Handover.cmj.org.pl

Clarifying Adverse Drug Events: A Clinician’s Guide to Terminology,
Documentation, and Reporting
Jonathan R. Nebeker, MS, MD; Paul Barach, MD, MPH; and Matthew H. Samore, MD
Adverse drug events cause substantial morbidity and mortality, yet
suspect drug and an adverse event. Examples and rationale for
they remain underappreciated and misunderstood. The terminol-
meaningful documentation of adverse drug events are provided,
ogy to describe errors and patient harm associated with medica-
along with an outline of the types of events that should be
tions causes much confusion. This article uses the case study of a
reported to regulatory agencies.
patient with multiple adverse drug events to clarify key terms,
such as adverse event, adverse drug reaction, adverse drug event,
medication error, and side effect. The case discussion illustrates
Ann Intern Med. 2004;140:795-801.
www.annals.org
clinical approaches to analyzing the causal connection between a
For author affiliations, see end of text.
Since the early 1990s, adverse drug events have received ibuprofen. Is this event a side effect, an adverse drug reac-
significant attention from researchers in quality and pa- tion, a medication error, or an exacerbation of his under- tient safety (1). Nationally recognized quality experts have identified adverse drug events as a top safety priority (2) Terms that initially arose from the field of pharma- because these events are the most common type of iatro- covigilance, such as adverse event and adverse drug reac- genic injury (3). Studies have indicated that adverse drug tion, can help physicians relate the edema and renal events occur almost daily in medium-sized hospitals and failure to ibuprofen. Pharmacovigilance is the study of outpatient panels (4 – 6). However, despite the high mor- drug-related injuries for the purpose of making warning bidity and mortality, physicians often do not recognize or or withdrawal recommendations for pharmaceutical appropriately treat instances of drug-related harm (7, 8).
products. The International Conference on Harmonisa- We believe that inadequate recognition and treatment tion of Technical Requirements for Registration of of drug-related harm are, in part, a result of what has been Pharmaceuticals for Human Use, of which the U.S.
called a Tower of Babel of terminology (1). Terms origi- Food and Drug Administration (FDA) and the World nally developed in the narrow context of drug effects in a Health Organization are members, defines an adverse clinical and regulatory setting are now being applied in the event as “any untoward medical occurrence that may broader context of quality improvement in health care de- present during treatment with a pharmaceutical product livery systems (9). As might be expected, the expanding but which does not necessarily have a causal relationship role of these terms has been coupled with their use in with this treatment” (15). The term adverse event is not contradictory ways, even within the same discipline (4, 7, particularly helpful to physicians, but it provides con- 10 –14). In this paper, we use the case of an actual patient text for the more clinically useful term adverse drug re- as a framework to explain the recognition, treatment, doc- action. The International Conference on Harmonisation umentation, and reporting of drug-related harm.
defines an adverse drug reaction as “a response to a drugwhich is noxious and unintended and which occurs atdoses normally used in man for prophylaxis, diagnosis, ADVERSE EVENTS VERSUS ADVERSE DRUG REACTIONS
or therapy of disease or for the modification of physio- Mr. J. was a 70-year-old man with nephrotic syndrome logic function” (15). Therefore, an adverse drug reac- (thought to be related to a congenital single kidney), pneumo- tion is an adverse event with a causal link to a drug.
coniosis, and a history of gout and myocardial infarction. He Table 1 (16 –20) summarizes these key terms.
presented to the hospital with increasing bilateral leg edemaand pain, for which he had been taking over-the-counter ibu-profen, 400 mg three times a day for 3 days and once a day for ASSESSING CAUSAL ASSOCIATIONS
the preceding 3 weeks. His other outpatient medications were After admission to the hospital, a battery of serologic tests, simvastatin, 40 mg at bedtime; aspirin, 81 mg once daily; and a microscopic urine examination, and abdominal ultrasonog- metoprolol, 50 mg twice daily. In the emergency department, raphy did not yield specific information about the origin of his serum creatinine level was 680 ␮mol/L (7.7 mg/dL), Mr. J.’s exacerbated renal failure. much higher than the baseline of 290 ␮mol/L (3.3 mg/dL) 11 Assessing causal connections between agents and dis- months earlier. He was admitted to the hospital. ease is fundamental to the practice of medicine and to the The patient experienced an adverse event while using understanding of adverse drug reactions (21, 22). In this Improving Patient Care is a special section within Annals supported in part by the U.S. Department of Health and Human Services (HHS) Agency for Healthcare Research and Quality(AHRQ). The opinions expressed in this article are those of the authors and do not represent the position or endorsement of AHRQ or HHS.
