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There is general agreement that drugs prescribed for disease are often themselves the cause of a serious amount of disease (adverse reactions) ranging from mere inconvenience to permanent disability and death. Since drugs are intended to relieve suffering, patients find it particularly offensive that they can also cause disease. It is estimated that adverse reactions cause 23 % of consultations in general practice, upto 3% of admissions to intensive care units and 0.3% of general hospital admissions are due to adverse drug reactions (ADR).1 A recent study done in Sweden has implicated ADRs as the 7th most common cause of death.2 Another study involving 19,000 admissions has shown that 6.5% of patient admissions were related to an ADR.3 Data from older studies on ADRs occurring in in-patients have suggested that 10-20% of patients experience ADRs in hospital.4-7 However these studies are decades old and with an increase in life expectancy and development in medicine over the years, there is a need for more data on the ADR in hospital in-patients. Though ADRs are of great concern to the general public, the medical profession, the pharmaceutical industry and the regulatory authorities, the concept of ADR reporting is still new in India. There are very few centres in India to monitor ADRs and hardly any detailed ADR surveys done in India are published.812 Hence a study was undertaken to record and analyze all adverse reactions among hospitalized patients in the medical wards of a tertiary care hospital in Mangalore, a South Indian city.
A total
of 1250 patients
admitted to the medical wards of Kasturba Medical College Hospital,
Attavar, Mangalore, for a period of 1 year were observed for possible
ADRs, as per W.H.O. definition. W.H.O. has defined ADR as a noxious
or unintended response to a drug which occurs at doses normally used
in humans for prophylaxis, diagnosis or treatment of a disease or for
modifying the physiological function.13 However the term
adverse event is now frequently used to describe any untoward medical
occurrence that may be present during treatment with a pharmaceutical
product but which does not necessarily have a causal relationship with
the treatment.14 ADRs were identified by 2 physicians and
confirmed by a clinical pharmacologist. When there were doubts/disagreements,
such cases were not included. ADRs that occurred outside the hospital
and got admitted in our hospital were also included. Those who were
identified to have ADRs were examined and the details recorded in a
proforma, where details of the drugs taken, observed reactions, measures
taken for untoward reactions, investigations and response to measures
were recorded. The results were analyzed under the following headings:
1. Type A or augmented reactions are those that will occur in everyone if enough of the drug is given because they are due to excess of normal, predictable, dose related pharmacodynamic effects of a drug. Type B or bizarre reactions are those that are not part of normal pharmacology of the drug, are not dose related and care due to unusual attributes of the patient interacting with the drug. The class includes idiosyncrasies and immunological processes and amount for most fatalities. 2. Severity of ADR Mild adverse reactions were defined as those which did not by itself require prolongation of hospitalization and could be managed by simple measures, moderate were those ADRs which needed prolongation of hospital stay of the patient for treatment of the same and severe were life threatening ADRs. 3. Consequences of ADRs were recorded under the following headings -
4. Systems involved Reactions were classified according to the system involved i.e., percentage of involvement of different systems. Eg. Cardiovascular system, central nervous system 5. Group of the offending drug Drugs were classified according to groups and frequency of ADRs noted in each group. 6. Details of types of reactions Type of reaction noted and the drugs commonly associated with the same were also recorded.
A total of 250 adverse events were observed and recorded during the study period. Type of adverse event Table 1 shows the Types of reactions
Severity (Table 2): We found a large fraction of ADRs (76.8%) to be of mild type while 17.2% of the reactions were of moderate type requiring prolongation of hospital stay of the patient for the treatment of the event. Six percent of the reactions were severe requiring intensive care and 3 patients (1.2%) died as a consequence of these events. Details of moderate and severe reactions are mentioned in Table 3 and 4 respectively.
Details of ADR death: Case 1: Elderly female of 70 years was prescribed corticosteroids for radiation pneumonitis which she developed following treatment of carcinoma breast. She was initially given a high dose of 60 mg/day prednisolone which was tapered to a maintenance dose of 10 mg/day. She developed acute abdominal pain and relatives gave diclofenac 1 tab thrice a day on day 1 and 2 tablets thrice a day on day 2. She died of massive upper gastrointestinal haemorrhage. Case 2: A young girl (18 yrs) was admitted for ibuprofen (for chondritis costo) induced gastritis and persistent vomiting. Intravenous fluids were started, and the patient developed stridor, hypotension and suddenly died. Autopsy did not reveal any other cause of death. Presumed cause of death was intravenous fluid induced anaphylaxis, as same batch of fluids was found to be contaminated with fungi. Case 3: An elderly male of 70 with COPD developed restlessness and hallucinations following intravenous ciprofloxacin for lower respiratory infection. He was sedated with diazepam (10 mg). The patient developed severe type II respiratory failure. Consequence of ADR: Table 5 shows the effect of ADR on the treatment of the primary disease.
Classes of drugs: When we analyzed the classes of drugs responsible for adverse events in the order of their frequency, we found that antimicrobial agents including antimalarials were the drugs which caused maximum number of adverse effects (Table 6). Anticancer drug related effects were only 4% because we have a separate unit for treatment of cancers. Among the hormones, most frequent offending agents were corticosteroids.
Systems involved: Table 7 shows the systems affected and the number of patients affected. Table 8 shows the type of reaction under each system and the offending drugs that were associated with the same.
