Incidence of lethal adverse drug reactions in the comprehensive hospital drug monitoring, a 20-year survey, 1974-1993, based on the data of Berne/St. Gallen.

OBJECTIVES: Realising the limitations of spontaneous drug monitoring systems concerning the epidemiological aspects, a comprehensive program was founded. It was based on previous publications from the US, Canada and Northern Ireland, mainly those of the BCDSP (Boston Collaborative Drug Surveillance Programme). METHODS: Drug monitoring was carried out by a group of physicians which included the medical head of each of the divisions of internal medicine, a statistician and an informatician. Only probable or definite drug event relationships were included. A probable event is defined as one in which the drug interaction was more likely to be the cause than any non-drug-related cause. The same criteria were valid for the lethal reactions. RESULTS: In the present evaluation, we found 26 probable lethal adverse drug reactions out of a total of 48,005 patients consecutively admitted to the divisions of internal medicine of three Swiss teaching hospitals during the years 1974-1993, an incidence of 0.054%. The median age of the cohort was 68 years (range 11-103 years), of which 49% were women. The median hospital stay was 14 days and the median number of drugs was eight per patient. CONCLUSION: The patients with a lethal outcome were presented under the eight pharmacologic-therapeutic classes of drugs and the classification proposed by NS Irey. This is based on long histopathologic experience and helps to identify preventable risks.

[Parenteral iron therapy: problems and possible solutions]. / Parenterale Eisentherapie: Probleme und mögliche Lösungen.

To investigate whether there are differences in the frequency of ADRs (adverse drug reactions) to parenteral iron preparations, we compared the results of 4 different data collections which contain observations in particular on i.m. or i.v. iron dextran and i.v. iron hydroxide sucrose complex, primarily in relation to anaphylactic/anaphylactoid reactions and common exanthemas. 1. In 206 patients of the department of general internal medicine in a city/teaching hospital (in association with the Swiss Foundation for Comprehensive Hospital Drug Monitoring--CHDM), 4 probably allergic reactions to i.m. iron dextran were found, one with acute severe dyspnea, cyanosis and flush, 3 with slight generalized, probably allergic reactions. Data from the USA on i.v. iron dextran do not show marked differences in the frequency of ADRs as compared with our data with i.m. administration. 2. A group of 400 otherwise healthy patients of the obstetric department of Zurich University Hospital were treated with i.v. iron sucrose for anemia due to iron loss during pregnancy or following childbirth. Seven generalized skin reactions, 4 in the form of flush and 3 of common exanthema, occurred. 3. In a retrospective study on patients on maintenance hemodialysis with chronic renal insufficiency and anemia, a questionnaire was answered by the medical heads of 17 selected hemodialysis units in Switzerland. Response was 100%. During around 8100 patient-years with approximately 160,000 ampoules of iron sucrose (with 100 mg elementary iron), not a single life threatening reaction was observed; only 5-7 situations of rapidly reversible blood pressure fall occurred, some 10 with flush, and one each with urticaria and vomiting/diarrhea. 4. The relatively good tolerance of i.v. iron sucrose in patients with chronic renal failure may be due either to reduced immune competence in patients with chronic renal insufficiency and/or to the use of the preparation itself, or probably both. 5. In ADRs of allergic appearance to iron sucrose, the 7 generalized skin reactions occurred on the first day of the injections, as did those under iron dextran. Preexisting hypersensitivity must be taken into consideration. 6. If our experience is confirmed, preventive measures with i.v. iron sucrose, mainly in patients with chronic renal insufficiency, could be reduced.

Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey.

