Since multidrug therapy is common in the intensive care unit (ICU), the risk of drug interactions is high. This study aimed to examine the prevalence of drug interactions and risk factors in patients who were admitted to ICUs. In a crosssectional study, the medication flow sheet of 101 patients was investigated in terms of the number and the type of drug interactions. The Drug Interaction Facts reference text book (2010 edition) was used to determine the type and the number of drug interactions. In total, 609 potential drug interactions were found. The mean number of drug interactions per patient was 6.1 (SD=5.6). Of all observed drug interactions, 66.9 were classified as harmful and 33.1 beneficial. In terms of the nature of interactions, delayed, moderate, and possible were the most common types. The most frequent harmful interaction was between phenytoin and omeprazole (63 occasions). Critically ill patients are at a higher risk of drug interactions. Although 33.1 of the drug interactions were considered beneficial, medical teams should be awarethat even beneficial interactions can have undesirable side-effects in the critically ill. © The Intensive Care Society 2013

Abdar, M.E.

Ahmadinejad, M.

Amiri, M.

Rafiei, H.

 Since multidrug therapy is common in the intensive care unit (ICU), the risk of drug interactions is high. This study aimed to examine the prevalence of drug interactions and risk factors in patients who were admitted to ICUs. In a cross-sectional study, the medication flow sheet of 101 patients was investigated in terms of the number and the type of drug interactions. The Drug Interaction Facts reference text book (2010 edition) was used to determine the type and the number of drug interactions. In total, 609 potential drug interactions were found. The mean number of drug interactions per patient was 6.1 (SD=5.6). Of all observed drug interactions, 66.9% were classified as harmful and 33.1% beneficial. In terms of the nature of interactions, delayed, moderate, and possible were the most common types. The most frequent harmful interaction was between phenytoin and omeprazole (63 occasions). Critically ill patients are at a higher risk of drug interactions. Although 33.1% of the drug interactions were considered beneficial, medical teams should be aware that even beneficial interactions can have undesirable side-effects in the critically ill. </jats:p

Hossein Rafiei

Mohammad Esmaeli Abdar

Masous Amiri

Mehdi Ahmadinejad

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Journal of the Intensive Care Society

The Study of Harmful and Beneficial Drug Interactions in Intensive Care, Kerman, Iran

