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Based on notifications to the Danish Committee on Adverse Drug Reactions and to the Central Death Register, 30 cases of fatal drug-induced anaphylactic shock were identified during the period 1968-1990. The most frequent causes were contrast media for X-ray examinations, antibiotics, and extracts of allergens. Nine cases occurred outside hospital; they were mainly caused by the use of allergen extracts of moulds for desensitization in general practice. Fatal drug-induced anaphylactic shock is rare, estimated in the present study at 0.3 case per million inhabitants per year.

Attempts have been made to obtain further experimental evidence in the development of hyperresponsiveness measured as mortality rate in terbutaline-treated animals after the administration of carbachol in rats and ovoalbumin in sensitized guinea pigs. The dose of terbutaline chosen was approximately the dose an asthmatic patient might use in an attack, and its effect on pancreatic insulin synthesis was studied in rats since it has been suggested that insulin is a pro-inflammatory hormone. Our results show that prolonged treatment with terbutaline increases the mortality from bronchoconstrictor stimuli. Increased levels of pancreatic insulin synthesis were also observed by immunocytochemical study carried out on pancreas from terbutaline-treated rats.

Objective: To document that idiopathic anaphylaxis may have a fatal or near fatal outcome., Design: Review of selected cases seen personally by authors during the past 16 years., Setting: University faculty practice and private practices., Patients: All cases of idiopathic anaphylaxis seen by the authors are not presented, but 10 cases were selected to demonstrate two fatalities and eight cases of near fatalities., Results: Two fatal cases had expired before emergency service therapy. Eight near fatal cases responded to acute therapy and subsequently were controlled. Remission of idiopathic anaphylaxis was then induced. Idiopathic anaphylaxis may be fatal or potentially fatal and must be treated to prevent a fatal outcome., Conclusions: The documentation of fatalities and near fatalities should help patients and their physicians accept intense management of idiopathic anaphylaxis that will result in control and induction of a remission in idiopathic anaphylaxis.

In this article we present a survey on the pathogenesis of allergic or pseudoallergic reactions in anaesthesia, the risk factors and the responsible substances. The incidence of anaphylactoid reactions is between 1:3500 and 1:20,000 anaesthetic cases. The estimated mortality rate amounts to 3-6%. Neuromuscular blocking drugs account for most of the cases of significant anaphylactoid reactions (59-70%). However, the incidence of latex-related reactions in increasing. Risk factors for anaphylaxis are a history of IgE-mediated drug allergy, repeated anaesthesias, atopy, hyperventilation tetany, and the use of neuromuscular blocking drugs in females. Risk factors for pseudoallergic reactions are emotional stress, atopic predisposition, increased sensitivity for histamin, hyperventilation tetany and female gender.

In the years 1978 to 1987 29 patients died in Switzerland following hymenoptera strings, most usually from honey bees and wasps (vespula). The vast majority of these fatalities were due to one single sting and thus most probably caused by IgE-mediated anaphylaxis. Three quarters of the victims were male. The mean age was 60 and most of the patients had a history or autopsy evidence of preexisting cardiovascular or pulmonary disease. Death occurred within 30 minutes of the sting in 50% and within 4 hours in 75% of the victims. Of the 10 patients with previously known hymenoptera sting allergy, none had a suitable emergency kit available when stung and none was on venom immunotherapy. Treatment by the emergency physician must be regarded as inadequate in one third of the patients.

