evaluation (Glasgow coma scale (GCS), Arterial Blood Pressure (ABP), Heart Rhythm (ER) and revised trauma score (RTS) initial and patients outcome. RESULTS: Two hundred and eighty seven patients were included during 32.5 months; 33% were women and 67% men. Mean age: 37 +/- 16 years. Median height of fall: three stairs (3-4). Final mortality: 34% including 22% death on site with or without resuscitation, 5% before hospitalization, 8% during the first day and 2% later. Independent prognostic factors were GCS (OR = 0.40; IC: 0.25 - 0.65; P = 0.0002), initial ABP (OR = 0.94; IC: 0.90 - 0.98; P = 0.008) and RTS (OR = 2.93; 1.19-7.24; P = 0.02). CONCLUSION: Immediate mortality after fall from heights is high and remains low after day 3. GCS, ABP and RTS are independent prognostic factors.

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.

Stroke associated with pulmonary embolism after air travel.

Prolonged air travel is associated with an increased incidence of thromboembolic events. The occurrence of stroke was studied in patients with pulmonary embolism after air travel in a review of all flights arriving at Charles de Gaulle Airport in Paris during an 8-year period. Thromboembolic stroke and patent foramen ovale were diagnosed in four patients with pulmonary embolus.

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.

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.

Randomized study comparing the "sniffing position" with simple head extension for laryngoscopic view in elective surgery patients.

BACKGROUND: The "sniffing position" is recommended for optimization of glottic visualization under direct laryngoscopy. However, no study to date has confirmed its superiority over simple head extension. In a prospective, randomized study, the authors compared the sniffing position with simple head extension in orotracheal intubation. METHODS: The study included 456 consecutive patients. The sniffing position was obtained by placement of a 7-cm cushion under the head of the patient. The extension position was obtained by simple head extension. The anesthetic procedure included two Laryngoscopies without paralysis: the first was used for topical glottic anesthesia. During the second direct laryngoscopy, intubation of the trachea was performed. The head position was randomized as follows: group A was in the sniffing position during the first Laryngoscopy and the extension position during the second, group B was in the extension position during the first laryngoscopy and the sniffing position during the second. Glottic exposure was assessed by the Cormack scale. RESULTS: The sniffing position improved glottic exposure (decreased the Cormack grade) in 18% of patients and worsened it (increased the Cormack grade) in 11% of patients, in comparison with simple extension. The Cormack grade distribution was not significantly modified between the two groups. Multivariate analysis showed that reduced neck mobility and obesity were independently related to improvement in laryngoscopic view with application of the sniffing position. CONCLUSIONS: Routine use of the sniffing position appears to provide no significant advantage over simple head extension for tracheal intubation in this setting. The sniffing position appears to be advantageous in obese and head extension-limited patients.

Severe pulmonary embolism associated with air travel.

BACKGROUND: Air travel is believed to be a risk factor for pulmonary embolism, but the relation between pulmonary embolism and distance flown has not been documented. The aim of this study was to investigate whether the duration of air travel is related to the risk of pulmonary embolism. METHODS: From November 1993 to December 2000, we systematically reviewed all cases of pulmonary embolism requiring medical care on arrival at France's busiest international airport. Data on the geographic origins of all flights and the numbers of passengers were collected in order to evaluate the incidence of pulmonary embolism per 1 million passenger arrivals as a function of the distance traveled. RESULTS: A total of 135.29 million passengers from 145 countries or other areas arrived at Charles de Gaulle Airport during the period of the study, of whom 56 had confirmed pulmonary embolism. The incidence of pulmonary embolism was much higher among passengers traveling more than 5000 km (3000 mi) (1.5 cases per million, as compared with 0.01 case per million among those traveling less than 5000 km). The incidence of pulmonary embolism was 4.8 cases per million for those traveling more than 10,000 km (6000 mi). CONCLUSIONS: A greater distance traveled is a significant contributing risk factor for pulmonary embolism associated with air travel.

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.

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.

Treatment of methanol and isopropanol poisoning with intravenous fomepizole.

CASE REPORT: We report a case of mixed methanol and isopropanol poisoning in a patient who refused dialysis but agreed to treatment with intravenous fomepizole. The patient was asymptomatic on arrival, with initial blood methanol and isopropanol concentrations of 146 mg/dL and 39 mg/dL, respectively. Blood ethanol was undetectable. The patient was treated with fomepizole twice daily intravenously until blood methanol was undetectable. No side effects of therapy, other than transient eosinophilia, were observed. The evolution was uneventful and no metabolites of either alcohol were detected at any time during the hospitalization. The decay of plasma methanol and isopropanol under fomepizole treatment were well described by first-order kinetics. The plasma elimination half-lives of methanol and isopropanol were 47.6 hours and 27.7 hours, respectively. Fomepizole appears to have been effective in blocking the toxic metabolism of both methanol and isopropanol and was associated with a favorable outcome.

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.

A survey of tracheal intubation difficulty in the operating room: a prospective observational study.

BACKGROUND: The purpose of this study is to describe all degrees of endotracheal intubation difficulty among patients attended by eight anesthesiologists during routine surgery over a six-month period. Airway characteristics were routinely assessed preoperatively, according to the anesthesiologists' usual practice. METHODS: Difficult tracheal intubation was evaluated by the Intubation Difficulty Scale (IDS), a quantitative score based on seven variables. An IDS value of 0 is consistent with a procedure without difficulty, and an IDS > 5 with a procedure involving moderate to major difficulty. RESULTS: For 1171 patients undergoing tracheal intubation, IDS was 0 in 55%, and greater than 5 in 8% of cases. External laryngeal pressure, repositioning the patient and added use of a stylet were the most frequent methods chosen to facilitate tracheal intubation. CONCLUSION: There was a high incidence (37%) of minor difficulties encountered during routine surgery.

Study of the "sniffing position" by magnetic resonance imaging.

BACKGROUND: The "sniffing position" is widely considered essential to the performance of orotracheal intubation and has become the cornerstone of training in anesthesiology. However, the anatomic superiority of this patient head position has not been established. METHODS: Eight healthy young adult volunteers underwent magnetic resonance imaging scanning in three anatomic positions: head in neutral position, in simple extension, and in the "sniffing position" (neck flexed and head extended by means of a pillow). The following measurements were made on each scan: (1) the axis of the mouth (MA); (2) the pharyngeal axis (PA); (3) the laryngeal axis (LA); and (4) the line of vision. The various angles between these axes were defined: alpha angle between the MA and PA, beta angle between PA and LA, and delta angle between line of vision and LA. RESULTS: Both simple extension and sniffing positions significantly improved (P < 0.05) the delta angle associated with best laryngoscopic view. Our results show that the beta value increases significantly (P < 0.05) when the head position is shifted from the neutral position (beta = 7 +/- 6 degrees ) to the sniffing position (beta = 13 +/- 6 degrees ), and the alpha value slightly (but significantly) decreases (from 87 +/- 10 degrees to 63 +/- 11 degrees; P < 0.05). Anatomic alignment of the LA, PA, and MA axes is impossible to achieve in any of the three positions tested. There were no significant differences between angles observed in simple extension and sniffing positions. CONCLUSIONS: The sniffing position does not achieve alignment of the three important axes (MA, PA, and LA) in awake patients with normal airway anatomy.

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.