shahrekord university of medical scinces

JICS Volume 14, Number 2, April 2013 155Communication from overseas© The Intensive Care Society 2013IntroductionA drug interaction occurs when the effect of a drug is alteredby other drugs; it may affect the drug’s pharmacokinetics orpharmacodynamics.1 In pharmacokinetic interactions, a drugalters the absorption, distribution, metabolism, or excretion ofanother drug; in pharmacodynamic interactions, the action of adrug is altered by other drugs.2 The occurrence and theseverity of a drug interaction is affected by many factors suchas the number of prescribed drugs, treatment duration,patient’s age, disease stage, and the number of physiciansprescribing the drugs.1,3 Critically ill patients are particularlyprone to drug interactions, as they have several related riskfactors such as higher age, multidrug therapy, and longduration of hospital stay.1,2,4-6Almeida et al1 conducted a study on the assessment of drug-drug interactions in the adult intensive care unit (ICU) of alarge private tertiary care hospital over a period of 30 days.They reported that potential drug interactions are common inICU patients and may potentially produce a significanteconomic and clinical impact. In another study carried out byRais et al in 2011, drug interactions in three different timeperiods were studied.7 They reported a high prevalence of druginteractions in ICU, and found that factors such as the numberof drugs taken, the duration of stay in ICU, and the types ofdrugs used were the most important factors. Moura et alstudied the correlation between drug interactions and theduration of stay in the ICU.8 They reported that patientsstaying longer in ICU suffer more from drug interactions. Inour previous study, we observed a high risk of drug interactionin patients after the first 24 hours in ICU. In addition, wefound that reasons such as number of administered drugs, thenumber of physicians visiting a patient, and the patients’ ages,were the most important factors increasing the risk of druginteractions in ICU patients.9Although drug interactions have already been studied inICU, most of these studies were limited in two ways – eitherthey considered theoretical interactions without taking accountof the duration of action of the drugs and/or they ignoredbeneficial drug interactions. As an example of the firstlimitation, a theoretical interaction between two drugs (oneadministered in the morning and the other in the evening) wasconsidered a drug interaction, which might not be the caseconsidering the duration of the effect of the drugs. The secondconfounder, which has been ignored in previous studies, wasbeneficial drug interactions, ie interactions which the medicalteam had been aware of and had intentionally used. Forexample Reis et al have reported severe drug interactionsbetween fentanyl and midazolam, without considering this wasprobably intentional.7The aim of the current study was to determine theprevalence of drug interactions in different work shifts and alsoto determine the number of beneficial versus harmfulinteractions in ICU patients.MethodsThis cross-sectional study was approved by the ethicalcommittee of Kerman Medical University. Each patient (if thepatient was able to respond) or their relative, was asked to fillin a written consent form. All research in Iran requiresapproval by a local ethical committee. These committeesusually comprise about 20 people who are specialist nurses ordoctors. In the Iranian healthcare system, hospitals and theirThe study of harmful and beneficial druginteractions in intensive care, Kerman, IranH Rafiei, M Esmaeli Abdar, M Amiri, M AhmadinejadSince multidrug therapy is common in the intensive care unit (ICU), the risk of drug interactions is high. This study aimedto examine the prevalence of drug interactions and risk factors in patients who were admitted to ICUs. In a cross-sectional study, the medication flow sheet of 101 patients was investigated in terms of the number and the type of druginteractions. The Drug Interaction Facts reference text book (2010 edition) was used to determine the type and thenumber of drug interactions. In total, 609 potential drug interactions were found. The mean number of drug interactionsper patient was 6.1 (SD=5.6). Of all observed drug interactions, 66.9% were classified as harmful and 33.1% beneficial. Interms of the nature of interactions, delayed, moderate, and possible were the most common types. The most frequentharmful interaction was between phenytoin and omeprazole (63 occasions). Critically ill patients are at a higher risk ofdrug interactions. Although 33.1% of the drug interactions were considered