2004 American College of Physicians 795
Improving Patient Care Clarifying Adverse Drug Events Table 1. Summary of Definitions Relevant to Drug-Related Harm
Definition*
Harm occurred
Harm in a patient administered a drug but not necessarily caused by a drug (16) Harm directly caused by a drug at normal doses† (16) An adverse drug event whose nature or severity is not consistent with the Effective definition in common practice: Harm caused by a drug or the inappropriate use of a drug Harm may have occurred
Inappropriate use of a drug that may or may not result in harm (19) A usually predictable or dose-dependent effect of a drug that is not the principal effect for which the drug was chosen; the side effect may be desirable, undesirable, Harm did not occur
Circumstances that could result in harm by the use of a drug but did not harm the * Definitions are abstracted from cited sources. See text for original definitions.
† The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use recently dropped the dose limits foradverse drug reactions, but it is not clear whether or when the U.S. Food and Drug Administration will adopt these revised definitions (20).
case, the treatment and prognosis for Mr. J.’s renal failurelargely depend on whether it was exacerbated by ibuprofen Table 2. Grades of Certainty That an Event Is Linked to
or was due to the progression of his underlying disease.
The discipline of pharmacovigilance has yielded tools Criteria
(16, 23–25) to assess the likelihood of a causal connection A clinical event, including an abnormal laboratory test between a drug and an adverse event on a case-by-case result, that occurs in a plausible time relationship to basis. These tools address the following criteria: time rela- drug administration and cannot be explained by tionships between the drug use and the adverse event, concurrent disease or other drugs or chemicals. Theresponse to withdrawal of the drug (dechallenge)† pathophysiology of the adverse event, competing causes for should be clinically plausible. The event must be the adverse event, response to dechallenge (for example, pharmacologically or phenomenologically definitive,with use of a satisfactory rechallenge† procedure if discontinuation of therapy with the drug or dose reduc- tion), and response to rechallenge (for example, drug re- Probable/Likely
administration). Table 2 organizes these criteria to gauge
A clinical event, including an abnormal laboratory test result, that occurs within a reasonable time the causal link between a drug and an adverse event in sequence to administration of the drug, is unlikely terms of 4 discrete levels of certainty (certain, probable/ to be attributed to concurrent disease or otherdrugs or chemicals, and follows a clinically reason- able response on withdrawal (dechallenge)†. Rechal- The causality criteria listed in Table 2 can be applied
lenge† information is not required to fulfill this defi-nition.
to the case of Mr. J. The timing and classic pathophysio-logic association of ibuprofen with the edema and worsen- Possible
A clinical event, including abnormal laboratory test ing renal failure may first seem to result in a certain causal result, that occurs within a reasonable timesequence to administration of the drug but could association. However, other explanations for the event, such also be explained by concurrent disease or other as advancing intrinsic renal failure or cardiac disease, are drugs or chemicals. Information on drug withdrawalmay be lacking or unclear.‡ present, and information on the effect of drug withdrawalis not available at this point in the hospitalization. These Unlikely
A clinical event, including an abnormal laboratory test conditions result in a possible causality rating, which accu- result, whose temporal relationship to drug adminis-tration makes a causal relationship improbable and rately captures the uncertainty in the causal analysis. The in which other drugs or chemicals or underlying strength of a causal association may be revised as more disease provides plausible explanations.
* Adapted with permission from Elsevier (The Lancet, 2000;356:1255-9) (16).
The day after admission, Mr. J. developed painful, swollen † For adverse drug events caused by withdrawal for or reduced dose of a drug, joints. After sodium urate crystals were found in the synovial fluid, dechallenge is restoring the previous drug dose and rechallenge is reducing the drugdose or withdrawing the drug again.
polyarticular gout was diagnosed and prednisone therapy was ‡ Although an adverse drug event may rate only as “possible” soon after discovery, started. Despite administration of a 1-L normal saline challenge it can be flagged as requiring more information and later be upgraded to probableor certain as appropriate.
