Prevalence of potential drug-drug interactions in the intensive care unit of a Brazilian teaching hospital

Aline Teotonio Rodrigues Rebeca Stahlschmidt Silvia Granja Diogo Pilger Antonio Luis Eiras Falcão Priscila Gava Mazzola About the authors

Abstract

Patients in intensive care unit are prescribed large numbers of drugs, highlighting the need to study potential Drug-Drug Interactions in this environment. The aim of this study was to delineate the prevalence and risk of potential drug-drug interactions between medications administered to patients in an ICU. This cross-sectional observational study was conducted during 12 months, in an adult ICU of a teaching hospital. Inclusion criteria were: prescriptions with 2 or more drugs of patients admitted to the ICU for > 24 hours and age of ≥18 years. Potential Drug-Drug Interactions were quantified and classified through MicromedexTM database. The 369 prescriptions included in this study had 205 different drugs, with an average of 13.04 ± 4.26 (mean ± standard deviation) drugs per prescription. Potential Drug-Drug Interactions were identified in 89% of these, with an average of 5.00 ± 5.06 interactions per prescription. Of the 405 different pairs of potentially interacting drugs identified, moderate and major interactions were present in 74% and 67% of prescriptions, respectively. The most prevalent interaction was between dipyrone and enoxaparin (35.8%), though its clinical occurrence was not observed in this study. The number of potential Drug-Drug Interactions showed significant positive correlations with the length of stay in the intensive care unit, and with the number of prescribed drugs. Acknowledging the high potential for Drug-Drug Interactions in the ICU represents an important step toward improving patient safety and best therapy results.

Uniterms:
Potential drug-drug interactions; Intensive care unit; Patient safety; University hospitals.

INTRODUCTION

A Drug-Drug Interaction is a pharmacological or clinical response to the administration of two or more drugs, which is different from the response triggered by the individual use of these agents (Tatro, 2012TATRO, D.S. Drug interaction facts 2013: the authority on drug interactions. Philadelphia: Lippincott Williams & Wilkins, 2012. p.2249.). Knowledge of the main characteristics of these interactions and access to databases with detailed information on them, including the mechanisms involved and their potential severity, can prevent the resulting adverse events and/or assist in their clinical management (Papadopoulos, Smithburger, 2010SMITHBURGER, P.L.; KANE-GILL, S.L.; BENEDICT, N.J.; FALCIONE, B.A.; SEYBERT, A.L. Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings. Ann. Pharmacother., v.44, n.11, p.1718-1724, 2010.; Magro, Moretti, Leone, 2012MAGRO, L.; MORETTI, U.; LEONE, R. Epidemiology and characteristics of adverse drug reactions caused by drug-drug interactions. Expert Opin. Drug Saf., v.11, n.1, p.83-94, 2012.; Dubova et al., 2007DUBOVA, S.V.; REYES-MORALES, H.; TORRES-ARREOLA, L.P.; SUÁREZ-ORTEGA, M. Potential drug-drug and drug-disease interactions in prescriptions for ambulatory patients over 50 years of age in family medicine clinics in Mexico City. BMC Health Serv. Res., v.7, p.147, 2007.). When the interactions present in the prescription are theoretically evaluated through databases and not by their actual occurrence, they are considered potential (Brunton et al., 2011BRUNTON, L.L.; CHABNER, B.A.; KNOLLMANN, B.C.; GOODMAN, L.S. Goodman & Gilman's the pharmacological basis of therapeutics. 12.ed. New York: McGraw-Hill, 2011. p.1808.).