beneficial, medical teams should be awarethat even beneficial interactions can have undesirable side-effects in the critically ill.Keywords: intensive care unit; drug interactions; beneficial; harmfulVolume 14, Number 2, April 2013 JICS156Communication from overseasICUs are categorised in three levels. This study was performedin a level one unit. In such a unit the head must be anintensivist. These ICUs usually have more than 20 beds. TheIranian Society of Intensive and Critical Care Medicine isresponsible for designing programmes and guidelines for ICU,but has no guidance regarding drug-drug interactions.Sampling was done in four distinct time periods in threedifferent work shifts – morning, evening, and night. Ourprevious studies in the same hospital had shown that theaverage duration of stay in ICU was about 18 days.9,10Therefore, four distinct samplings were done at intervals of 20days. To collect the required data, the ICU flow sheetscompleted by the ICU nurses were used because they wereconsidered the most reliable. The data on the number of drugstaken, the name of the drugs, the routes of administration, anddemographic variables, including the patients’ age and gender,were obtained. The extent of occurrence and frequency ofpotential drug interactions were investigated based on thereference textbook ‘Drug Interaction Facts’ published in 2010.11This textbook is considered the gold standard for identifyingdrug interactions in Iran. Potential drug interactions identified were classified by: • severity– minor: ‘the effects are usually mild; consequences may bebothersome or unnoticeable but should not significantlyaffect the therapeutic outcome. Additional treatment isusually not required’– moderate: ‘the effect may cause deterioration in a patient’sclinical status. Additional treatment, hospitalisation or anextended hospital stay may be necessary’ – major: ‘the effects are potentially life-threatening orcapable of causing permanent damage’.• onset of action– rapid: ‘the effect will be evident within 24 hours ofadministration of the interacting drug’ – delayed: ‘the effect will not be evident until theinteracting drug is administered for a period of days orweeks’.• documentation– established: ‘proven to occur in well controlled studies’– probable: ‘very likely but not proven clinically’ – suspected: ‘may occur; some good data; need more study’ – possible: ‘could occur but data are limited’– unlikely: ‘doubtful; no good evidence of an alteredclinical effect’. According to this textbook drug interactions, which themedical team had been aware of and had been intentionallyinduced to gain advantage, were considered beneficialinteractions (eg, interactions between antibiotics). Interactionsthat the medical team had not been aware of were consideredharmful. Nutritional supplements, ointments, drops, serums,electrolytes, and vitamins were excluded from the datacollection. Drugs which are not registered in the textbook wereconsidered to be without potential drug interaction All datawere analysed using SPSS 18·00 statistical software and avariable was found to be statistically significant if p <0·05.Descriptive statistics (expressed as mean and standarddeviation (SD)), Pearson correlation test and independent t-testwere used.ResultsThe sample consisted of 101 patients, 75.2% of whom weremen. The mean age was 37.2 ± 21.5 years. The mean numberof administered drugs for each patient was 23.6 ± 9.1. Of allthe drugs administered, 44.5% were during the morning shifts,23.3% in evening shifts, and 32.2% in night shifts. Overall58.5% of the drugs were injected and the rest taken orally. Sixhundred and nine drug interactions were documented inpatients’ flow sheets (6.1 ± 5.6 per patient). Of all the druginteractions, 66.9% were potentially harmful, and 33.1%beneficial. Of 202 beneficial drug interactions, 100 cases wererelated to interaction between phenytoin and midazolam. Interms of distribution among various work-shifts, 53% ofinteractions were in the morning shifts, 16.1% in the eveningshifts, and 30.9% in the night shifts. With regard to the typesof interactions, most of the interactions were of delayed,moderate, and possible types. Table 1 shows the types ofinteractions in terms of starting time, severity, and the degreeof proof in the three various shifts. In terms of the number ofdrug interactions, the highest frequency of interaction occurredbetween phenytoin and omeprazole, (Table 1). Of all theinteractions, 15 were major (Table 3) and 74 cases ofClassification Morning Evening NightSeverity Major 8 2.4% Major 4 4.0% Major 3 1.6%Moderate 230 71.1% Moderate 73 73.7% Moderate 152 81.3%Minor 85 26.5% Minor 22 22.3% Minor 32 17.1%Onset