and subsequent high-dose furosemide, the patient remained oligu- 796 18 May 2004 Annals of Internal Medicine Volume 140 • Number 10
www.annals.org
Clarifying Adverse Drug Events Improving Patient Care ric with an elevated creatinine level. Before dialysis could begin, clature; compounding; dispensing; distribution; adminis- he became hypertensive; the metoprolol dose was increased to 100 tration; education; monitoring; and use. (19) mg twice a day. Within 2 hours of the increased metoprolol dose, Most medication errors do not harm patients. Some the patient developed respiratory distress and was transferred to authors estimate that less than 1% of medication errors result the medical intensive care unit, where he was intubated and in harm (26). Some types of errors may present minimal po- tential for harm, such as a missed dose of simvastatin. Other Admitted because of 2 adverse events— edema and re- types of errors pose substantial risk to the patient but are nal failure—Mr. J. developed 4 subsequent adverse events: intercepted before reaching the patient; these have been called a gout flair, hypertension, pulmonary edema, and respira- near misses, close calls, or potential adverse drug events (27). For tory distress. A consideration of pathophysiologic pathways example, the nurse who was about to administer the tirofiban and causal associations can also help the physician identify to Mr. J. might have noticed that the dose was inappropriate adverse drug reactions in complex clinical scenarios.
and could have returned the drug to the pharmacy.
The basic unit of an adverse event is the sequence of pathophysiologically related events originating from one phar-macologic effect of the drug. In Mr. J.’s case, the presumed ADVERSE DRUG EVENT VERSUS ADVERSE DRUG
pharmacologic effect was the inhibited production of prosta- REACTION
glandin in the afferent glomerular arteriole, which led to de- Several days after Mr. J. was transferred back to the med- creased plasma filtration. The consequent events of uric acid ical ward, his gout recurred. It was discovered that the intern retention, sodium retention, and fluid retention all resulted did not include the prednisone prescription when she wrote from ibuprofen’s inhibition of prostaglandin production.
orders for the patient’s transfer back to the medical ward. In general, a drug may be considered a contributory cause The overdose of tirofiban and the recurrence of gout of an adverse event if, had the drug not been administered, 1) are 2 medication errors that help illustrate the differences the event would not have happened at all, 2) the event would between an adverse drug reaction and an adverse drug event.
have occurred later than it actually did, or 3) the event would An adverse drug reaction occurs at usual doses and is caused have been less severe. Ibuprofen may have contributed to the by the action of the drug, such as renal failure due to ibupro- edema and may have exacerbated renal failure. The fluid bolus fen. Because the hematoma from tirofiban was the result of an increased the fluid overload and may have caused hyperten- abnormally high dose, it does not qualify as an adverse drug sion. The subsequent increase in metoprolol probably contrib- reaction. The gout recurrence was a consequence of the un- uted to cardiac decompensation and pulmonary edema. In masking of the underlying disease rather than the action of a contrast, the gout flair is a renal failure–mediated secondary or drug itself, so this too is not an adverse drug reaction. Phar- indirect effect (17) of ibuprofen and does not merit consider- macovigilance, as practiced by regulatory bodies, is primarily ation as a separate adverse drug reaction.
concerned with adverse drug reactions—the properties of thedrug under normal use. The patient safety community is in-terested in harm resulting from a broader range of events, such MEDICATION ERROR
as these 2 medication errors. The broader interests of the pa- After spending 2 days in the medical intensive care unit tient safety movement have reinforced the need for a term and having several liters of fluid removed by dialysis, Mr. J. other than adverse drug reaction and have led to the adoption was extubated and prepared for transfer to the medical ward. of the term adverse drug event.
Just before transfer, he became tachycardic and diaphoretic; an The use of the term adverse drug event is consistent electrocardiogram showed new precordial T-wave inversions. both between the pharmacovigilance and patient safety After consultation with the cardiologist, the intern prescribed communities and within the patient safety community it- 12.5 ␮g of tirofiban. The pharmacy prepared and the nurse self. The FDA recognizes the term adverse drug event to be administered 12.5 mg—a thousand-fold overdose. The pa- a synonym for adverse event, in which a causal association tient developed a 3-cm hematoma on the back of his hand at may not exist between the event and the drug (28). In the a previous venipuncture site and oozing from his dialysis cath- patient safety literature, the terms adverse drug event and eter site. He underwent urgent, prolonged dialysis and multi- adverse event usually denote a causal association between the drug and the event (3), but there is a wide spectrum of Misreading physician orders and preparing a danger- definitions for these terms, including harm caused by a ous dose of a drug is a classic medication error. Medication drug (7, 10), harm caused by drug use (4), and a medica- error is commonly defined as any preventable event that tion error with or without harm (29).