Studies on the epidemiology of common adverse cutaneous drug reactions have rarely been reported, since they can only be successfully conducted in clinics of internal medicine employing consultant dermatologists and having a comprehensive or intensive system of monitoring. Between 1974 and 1993, the adverse skin reactions occurring in divisions of general internal medicine of three different hospitals were monitored by a computerized comprehensive system. The "drug-monitoring patient" was defined as the recipient of at least one drug during hospitalization. The relationship of the skin reactions to drug causality in these patients had to be either definite (proven by re-exposure) or probable (drug relation greater than that of nondrug causality). The skin reactions were classified into four diagnostic groups. Maculopapular exanthema, urticaria, and vasculitis were the three main groups. The fourth group comprised cases of nonhomogeneous but clinically well-defined special exanthema. For selected drugs and years of observation, special emphasis was placed on the study of time patterns (reaction time, exposure time). A total of 1317 definite or probable drug-induced skin reactions occurred during the hospitalization of 48,005 consecutively admitted "drug-monitoring patients": 1201 cases of maculopapular exanthema, 78 cases of urticaria, 18 cases of cutaneous vasculitis, and 20 cases of special exanthema (five of erythema multiforme minor, six of fixed eruption, one of photosensitivity reaction, and eight of acneiform eruption). The main drugs involved did not differ for the three main types of skin reactions, penicillins ranking in the first place, followed by sulfonamides--most often combined with trimethoprim--and in the third place nonsteroidal anti-inflammatory drugs. The reaction time (time from last drug exposure to first skin manifestation) for urticaria showed a relevant proportion of the acute type (within 1 h) and most of the subacute type (1-24 h). For maculopapular exanthema, the subacute or, rarely, the latent type (1-8 days, exceptionally more than 8 days) predominated. For aminopenicillins, the rate of occurrence of skin reactions increased with increasing exposure time up to 12 days, and then markedly diminished. Possibly due to the tendency to withdraw suspected drugs even in the case of minor (e.g., maculopapular) skin reactions, no severe events such as erythema multiforme major/Stevens-Johnson syndrome or toxic epidermal necrolysis occurred.

Drug-induced attack of bronchial asthma in inpatients: a 20-year survey of the Comprehensive Hospital Drug Monitoring Programme on adverse drug reactions, Berne/St. Gallen.

Epidemiological aspects of attacks of bronchial asthma related to drugs are prospectively studied in inpatients of three teaching hospitals in the Comprehensive Hospital Drug Monitoring (CHDM)-programme. Results are based on 34,840 individual patients (among 48,005 consecutive admissions) in the years 1974-1993. Between 1974 and 1993, every patient admitted to any of the three medical clinics in the CHDM programme was monitored for any suspicion of an adverse drug reaction (ADR); every drug exposure period during hospital stay was registered. Nineteen patients (0.05% of the 34,840 individual patients) had at least one attack of bronchial obstruction during hospitalisation, considered as probable or definite ADR. The frequency related to exposure periods in response to penicillins is 0.014%, to non-steroidal anti-inflammatories (NSAIDs) 0.0145, to acetyl salicylic acid (ASA) 0.018%, to paracetamol 0.008% and to beta-adrenoceptor blockers 0.26%. Of the 12 patients reacting to a drug with an allergic or idiosyncrasy/intolerance type of bronchial obstruction, 7 had a history of bronchial asthma (extrinsic or intrinsic), and 3 had the diagnosis chronic obstructive pulmonary disease (COPD). A history of bronchial asthma or COPD is confirmed to be a risk factor for this particular ADR. Of the seven patients with a bronchial obstruction to beta-adrenoceptor blockers, five were diagnosed with COPD, while two had neither COPD nor bronchial asthma. The relative risk for this pharmacological reaction in COPD patients was 96 (95% confidence interval 45-208) compared with non-COPD patients in the group of 3244 exposed to beta-adrenoceptor blockers.

[Heparin-induced thrombocytopenia. Results from the Comprehensive Hospital Drug Monitoring (CHDM) Bern/St. Gallen]. / Heparininduzierte Thrombozytopenie (HIT). Ergebnisse aus dem Comprehensive Hospital Drug Monitoring (CHDM) Bern/St. Gallen.

