Francesco Maria Avato

Lethal poisoning by zipeprol in drug addicts

Two cases of lethal intoxication involving or due to oral ingestion of zipeprol are described. The two cases concerned abusers of the substance for nonmedical purposes. Data regarding the distribution of the unmodified drug in biological fluids and tissues are presented.

A fatal case of anaphylactic shock during paragliding.

Abstract:  The growth in popularity of flying ultralight aircraft and paragliding has been associated with an increased involvement of Emergency Medical Services because of various types of trauma suffered from both inexperienced and skilled individuals. This case presentation reports on a paraglider pilot, who was seen spinning “unusually” rapidly toward the ground, without visible attempts to regain control of the aircraft. Besides the bilateral mydriasis and the absence of any ECG activity, there was a significant swelling of face, lips, neck, and tongue. Upon opening the mouth, a dead bee was found over the tongue, underneath the palate. A fatal anaphylactic shock was the likely cause of death of the pilot while still “in mid‐air.” This case is certainly different from the commonly reported accidents during paragliding. An updated review of the medical literature shows no reported cases of fatal anaphylactic shock during the practice of paragliding.

The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study.

Objectives Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3’-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. Methods 133 OAT patients were recruited and assessed for warfarin/3’-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups Results In the whole OAT group both warfarin and 3’-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3’-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3’-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3’-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3’-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles Conclusion Our results overall suggest that 3’-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators.

Unusual Displacement of a Mobilised Dental Bridge during Orotracheal Intubation

Dental trauma during tracheal intubation mostly happens in case of poor dentition, restricted mouth opening, and/or difficult laryngoscopy. 57-year-old man undergoing laparoscopic radiofrequency ablation of unresectable hepatocellular carcinoma had his dental work detached at induction of anesthesia. Oropharyngeal direct view, manual inspection, fibreoptic nosendoscopy, tracheobronchoscopy, and fiberoptic inspection of the esophagus and stomach were unsuccessful in locating the dislodged bridge. While other possible exams were considered, such as lateral and AP x-ray of head and neck, further meticulous manual “sweepings” of the mouth were performed, and by moving the first and second fingers below the soft palate deep towards the posterolateral wall of the pharynx, feeling consistent with a dental prosthesis was detected in the right pharyngeal recess. Only after pulling the palatopharyngeal arch upward was it possible to grasp it and extract it out with the aid of a Magill Catheter Forceps. Even though the preexisting root and bridge deficits were well reported by the consultant dentist, the patient was fully reimbursed. The lack of appropriate documentation of the advanced periodontal disease in the anesthesia records, no mention of potential risks on anesthesia consent, and insufficient protective measures during airway instrumentation reinforced the reimbursement claim.

The perils of dental vacation: possible anaesthetic and medicolegal consequences

Introduction The aim of this paper is to emphasize anaesthesiologists’ difficulty in detecting poor dentition in cases of poorly applied prostheses and/or advanced periodontal disease, and to establish whether it is possible, and in which conditions, to calculate compensation in cases of dental damage postlaryngoscopy and/or intubation. The main complex problem here lies in trying to reconstruct exactly what the dental situation was before the teeth were damaged. For this reason the important preoperative factors (dental prostheses, crown fractures, parodontal disease, etc.) must be clearly shown before surgery on a dental chart. Clinical cases Two cases of interest, both to anaesthesiologists practising intubation and medicolegal physicians who have to deal with potential claims, are briefly reported. The first patient was a 55-year-old diabetic patient, who underwent emergency surgery for acute abdominal pathology. He had gone outside Italy for dental treatment three years previously and now presented with very poor pre-existing dentition, carefully noted on an anaesthetic chart. He now demanded compensation for dental damage due to intubation in Italy; the resulting dental treatment was very expensive because substantial remedial work was required. The second patient had received treatment outside Italy, work which involved cosmetic coating of the teeth. After surgery in Italy, she demanded compensation because one tooth, which had been coated and appeared to be healthy, was broken after emergency intubation. In both cases, the patients demanded very high compensation. Comment Dental tourism alone accounts for more than 250,000 patients each year who combine a holiday with dental treatment in Eastern Europe. However, if prosthetic devices or conservative treatments are not applied correctly, it should be noted that durability may be poorer than expected, but iatrogenic damage may also be caused.