In clinical practice, potential Drug-Drug Interactions (pDDIs) can lead to serious problems, such as severe adverse events and ineffective drug therapy (Mannheimer, Eliasson, 2010MANNHEIMER, B.; ELIASSON, E. Drug-drug interactions that reduce the formation of pharmacologically active metabolites: a poorly understood problem in clinical practice. J. Intern. Med., v.268, n.6, p.540-548, 2010.; Reimche, Forster, Van Walraven, 2011REIMCHE, L.; FORSTER, A.J.; VAN WALRAVEN, C. Incidence and contributors to potential drug-drug interactions in hospitalized patients. J. Clin. Pharmacol., v.51, n.7, p.1043-1050, 2011.). Patients in the intensive care unit (ICU) routinely receive large numbers of drugs with pDDIs, highlighting the need to study these interactions in this environment (Papadopoulos, Smithburger, 2010SMITHBURGER, P.L.; KANE-GILL, S.L.; BENEDICT, N.J.; FALCIONE, B.A.; SEYBERT, A.L. Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings. Ann. Pharmacother., v.44, n.11, p.1718-1724, 2010.; Reimche, Forster, Van Walraven, 2011; Kopp et al., 2006KOPP, B.; ERSTAD, B.L.; ALLEN, M.E.; THEODOROU, A.A.; PRIESTLEY, G. Medication errors and adverse drug events in an intensive care unit: direct observation approach for detection. Crit. Care Med., v.34, n.2, p.415-425, 2006.). Reducing unnecessary risks to the patient is improving patient safety. As the risks profiles are established, reduction of risks and avoidable adverse events can also improve patient safety. (Benkirane et al., 2009BENKIRANE, R.R.; ABOUQAL, R.; HAIMEUR, C.C.; EL KETTANI, S.S.E.C.; AZZOUZI, A.A.; ALAOUI, A.A.M.I; THIMOU, A.A.; NEJMI, MM.; MAAZOUZI, W.W.; MADANI, N.N.; R-EDWARDS, I.; SOULAYMANI, R.R. Incidence of adverse drug events and medication errors in intensive care units: a prospective multicenter study. J. Patient Saf., v.5, n.1, p.16-22, 2009.; Cullen et al., 1997CULLEN, D.J.; SWEITZER, B.J.; BATES, D.W.; BURDICK, E.; EDMONDSON, A.; LEAPE, L.L. Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units. Crit. Care Med., v.25, n.8, p.1289-1297, 1997.; Kopp et al., 2006; Mcdowell, Ferner, Ferner, 2009MCDOWELL, S.E.; FERNER, H.S.; FERNER, R.E. The pathophysiology of medication errors: how and where they arise. Br. J. Clin. Pharmacol., v.67, n.6, p.605-613, 2009.).

PDDIs often are between drugs that are metabolized by the same cytochrome P450 (CYP450) enzymes, and/or due to the administration of drugs that inhibit or induce these enzymes systems (Spriet et al., 2009SPRIET, I.; MEERSSEMAN, W.; DE HOON, J.; VON WINCKELMANN, S.; WILMER, A.; WILLEMS, L. Mini-series: II. Clinical aspects. Clinically relevant CYP450-mediated drug interactions in the ICU. Intens. Care Med., v.35, n.4, p.603-612, 2009.; Klein, Gueorguieva, Aarons, 2012KLEIN, K.; GUEORGUIEVA, I.; AARONS, L. Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug-drug interaction studies for CYP2C9. J. Pharmacokinet. Pharmacod., v.39, n.2, p.147-160, 2012.; Mouly, Meune, Bergmann, 2009MOULY, S.; MEUNE, C.; BERGMANN, J.F. Mini-series: I. Basic science. Uncertainty and inaccuracy of predicting CYP-mediated in vivo drug interactions in the ICU from in vitro models: focus on CYP3A4. Intens. Care Med., v.35, n.3, p.417-429, 2009.). Drugs metabolized by this route include midazolam, tacrolimus, cyclosporine, and phenytoin, all of which are widely used in the ICU. CYP450 inducers and inhibitors include drugs such as amiodarone, fluconazole, and carbamazepine, which are often used in the ICU (Papadopoulos, Smithburger, 2010SMITHBURGER, P.L.; KANE-GILL, S.L.; BENEDICT, N.J.; FALCIONE, B.A.; SEYBERT, A.L. Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings. Ann. Pharmacother., v.44, n.11, p.1718-1724, 2010.; Mannheimer, Eliasson, 2010MANNHEIMER, B.; ELIASSON, E. Drug-drug interactions that reduce the formation of pharmacologically active metabolites: a poorly understood problem in clinical practice. J. Intern. Med., v.268, n.6, p.540-548, 2010.).