of action Rapid 36 11.1% Rapid 18 18.1% Rapid 20 10.6%Delayed 287 88.9% Delayed 81 81.9% Delayed 168 89.4%Documentation Established 23 7.1% Established 10 10.1% Established 15 8.9%Probable 21 6.5% Probable 6 6.1% Probable 8 4.8%Possible 143 44.3% Possible 50 50.3% Possible 84 50.0%Suspected 127 39.4% Suspected 25 25.1% Suspected 53 31.5%Unlikely 9 2.7% Unlikely 8 8.1% Unlikely 8 4.8%Table 1 Drug interactions classified by severity, onset of action and documentation.JICS Volume 14, Number 2, April 2013 157Communication from overseasinteraction were rapid (Table 4). Among the drugs used in theICU, the most frequently used ones were morphine (222times), phenytoin (170 times), and midazolam (155 times).Drug reactions appeared to be commoner among men thanwomen (7.1 vs 6.2) but this was not confirmed statistically.Pearson correlation test showed a significant correlationbetween number of potential drug interactions and number ofprescribed drugs (r=0.561, p<0.05).DiscussionThere were 690 interactions documented confirming that ICUpatients are at high risk of this complication. Although thefindings showed that approximately one third of theinteractions were beneficial, it remains important for theclinical team to remain aware of all reactions. Previous studies have reported that the incidence of druginteractions is high in ICU patients,1,2,4-6,12 however, thereremains controversy. For example, in our previous study, weassessed drug interactions only in the first 24 hours afteradmission.9 We reported that on average, each patient received5.6 drugs, which is lower than what we found in the currentstudy (23.6 drugs per patient). Unsurprisnigly therefore, the6.1 drug interactions per patient, observed in this study, ismore than reported in our previous study (mean of 1.9interactions per patient).9 Apparently, the longer the patientsstay in ICU, the higher the number of drugs is prescribed andthe greater the possibility for drug interactions. Results of the present study showed that the most commontype of potential drug interactions among critically ill patientswere delayed, moderate and possible. Similarly, Hammes et alfound that 59.7% of potential drug interactions in ICU aredelayed.4 They also reported that moderate and possibleinteractions are higher than other types of interactions amongcritically ill patients.4 This issue could be explained by twofacts: phenytoin was responsible for a high percentage ofinteractions in our study, and phenytoin’s interactions aremostly delayed, moderate, and possible; therefore these typesof interactions would be more frequent than others. The interaction between phenytoin and omeprazole is themost frequent in our study. Phenytoin and omeprazole are themost common anticonvulsant and antacid drugs used in theICU respectively.13.14 Omeprazole inhibits CYP2C19 anddecreases the clearance of phenytoin.15 In Iranian ICUs bothphenytoin and omeprazole are administered enterally.Omeprazole is administered once daily (9 am) and phenytointhree doses daily (9 am, 5 pm and 1 am). Omeprazole has ashort plasma half-life (0.5-2 hours),15 but considering the useof omeprazole and phenytoin simultaneously (9 am), thechance of an actual interaction between the two drugs inpatients in the present study is high. In line with the results obtained by other studies1,2,5 thepresent study found that the risk of drug interactions increasedwith increasing number of prescribed drugs for patients. Itseems intuitive that with increasing numbers of prescribeddrugs there would be an increased rate of drug reactions, but inaddition critically ill patients are often seen by many differentclinicians who may prescribe without proper consideration ofthe risk of interactions. ConclusionCritically ill patients are at a high risk of drug interactions.Although one-third of drug interactions were beneficial,medical teams should be aware that even beneficial interactionscould have unfavorable side effects in the critically ill. Factorssuch as multidrug therapy, administering phenytoin,Drug Interaction (n) Type of interaction Drug Interaction Type of interactionPhenytoin + omeprazole (63) Delayed, moderate, possible Paracetamol + phenytoin (24) Delayed, moderate, suspectedOmeprazole + midazolam (52) Delayed, minor, suspected Furosemide + phenytoin (19) Delayed, minor, suspectedPhenytoin + dexamethasone (39) Delayed, moderate, established Methadone + phenytoin (16) Delayed, moderate, suspectedMetronidazole + phenytoin (31) Delayed, moderate, possible Ranitidine + midazolam (12) Delayed, moderate, possibleRanitidine + phenytoin (29) Delayed, moderate, possible Haloperidol + phenytoin (8) Rapid, minor, unlikelyTable 2 Ten most