Mirtazapine fatal poisoning

Mirtazapine is a noradrenergic and specific serotoninergic antidepressant agent that stimulates norepinephrine and serotonin release while also blocking serotonin receptors (5-HT2 and 5-HT3). Although the drug is used extensively, at present we do not know of any fatal cases due to mirtazapine alone. On the contrary, the published literature describes several fatal poisoning cases related to the intake of mirtazapine together with other drugs. Here we describe a fatal case of mirtazapine self-poisoning, since the other drug detected (lorazepam), was within the therapeutic range. Analyses were performed by LC-MS/MS on body fluids and a hair sample and mirtazapine concentration measured in blood was very high: 9.3mg/L. N-Desmethylmirtazapine was also quantitated. We then compared our results with those of previously published cases. In conclusion, even though mirtazapine can be considered a relatively safe drug, taking a large amount alone or in combination with other drugs, could lead to death.

Authors' response to comments on: A fatal case of anaphylactic shock during paragliding

We would like to thank Prof. Kounis et al. for the commentary letter on our case report, A Fatal Case of Anaphylactic Shock During Paragliding, J Forensic Sci. 2012 by Feltracco et al. They suggest considering coronary spasm and concomitant Kounis syndrome (1) as probable cause of anaphylactic death. We have appreciated the reporting of pathophysiological mechanisms involved in systemic vasodilation, reduced venous return, extravascular fluid leakage as well as the details on coronary hypoperfusion and myocardial damage. They conclude that in similar clinical cases, the heart and coronary arteries should always be examined in postmortem screening as they represent one of the primary targets of anaphylaxis. In this case, we have described that coronary arteries and myocardium were indeed explored on autopsy but significant disease was not discovered. Lack of detection of preexisting atherosclerotic coronary vascular disease and the absence of any implanted intracoronary stent allow therefore to exclude the characteristics of type II and type II variants of Kounis syndrome (1). Signs and symptoms of type I variant (i.e., severe coronary spasm in normal arteries) could have probably occurred in a previously sensitized individual after the bee sting; however, the way the dramatic event occurred and the delay in first rescue arrival obviously precluded any clinical investigation focused on detecting the particular features of “allergic” myocardial infarction. It can be speculated that a simultaneous combination of intense coronary vasoconstriction and severe laryngeal and epiglottic edema, airway edema, and strict bronchospasm very likely occurred. On ground examination of oral cavity, tongue, and lips by helicopter medical staff, along with the discovery of the bee in his mouth was consistent with an asphyxiating mechanism as the first cause of loss of consciousness and likely of death thereafter. Very likely the marked facial angioedema, massive lingual edema, and severe swelling of oro-pharyngeal mucosa were associated with tightened vocal cords and severe bronchospasm, with no space for alveolar air to enter even under forced insufflations. In this case, sudden brain hypoxia may have occurred prior to the onset of any other symptoms. Nevertheless, an important contribution to the drop in blood pressure and sudden shock could have been determined by severe bradycardia and lethal myocardial ischemia. However, even if realistically concurrent with the other manifestations of anaphylactic reaction, the possible onset of allergic angina progressing rapidly to acute myocardial infarction and circulatory collapse would have been impossible to recognize in such a setting. Only the absence of electrical activity and no electrocardiographic abnormalities consistent with acute myocardial ischemia were detected at rescue arrival. Even if tested, the cardiac enzymes and troponins would have been questionable and complicated in interpreting. Hymenoptera sting-induced Kounis syndrome causing unexplained death has already been described (2), but the acute cardiovascular manifestations of anaphylaxis, that is, the rapid onset of shock with peripheral circulatory failure, cannot always be promptly ascribed to a “coronary hypersensitivity” syndrome leading rapidly to myocytes death. For this reason, Kounis syndrome may certainly develop but it might be unrecognized or remain masked. Physical examination by medico-legal staff only reported massive facial and light systemic swelling; no positive significant findings relevant to the cause of death were identified at autopsy. Serum tryptase measurements would have been useful, as raised serum tryptase level is suggestive of an antemortem anaphylactic event, but unfortunately it was not done. It is worth noting that at postmortem investigation, remarkable changes in terms of coronary vascular or bronchial tone, or glottis edema, or systemic arteriolar tone, or interstitial blood extravasation, and shift of fluid volume are often lacking in the case of anaphylactic shock (3). Mast cell infiltration at the site of coronary artery spasm (4) was not searched as no coronary spasm was detected at postmortem examination. As no visible findings of myocardial damage or evident endothelial injury resulted, the signs of recent inflammatory cell response at coronary wall layers were not investigated. In conclusion, the primary involvement of severe coronary vasoconstriction and concomitant Kounis syndrome, even if not proven on either a clinical or histopathological basis, may have contributed, in association with sudden onset of intolerable hypoxia, to the death of the pilot while still “in midair.”