The large number of pDDIs between drugs prescribed to ICU patients has been documented by several studies (Smithburger, Kane-Gill, Seybert, 2012SMITHBURGER, P.L.; KANE-GILL, S.L.; SEYBERT, A.L. Drug-drug interactions in the medical intensive care unit: an assessment of frequency, severity and the medications involved. Int. J. Pharm. Pract., v.20, n.6, p.402-408, 2012.; Smithburger et al., 2010; Rivkin, Yin, 2011RIVKIN, A.; YIN, H.J. Evaluation of the role of the critical care pharmacist in identifying and avoiding or minimizing significant drug-drug interactions in medical intensive care patients. J. Crit. Care, v.26, n.1, p.6, 2011.; Kane-Gill et al., 2012). A recent study conducted in the USA showed that 46.3% of ICU prescriptions included pDDIs (Smithburger, Kane-Gill, Seybert, 2012), while Brazilian studies have reported a prevalence of 67% or 70% (Hammes et al., 2008HAMMES, J.A.; PFUETZENREITER, F.; SILVEIRA, F.; KOENIG, Á.; WESTPHAL, G.A. Prevalência de potenciais interações medicamentosas droga-droga em unidades de terapia intensiva. Rev. Bras. Ter. Intensiva, v.20, n.4, p.349-354, 2008.; Moreira, Cassiani, 2011MOREIRA, A.M.R.; CASSIANI, S.H.D.B. Prevalence of potential drug interactions in patients in an intensive care unit of a university hospital in Brazil. Clinics, v.66, n.1, p.9-15, 2011.). In addition, there are international differences in drug availability that may contribute to regional variations in the number of pDDIs (Moreira, Cassiani, 2011; Moura, Prado, Acurcio, 2011MOURA, C.; PRADO, N.; ACURCIO, F. Potential drug-drug interactions associated with prolonged stays in the intensive care unit: a retrospective Cohort Study. Clin. Drug Invest., v.31, n.5, p.309-316, 2011.; Moura et al., 2012).

Preventing adverse events caused by pDDIs and managing these interactions are central to the Clinical Pharmacy practice in an ICU (Rudis, Brandl, 2000RUDIS, M.I.; BRANDL, K.M. Position paper on critical care pharmacy services: Society of Critical Care Medicine and American College of Clinical Pharmacy Task Force on Critical Care Pharmacy Services. Crit. Care Med., v.28, n.11, p.3746-3750, 2000.). This justifies the elevated number of publications in this matter (Rivkin, Yin, 2011RIVKIN, A.; YIN, H.J. Evaluation of the role of the critical care pharmacist in identifying and avoiding or minimizing significant drug-drug interactions in medical intensive care patients. J. Crit. Care, v.26, n.1, p.6, 2011.; Kane, Weber, Dasta, 2003KANE, S.L.; WEBER, R.J.; DASTA, J.F. The impact of critical care pharmacists on enhancing patient outcomes. Intensive Care Med., v.29, n.5, p.691-698, 2003.; Moura et al., 2012MOURA, C.S.; PRADO, N.M.; BELO, N.O.; ACURCIO, F.A. Evaluation of drug-drug interaction screening software combined with pharmacist intervention. Int. J. Clin. Pharm., v.34, n.4, p.547-552, 2012.; Papadopoulos, Smithburger, 2010SMITHBURGER, P.L.; KANE-GILL, S.L.; BENEDICT, N.J.; FALCIONE, B.A.; SEYBERT, A.L. Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings. Ann. Pharmacother., v.44, n.11, p.1718-1724, 2010.; Mannheimer, Eliasson, 2010MANNHEIMER, B.; ELIASSON, E. Drug-drug interactions that reduce the formation of pharmacologically active metabolites: a poorly understood problem in clinical practice. J. Intern. Med., v.268, n.6, p.540-548, 2010..; Moreira, Cassiani, 2011MOREIRA, A.M.R.; CASSIANI, S.H.D.B. Prevalence of potential drug interactions in patients in an intensive care unit of a university hospital in Brazil. Clinics, v.66, n.1, p.9-15, 2011.).

The aim of this study was to evaluate the prevalence of pDDIs in prescriptions in the ICU of a university hospital in the Brazilian public health system. Were quantified and classified the pDDIs per their degree of severity, to analyse the risks to patient management. Both pharmacokinetic and pharmacodynamic interactions were evaluated, as all PDDIs were included.