may cause or lead to inappropriate medication use or pa- We recommend the definition of adverse drug event tient harm while the medication is in the control of the adopted by the Institute of Medicine: “an injury resulting health care professional, patient, or consumer. Such events from medical intervention related to a drug” (3, 4), which may be related to professional practice, health care prod- has been simplified to “an injury resulting from the use of ucts, procedures and systems, including prescribing; order a drug” (18). Under this definition, the term adverse drug communications; product labeling, packaging and nomen- event includes harm caused by the drug (adverse drug re- www.annals.org
18 May 2004 Annals of Internal Medicine Volume 140 • Number 10 797
Improving Patient Care Clarifying Adverse Drug Events Figure. Relationships of key terms.
nursing data may provide the only indication for 40% ofall adverse drug events (31). Physicians also commonlyclassify gastrointestinal adverse drug reactions as “side ef-fects” and believe them to be common and unavoidableconsequences of medical care, not clinically significantmanifestations of disease. Constipation from narcotics andnausea from antibiotics are examples of adverse drug reac-tions that frequently occur but seldom cause serious out-comes. However, even though only a small percentage ofthese events are serious, these “side effects” are so commonthat serious manifestations, as exemplified by Mr. J.’s case,are not rare (4, 7, 18, 32). The international pharmaco-vigilance community has recognized that the term side ef-fect tends to minimize the injury from drugs and has rec- The gray areas represent injuries caused by drug use (adverse drug ommended that this term no longer be used (17).
events). The dark gray area represents harm caused by a drug (adverse The failure to recognize an adverse drug reaction as drug reactions). The light gray area represents harm from appropriate such may lead the physician to inappropriately treat the drug use that is generally excluded from studies of adverse drug events.
Medication errors are much more common than adverse drug events, but adverse drug event (33). In this case, the physician did not they result in harm less than 1% of the time (30). Conversely, about one pursue a diagnosis for the nausea and abdominal pain but quarter of adverse drug events are due to medication errors (4).
instead treated the symptoms with droperidol. The perva-sive problem of treating each successive drug-related symp-tom with another medication exposes the patient to addi- actions and overdoses) and harm from the use of the drug tional drug hazards. In this case, the patient was put at risk (including dose reductions and discontinuations of drug for sedation, delirium, or cardiac dysrhythmias from the therapy). The term adverse drug event does not include droperidol. To avoid multiple adverse drug events, the failure to use a drug in the first place, which is not a use of more appropriate action often is to discontinue therapy a drug. Although this definition is broad, the patient safety literature generally limits adverse drug event by excludingnonserious injuries resulting from appropriate dose titra-tion and disease recurrences resulting from appropriate re- DOCUMENTING ADVERSE DRUG EVENTS
ductions or discontinuations of therapy with the drug.
The purpose of documenting adverse drug events in a These implicit limitations according to appropriateness patient’s chart is to help prevent the recurrence of the have resulted in a close relationship between the terms harm. The more likely an event is to recur and the more medication error and adverse drug event (medium gray area serious the event, the stronger the case for documentation in the Figure) (30).
and the stronger the incentive to guard against similar useof the drug in the future. Events that are likely to recur are RECOGNIZING AND TREATING ADVERSE DRUG EVENTS
those that have a high causal association with the drug and The day after the tirofiban overdose, the patient reported that result from a common use of the drug. Thus, probable lower abdominal pain. Since admission, the patient had been and certain adverse drug reactions are nearly always appro- taking narcotics and, when not intubated, calcium carbonate, priate to document in the patient chart. For events that are 1.25 g 3 times a day. Nursing flow sheets and dietary notes less likely to recur, the physician must consider the serious- indicated almost daily that, despite eating, the patient had not ness and nature of the event. For example, a life-threaten- passed stool since admission. On hospital day 13, the patient ing, possible adverse drug reaction merits documentation.