Of 23,520 consecutive hospitalizations from 1980-1988 (corresponding to 16,628 individual patients) in three departments of general internal medicine, 8261 were treated with heparin. All observations of patients displaying a probable, possible or questionable relationship of thrombocytopenia to heparin (administered i.v. or subcutaneously) were electronically collected by the CHDM program, revised on the basis of the primary case records and selected by standardized criteria. 13 of the 8261 patients exposed to heparin were considered to have a probable or possible HIT, corresponding to a frequency of 0.157%. In two of them severe thrombocytopenia was observed (corresponding to 0.024%) accompanied in one case by a white clot syndrome. Thrombocytopenia was defined as a platelet value below 100 x 10(9)/l and severe thrombocytopenia as one below 30 x 10(9)/l. In the literature we found slight, asymptomatic thrombocytopenia in < or = 1-8% of heparin treated patients. Our result of 11 out of 8261 (corresponding to 0.133%) is low, partly because the thrombocyte count was not controlled systematically, the heparin used was mainly produced from swine intestinal mucosa, and no antibody tests had been carried out. To prevent severe thrombocytopenia from heparin we propose monitoring the platelet count if the treatment is to be continued for more than 5 days. The newer low molecular weight heparins, all of swine origin, are much safer compared to the traditional preparations in regard to risk of HIT and white clot syndrome.

[Frequency of antibiotics-associated colitis in hospitalized patients in 1974-1991 in "Comprehensive Hospital Drug Monitoring", Bern/St. Gallen]. / Die Häufigkeit der Antibiotika-assoziierten Kolitis bei hospitalisierten Patienten der Jahre 1974-1991 im "Comprehensive Hospital Drug Monitoring" Bern/St. Gallen.

In 3 divisions of internal medicine of teaching hospitals of the Comprehensive Hospital Drug Monitoring (CHDM) Foundation Bern/St Gallen, 42,920 patients consecutively admitted between 1974-1991 were investigated for adverse drug reactions. Of these 16,150 patients (38%) had received at least one systemically administered antibacterial drug during the hospital stay. Antibiotic-associated colitis included the following diagnoses: pseudomembranous colitis, hemorrhagic colitis and milder forms of colitis. We collected the data of these patients by searching for all diagnoses which might represent antibiotic-associated colitis (from the list of WHO adverse drug reaction terminology). 9 individual patients with one episode of probable antibiotic-associated colitis were found. In 5 of these cases, only one drug given during the hospital stay seemed to be implicated. An additional 32 patients were admitted with antibiotic-associated colitis in relation to treatment with the same groups of drugs before hospital admission. Based on the exposure pattern of the 9 patients with antibiotic-associated colitis compared to all patients exposed during hospital stay, we estimated the following frequencies related to the drug groups with at least 1,000 patients exposed: for all antibacterial chemotherapeutics 0.6/1000 (0.25-1.06); all penicillins 0.6/1000 (0.22-1.32), for benzyl-, phenoxy-, ureido-, isoxazolyl penicillins and methicillin 2.0/1000 (0.42-5.92) and aminopenicillin or analogues, with or without clavulanic acid 0.6/1000 (0.18-1.35). For cephalosporins the frequency is 1.4/1000 (0.17-5.12). Under sulfonamides combined with trimethoprim or related substances (5077 exposed patients) and fluoroquinolones (1043 exposed patients) no case was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretic-related hypokalaemia: the role of diuretics, potassium supplements, glucocorticoids and beta 2-adrenoceptor agonists. Results from the comprehensive hospital drug monitoring programme, berne (CHDM).