METHODS

This cross-sectional observational study was conducted for 12 months (from August 2014 to September 2015) in the adult ICU of Clinics Hospital of the State University of Campinas (HC-UNICAMP) that has 403 beds. Inclusion criteria were: prescriptions with 2 or more drugs of patients admitted to the ICU for > 24 hours and age of ≥ 18 years, one random prescription per patient. Patients that were admitted and discharged to the ICU on weekends did not have their prescriptions included in the study. Data was retrieved from patients' prescriptions and the hospital's database. This research received approval from the Ethics Committee of the School of Medical Sciences, University of Campinas (Campinas, São Paulo, Brazil); protocol number CAAE: 0882.0.146.000-10.

The search for pDDIs within the prescriptions was performed using the MicromedexTM database (MICROMEDEX, 2011), where pDDIs are classified as follows: contraindicated (the drugs are contraindicated for concurrent use); major (the interaction may be life-threatening and/or require medical intervention to minimize or prevent serious adverse effects); moderate (the interaction may result in exacerbation of the patient's condition and/or require an alternative therapy); or minor (the interaction would have limited clinical effects; manifestations may include an increase in the frequency or severity of the side effects but generally would not require a major change in therapy) In addition, it was possible to correlate the presence of pDDIs with other parameters including length of stay, death in the ICU, the number of prescribed drugs, patient age, and gender. This analysis was conducted by critically analysing pDDI data with a database of ICU patient clinical records that was updated daily. The purpose of this database is to continuously monitor the safety and quality of the ICU and it provides a very useful research tool. The database was organized by admission number, assuring patient confidentiality. Only professionals and researchers directly involved had access to the records database.

All the analysed medication information was transposed to a Microsoft ExcelTM spreadsheet and interaction information was constantly updated during the study, through frequent consultations of the MicromedexTM database (MICROMEDEX, 2011).

After analysis, these drugs were classified according to the Anatomical Therapeutic Chemical (ATC) classification system that is recommended by the WHO for drug utilization studies (WHO Collaborating Centre for Drug Statistics Methodology, 2012). This study determined the frequency of usage of prescribed drugs that were monitored by the FAST HUG strategy. FAST HUG is a mnemonic used to facilitate the continuous monitoring of patients in relation to: Feeding; Analgesia; Sedation; Thromboembolic prophylaxis; Head-of-bed elevation; stress Ulcer prophylaxis; and Glycaemic control. These parameters should be monitored daily and relate to factors involving drug therapy, as well as non-pharmacological actions (Vincent, 2005VINCENT, J. Give your patient a fast hug (at least) once a day. Crit. Care Med., v.33, n.6, p.1225-1229, 2005.).

To determine a statistically significant sample size, a pilot study with 88 prescriptions was conducted for three months. Descriptive statistics were used to describe the sample profile. To analyse correlations between variables, the Spearman correlation coefficient (rs) was used. The significance level for statistical tests was 5%, or p < 0.05. The Statistical Analysis System (SAS) for Windows, version 9.2 (SAS Institute Inc., 2002-2008, Cary, NC, USA), was used for statistical analyses.

RESULTS

During the study period, the prescriptions of 369 patients were analysed over one 24-h period, one prescription per patient. The study group (205 men and 164 women) represented approximately 37% of the population admitted into the ICU during this period. The study group was heterogeneous, comprising both surgical and clinical patients. Since this study was performed at a general ICU, the reasons for patient hospitalization were very diverse, including elective surgeries that demanded postoperative intensive care, grave clinical conditions that required life support, such as stroke, among others. During the assessed period, 205 different drugs were prescribed. Table I describes the clinical characteristics and demographics of the patients.

TABLE I
Patient clinical and demographic characteristics

Many of the most commonly prescribed drugs were associated with standard protocols in ICU medicine, as illustrated in Table II. This Table shows the percentage of patients prescribed each of the indicated drugs and highlights their relation to FAST HUG protocols. Table II also shows the frequency of pDDIs present in prescriptions involving these drugs.

TABLE II
Prescribed drugs related to FAST HUG and their potential Drug-Drug Interactions (pDDIs)

During the study, 1844 pDDIs were identified, quantified, and classified; these included 405 different pDDIs between the prescribed drugs.