Background: The Committee on Allergen Standardization of the American Academy of Allergy and Immunology (AAAI) began a study of fatalities associated with skin testing and immunotherapy in an effort to identify risk factors and to ascertain whether any additional precautions are required to prevent and treat serious reactions., Methods: Questionnaire data was obtained from members of the AAAI and the American College of Allergy and Immunology, regarding 17 fatalities associated with immunotherapy for the years 1985 to 1989. In this period, no fatalities were reported with skin testing. The mean age of patients who died was 36.0 years (range: 10 to 77 years), and 69% were female. Of the patients who died, 76% had asthma, and most were reported to have had factors associated with severity (i.e., lability, required steroids, and/or prior hospitalizations). The only patient who had rhinitis alone had cardiovascular disease and was receiving a beta-blocker. High sensitivity by skin test or RAST was reported by 71%, and 36% reported prior systemic reactions. Sixty-five percent of the patients were undergoing build-up therapy. Fatalities involved use of allergen doses between 1:1 million to 1:10 wt/vol. Other factors associated with fatalities were: changing to a new vial of extract, 5; dosing error or inappropriate dose adjustment, 5; allergen season, 5; symptomatic before injection, 4; not waiting after injection, 2; and home injection, 1. Onset of anaphylaxis occurred within 20 minutes in eleven patients, within 20 to 30 minutes in one, and after more than 30 minutes in one. In eleven cases the cause of death was associated with respiratory compromise. These data reinforce the need for special precautions in treating high-risk patients with asthma. The annual fatality rate from administration of allergenic extracts in the United States remains very low: 1 fatality per 2 million doses, but additional educational efforts to further reduce the fatality rate are needed.

Very few population-based studies have evaluated fatal therapeutic misadventures, in particular the adequacy of their detection. We therefore assessed the adequacy of the reporting and detection of fatal therapeutic misadventures in an urban setting medico-legal system. The coroner's files and the related hospital records were reviewed as to the circumstances of the incidents and the adequacy of notification by the care providers in Allegheny County, Pennsylvania, for the period of January 1, 1982 through December 31, 1991. The annual average rate of fatal misadventures was 2.2 per 100,000 hospital admissions or 4.7 per million inhabitants (total 63 cases). The survival time from the occurrence of the misadventure was within 24 h in 60% of the cases. University-related hospitals had double the rate of misadventure fatalities (118.2 per 100,000 beds per year), compared to that in community-based hospitals (53.9 per 100,000 bed per year). In more than half of the cases, the hospitals reported the incidents within an hour from the pronouncement of death, 28.6% within 5 h, and 19% after more than 5 h. In 10 cases (15.9%), the notification by the hospitals was clearly deficient in determining the manner of death. In a few cases, the incident was initially reported by the relatives, by the hospital pathologists, or by the media. A high likelihood of under-reporting of fatal misadventures to the medico-legal system is substantiated by comparing with the results reported by others. The possible measures to increase the monitoring and reporting, and to reduce the related mortality are further discussed.

Repeated exposure of guinea pigs to microwave radiation (1 mW/cm2) caused in some animals inhibition of anaphylactic response accompanied by increasing the content of histamine, epinephrine and norepinephrine in the blood. This increase was more pronounced in irradiated guinea pigs died from anaphylactic shock than in nonirradiated animals. The long-term stay in the perturbed and weak geometric field reduced the effect induced by microwave radiation.

Background and Methods: Reports of fatal or near-fatal anaphylactic reactions to foods in children and adolescents are rare. We identified six children and adolescents who died of anaphylactic reactions to foods and seven others who nearly died and required intubation. All the cases but one occurred in one of three metropolitan areas over a period of 14 months. Our investigations included a review of emergency medical care reports, medical records, and depositions by witnesses to the events, as well as interviews with parents (and some patients)., Results: Of the 13 children and adolescents (age range, 2 to 17 years), 12 had asthma that was well controlled. All had known food allergies, but had unknowingly ingested the foods responsible for the reactions. The reactions were to peanuts (four patients), nuts (six patients), eggs (one patient), and milk (two patients), all of which were contained in foods such as candy, cookies, and pastry. The six patients who died had symptoms within 3 to 30 minutes of the ingestion of the allergen, but only two received epinephrine in the first hour. All the patients who survived had symptoms within 5 minutes of allergen ingestion, and all but one received epinephrine within 30 minutes. The course of anaphylaxis was rapidly progressive and uniphasic in seven patients; biphasic, with a relatively symptom-free interval in three; and protracted in three, requiring intubation for 3 to 21 days., Conclusions: Dangerous anaphylactic reactions to food occur in children and adolescents. The failure to recognize the severity of these reactions and to administer epinephrine promptly increases the risk of a fatal outcome.