common harmful drug interactions.Drug Interaction (n) Type of interactionFurosemide + amikacin (6)  Rapid, major, probableAtracurium + amikacin (5) Rapid, major, probableFurosemide + tobramycin (3) Rapid, major, probableFurosemide + digoxin (1) Delayed, major, probableTable 3 List of harmful major drug interactions.Drug Interaction (n) Type of interaction Drug interaction (n) Type of interactionRanitidine + midazolam (16) Rapid, minor, unlikely Theophylline + midazolam (5) Rapid, minor, suspectedAtracurium + vancomycin (12) Rapid, moderate, probable Omeprazole + theophylline (6) Rapid, minor, probableAtracurium + phenytoin (8) Rapid, moderate, probable Atracurium + amikacin (5) Rapid, major, probableErythromycin + midazolam (6) Rapid, moderate, suspected Furosemide + ciprofloxacin (5) Rapid, minor, possibleFurosemide + amikacin (8) Rapid, major, probable Furosemide + tobramycin (3) Rapid, major, probableTable 4 List of harmful rapid drug interactions.Volume 14, Number 2, April 2013 JICS158Communication from overseasomeprazole, dexamethasone, furosemide, atracurium,midazolam, amikacin, and paracetamol simultaneously,absence of clinical pharmacologists, high number ofprescribing physicians and poor knowledge of medical andnursing teams could all be important causes. Use of suitablesoftware to detect drug interactions may be helpful indecreasing rate of drug interactions in ICU, although thisneeds more study. Finally, it is important to highlight that druginteractions and their side-effects could be lethal and costly;therefore it is necessary to limit this risk through correctplanning by the medical and nursing team.DisclosureNo grant numbers supplied. No conflict of interest has beendeclared by the authors.References1. Almeida SM, Gama CS, Akamine N. Prevalence and classification ofdrug-drug interactions in intensive care patients. Einstein 2007;5:347-51.2. Nazari MA, Moghadam N. Evaluation of pharmacokinetic druginteractions in prescriptions of intensive care unit (ICU) in a teachinghospital. Iranian J Pharm Res 2006;3:215-18.3. Papadopoulos J, Smithburger PL. Common drug interactions leading toadverse drug events in the intensive care unit: Management andpharmacokinetic considerations. Crit Care Med 2010; 38:126-35.4. Hammes JA, Pfuetzenreiter F, Silveira FD et al. Potential druginteractions prevalence in intensive care units. Rev Bras Ter Intensiva2008;20:349-54.5. Lima FE, Cassiani SH. Potential drug interaction in intensive carepatients at a teaching hospital. Rev Latino-am Enfermagem 2009;17:222-27.6. Hajebi G, Mortazavi SA. An investigation of drug interactions in hospitalpharmacy prescriptions. Iranian J Pharm Res 2002;1:15-19.7. Reis AM, Cassiani SH. Prevalence of potential drug interactions inpatients in an intensive care unit of a university hospital in Brazil. Clinics2011:66:9-15. 8. Moura C, Prado N, Acurcio F. Potential drug-drug interactionsassociated with prolonged stays in the intensive care unit: a retrospectivecohort study. Clin Drug Investig 2011;31:309-16.9. Rafiei H et al. The prevalence of potential drug interaction in intensivecare unit. Iranian J Crit Care Nurs 2012;4:191-96.10.AhmadiNejad M, Rafiei H. Pressure ulcer incidence in intensive care unitpatients in BahonarHospital Kerman. J Iran Soc Anaesthesiol Intensive Care2011;57:10–16.11.Tatro D S. Drug Interaction Facts. St Louis, Walters Kluwer Health. 2010.12.Rafiei H, Esmaeili MA, Moghaddasi J. Prevalence of potential druginteractions among elderly critically ill patients in intensive care unit.Iranian J Ageing 2012;22:121-28.13.Adams MP, Holamd LN. Pharmacology for Nurses. A PathophysiologicApproach, 3ed. Boston: Pearson. 2011:165.14.Marino PL. The ICU Book 3ed. Philadelphia: Lippincott Williams &Wilkins.2007:930.15.Abram AC, Pennington SS, Lammon CB. Clinical Drug Therapy, 9 ed.Philadelphia: Lippincott Williams & Wilkins.2009:25.Hossein Rafiei   Department of Intensive and Critical Care,School of Nursing and Midwifery, Shahrekord University of MedicalSciences, Shahrekord, IranMohammad Esmaeli Abdar   Razi School of Nursing andMidwifery, Kerman University of Medical Sciences, Kerman, IranMasous Amiri   Social Health Determinants Research Centerand Department of Epidemiology and Biostatistics, School ofHealth, Shahrekord University of Medical Sciences, Shahrekord,IranMehdi Ahmadinejad   Department of Critical Care Medicine,School of Medicine, Kerman University of Medical Sciences,Kerman, Iran mehdia50@gmail.com

The study of harmful and beneficial drug interactions in intensive care, Kerman, Iran

The study of harmful and beneficial drug interactions in intensive care, Kerman, Iran

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