All 5,047 consecutive inpatients admitted to the Internal Medicine Division of a teaching hospital (Zieglerspital, Berne) between 1982 and 1985 were registered in accordance with the CHDM (Comprehensive Hospital Drug Monitoring) questionnaire of adverse drug reactions (ADRs). Of them, 2,439 were treated with at least one potassium losing diuretic. The hospital records of the patients were reviewed with particular regard to serum potassium levels, and on the basis of this evaluation, the patients were assigned to four different diuretic treatment groups, and the incidence of hypokalaemia related to diuretic treatment was estimated. The overall rate of occurrence of hypokalaemia was 21.1% at a serum potassium level < 3.5 mmol.l-1, and 3.8% < 3.0 mmol.l-1. Hypokalaemia of less than 3.5 mml.l-1 developed 24.9% (217/870) of patients treated with potassium losing diuretics alone; in 19.7% (101/513) treated with potassium losing diuretics in conjunction with potassium substitution, in 15.1% (66/438) treated with a combination of diuretics (potassium losing with potassium sparing), and in 20.0% (12/60) treated with combined diuretics and potassium substitution. Only the differences between the first and the two subsequent groups were statistically significant. The overall incidence of hypokalaemia below 3.0 + mmol.l-1 was significantly lower in the patients on combined diuretics without potassium substitution than in the patients on potassium losing diuretics with potassium substitution. Oral or parenteral administration of glucocorticoids (prednisone 5 to 2,000 mg/d) was a significant risk factor for hypokalaemic events. beta 2-Adrenoceptor agonists had not effect. The patient's age, sex, renal function and numbers of drugs received were evaluated in a multivariate analysis, in order to take into account their influence on the risk of developing hypokalaemia. The number of drugs above 12 (and, less importantly, female sex) was the main risk factor for this ADR. The comparison between hypokalaemia and hyperkalaemia in this group of inpatients showed the significance of reduced renal function in the occurrence of hyperkalaemia.

[Incidence of drug side effects by symptoms and syndromes. From the experiences of the Comprehensive Hospital Drug Monitoring and the Swiss Drug Side Effect Center. As an example: allergic and pseudo-allergic reactions with mild analgesics and NSAID]. / Die Häufigkeit von unerwünschten Arzneimittelwirkungen nach Symptomen und Syndrome. Aus den Erfahrungen des CHDM und der SANZ. Als Beispiel: die allergischen und pseudoallergischen Reaktionen unter leichten Analgetika und NSAIDs.

From 1974 to 1989, 37,392 patients were admitted to the divisions of general internal medicine of the CHDM hospitals. 19,082 of them were treated with a minor analgesic or an NSAID. In 95 of the exposed patients, an allergic or a pseudoallergic reaction to one or two of these drugs was observed. From 1981 to 1990, general practitioners, hospitals and the pharmaceutical industry reported to SANZ 158 individual cases with comparable reactions to 175 exposures of the same kind. Of the 15 different syndromes and symptoms registered in both institutions, most were reactions of the skin, mainly the usual maculopapular exanthemas (rash), urticaria and angioedema. In the CHDM, allergic or pseudoallergic reactions were observed in 0.23% of patients exposed to minor analgesics (including ASA preparations on a daily dose up to 1.0 g and pyrazolones, mainly metamizole, propyphenazone) and in 0.81% of patients exposed to NSAIDs (including the pyrazolone oxyphenbutazone). In the experience of the Comprehensive Hospital Drug Monitoring in Berne and St. Gallen (CHDM) and the Spontaneous Adverse Drug Reactions Center of Switzerland (SANZ).

[Palpable purpura]. / [Palpable Purpura]

Non-thrombocytopenic palpable purpura is a characteristic lesion of cutaneous leukocytoclastic vasculitis. In association with manifestations in the gastrointestinal tract, kidney and/or joints, it forms the clinical entity of Henoch-Schönlein purpura. Among 27,510 inpatients in the years 1974 to 1989 from the CHDM Berne/St. Gallen, 2 developed one, and a further patient as many as 4 episodes of leukocytoclastic vasculitis limited to the skin, which were probably related to drugs (most often compounds containing a sulfonamide, related structures or a penicillin). In contrast, among 8 additional cases from the same cohort, in which Henoch-Schönlein syndrome was diagnosed on admission to hospital, a drug etiology was suspected only in one patient. In these patients an involvement in addition to that of the skin of at least two other organ systems was documented. In our experience, a drug etiology should be considered in every case of leukocytoclastic vasculitis, but will mainly be validated in cases in which the lesions are limited to the skin.

Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone sodium for 4 weeks. Efficacy and outpatient treatment feasibility.

