Abstract
Aims
This study aimed to determine the occurrence of adverse drug reactions (ADRs) that caused admission to the intensive care unit (ICU) of a university hospital.
Methods
Clinical records were reviewed for patients meeting the inclusion criteria who were admitted to the ICU between September and December 2012. Suspected cases of ADRs were documented. Nine researchers later evaluated causality using the Naranjo Algorithm, preventability using the Schumock and Thornton criteria, and clinical classification based on the dose–time–susceptibility system.
Results
In total, 96 patients presented 108 cases of ADR (13.8%, 95% confidence interval 11.2–16.4%) as the cause of admission. The most frequent ADRs were bradyarrhythmias and upper gastrointestinal bleeding (12%). Therapeutic failure accounted for 20%. The most commonly associated medications were acetylsalicylic acid (16%) and losartan (10%). Forty‐six cases were categorized as possible, and only one as definite. According to the dose–time–susceptibility classification, in 82% of the cases, the dosage was collateral (within the therapeutic range), and 90% were independent of time; the factors most associated with susceptibility to ADRs were comorbidities (42%) and age (49%). Forty‐four percent of the ADRs were considered possibly preventable.
Conclusions
ADRs contribute significantly to ICU admissions, and a significant number of ADRs are preventable. National studies are needed to assess their incidence and to establish classification standards to reduce their clinical impact.
Keywords: drug‐related side effects and adverse reactions, intensive care units, patient admissions, pharmacovigilance, postmarketing, product surveillance
What is Known About this Subject
There are no published studies on adverse drug reactions (ADRs) as the cause of intensive care unit (ICU) admissions in Colombian patients. However, a small number of studies in other countries have estimated that the frequency of ADRs ranges between 1% and 37%.
Similarly, the associations of therapeutic failures as serious ADRs that result in hospitalization are virtually unknown.
Although the dose–time–susceptibility classification system has been shown to be useful for assessing ADRs in already hospitalized patients, it has not been used in practice to evaluate ADRs as the reason for hospitalization.
What this Study Adds
The frequency of ADRs as a reason for hospitalization in an ICU among a sample of Colombian patients is not negligible, and the incidence is similar to those reported by other countries in the literature.
In our study, therapeutic failures accounted for 20% of ICU admissions.
The dose–time–susceptibility system is a very practical method of assessing the clinical characteristics of ADRs as a cause of admission to the ICU.
Tables of Links
These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2.
Introduction
Adverse drug reactions (ADRs) are defined by the World Health Organization as a harmful and unintentional response to “doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function” 3.
ADRs pose a public health problem, as they are responsible for 5–10% of hospitalizations 4, 5 and also increase the length of stay 3. In some countries, ADRs are between the fourth and sixth leading causes of death 6, 7, 8. Additionally, they have economic repercussions; Segura and Maldonado 9 estimated that in 2010, ADRs cost approximately 55 billion dollars (USD) in Colombia.
More than 30% of ADRs are potentially avoidable if the role of the drug is detected at each step of the medication process 10.
However, Ferner and Aronson 11 reported that previous estimates of the extent to which ADRs are avoidable in a population are likely to be misleading. For that reason, they proposed the dose–time–susceptibility (DoTS) and EIDOS (the Extrinsic chemical species (E) that initiates the effect; the Intrinsec chemical species (I) that it affects; the Distribution (D) of these species in the body; the Outcome (O); and the Sequela (S)) methods as prospective preventive strategies and as tools for determining retrospectively whether an adverse effect in an individual could have been prevented 12.
There have been few studies on ADRs as the causes of admission to intensive care units (ICUs) in the last 30 years. Of them, Trunet et al. 13 in 1980 concluded that 12.6% of ICU admissions were related to iatrogenic causes, including ADRs.
A 1‐year retrospective study conducted by Darchy et al. 14 in an ICU in France aimed to determine the rate of admissions to ICUs for iatrogenic diseases. The results were compared with previous data recorded in 1979 (admission rate: 12.6%, mortality: 20%, preventable events: 47%). They found that in 1994, 68 (10.9%) of 623 patients were admitted to the ICU for iatrogenic diseases, and 41 cases (6.6%) were related to drugs. In addition, the number of prescribed drugs was considered a risk factor for iatrogenic diseases 14.