Pharmacological profiles of a novel specific platelet activating factor (PAF) antagonist, TCV-309 (3-bromo-5-[N-phenyl-N-[2-[2- (1,2,3,4-tetrahydro-2-isoquinolycarbonyloxy)ethyl] carbamoyl]ethyl] carbamoyl]-1-propylpyridinium nitrate] and its beneficial effects in shock were examined. TCV-309 specifically inhibited PAF-induced aggregation of rabbit and human platelets, and [3H]PAF binding to rabbit platelet microsomes with IC50 values of 33, 58 and 27 nM, respectively. It was as potent as WEB 2086 and more potent than CV-6209 and CV-3988. TCV-309 did not cause hemolysis in human or rat blood due to a detergent-like action. In rats, TCV-309 selectively inhibited the PAF-induced hypotension, hemoconcentration and death with ED50 values of 2.7, 6.4 and 1.7 micrograms/kg (i.v.), respectively. TCV-309 most potently protected mice from death induced by PAF and due to anaphylactic shock with ED50 values of 2.1 and 2.6 micrograms/kg (i.v.), respectively, when compared with CV-3988, CV-6209, WEB 2086 (i.v.) and L-652731 (p.o.). TCV-309 also reversed PAF-induced hypotension and endotoxin-induced hypotension in rats with ED50 values of 3.3 and 1.2 micrograms/kg (i.v.), respectively. There was a significant linear relationship between the ability (ED50 value) of these PAF antagonists to prevent death induced by PAF and death due to anaphylactic shock in mice, and between their reversing ability (ED50 value) for the hypotension induced by PAF and endotoxin in rats. TCV-309 (100 micrograms/kg i.v.) protected rats from death induced by endotoxin. Thus, PAF may be a lethal mediator in anaphylactic shock and a hypotensive mediator in endotoxin shock in rodents.

This chapter will first briefly deal with some of the controversial issues surrounding allergic reactions to anaesthetics. Other points which appear to be of fundamental importance and which need further investigation will also be mentioned. Readers are referred to other chapters for further information on some of the issues.

We compared the changes in heart rate (HR), pulmonary dynamic compliance (Cdyn), and pulmonary conductance (GL) associated with three different models of anaphylaxis in genetically mast cell-deficient WBB6F1-W/Wv and congenic normal (+/+) mice. Intravenous infusion of a monoclonal rat anti-mouse IgE produced a marked tachycardia, diminutions in Cdyn and GL, and death in +/+ but not W/Wv mice, and +/+ mice sensitized to develop high circulating levels of IgE exhibited HR, Cdyn, and GL responses to rat anti-IgE challenge which were significantly less intense than those in nonimmunized +/+ mice. By contrast, virtually identical cardiopulmonary responses were observed in either +/+ or W/Wv mice challenged to elicit pure active anaphylactic responses or simultaneous active and anti-IgE-dependent anaphylaxis. These findings show that anaphylactic responses associated with significant tachycardia, reductions in Cdyn and GL, and death can occur in the virtual absence of tissue mast cells. This is true even though, in normal mice, such responses are associated with extensive degranulation of tissue mast cells. By contrast, certain models of anaphylaxis, such as that induced in nonsensitized mice by anti-mouse IgE, can not be elicited in the absence of mast cells.

Some samples of cow milk proteins and enzymatic hydrolysates prepared on their basis were investigated in experiments on male guinea pigs to elucidate their sensitizing properties and influence on sensitivity to histamine LD50. The data obtained are discussed with respect to a possible modulation of allergic reactions by the products of incomplete enzymatic proteolysis.