was given 1 dose of milk of magnesia and began receiving However, documentation is unlikely to prevent the recur- docusate sodium. The patient responded with 1 small bowel rence of an adverse drug event due to an unusual error, movement. Indomethacin was started, presumably to reduce such as the tirofiban overdose. These types of errors are the patient’s narcotic requirement. Several days later, Mr. J. better reported through an institution’s incident reporting vomited and was given droperidol. Otherwise, Mr. J. was improving and was discharged from the inpatient medicine Documentation is most likely to prevent future ad- service to the rehabilitation service. The next morning the verse drug events when it serves either to caution against patient had a second bowel movement—5 days after the first. the use of a drug at any dose or to establish practical, About an hour later, the patient vomited during breakfast, unsafe dosing ranges. Allergies are common examples of developed respiratory distress, and was reintubated. idiosyncratic reactions that make the drug’s use inappro- Physicians fail to recognize a majority of adverse drug priate at any dose. Dose-dependent reactions are nearly 8 events (7, 8) for many reasons. Many physicians find nurs- times more frequent than idiosyncratic reactions (7); not ing notes difficult to read and may ignore these data, but including dose information in documentation is a major, 798 18 May 2004 Annals of Internal Medicine Volume 140 • Number 10
www.annals.org
Clarifying Adverse Drug Events Improving Patient Care missed opportunity for injury prevention. In Mr. J.’s ex- Table 3. Suggested Components and Examples of Meaningful
ample, metoprolol was well tolerated at 25 and 50 mg Documentation of Adverse Drug Events
twice a day but not at higher doses. (A second episode ofpulmonary edema also occurred after he received two Components
Drug, dose (for dose-dependent adverse drug events), causality assess- 50-mg doses several hours apart.) Although high doses are ment, description of events/outcomes, including contributing factors more likely to cause adverse drug reactions (4), doses that Examples
are too low might also unmask disease. When drugs are Ibuprofen, 400 mg 3 times daily, possibly exacerbated renal failure, suppressing a chronic disease, such as a dysrhythmia or with creatinine level increasing from 290 to 680 ␮mol/L (3.3 to 7.7 seizure disorder, and the disease recurs after discontinua- tion of therapy with the drug or dose reduction, the unsafe Metoprolol, 100 mg twice daily, probably precipitated congestive heart dose should be documented to avoid unmasking the dis- failure and respiratory failure within 2 hours of the increased dose:once in the setting of renal failure, fluid overload, and aspiration and once in the setting of aspiration alone. Metoprolol, 25–50 mg twice A meaningful and useful record of an adverse drug event combines all 3 of these factors: the severity of the event, the Intravenous morphine, 2 mg 3–4 times daily, possibly led to severe causal association between the drug use and the event, and constipation and probably contributed to nausea and vomiting result-ing in aspiration and intubation. Contributors were calcium carbonate dosing variables. In this case, for example, intravenous mor- for constipation and indomethacin for nausea and vomiting.
phine at 2 mg 3 to 4 times daily possibly led to severe consti- Indomethacin, 50 mg 3 times daily, possibly led to gastritis, nausea, pation (no stool for 13 days) and probably contributed to and vomiting, resulting in aspiration and intubation. Prednisone may nausea and vomiting that resulted in aspiration and intuba- have contributed to gastritis, and morphine may have contributed tonausea and vomiting.
tion. Contributors were calcium carbonate for the constipa-tion and indomethacin for nausea and vomiting.
(The hematoma from the tirofiban overdose and the gout recurrence from the inadvertently discontinued prednisone are medication errors Finally, it is important to document adverse drug that should not be documented in the adverse drug event section of events in an accessible part of the medical record. Although many physicians discuss the differential diagnosis of ad-verse drug events in their progress notes, they may noteonly the drug’s name in the allergy section of the chart. Amore detailed description in the allergy section may help define serious events as those resulting in death, life-threat- another physician decide whether subsequent use of the ening experiences, prolonged or initial hospitalization, sig- drug is contraindicated. Because most hospitalizations and nificant or persistent disability, or a congenital anomaly or clinic visits do not involve an adverse drug event, the bur- requiring intervention to prevent one of these outcomes den of improved documentation is small. Table 3 provides
(28). The FDA has discouraged reports on events that are other examples of meaningful documentation for some of neither unexpected nor serious, except for events associated Mr. J.’s adverse drug reactions. In all, Mr. J. had at least 10 with newly marketed drugs (34). While nearly all of Mr.
adverse drug events; none of his events were documented J.’s adverse drug events were serious, none is convincingly in the allergy or adverse drug event section of the medical The FDA has set up a voluntary reporting system for Mr. J.’s respiratory status rapidly improved, and he was physicians called MedWatch that encourages and facilitates extubated the next day. Shortly afterward he had a dark, the reporting of serious, unexpected adverse drug reactions.
guaiac-positive stool; therapy with indomethacin was stopped. MedWatch forms can be obtained at www.fda.gov Two days later and hours before anticipated discharge, the /medwatch/report/hcp.htm or through the pharmacy de- patient vomited and aspirated his breakfast. He developed partments at most hospitals. Online reporting is also avail- extensive bilateral pneumonitis and pneumonia. Mr. J. died After a drug is marketed, physicians may be the only source of information the FDA has for rare and potentially fatal adverse drug events. However, physicians frequently ne- EPORTING TO REGULATORY AGENCIES
glect this crucial role. As few as 1% of serious and unexpected It might appear that at least one of Mr. J.’s adverse events are estimated to be reported to the FDA (35). Under- drug events should be reported to the FDA, but this is notthe case. Documenting adverse drug events in the patient’s reporting can lead to substantial delays in dissemination of chart and reporting adverse drug reactions to regulatory warnings and product labeling changes (36). Most insti- agencies are distinctly different activities (Table 4). The
tutions facilitate reporting by making pharmacists avail- FDA is interested in receiving reports on serious, unex- able to complete and submit these reports. If a pharma- pected adverse drug reactions (not adverse drug events) cist is not available in the outpatient setting, the from marketed drugs. Unexpected reactions are those physician can use online tools to fill out a MedWatch whose nature or severity is not consistent with the product report; personnel at the FDA will communicate with the label (17). The FDA and international regulatory bodies physician if the report needs clarification or correction.