UNLABELLED: OBJECTIVE--To evaluate the efficacy and safety of ceftriaxone sodium in the treatment of streptococcal endocarditis. DESIGN--An open, multicenter, noncomparative study with a follow-up of patients for 4 months to 5 years. SETTING--Internal medicine wards and outpatient clinics of hospitals of various sizes in three European countries. PATIENTS--Fifty-nine patients with defined criteria for streptococcal endocarditis. INTERVENTION--Ceftriaxone sodium administered at a once-daily dose of 2 g for 4 weeks. MAIN OUTCOME MEASURES--Clinical outcome and microbiological cure rate. RESULTS--Among the 59 patients, 55 completed the treatment and were followed up for 4 months to 5 years. No patients showed evidence of relapse. Treatment was completely uneventful in 42 patients (71%). A cardiac valve was replaced in four patients (7%) receiving antimicrobial therapy and in six patients (10%) who had completed antimicrobial therapy. One of the 10 valves taken for culture at surgery was positive, but only for microorganisms that were different from the microorganism isolated before the treatment. The treatment had to be interrupted in four patients because of drug allergy. Other side effects were mild except for two cases of reversible neutropenia. The treatment was easy to administer: 27 patients (46%) had no permanent intravenous catheter at any time, seven patients (12%) had such a catheter for less than 4 days. Twenty-three patients (39%) were discharged from the hospital less than 2 weeks after admission. CONCLUSIONS: --Ceftriaxone sodium administered at a once-daily dose of 2 g appears to be an effective and safe treatment of streptococcal endocarditis. In hospitals, this agent may be more convenient to administer than penicillin G with or without aminoglycosides. Some patients may even be treated as outpatients.

Risk factors for adverse drug reactions communication of the CHDM.

In the CHDM (Comprehensive Hospital Drug Monitoring for Adverse Drug Reactions, Bern/St. Gallen), the data of the 34,838 computer registered patient admissions 1974-1988 were available for evaluation. We summarize the results of three different studies: 1. A multivariate analysis of the risk factors to developed an ADR during hospital stay, mainly the number of drugs, age, sex and renal function. 2. The occurrence rate of hyperkalemia under the treatment with diurectics, mainly potassium (K+)-losing with K+ substitution compared to the combination of K(+)-sparing with K(+)-losing preparations. 3. The occurrence-rate of exanthema in relation to amino-penicillin preparations an allopurinol. The results are presented in the communication. (Tab 7, Fig. 1, Ref. 15). Ref. 15.).

[Hyperkalemia with potassium-sparing and potassium-losing diuretics. Results from the Comprehensive Hospital Drug Monitoring Bern (CHDM)]. / Hyperkaliämien unter kaliumsparenden und kaliumverlierenden Diuretika. Ergebnisse aus dem Comprehensive Hospital Drug Monitoring Bern (CHDM).

Of 5047 in-patients in the Division of Internal Medicine, Zieglerspital Bern (regional/teaching hospital), admitted from 1982 to 1985, 2412 were treated with at least one diuretic. The hospital records of these patients were reviewed with regard in particular to serum potassium and creatinine values as well as potassium supplementation. On the basis of this evaluation the patients were assigned to 6 different treatment groups and the relative occurrence rate of hyperkalemia probably related to drug treatment was determined. Of the 590 patients treated with only potassium losing diuretics, none was found to show a hyperkalemia event; of the 742 patients on potassium losing diuretics and potassium supplementation, 27 (3.6%) developed hyperkalemia. In the 439 patients under combined diuretics (potassium sparing with potassium losing) without potassium substitution, 76 (17.3%), and in the 381 under combined diuretics with potassium substitution 24 (6.3%), developed hyperkalemia. The further groups of patients are also described. Renal function was estimated by the formula of Cockcroft and Gault. Reduced renal function is a significant risk-factor for hyperkalemic events under combined diuretics. All hyperkalemic events were within a serum potassium range of 5.1-7.0 mmol/l.

[Acute severe dyspnea as a side effect of drugs. Report from the CHDM (Comprehensive Hospital Drug Monitoring)]. / Akute schwere Dyspnoe als Medikamentennebenwirkung. Mitteilung aus dem CHDM (Comprehensive Hospital Drug Monitoring).