Previously unreported ADRs 1. Etoposide induced pancreatitis: An adult male (35 yrs) suffering from seminoma testis was treated with etoposide as part of a multidrug regimen. With the first dose of etoposide, patient developed acute pancreatitis. Etoposide was stopped and the patient recovered. But, etoposide was repeated as part of the regimen following which pancreatitis developed again. This established the cause - effect relationship beyond reasonable doubt as definite (rechallenge). The drug was never repeated in the patient. The case has been reported15. 2. IV fluids induced anaphylaxis: Though reactions to intravenous fluids have been mentioned in the literature, to the best of our knowledge, no cases of intravenous fluid induced anaphylaxis have been reported. The current practices of using delicate containers make them more susceptible to damage and lead to contamination. A case has been described above.
Adverse drug reactions are a common occurrence, but are often not recognized. Even if they are recognized they are under-reported as many physicians are unaware that clinically important ADRs should be reported to ADRs monitoring centres. In our series of 1250 hospitalized patients we found a high incidence of ADR 16.66% of which 1.2% were fatal ADRs. In a meta analysis of all prospective studies of ADRs in US hospitals16 by Lazarou et al an overall incidence of 15.1% ADR was detected of which 6.7% were serious ADRs with a fatal ADR incidence of 0.32%. Our results are comparable. The majority of our reactions were Type B reactions (68%) which indicate that most of our reactions were inevitable and unavoidable in contrast to the meta analysis by Lazarou et al16, where 76.2% were Type A reactions. The cause for this discrepancy may be due to inclusion of large number of reactions to antimalarials and other antimicrobials (42.4%) in our set up. Majority of our patients had mild reactions while 23.2% of cases had moderate to severe reactions of which 6% had serious reactions and of them 1.2% were fatal. Various other studies have quoted an incidence of serious ADRs to be 0 - 20% with a fatality rate of 0 0.8%. Table 9 shows various studies of ADRs on the incidence and severity and their comparison with the present study. A pilot study of 125 in-patients done in UK showed that 19% of patients suffered from ADRs with patients spending 6.5 days longer in hospital than those without ADRs.17 However many of the studies have included only patients admitted to the hospitals for ADR or patients who developed ADR after admission to the hospital. Our study has included both the groups. It is interesting to note that 30% of ADRs had to be treated with another drug adding to the cost of therapy and prolonging hospitalization. Cassen et al18 have proved in a study that attributable lengths of stay and costs of hospitalization for ADRs are substantial and they have also concluded that it is responsible for 2 fold increased risk of death. Bates et al19 in an article have estimated that the annual costs attributable to all ADE for a 700 bed teaching hospital is 5.6 million dollars. Regarding class of drugs associated with ADRs antimicrobials rank high in the list as they are the most commonly prescribed drugs in our set up. Similar observation was noted in an Indian study.2 In a study by Caranasos20 et al, antimicrobials were the second most common cause of ADRs while non narcotic analgesics topped the list. Kanjanarat et al21 noted cardiovascular drugs to be causative in 17.9% of ADRs while Lakshmanan et al22 in a study of hospital admissions due to iatrogenic illness, found antihypertensives to be responsible for most of the iatrogenic admissions. However the latter study included moderate to severe reactions only and our study has included mild side effects also. Steel et al23 also have found low percentage of antibiotic related iatrogenic illness. Bates et al24 in a study of 247 patients found 30% of ADRs to be due to analgesics, 24% due to antibiotics, 8% due to sedatives and 7% due to antineoplastic drugs. Davies et al in UK25, have found the most frequent ADR causative drugs relative to usage to be opioid analgesics, anticoagulants, fibriolytics, systemic glucocorticoids, diuretics and antibiotics. However, these differences seen in different places could also be due to the variation in drug usage and disease prevalence in different places.
When we analyzed the systems affected most of them were CNS side effects (23.1%) which is much lower than 77.2% reported in a systematic review of ADRs by Thomsen et al.26 This is in contrast to previous studies where gastrointestinal side effects were more frequent as in the study by Natalie et al.27 However they too noted that neuromuscular problem was quite frequent with an incidence of 22.6% whereas Caranasos20 et al found 22.2% cardiovascular ADRs and 18.5% gastrointestinal ADRs with only 11.1% neurologic ADRs in a study of 189 ADRs. This discrepancy may be due to inclusion of large number of antimalarials which produced CNS side effects. Among moderate to severe reactions, combinations of drugs (drug interactions) were responsible for a large percentage of ADRs. 41.1% of ADRs in severe reactions, 29% of cases in moderate reactions and 66.6% of fatal reactions were all due to combination of drugs. One important observation was that of inadvertent use of antipsychotics and sedatives for patients with respiratory failure in 4 cases of which one died. As patients with respiratory failure may present with psychotic symptoms one should be careful about sedating a patient with preexisting respiratory failure. Drug-drug interactions were linked to 59% of ADRs in a study by Davies et al.25 Polypharmacy was implicated by them to be the cause in a large percentage of cases where incidence of ADR was higher in patients receiving higher number of drugs compared to those receiving fewer drugs. It is important to note that commonly used drugs such as chloroquin can produce serious neuropsychiatric problems such as extrapyramidal reactions, convulsions and psychosis as seen in 11 of our patients. If this fact is not considered, these patients may end up with unnecessary investigations such as lumbar puncture, EEG and a CT scan. Our study has included reactions to water for injections and IV fluids. Although it cannot be considered as a true ADR, it can be considered as an adverse drug event. Intravenous fluids have been associated with reactions such as rigors and rarely anaphylaxis. In one of our fatal cases this is suspected, because an IV fluid bottle of the same company was found to have overt fungal growth in a few bottles. We also found a case of etoposide induced pancreatitis15 which was unknown previously. In conclusion, ADR monitoring has to be carried out by all the doctors, as the pattern of ADR may vary from place to place and time to time. By early recognition of these reactions, necessary action can be taken to prevent mortality and morbidity from such reactions.
The authors are grateful to the Department of Pharmacology, KMC Mangalore for their help in framing the proforma.
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