www.annals.org
18 May 2004 Annals of Internal Medicine Volume 140 • Number 10 799
Improving Patient Care Clarifying Adverse Drug Events Table 4. Comparison of Documentation and Reporting of Adverse Drug Events*
Events and Reports
Document in Patient’s Chart
Report to FDA
Types of events
Probable or certain adverse drug reactions Unexpected and serious adverse drug reactions: Life-threatening, possible adverse drug events Serious reactions result in death, life-threatening expe-riences, prolonged or initial hospitalization, clinically Dosing ranges specific to the patient that resulted in significant or persistent disability, or a congenital anomaly or require intervention to prevent one of the Adverse drug events resulting from medication errors that may be repeated with normal drug use Not usually relevant (Confusing drug labeling is an Properties of reports
Prevent recurrence of an adverse drug event in one Contribute to labeling or withdrawal recommendations Physician determines casual link between drug and FDA determines causation from multiple cases. Physician provides information to facilitate this determination.
Physician documents in allergy or adverse drug event Physician (or, for inpatients, usually pharmacist) submits MedWatch report to FDA: www.fda.gov/medwatch * FDA ϭ U.S. Food and Drug Administration.
CONCLUSION AND TAKE-HOME POINTS
from medication errors; they are the targets of broader We propose that a better understanding of terms will help clinicians recognize and treat drug-related injuries All adverse drug events, including those that are com- (Table 5). Adverse drug reactions are injuries caused by
mon symptoms, warrant careful attention and evaluation, drugs administered at usual doses; they are the primary rather than rote management via standing orders. Nursing focus of regulatory agencies and postmarketing surveil- documentation is a rich source of information about ad- lance. Adverse drug events are injuries caused by drug use verse drug events that manifest as patient discomfort.
that encompass adverse drug reactions and harm resulting The clinical value of accurate documentation of ad- verse drug events is that it assists future determinations of Table 5. Key Points for Definitions, Causal Assessment,
whether the risks of prescribing a specific drug or drug class Documentation, and Reporting
outweigh the drug’s potential benefits for an individualpatient. Providing information on the causal association of Definitions
the drug and the event is therefore useful. Physicians or Adverse event and adverse drug reaction are regulatory terms; the first does not require a causal link between the drug and the event, the pharmacists are strongly encouraged to report unexpected, serious adverse drug reactions to the FDA using the Med- Adverse drug events extend beyond adverse drug reactions to include Watch system, which requires information similar to but harm from overdoses and underdoses usually related to medicationerrors. A minority of adverse drug events are medication errors, and more extensive than that recommended for documentation medication errors rarely result in adverse drug events.
The term side effect should be avoided.
Health care institutions must integrate allergy and ad- Causal assessment: grades of causation
verse drug event reports into the care delivery process. The Certain: dechallenge and rechallenge information corroborates causation first step is to expand allergy documentation to accommo- Probable: dechallenge information corroborates causationPossible date all types of adverse drug events. An important next goal is to integrate the reports electronically into the order-checking process to give nursing and pharmacy personnel Documentation
Documentation helps determine whether subsequent use of a drug in the opportunity to intercept potential adverse drug events possibly different circumstances is contraindicated.
Considerations of seriousness and causation should drive the decision about whether to document adverse drug reactions.
Meaningful descriptions of adverse drug events include the grade of From Veterans Affairs Salt Lake City Health Care System and University causation, a description of the event or outcome, contributing or of Utah School of Medicine, Salt Lake City, Utah; and Jackson Memo- competing factors, and dose information.
rial Hospital, University of Miami, Miami, Florida.
Reporting
Serious and unexpected adverse drug events should be reported to the Grant Support: By the Geriatric Education and Clinical Center
(GRECC) of the Veterans Affairs Salt Lake City Health Care System and Information for causal assessment is a crucial and often neglected por- by Health Services Research & Development grants SAF 98-122, TRP02-147, and RCD 02-176.