In a multicentre study by Lehmann et al. 15, 66 (1.2%) patients were identified as having an iatrogenic medical event as their main reason for ICU admission. Twenty‐two (34%) cases were preventable. The majority of events were secondary to technical errors (45%) or were drug‐related (33%) 15.
Another study reviewed adult admissions to ICUs prospectively for 6 weeks. Seventy‐six of 280 patients (27%) experienced 104 iatrogenic events, 17% of which were classified as drug‐related 16.
A systematic review conducted by Vlayen et al. 17 of 27 studies found that the percentage of surgical and medical adverse events that required ICU admission, including drug‐related events, ranged from 1.1% to 37.2%.
In Colombia, there have been no published studies on the importance of ADRs in causing admissions to the ICU. We conducted this study accordingly, using the DoTS classification for ADRs proposed by Aronson and Ferner 18 in 2003, while accounting for the fact that patients had emergency admissions in most cases and that their admissions may have been due to a major health problem (for which hospitalization and close monitoring were required) that could have been drug‐related.
Materials and methods
We reviewed the medical charts of patients who were admitted to the ICU during a 4‐month period between September and December 2012; the objective was to identify patients who were taking one or more drugs at the time of admission, whose admission was thought to be drug‐related, and who were admitted to the ICU of the Hospital Universitario Mayor, a tertiary‐level care hospital in Bogota. All patients were admitted to the ICU on the day of their admission, and most were brought to the hospital by ambulance from their homes (and were not in the hospital before that). When necessary, additional information was obtained through personal interviews with the patients' relatives or treating physicians.
Medical records were reviewed, and assessments performed without any interventions or modification of current therapies. This study followed the Good Clinical Practices for Investigation in humans established in the Declaration of Helsinki and the 1993 Resolution 8430 of the Colombian Ministry of Health.
The confidentiality of the information was ensured. The study was approved by the Ethics Committee of Research of the Universidad del Rosario and the Hospital Universitario Mayor.
Information was collected by a resident in clinical toxicology, and each case was validated and analysed by a research team composed of two pharmacologists, two emergency department physicians and five general practitioners; this team used Naranjo's algorithm to assess the causality of ADRs 19, DoTS criteria proposed by Aronson and Ferner 18 to conduct the clinical assessment, and the preventability criteria of Schumock and Thornton 20. The imputation of causality was based on prior probabilities.
Statistical methods included descriptions of categorical variables by percentages and descriptions of continuous variables by central trend and dispersion measures, using 95% confidence intervals. Analyses were conducted according to the observed distribution, which was verified using Shapiro–Wilk's test.
Results
During the analysis period, 697 patients were admitted to the ICU, all of whom were evaluated. Ninety‐six of these patients had at least one ADR as their cause of admission (13.8%, 95% CI 11.2–16.4%), with a total of 108 drug‐reaction pairs, as some patients had more than one ADR (between one and three reactions). Some of the characteristics of these patients are shown in Table 1. The mean age of the patients who experienced ADRs was 69 years (range 17 to 94 years), and 77% were over 60 years old. Among patients with ADRs, 51% were female, with a mean age of 72 years, and 49% were male, with a mean age of 66 years. None of the women were pregnant.
Table 1.
Characteristics of the patients (n = 96)
| Variable | n | % | 95% CI |
|---|---|---|---|
| Sex: Female | 49 | 51 | 41–61 |
| Age (years) | |||
| 17–60 | 22 | 23 | 16–32 |
| 61–73 | 30 | 31 | 23–41 |
| 74–80 | 21 | 22 | 16–32 |
| 81–94 | 23 | 24 | 17–33 |
| Medical history | |||
| Liver disease | 1 | 1 | 0–6 |
| Kidney disease | 19 | 20 | 13–28 |
| Hypoalbuminaemia | 2 | 2 | 0–7 |
| Number of drugs | |||
| 1–3 | 27 | 28 | 20–38 |
| 4–5 | 19 | 20 | 13–29 |
| 6 | 13 | 14 | 9–23 |
| 7–8 | 21 | 22 | 15–31 |
| 9–16 | 16 | 17 | 11–27 |
CI, confidence interval
The participants were taking between one and 16 drugs (Table 1). The adverse drug reactions and related drugs are presented in Table 2.