This "syndrome" has been observed in 4 of 23,935 in-patients registered in the years 1974-1987 in the Comprehensive Hospital Drug Monitoring (Bern/St. Gallen), with 6 reactions. Signs of an attack of bronchial asthma, laryngeal or pulmonary edema or a (heart-)circulatory event were not observed. Each patient was cyanotic and 3 had the feeling of impending death. The eliciting drugs were penicillin-G (twice) and cefazolin (once), given i.v.; iron dextran i.m. (once); pitressin tannate i.m. (once) and dicobalt edetate (Kelocyanor) i.v.(once). In each case the reaction started during or shortly after injection of the drug; the duration of the reaction in 5 of these events was 20-80 minutes. The pathomechanism could be a special form of anaphylactic reaction with acute pulmonary hypertension, comparable to IgE-induced anaphylaxis in the rabbit or aggregate anaphylaxis in the monkey or the dog. Further observations are needed for more detailed study.

Risk of acute upper gastrointestinal bleeding in patients with ulcerative disease and treatment with non-steroidal anti-inflammatory drugs (NSAIDs). Results from the Comprehensive Hospital Drug Monitoring Berne (CHDM).

The hospital prevalence rate for upper gastrointestinal ulcerative disease in 28,531 inpatients consecutively admitted in two teaching hospitals in the Comprehensive Hospital Drug Monitoring (CHDM) in Berne, from 1974 to 1985, was 2.2% (1.8% for gastric or duodenal ulcer, and 0.4% for erosive gastritis). This was based on the evaluation of 634 patients after exclusion of the subgroup of patients with hepatic cirrhosis or upper gastrointestinal neoplasia. After exclusion of patients on anticoagulant therapy (n = 73), 561 (= 100%) patients could be further studied. Of them, 33.3% (n = 187) were found to have been exposed to non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, within 21 days prior to confirmation of the diagnosis. The observed relative risk (RR) of developing a substantial acute upper gastrointestinal bleeding (Hb less than 10 g/100 ml for men, and less than 9 g/100 ml for women, or a decrease in Hb of more than 25%) was 1.61 when patients exposed to NSAIDs (n = 187) were compared to patients not exposed to those drugs (n = 374). Although there was no significant sex difference overall, the RR for gastrointestinal bleeding differed considerably in the various age-groups; it was elevated in men under 40 years (RR = 2.86) and in women over 60 years of age (RR = 1.89), as compared to the mean RR of 1.61.

Time pattern of allergic reactions to drugs.

Generalized, allergic reactions to drugs show time patterns different from those based on pharmacological concepts. We distinguish three types of reactions: acute reactions (reaction time (RT): 0-60 minutes), subacute reactions (RT: 1-24 hours) and reactions of the latent type (RT: 1 day to several weeks). In this study, allergic reactions in the strict sense are supplemented by reactions considered to be based on intolerance or idiosyncrasy to aspirin, pyrazolones, paracetamol, NSAIDs, quinidine, iodine-containing contrast media and some as yet not understood reactions to local anaesthetics. Out of a total of 23,935 drug monitoring patients with 32,317 hospitalizations in the clinical divisions of internal medicine at three Swiss hospitals during the 1974-1987 period, 951 patients with 1,040 probably or definitely drug-related events of the selected type were recorded. Ultimately, 287 patients with 310 adverse drug reactions (ADRs) fulfilled our selection criteria and were classified into six groups of syndromes (Table 1). (Of the reactions described as maculopapular rash, unspecified rash and special exanthema, only the 159 reactions from the 1985-1987 period out of a total of 889 reactions of this type observed during the whole study period were included in our secondary evaluation.) The total number of 310 reactions (100%) showed the following RT distribution: 36 (11.6%) were of the acute type, 13 (4.2%) of the latent type, 12 (3.9%) could be interpreted as two distinct possible types of reaction to different drugs, and for 3 (1.0%) reactions, the type of reaction was indeterminable. The majority of reactions, 246 (79.4%), were of the subacute type starting within 24 hours of the last drug exposure. Among the 36 reactions of the acute type, 7 events of acute severe dyspnoea were observed which seemed to be as life-threatening as anaphylactic or anaphylactoid shock. These hospital-epidemiological data are of interest for focusing basic research and developing further principles of drug safety.