At least one pDDI was identified in 89% of the patient prescriptions included in this study, and those classified as moderate and major were present in 74% and 67% of the prescriptions, respectively. A wide variety of pDDIs types were identified. A total of 405 interactions were found: 12 contraindicated; 130 major; 225 moderate; and 38 minor. For 52 of these interactions, the management recommendations state that their concomitant use should be avoided and suggest the suspension of one drug, while monitoring is recommended for 306 of the pDDIs. Dipyrone was involved in the largest number of pDDIs. This analgesic and antipyretic drug is widely used in Brazil but has a restricted use in several countries and is not available in the USA. Table III provides information on the 10 most common pDDIs and their frequencies in the analysed prescriptions. The 12 contraindicated pDDIs observed have extremely careful management recommendations to either suspend use of one of the medications or when keeping both drugs, cautiously watch for adverse event signs.

TABLE III
Most frequent relevant potential Drug-Drug Interactions

The results were subjected to statistical analysis to evaluate the correlations between the number of pDDIs and the number of prescribed drugs, the length of stay in ICU (days), and patient age. There was a statistically significant correlation showing that the higher the total of pDDIs in a prescription, the longer the ICU stay (p = 0.0027), and major pDDIs were related to longer ICU stay (p < 0001). Also, there were more pDDIs in prescriptions with more drugs (p < 0001). The other variables analysed did not show statistically significant correlations.

DISCUSSION

With 89% of the analysed prescriptions including at least one pDDI, the need for their evaluation and monitoring is evident. Other studies, with different designs and sample sizes, have confirmed this alarmingly high number, which included all classes of pDDIs (from contraindicated to minor) (Papadopoulos, Smithburger, 2010SMITHBURGER, P.L.; KANE-GILL, S.L.; BENEDICT, N.J.; FALCIONE, B.A.; SEYBERT, A.L. Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings. Ann. Pharmacother., v.44, n.11, p.1718-1724, 2010.; Reimche, Forster, Van Walraven, 2011REIMCHE, L.; FORSTER, A.J.; VAN WALRAVEN, C. Incidence and contributors to potential drug-drug interactions in hospitalized patients. J. Clin. Pharmacol., v.51, n.7, p.1043-1050, 2011.; Kane-Gill et al., 2012; Arques-Armoiry et al., 2010; Rodrigues et al., 2015RODRIGUES, A.T.; STAHLSCHMIDT, R.; GRANJA, S.; FALCÃO, A.L.E.; MORIEL, P.; MAZZOLA, P.G. Clinical relevancy and risks of potential drug-drug interactions in intensive therapy. Saudi Pharm. J., v.23, n.4, p.366-370, 2015.). The relationship between the number of prescribed drugs and the number of pDDIs has been reported previously. This correlation illustrates the inherent risk of prescribing a wide range of drugs (Papadopoulos, Smithburger, 2010; Reimche, Forster, Van Walraven, 2011; Kane-Gill et al., 2012).

Moderate pDDIs comprise much of interactions found in this study and are also the most frequently reported by other ICU researches (Smithburger, Kane-Gill, Seybert, 2012SMITHBURGER, P.L.; KANE-GILL, S.L.; SEYBERT, A.L. Drug-drug interactions in the medical intensive care unit: an assessment of frequency, severity and the medications involved. Int. J. Pharm. Pract., v.20, n.6, p.402-408, 2012.; Smithburger et al., 2010; Hammes et al., 2008HAMMES, J.A.; PFUETZENREITER, F.; SILVEIRA, F.; KOENIG, Á.; WESTPHAL, G.A. Prevalência de potenciais interações medicamentosas droga-droga em unidades de terapia intensiva. Rev. Bras. Ter. Intensiva, v.20, n.4, p.349-354, 2008.; Rodrigues et al., 2015RODRIGUES, A.T.; STAHLSCHMIDT, R.; GRANJA, S.; FALCÃO, A.L.E.; MORIEL, P.; MAZZOLA, P.G. Clinical relevancy and risks of potential drug-drug interactions in intensive therapy. Saudi Pharm. J., v.23, n.4, p.366-370, 2015.). In this study, the interactions classified as contraindicated, major, and moderate by MicromedexTM were clinically relevant. In addition, the real impact of these pDDIs should be determined on an individual basis and this requires careful evaluation of the risk-benefit relationship between the suspension of therapy, or its maintenance with continuous monitoring. This approach is followed by most management guidelines, which always perform a risk-benefit analysis (MICROMEDEX, 2011). Moreover, it is worth remembering that drugs such as dipyrone are often prescribed "if needed" and are not usually administered concomitantly with the potentially interacting drugs.