Table 2.
Adverse reactions (n = 108) and related drugs
| Adverse reaction | n | Percentage of the total, % (95% CI) | Related cases | Related number of cases per drug |
|---|---|---|---|---|
| Arrythmia (bradycardia/heart block) | 13 | 12 (7–20) |
Metoprolol Clonidine Carvedilol Digoxin Nebivolol Propranolol Verapamil |
4
3 2 1 1 1 1 |
| Upper gastrointestinal bleeding | 13 | 12 (7–20) |
Acetylsalicylic acid Clopidogrel Dalteparin Enoxaparin Naproxen |
9
1 1 1 1 |
| Therapeutic failure – seizures | 12 | 11 (6–19) |
Valproic acid Carbamazepine Phenytoin Phenobarbital |
5
3 3 1 |
| Hyperkalaemia | 10 | 9 (5–16) |
Losartan Enalapril Spironolactone |
6
2 2 |
| Therapeutic failure – hypertension | 9 | 8 (4–15) |
Losartan Clonidine Amlodipine Furosemide Spironolactone |
5
1 1 1 1 |
| Cerebrovascular haemorrhagic disease | 7 | 7 (3–13) |
Acetylsalicylic acid Clopidogrel Enoxaparin Warfarin |
4
1 1 1 |
| Hypoglycaemia | 4 | 4 (1–9) |
Regular insulin Nph insulin |
2 2 |
| Overanticoagulation | 4 | 4 (1–9) | Warfarin | 4 |
| Subdural haematoma | 3 | 3 (1–8) |
Acetylsalicylic acid Clopidogrel Enoxaparin |
1
1 1 |
| Lower gastrointestinal bleeding | 3 | 3 (1–8) |
Acetylsalicylic acid Warfarin |
2 1 |
| Hypokalaemia | 3 | 3 (1–8) | Hydrochlorothiazide | 3 |
| Chronic kidney disease exacerbation | 3 | 3 (1–8) |
Ibuprofen Contrast agent |
1 2 |
| Immunosupression | 3 | 3 (1–8) |
Etanercept Methylprednisolone Mycophenolate |
1
1 1 |
| Ascites | 2 | 2 (1–7) |
Furosemide Spironolactone |
1 1 |
| Hyponatraemia | 2 | 2 (1–7) |
Furosemide Hydrochlorothiazide |
1 1 |
| Hypotension | 2 | 2 (1–7) |
Amlodipine Enalapril |
1 1 |
| Bicytopenia (neutropenia and thrombocytopenia) | 1 | 1 (0–5) | Clindamycin | 1 |
| Seizures | 1 | 1 (0–5) | Carbamazepine | 1 |
| Delirium | 1 | 1 (0–5) | Bromocriptine | 1 |
| Respiratory depression | 1 | 1 (0–5) | Morphine | 1 |
| Stroke | 1 | 1 (0–5) | Warfarin | 1 |
| Therapeutic failure – diabetic ketoacidosis | 1 | 1 (0–5) |
Regular insulin Nph insulin |
1 1 |
| Epidural haematoma | 1 | 1 (0–5) | Warfarin | 1 |
| Psoas haematoma | 1 | 1 (0–5) | Enoxaparin | 1 |
| Subarachnoid haemorrhage | 1 | 1 (0–5) | Acetylsalicylic acid | 1 |
| Upper and lower gastrointestinal bleeding | 1 | 1 (0–5) | Warfarin | 1 |
| Hypocalcaemia | 1 | 1 (0–5) | Zoledronic acid | 1 |
| Ileus | 1 | 1 (0–5) | Tramadol | 1 |
| Leukopenia | 1 | 1 (0–5) | Capecitabine | 1 |
| Pancytopenia | 1 | 1 (0–5) | 5‐fluorouracil | 1 |
| Thrombocytopenia | 1 | 1 (0–5) | Valproic acid | 1 |
CI, confidence interval
The causality of the ADRs was classified as follows: possible in 46 cases (42.5%), probable in 35 cases (32.4%) and definitive in one case (0.9%), which was related to hydrochlorothiazide. There were 22 therapeutic failures (20% of all the cases), and four of the cases (3.7%) were secondary to drug withdrawal.