800 18 May 2004 Annals of Internal Medicine Volume 140 • Number 10
www.annals.org
Clarifying Adverse Drug Events Improving Patient Care Acknowledgments: The authors thank Adam R. Nebeker, MD, and
17. Cobert BL, Biron P. Pharmacovigilance from A to Z. Malden, MA: Black-
Seth R. Lewis, MD, for their critical reviews of the manuscript.
well Science; 2002.
18. Gurwitz JH, Field TS, Avorn J, McCormick D, Jain S, Eckler M, et al.
Potential Financial Conflicts of Interest: None disclosed.
Incidence and preventability of adverse drug events in nursing homes. Am J Med.
2000;109:87-94. [PMID: 10967148] Requests for Single Reprints: Jonathan R. Nebeker, MS, MD, Salt
19. What Is a Medication Error? Rockville, MD: National Coordinating Council Lake Informatics, Decision Enhancement And Surveillance (IDEAS) for Medication Error Reporting and Prevention; 1998. Accessed at www.nccmerp Center, GRECC 182, 500 Foothill Drive, Salt Lake City, UT 84148; e-mail, [email protected].
20. Post-Approval Safety Data Management: Definitions and Standards for Ex-pedited Reporting E2D. Geneva, Switzerland: International Conference on Har-monisation of Technical Requirements for Registration of Pharmaceuticals for Current author addresses are available at www.annals.org.
Human Use; 2003. Accessed at www.ich.org/MediaServer.jser?@_IDϭ631&@_TYPEϭMULTIMEDIA&@_TEMPLATEϭ616&@_MODEϭGLB on 17December 2003.
References
21. Venulet J, ten Ham M. Methods for monitoring and documenting adverse
1. Ross SD. Drug-related adverse events: a readers’ guide to assessing literature
drug reactions. Int J Clin Pharmacol Ther. 1996;34:112-29. [PMID: 8705089] reviews and meta-analyses. Arch Intern Med. 2001;161:1041-6. [PMID: 11322836] 22. Meyboom RH, Hekster YA, Egberts AC, Gribnau FW, Edwards IR. Causal
2. Shojania KG, Duncan BW, McDonald KM, Wachter RM. Safe but sound:
or casual? The role of causality assessment in pharmacovigilance. Drug Saf. 1997; patient safety meets evidence-based medicine [Editorial]. JAMA. 2002;288:508- 23. Michel DJ, Knodel LC. Comparison of three algorithms used to evaluate
3. Kohn LT, Corrigan JM, Donaldson MS. To Err Is Human: Building a Safer
adverse drug reactions. Am J Hosp Pharm. 1986;43:1709-14. [PMID: 3752106] Health System. Washington, DC: National Academy Pr; 1999.
24. Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm
4. Bates DW, Cullen DJ, Laird N, Petersen LA, Small SD, Servi D, et al.
for the operational assessment of adverse drug reactions. I. Background, descrip- Incidence of adverse drug events and potential adverse drug events. Implications tion, and instructions for use. JAMA. 1979;242:623-32. [PMID: 449002] for prevention. ADE Prevention Study Group. JAMA. 1995;274:29-34. [PMID: 25. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A
method for estimating the probability of adverse drug reactions. Clin Pharmacol 5. Gandhi TK, Weingart SN, Borus J, Seger AC, Peterson J, Burdick E, et al.
Adverse drug events in ambulatory care. N Engl J Med. 2003;348:1556-64.
26. Bates DW. Medication errors. How common are they and what can be done
to prevent them? Drug Saf. 1996;15:303-10. [PMID: 8941492] 6. Fattinger K, Roos M, Vergeres P, Holenstein C, Kind B, Masche U, et al.
27. Schaaf T, Van der Lucas DA, Hale AR, eds. Near Miss Reporting as a Safety
Epidemiology of drug exposure and adverse drug reactions in two swiss depart- Tool. Oxford: Butterworth-Heinemann; 1991.
ments of internal medicine. Br J Clin Pharmacol. 2000;49:158-67. [PMID: 28. Guideline for Postmarketing Reporting of Adverse Drug Experiences. Rock- ville, MD: U.S. Food and Drug Administration; 1992. Accessed at www.fda.gov 7. Classen DC, Pestotnik SL, Evans RS, Burke JP. Computerized surveillance of
/medwatch/safety/ade/t_cder.htm on 16 December 2003.
adverse drug events in hospital patients. JAMA. 1991;266:2847-51. [PMID:1942452] 29. Andrews LB, Stocking C, Krizek T, Gottlieb L, Krizek C, Vargish T, et al.