Simultaneous parenteral vaccination against typhoid and cholera lead to death through either anaphylactic shock or endotoxic shock in a 36-year-old male. At autopsy the charactertic features of shock as well as chronic interstitial myocarditis were noted. Moreover, fresh histiocytic and lymphocytic nodules were found in the liver, heart and meninges. A review of the literature dealing with lethal complications following parenteral tyhoid vaccinations shows an increased risk in debilitated persons (emaciation, stress, cold). Most of the fatalities occurred in persons who had previous disturbances of the cardiovascular system, as in the case reviewed here. Cardiac failure, Landry's paralysis, renal failure and disturbances of skin, joints and intestines may also follow typhoid vaccinations. However, these latter complications are usually not lethal. The patients presented here had many of the conditions which are known to aggravate the situation and to lead to a lethal culmination. The review of this case and the disucussion following it shows that only healthy persons should receive the parenteral typhoid vaccination. Hopefully, the presentation of this material will help prevent fatalities of this type in the future.

During an experiment of shaking in El mice, a strain which was less susceptible to convulsion was found out. In this strain (ASK), the mortality to anaphylactic shock and susceptibility to audiogenic seizure were compared with five other strains of mice. Six strains of mice (ASK, EL, IDT, JCC-ICR, dd, C57BL/6J) were sensitized by two subcutaneous injections with 2 mg/head of crystalline egg albumin at five and six weeks of age, and then challenged by the intravenous injection of 0.125, 1, 8, 64, 512 and 4096 mug/head at seven weeks of age. In both sexes of ASK strain, the mortality was the maximum (75--95%) after the challenge of 8--4096 mug egg albumin. The mortality of the female El and IDT and the both sexes of JCL-ICR strains was middle (55--70%) after the challenge with 64 mug egg albumin, while that of other strains (dd and C57BL/6J) was very low (0--20%). The susceptibility of 3-weeks-old mice of ASK, El, IDT, JCL-ICR and dd strains was low (1.9--19.0%), whereas mice of DBA/2 strain showed a very high susceptibility (80%) to 110 phons.

Many of the large number of people who are stung each year by bees experience frightening systemic reactions, but the vast majority of such reactions are not life-threatening. There is no evidence that the very few who die as a result of a bee sting come from the pool of those who once before sustained a systemic reaction. On the contrary, no reaction at all may be a more ominous predictor of a lethal outcome on a subsequent sting. Death comes about through multiple mechanisms, and not through anaphylaxis alone. Like most cases of sudden death, underlying coronary atherosclerosis appears to be the principal mechanism. External factors that affect mortality include environmental temperature and site of sting. In general, however, because the numbers of deaths are so small, death comes unpredictably, and those at risk have not been identified. Immunotherapy, whether with venom or whole-body extract, has not been proven to prevent death from a bee sting.

Protracted anaphylactic shock of guinea pigs led to death in over 90% of the animals, and good protection was obtained with an infusion of adrenaline after dibenamine pretreatment. Adrenaline alone, in doses which prevented the anaphylactic fall of arterial blood pressure, had no beneficial effect. Practolol abolished the therapeutic action of the combination of dibenamine/adrenaline. Stimulation of beta-receptors by isoproterenol did not increase the survival rate. With dopamine, however, a significant prolongation of the survival times was obtained.

Fatal food-induced anaphylaxis is rarely reported. In 16 months, we identified seven such cases involving five males and two females, aged 11 to 43 years. All victims were atopic with multiple prior anaphylactic episodes after ingestion of the incriminated food (peanut, four; pecan, one; crab, one; fish, one). In six cases the allergenic food was ingested away from home. Factors contributing to the severity of individual reactions included denial of symptoms, concomitant intake of alcohol, reliance on oral antihistamines alone to treat symptoms, and adrenal suppression by chronic glucocorticoid therapy for coexisting asthma. In no case was epinephrine administered immediately after onset of symptoms. Premortem or postmortem serum samples were available from six victims; in each case elevated levels of IgE antibodies to the incriminated food were demonstrated. Food-sensitive individuals must self-administer epinephrine promptly at the first sign of systemic reaction. Emergency care providers should be aware of cricothyrotomy as a life-saving procedure.