When classifying the ADRs according to the six types proposed by Edwards and Aronson in 2000 21, the following distribution was found: A, 75 (69%); B, 2 (2%); C, 5 (5%); E, 4 (4%); and F, 22 cases (20%). ADRs of type D were not identified.
We classified ADRs as type B when they met the following criteria proposed by Edwards and Aronson 21: were uncommon, not related to a pharmacological action of the drug; unpredictable; and potentially associated with high mortality. Specific cases included blood dyscrasias with a prevailing immunological component: neutropenia and thrombocytopenia with clindamycin, and thrombocytopenia with valproic acid.
Regarding the DoTS criteria, the following distribution was established: collateral reactions, 82%; hypersusceptibility reactions, 2.8%; and toxic reactions, 5.6%. Because of a lack of information in the medical history, 10 cases were not assessed. Regarding the time‐course of the reactions, 97 cases were time‐independent (90%), two cases were intermediate (1.8%), four cases were late (3.7%) and five cases were not assessable (4.6%).
In 53 of the cases (49%), age was considered a major susceptibility factor. Comorbidities (e.g., renal failure, hypoalbuminaemia) influenced the occurrence of the ADR in 45 cases (42%), and exogenous factors (e.g., drug interactions) in 32 cases (30%). In 15 cases (14%), a susceptibility factor could not be identified.
In Table 3, all adverse reactions are summarized according to the Schumock and Thornton preventability criteria 20. In total, 44% of the assessable ADRs were classified as preventable. More than half of the ADRs occurred because of insufficient monitoring.
Table 3.
Criteria for the classification of preventability (n = 48)
| Preventable (n = 48) | |||
|---|---|---|---|
| Criterion | n | % | 95% CI |
| 1 | 6 | 12 | 5–25 |
| 2 | 13 | 27 | 15–42 |
| 3 | 2 | 4 | 1–14 |
| 4 | 27 | 56 | 41–71 |
| 5 | 2 | 4 | 1–14 |
| 6 | 6 | 13 | 5–25 |
| 7 | 28 | 58 | 43–72 |
CI, confidence interval
Schumock and Thornton criteria 20
1. Was there a history of allergy or previous reactions to the drug?
2. Was the drug involved inappropriate for the patient's clinical condition?
3. Was the dose, route or frequency of administration inappropriate for the patient's age, weight or disease state?
4. Was required therapeutic drug monitoring or other necessary laboratory tests not performed?
5. Was a drug interaction involved in the adverse drug reaction?
6. Was poor compliance involved in the adverse drug reaction?
7. Was a toxic serum drug concentration (or laboratory monitoring test) documented?
Discussion
The frequency of suspected ADRs in our study was 14%, and these results provided the first evidence on the frequency of ADRs as a cause of admission to the ICU in the Colombian population. This value is within the range established in the literature, which is approximately 1–37% 13, 14, 15, 16, 17.
However, focusing the analysis on the ADRs that were defined as definite or probable in Naranjo's algorithm, the frequency fell considerably to 5.2%, which is similar to the results of other international studies; for example, in Rivkin 22 and Pedrós et al. 23, the frequencies of ADRs were 7.5% and 4.2%, respectively, the first regarding ICU admissions and the second referring to hospitalizations. Regarding other studies in Latin America, a study by Giachetto et al. 24 that assessed ADRs causing hospitalizations or requiring drug withdrawal in a hospital in Uruguay reported a frequency of admissions of 4.2%, which was lower than the rate in our study.
The analysis underlined the difficulty with using the Naranjo algorithm: almost all of the outputs were ‘possible’ or ‘probable’, which corresponds with the inputs that led to the initial presumptive diagnosis of ADR.
The mean age of the patients with an ADR (69 years) was close to the value described in the literature, and ADRs have been related to different factors in this demographic segment, including reduced functional reserve, pharmacodynamic and pharmacokinetic changes, comorbidities, polypharmacy, cognitive decline, social problems, and functional limitations 25.
The most frequent ADRs were cardiac bradyarrhythmias, and the patients affected had a higher mean age than the rest of the assessed population (78 vs. 69 years). Similarly, Marcum et al. 26 conducted a retrospective cohort study of the elderly and found that bradyarrhythmias were the main cause of hospitalizations after ADRs, as in our study.
