Adverse Drug Reactions in Hospitalized Patients

Jerrold H. Levy, MD
Professor of Anesthesiology
Deputy Chairman for Research
Emory University School of Medicine
Emory Healthcare
Atlanta, Georgia


All medications administered for therapeutic or diagnostic purposes can be associated with unintended consequences or side effects.1 When this problem occurs, the untoward event is referred to as an adverse drug reaction. In fact, any agent that the patient is exposed to via parenteral, cutaneous, inhaled, or enteral routes has the potential to produce some form of an adverse reaction.1 Attention is increasing being focused on adverse drug reactions as evidenced by a recent bill passed by the United States Senate requiring pharmaceutical companies to provide adverse drug reaction information to consumers.2

In the critically ill or hospitalized patient, a diversity of parenteral agents are administered, or patients are exposed to multiple foreign substances.1 Any administered drug has the potential to produce a variety of both predictable and unpredictable adverse reactions. The most life-threatening form of an adverse reaction is anaphylaxis.1 One of the major problems for the patient who is hospitalized, is the potential for exposure to occult antigens such as latex or drug additives/preservatives. With this in mind, serious adverse drug reactions may be more frequent than generally recognized.2-4 Fatal adverse drug reactions appear to be between the fourth and sixth leading cause of death.4-6 The costs associated with adverse drug reactions may be very high. Research to determine the hospital costs directly attributable to adverse drug reactions estimated they may lead to an additional $1.56 to $4 billion in direct hospital costs per year in the United States.3,4,5,6

Approximately 5% of adults in the United States are allergic to one or more drugs, and as many as 15% believe they may be or have been labeled as being allergic to one or more drugs.7 Unfortunately, most patients often do not know whether they have a specific drug allergy due to occult exposure from prior hospitalizations or therapies. Further, a precise diagnosis of drug allergy can often be difficult to establish especially in critically ill patients or in the perioperative setting because cardiopulmonary dysfunction can occur due to multiple factors.1 Patients and physicians may also mistakenly refer to these predictable adverse drug effects as being allergic.1 The Boston Collaborative Drug Surveillance Program has suggested that 30% of medical inpatients develop an adverse drug reaction at some time during hospitalization and that approximately 3% of all hospital admissions are due to adverse drug reactions.8,9 Drug-attributed deaths occurred in 0.01% of surgical inpatients and 0.1% of medical inpatients.7,10,11 Allergic drug reactions account for 6% to 10% of all observed adverse drug reactions, and the risk of an allergic reaction is approximately 1% to 3% for most drugs 7,12. This report will review life threatening allergic drug reactions will therefore be reviewed within the context of predictable and unpredictable adverse reactions.

Definition of adverse drug reactions

The definition of adverse drug reactions according to the World Health Organization definition, is any noxious, unintended, and undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis, or therapy.13 This definition excludes therapeutic failures, intentional and accidental poisoning (ie, overdose), and drug abuse.13 Also, this does not include adverse events due to errors in drug administration or noncompliance (administering more or less of a drug than the prescribed amount).13 Recently, the term adverse drug event has been introduced, which is an injury resulting from administration of a drug.5 In contrast to the World Health Organization definition of adverse drug reaction, the definition of an adverse drug event includes errors in administration.5 Serious adverse drug reactions require hospitalization, prolongs hospitalization, are permanently disabling, or result in death.5 Anaphylaxis is an important example of a serious adverse drug reaction, although other reactions including hepatic or renal injury can also be serious.5,6

Predictable Adverse Drug Reactions

Predictable adverse drug reactions are the most common adverse events produced by pharmacologic agents.1 Predictable reactions are dose dependent, related to the known pharmacologic actions of the drug, occur in otherwise normal patients, and account for approximately 80% of adverse drug effects.1 Most serious predictable adverse drug reactions are toxic in nature and directly related to either the amount of drug in the body (over-dosage); inadvertent route of administration (e.g., lidocaine-induced seizures after accidental intravascular injection); impaired excretion or metabolism; or individual intolerance.1 Side effects are the most common adverse drug reactions, and are undesirable but often unavoidable pharmacologic actions of the drugs at the usual prescribed dosages (e.g., opioid-related nausea or respiratory depression).1 Secondary effects are indirect consequences of the drug's primary pharmacologic action (e.g., nonimmunologic histamine release from mast cells or aspirin induced tinnitus).1 Drug interactions are also a major source of predictable adverse reactions. Intravenous opioid administration to a patient who has just received intravenous benzodiazepines or other intravenous sedative/hypnotic drugs can cause precipitous hypotension resulting from decreased sympathetic tone in a critically ill patient.1

Unpredictable Adverse Drug Reactions

Unpredictable adverse drug reactions are usually both dose independent and unrelated to the drug's pharmacologic actions, but are related to either intolerance, idiosyncratic effects, or the immunologic response (allergy) of the person.1 Intolerance refers to a lowered threshold of reaction to a drug, which may have a genetic basis or may simply represent one extreme of a dose-response curve for pharmacologic effects. On occasion, adverse reactions can be related to genetic differences (e.g., idiosyncratic) occurring among susceptible people who possess an isolated genetic enzyme deficiency.1 Although drug intolerance suggests an increased pharmacodynamic effect occurring among susceptible people, idiosyncratic and allergic reactions are unrelated to the amount of drug in the body and cannot be explained by an understanding of the normal pharmacodynamics of the drug given in usual therapeutic doses.7 Because any parenterally administered agent can cause death from an allergic reaction, anesthesiologists must diagnose and treat the acute cardiopulmonary changes that occur in anaphylaxis, the most severe form of an allergic reaction.1 Studies suggest approximately one in every 2700 hospitalized patients experiences drug induced anaphylaxis.14 When life-threatening allergic reactions mediated by antibodies occur, they are defined as "anaphylactic."1 When antibodies are not responsible for the reaction or when we are unable to prove antibody involvement in the reaction, the reaction is called "anaphylactoid."1 Anaphylactic reactions will be considered later.