The plasma ascorbate level after a single intraperitoneal dose of 25, 100 or 250 mg Na-ascorbate was followed up in vivo over a period of 24 hours. Intraperitoneal administration of Na-ascorbate caused a rapid increase of ascorbic acid plasma concentration. Maximum ascorbic acid plasma level was obtained 30 minutes after parenteral administration of the test dose. No great difference was found between the 12- and 24-hour ascorbic acid plasma values. The effect of Na-ascorbate on fatal anaphylaxis was also investigated in 18 guinea pigs. The animals treated with 281 mg/day Na-ascorbate rarely developed anaphylactic shock or the shock was of weaker intensity. Mortality was reduced from 40% (control group) to 11% when Vitamin C was given for four days before and one day after passive transfer of rabbit anti-HGG (human gamma globulin) antibody. A possible protective role of ascorbic acid by preventing anaphylaxis is discussed. Passive administration of ascorbic acid was found to protect guinea pigs from fatal anaphylaxis.

During the experiment conducted upon 85 guinea-pigs it has been found that the injection of naloxone at the dose of 0.5 g/kg half an hour before the reproduction of anaphylactic shock (AS) by the use of horse serum increases the number of cases of the retarded development of pathological reaction and survival of the animals. Except for the quantitative differences mentioned any peculiarities characterizing the effect of naloxone were not found. As to the morphological differences of variants in the course of AS they are distinctly defined only at the analysis of film preparations of the intestinal mesentery. The typical AS becomes apparent by haemorrhages, by dilatation of all the vessels of blood circulation and by forming of erythrocytic aggregates in them. At the retarded development of AS a spasm of precapillaries is observed. After convalescence of the animals the aggregates of erythrocytes can be revealed only in venules. Studying the animals recovered after AS one can find that for a long time these animals had the erythrocytic aggregates in the clearances of venules, as well as the signs of new formation of the capillaries.

Among 520 cases of drug anaphylactic shock there were 48 (9.2%) fatal outcomes. Analysis of the pathomorphological changes in shock showed them to have characteristic features consisting in blood redistribution (decentralization), its deposition in parenchymatous organs with marked disorders in microcirculation and diapedetic hemorrhages in serous, mucous membranes, and tissue of nearly all the organs, as well as signs of stasis and leukocyte aggregation, perivascular and pericellular edema and swelling of cells of different organs. In a protracted course of shock, marked degenerative changes of parenchymatous organs were observed. In the acute course and rapid fatal outcome pathomorphological changes were less marked than in a protracted and recurrent course which was characterized by the development of secondary pathological changes such as inflammatory, degenerative, and necrotic processes.

The experience of using sombrevin anesthesia in 3644 cases and its 3 severe complications which resulted in the development of terminal states up to the clinical death (reanimation was successful) is analyzed. This anesthesia is shown to be necessary under conditions providing a possibility of immediate fulfillment of the complex of highly skilled reanimation measures, with early solution of problems of succession between the polyclinic link and the reanimation hospital. Special attention is called to strict observation of the principle of the preliminary (the day before operation) examination by an anesthesiologist of the patients who are to be subjected to planned short operative interventions, for the individual choice of the method of anesthesia and prevention of severe complications after narcosis.