The second most frequent ADR was upper gastrointestinal haemorrhage. The combined frequency of all ADRs related to bleeding (including the gastrointestinal and central nervous systems) was 21%, which is consistent with the results of similar studies 22.
Electrolyte disturbances such as hyperkalaemia, hyponatraemia, hypokalaemia and hypocalcaemia were also frequent and were most common if considered as a whole.
Acetylsalicylic acid was associated with the highest frequency of ADRs (16%), when considering a denominator of the number of ADRs. Salvi et al. 27 reported that ADRs related to antiplatelet drugs, including clopidogrel and ticlopidine, accounted for 19% of hospitalizations. Losartan was the second most common drug associated with ADRs. This is similar to the results of a study by Pedrós et al. 23, who found that renin–angiotensin–aldosterone blockers were most commonly associated with ADRs. However, in this study, ADRs were linked to acute renal impairment.
A bivariate analysis showed that patients with ADRs who were taking six or more drugs had lower scores on Naranjo's algorithm. The use of a higher number of drugs may affect the score, as a drug other than that suspected may actually be the cause of the response.
We also evaluated ADRs using the DoTS system; 82% were collateral reactions, i.e., occurring in the therapeutic dosage range, while only 5.6% were toxic reactions (i.e., at supratherapeutic doses). This finding is similar to the results reported by Calderón‐Ospina and Bustamante in Colombian hospitalized patients 28. However, unlike that study, most of the ADRs in this study were considered to have been time‐independent (90%). Susceptibility factors such as age, comorbidities, and exogenous factors in this study differed in frequency from those of the aforementioned study 28. These findings suggest that the factors that predispose outpatients to serious ADRs may not be the same as those that predispose hospitalized patients to ADRs.
ADRs that were considered preventable according to the Schumock and Thornton criteria 20 constituted 44.4% (95% CI 35.4 – 53.8%) of the cases. This figure is comparable with the results of a meta‐analysis by Hakkarainen et al. 29, who found that preventable ADRs occurred in 52% of the cases. In our study, inadequate monitoring contributed to more than half of the preventable cases, indicating a training opportunity to optimize the use of drugs.
As collateral adverse reactions occur at therapeutic doses, these are generally considered not preventable. These types of reactions accounted for 82% of the ADRs in our study, while 44% were considered preventable. This discrepancy can be explained by the fact that many reactions were considered preventable according to criteria other than the use of a supratherapeutic dose, for example, the drugs were not appropriate for the patient's clinical condition, therapeutic drug monitoring was not sufficiently implemented, the patient had a history of allergy to the administered drug, and drug interactions could have occurred.
Regarding the limitations of this study, it was retrospective in nature and based on medical records. As we explored the occurrence of ADRs in a single hospital and a specific service with unique characteristics (the ICU), the results cannot be generalized to other settings.
Conclusions
ADRs are a frequent cause of ICU admissions and can be evaluated using different assessment systems. A significant number of ADRs are preventable. National studies are needed to assess their incidence and to establish standards of classification to reduce their impact. In addition, it is important to create pharmacovigilance programmes for elderly people and for patients who are exposed to polypharmacy.
Competing Interests
There are no competing interests to declare.
We are grateful to Dr J.K. Aronson for designing the protocol and for the helpful comments on an early draft of this paper. Additionally, we are grateful to Dr. A.J. Idrovo for contributing to the statistical analysis, and Dr. D.F. Cardona and Dr. J.S. Franco for supporting the collection of information.
This research received no specific grant from any funding agency in the public, commercial or not‐for‐profit sectors.
Rojas‐Velandia, C. , Ruiz‐Garzón, J. , Moscoso‐Alcina, J.‐C. , Vallejos‐Narvaéz, Á. , Castro‐Canoa, J. , Bustos‐Martínez, Y. , Flórez‐Cutiva, M. , Contreras‐Muñoz, M. , Gómez‐Gil, J.‐C. , and Calderón‐Ospina, C.‐A. (2017) Characterization of adverse drug reactions causing admission to an intensive care unit. Br J Clin Pharmacol, 83: 1134–1140. doi: 10.1111/bcp.13199.
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