Clinical relevancy of pDDIs in intensive therapy is not a subject with settled theoretical concepts. Although clinical decision support systems, as Micromedex(tm), contribute to this discussion, the inherent risk of each pDDI in clinical practice is individually evaluated using the theoretical information along with the specifics of each case. It is not possible to observe complete agreement among classification of severity of pDDI in intensive therapy publishing (Papadopoulos, Smithburger, 2010SMITHBURGER, P.L.; KANE-GILL, S.L.; BENEDICT, N.J.; FALCIONE, B.A.; SEYBERT, A.L. Grading the severity of drug-drug interactions in the intensive care unit: a comparison between clinician assessment and proprietary database severity rankings. Ann. Pharmacother., v.44, n.11, p.1718-1724, 2010.; Smithburger et al., 2010; Rodrigues et al., 2015RODRIGUES, A.T.; STAHLSCHMIDT, R.; GRANJA, S.; FALCÃO, A.L.E.; MORIEL, P.; MAZZOLA, P.G. Clinical relevancy and risks of potential drug-drug interactions in intensive therapy. Saudi Pharm. J., v.23, n.4, p.366-370, 2015.).

The prescriptions analysed in this study demonstrated the major therapeutic drug classes are associated with standardized protocols employed in the ICU, highlighting the correlation between the frequency of these prescribed drugs and international guidelines that promote continuous checking of seven clinical parameters that are essential to the safety of critically ill patients, known by the mnemonic, FAST HUG (Vincent, 2005VINCENT, J. Give your patient a fast hug (at least) once a day. Crit. Care Med., v.33, n.6, p.1225-1229, 2005.).

The ICU in the present study used international guidelines and FAST HUG, making its therapeutic profile very similar and comparable ICUs in the USA and Europe. However, there are some differences in the specific drugs used in ICUs in Brazil and other countries owing to international differences in drug licensing. An example of this difference is the use of dipyrone, which is widely prescribed in Brazil but is not marketed in the USA or in some European countries. The higher number of pDDIs in Brazil and in developing countries may reflect the more recent development of clinical pharmacy services with a focus on adverse events and their prevention, as compared to countries with well-established services (Dubova et al., 2007DUBOVA, S.V.; REYES-MORALES, H.; TORRES-ARREOLA, L.P.; SUÁREZ-ORTEGA, M. Potential drug-drug and drug-disease interactions in prescriptions for ambulatory patients over 50 years of age in family medicine clinics in Mexico City. BMC Health Serv. Res., v.7, p.147, 2007.; Hammes et al., 2008HAMMES, J.A.; PFUETZENREITER, F.; SILVEIRA, F.; KOENIG, Á.; WESTPHAL, G.A. Prevalência de potenciais interações medicamentosas droga-droga em unidades de terapia intensiva. Rev. Bras. Ter. Intensiva, v.20, n.4, p.349-354, 2008.; Moreira, Cassiani, 2011MOREIRA, A.M.R.; CASSIANI, S.H.D.B. Prevalence of potential drug interactions in patients in an intensive care unit of a university hospital in Brazil. Clinics, v.66, n.1, p.9-15, 2011.).

The significant correlation between the number of pDDIs and the length of stay in the ICU observed in this study was consistent with earlier studies (Moreira, Cassiani, 2011MOREIRA, A.M.R.; CASSIANI, S.H.D.B. Prevalence of potential drug interactions in patients in an intensive care unit of a university hospital in Brazil. Clinics, v.66, n.1, p.9-15, 2011.). Although this correlation exists, it is not obvious whether the pDDIs caused the increased stay, or vice-versa. It is possible that the number of pDDIs is elevated in patients with prolonged ICU stay because these patients tend to be seriously ill and therefore require a larger number of drugs. Again, greater exposure to adverse events caused by pDDIs may have increased the length of stay. This issue should be investigated in future studies.