An alternative strategy for studying adverse events in medical care. Lancet. 1997;
8. Tegeder I, Levy M, Muth-Selbach U, Oelkers R, Neumann F, Dormann H,
et al. Retrospective analysis of the frequency and recognition of adverse drug
reactions by means of automatically recorded laboratory signals. Br J Clin Phar-
30. Bates DW, Boyle DL, Vander Vliet MB, Schneider J, Leape L. Relationship
between medication errors and adverse drug events. J Gen Intern Med. 1995;10:199-205. [PMID: 7790981] 9. Nebeker JR, Hurdle JF, Hoffman JM, Roth B, Weir CR, Samore MH.
Developing a taxonomy for research in adverse drug events: potholes and sign-
31. Hurdle JF, Weir CR, Roth B, Hoffman J, Nebeker JR. Critical gaps in the
posts. J Am Med Inform Assoc. 2002;9(6 Suppl):S80-5.
world’s largest electronic medical record: ad hoc nursing narratives and invisible 10. Schlienger RG, Luscher TF, Schoenenberger RA, Haefeli WE. Academic
adverse drug events. Proc AMIA Symp. 2003:309-12. [PMID: 14728184] detailing improves identification and reporting of adverse drug events. Pharm 32. Hanlon JT, Schmader KE, Koronkowski MJ, Weinberger M, Landsman
World Sci. 1999;21:110-5. [PMID: 10427579] PB, Samsa GP, et al. Adverse drug events in high risk older outpatients. J Am
11. Johnstone DM, Kirking DM, Vinson BE. Comparison of adverse drug
Geriatr Soc. 1997;45:945-8. [PMID: 9256846] reactions detected by pharmacy and medical records departments. Am J Health 33. Evans RS, Pestotnik SL, Classen DC, Bass SB, Burke JP. Prevention of
Syst Pharm. 1995;52:297-301. [PMID: 7749958] adverse drug events through computerized surveillance. Proc Annu Symp Com- 12. Sivaram CA, Johnson S, Tirmizi SN, Robertson V, Garcia D, Sorrells E.
put Appl Med Care. 1992:437-41. [PMID: 1482913] Morning report: a forum for reporting adverse drug reactions. Jt Comm J Qual 34. Lucas LM, Colley CA. Recognizing and reporting adverse drug reactions.
West J Med. 1992;156:172-5. [PMID: 1536067] 13. Thatcher C. ADR: reporting problems. Can Pharm J. 2002;134:11.
35. Wood AJ, Stein CM, Woosley R. Making medicines safer—the need for an
14. Hofer TP, Kerr EA, Hayward RA. What is an error? Eff Clin Pract. 2000;
independent drug safety board. N Engl J Med. 1998;339:1851-4. [PMID: 15. Clinical Safety Data Management: Definitions and Standards for Expedited 36. Ladewski LA, Belknap SM, Nebeker JR, Sartor O, Lyons EA, Kuzel TC, et
Reporting. London: European Agency for the Evaluation of Medicinal Products, al. Dissemination of information on potentially fatal adverse drug reactions for
Human Medicines Evaluation Unit; 1995. Accessed at www.emea.eu.int/pdfs cancer drugs from 2000 to 2002: first results from the research on adverse drug /human/ich/037795en.pdf on 16 December 2003.
events and reports project. J Clin Oncol. 2003;21:3859-66. [PMID: 14551305] 16. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and
37. Ahmad SR. Adverse drug event monitoring at the Food and Drug Admin-
management. Lancet. 2000;356:1255-9. [PMID: 11072960] istration. J Gen Intern Med. 2003;18:57-60. [PMID: 12534765] www.annals.org
18 May 2004 Annals of Internal Medicine Volume 140 • Number 10 801
Current Author Addresses: Dr. Nebeker: Salt Lake Informatics, Deci-
Dr. Samore: Division of Clinical Epidemiology, Salt Lake Informatics, sion Enhancement And Surveillance (IDEAS) Center, GRECC 182, 500 Decision Enhancement And Surveillance (IDEAS) Center, 50 North Foothill Drive, Salt Lake City, UT 84148.
Medical Drive, Salt Lake City, UT 84132.
Dr. Barach: Department of Anesthesiology, Jackson Memorial Hospital,University of Miami, North Wing 109, 1611 NW 12th Avenue, Miami,FL 33136.
E-802 American College of Physicians

Source: http://handover.cmj.org.pl/upload/library/fgjexh4it1cyuuz3762qe.pdf