A recognized side effect of chemonucleolysis is life-threatening anaphylaxis to chymopapain. In the clinical trials of chymopapain, 13 cases of anaphylaxis were reported in 1585 administrations (0.82%). Two patients died. Data from a postmarketing survey (48,239 questionnaires) were reviewed to identify factors influencing the incidence and severity of anaphylaxis. The results indicate the incidence of anaphylaxis decreased to 0.44% in the 1983-1984 period (126/23,736), a level significantly (P less than or equal to 0.001) below the incidence of 0.82% observed in initial clinical trials. Only three deaths from complications related to anaphylaxis occurred in approximately 75,000 administrations (producing 252 anaphylactic episodes) reported since December 1982. The prophylactic use of antihistamines and pretreatment with intravenous fluids coincide with the dramatic reduction in mortality due to anaphylaxis. However, overdiagnosis of anaphylaxis in the clinical trials and avoidance of chemonucleolysis in patients with IgE antibodies to chymopapain may account, in part, for the reduction in incidence.

This report records the first reported case of a fatal anaphylactic reaction to an intravenous infusion of iron dextran. An elderly woman was given an infusion of iron dextran in 5% dextrose. Shortly after the infusion started, she developed laryngeal stridor, shock, respiratory arrest, and died despite attempts at resuscitation. Necropsy findings are described and are consistent with death due to anaphylaxis. With the increased parenteral use of dextran and iron dextran complexes it is important for the clinician to be aware of the hazards of anaphylactic reactions. Since the reactions generally occur shortly after the administration has begun, a physician should be in attendance during the infusion of the first 25 cm3 (5 to 10 min). He should be able to promptly recognize and treat the asphyxia and hypotension should it occur. It is also important for the pathologist to be aware of the occurrence of anaphylaxis after the use of these drugs. However, the cause of death should not be based solely on the presence of classic clinical features of fatal anaphylaxis. Specific features of anaphylaxis should be searched for at autopsy and other causes of sudden death must be ruled out.

During a 21-year period in Denmark a total of 26 deaths were caused by wasp or bee stings (according to the National Health Service). The deaths might be classified, with some overlapping, as caused by either anaphylactic/anaphylactoid shocks (between 65% and 80%), suffocation after stings in the airways (about 15%) or preexisting diseases, especially arteriosclerotic heart disease (approx. 20%). Characteristically, in most persons with shock reactions unconsciousness and death occurred very shortly after the sting (within 45 min), while the interval between sting and death was longer (30 min to a couple of hours) when death was caused by suffocation. In more than 21 of the 26 cases it seemed reasonable to assume that insect allergy might have contributed to the fatal outcome. Six of these cases had a previous history of abnormal reactions to insect venom, thus only a small group would have benefited from the prophylactic effect of hyposensitisation. There was no known previous history of reactions to insect stings in the other cases, but it is likely that more than six persons had had severe reactions to insect stings on other occasions. Presumably many deaths where insect stings have been involved--through not verified as causal--are classified as inexplicable or accidental, thus the real number of deaths caused by wasp or bee stings could be substantially greater. Consequently hyposensitisation after severe insect sting reactions of verified allergic genesis can still be advised.

A physician questionnaire survey was conducted by the Fire Ant Subcommittee of the American Academy of Allergy and Immunology to document deaths caused by imported fire ant stings. From the 29,300 physicians surveyed, reports of 83 fatal and two near-fatal fire ant-sting reactions were received. Most anaphylactic deaths were reported from Florida (22) and Texas (19). After excluding duplicate reports, four confirmed deaths were documented in Alabama, 10 in Florida, two in Georgia, two in Louisiana, and 14 in Texas.

Sera administered intravenously to mice hypersensitized with normal horse serum and with horse serum of anti-lymphocytic activity, produce reactions that differ considerably in mice treated in different ways. The experiments of the authors indicate that the anaphylactogenic effect of ATS is substantially stronger than that or normal horse serum. The paper discusses the clinical and theoretical conclusions to be drawn from this phenomenon observed in the experiments.

Studying the shock-inducing effect of ATS and NHS in young (10-day-old) mice weighing 10-11 g, the authors have found that normal serum proved to be a significantly stronger sensitizing agent. Such a difference in the shock-inducing effect of the two sera can no longer be observed in the course of challenge. The paper discusses the observed phenomenon, taking into account the data available on the ontogeny of the immune apparatus of the mice.