Analgesics (dipyrone), antithrombotic (enoxaparin, warfarin), antifungal (miconazole), antidiabetics (insulin), beta blockers (metoprolol), ECA inhibitors (enalapril) drugs are involved in the 10 most occurring pDDI on this study, as were identified by other studies (Askari et al., 2013ASKARI, M.; ESLAMI, S.; LOUWS, M.; WIERENGA, P.C.; DONGELMANS, D.A.; KUIPER, R.A.; ABU-HANNA, A. Frequency and nature of drug-drug interactions in the intensive care unit. Pharmacoepidemiol. Drug Saf., v.22, n.4, p.430-437, 2013.; Uijtendaal et al., 2014UIJTENDAAL, E.V. ; VAN HARSSEL, L.L.; HUGENHOLTZ, G.W.; KUCK, E.M.; ZWART-VAN RIJKOM, J.E.; CREMER, O.L.; EGBERTS, T.C. Analysis of potential drug-drug interactions in medical intensive care unit patients. Pharmacotherapy, v.34, n.3, p.213-219, 2014.). The pDDI pair dipyrone and enoxaparin was the most prevalent in this study and is usually little noticed by the intensivists. However, it cannot be ignored since it is classified as a major pDDI and has good documentation (MICROMEDEX, 2011). Other pDDIs with acknowledged adverse events, such as antidiabetic agents, have an important clinical relevancy in an intensive care environment (Vanham et al., 2016VANHAM, D., SPINEWINE, A.; HANTSON, PH.; WITTLEBOLE, X.; WOUTERS, D.; SNEYERS, B. Drug-drug interactions in the intensive care unit: do they really matter? J. Crit. Care, v.38, p.97-103, 2016.). Identifying which pDDIs are clinically relevant and manage their alerts to the multidisciplinary team is essential to improve patient safety (Rodrigues et al., 2015RODRIGUES, A.T.; STAHLSCHMIDT, R.; GRANJA, S.; FALCÃO, A.L.E.; MORIEL, P.; MAZZOLA, P.G. Clinical relevancy and risks of potential drug-drug interactions in intensive therapy. Saudi Pharm. J., v.23, n.4, p.366-370, 2015.).

The present study delineated the most common pDDIs in this ICU. This study had limitations, since it was not possible to randomize the data collection and a convenience sampling approach was used. In addition, the results of this research were based on the MicromedexTM version available during the study period.

The prescription of potentially dangerous drugs is more frequent in the ICU, where there is also a higher number of adverse events than in other hospital departments and reinforces the need for vigilance with respect to pDDIs (Manias et al., 2014MANIAS, E.; WILLIAMS A.; LIEW D.; RIXON S.; BRAAF S.; FINCH S. Effects of patient, environment and medication-related factors on high-alert medication incidents. Int. J. Qual. Health C., v.26, n.3, p.308-320, 2014.; Aljadhey et al., 2013ALJADHEY, H. MAHMOUD, M.A.; MAYET, A.; ALSHAIKH, M.; AHMED, Y.; MURRAY, M.D.; BATES, D.W. Incidence of adverse drug events in an academic hospital: a prospective cohort study. Int. J. Qual. Health C., v.25, n.6, p.648-655, 2013.).

CONCLUSION

This study showed that the clear majority of ICU prescriptions had at least one pDDI and the most prevalent ones were classified as moderate. The theoretical risks of these pDDIs are known, but their real impact should be determined on an individual basis evaluating the risk-benefit relationship between the suspension of therapy, or its maintenance with continuous monitoring. Acknowledging the high potential for Drug-Drug Interactions in the ICU represents an important step toward improving patient safety and best therapy results.

ACKNOWLEDGEMENTS

We gratefully acknowledge the cooperation of the ICU multidisciplinary team and pharmacy service of the Clinics Hospital at the University of Campinas. The authors also thank Mécia de Marialva, Director of Pharmacy Services, for her kind collaboration during the study. We thank the hospital's medical archives service (SAME) team and nurse Claudinéia Muterle Logato Marmirolli for their assistance with the data and the archives used in this research‬.

This work was supported by the National Council of Technological and Scientific Development (CNPQ) and the São Paulo Research Foundation (FAPESP).

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  • SOURCE OF FUNDING

    This work was supported by the National Council of Technological and Scientific Development (CNPq. Brasília, DF, Brazil) and the São Paulo Research Foundation (FAPESP. São Paulo, SP, Brazil).

Publication Dates

  • Publication in this collection
    2017

History

  • Received
    09 June 2016
  • Accepted
    16 Nov 2016
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br