Safety and pharmaceutical agents

An important point regarding regulatory approval of pharmaceutical agents are safety issues. For a drug to be approved by the Food and Drug Administration (FDA) in the United States, not only is efficacy important, the investigating company must also show the drug or biologic agent is safe to administer. Costs also drive considerations of how pharmaceutical agents are used in clinical practice or approved by regulatory agencies. Generic drugs can be approved without the rigorous testing required of most drugs that enter into phase 1 to phase 4 clinical studies. Generic propofol contains a sulfiting agent, and currently, there is little data regarding its safety in prospectively designed, placebo controlled studies where the potential for adverse drug reactions has been prospectively evaluated and captured as part of the normal, rigorous approval process required by the FDA for new pharmaceutical agents.

Costs also drive the use of pharmaceutical agents. Clinicians may accept the lack of safety data when one agent is significantly cheaper to use. Another useful example of this dichotomy among clinicians is the controversy comparing epsilon aminocaproic acid and tranexamic acid, both lysine analogs, to aprotinin regarding efficacy to reduce bleeding following cardiopulmonary bypass and cardiac surgery.15 Although epsilon aminocaproic acid is widely used and relatively inexpensive, there is a paucity of safety data on its use.15 When new pharmaceutical agents are under development, they are studied in highly monitored prospective, placebo or otherwise controlled, often blinded clinical studies undertaken to obtain regulatory approval. Safety data incurs significant costs to obtain. More importantly, there are significant costs associated with severe adverse drug reactions when they occur.

Costs of adverse drug reactions

Bates reported results from an Adverse Drug Event Prevention Study that was designed to better understand the incidence of adverse drug reactions, why they occur, and to develop strategies to prevent them.6,16,17 The authors reported the overall rate of adverse drug reactions was 6.5 per 100 admissions of which, 28% were judged preventable and were more likely to be serious. Adverse drug reactions in hospitalized patients are costly, and increase length of stay 1.9 days and increase hospital costs of $1939, not including malpractice costs or the costs of injuries to patients.18-20 Adverse drug reactions frequently result in malpractice claims, and in a large study of closed claims, drug injuries accounted for the highest total expenditure of any type of procedure-related injury.21 The annual national cost of drug-related morbidity and mortality was recently estimated at $76.6 billion, with the majority ($47 billion) related to hospital admissions associated with drug therapy or the absence of appropriate drug therapy.22,23

To better define the costs associated with adverse drug reactions, Bates performed a prospective study to compare the length of stay and total charges for patients with adverse drug reactions vs those for all patients, and to evaluate the increases in length of stay, total charges.6,22 Study patients included all adults at 2 large tertiary care hospitals in Boston, at the Brigham and Women's Hospital (726 beds) and Massachusetts General Hospital (846 beds), admitted to any of 11 units over a 6-month period between February and July 1993. Bates reported 247 adverse drug reactions in 204 patients. Of the reactions, 57% were judged significant, 30% serious, 12% life-threatening, and 1% fatal. Analgesics (30%) and antibiotics (30%) accounted for the largest percentages of nonpreventable adverse drug reactions, followed by antineoplastic agents (8%) and sedatives (7%). The largest percentages of preventable adverse drug reactions were caused by analgesics (29%), sedatives (10%), antibiotics (9%), and antipsychotics (7%). Allergic complications occurred in 7% of patients, and cardiovascular complications in 16%. Bates reported that an adverse drug reaction was associated with $2595 of additional costs to the hospital; for preventable adverse drug reactions this figure was almost twice as high. These estimates do not include the costs of injuries to patients or malpractice costs. Thus, adverse drug reactions are costly, and interventions to reduce their frequency can be justified economically as well as justified to improve the quality of care.22

Bates estimates that the annual costs of adverse drug reactions for two of the Harvard hospitals are $5.6 million.22 In 1993, th ere were approximately 25 million non-obstetrical admissions to short-term hospitals in the United States.24 If the adverse drug reaction and preventable reaction rates and associated costs we found are representative of those among the nation's acute care hospitals, the total hospital costs of adverse drug reactions occurring during hospitalization would be $4 billion. The hospital costs of preventable adverse drug reactions alone would be $2 billion. However, Bates evaluated only two tertiary care hospitals in Boston. Because patients in tertiary care centers tend to be sicker than patients in other hospitals, both the numbers and costs of these events are probably overestimated. However, Bates suggests the two Harvard hospitals in the study are perceived as 2 of the country's leading hospitals and may have lower event rates than other hospitals.

The costs of adverse drug reactions are substantial. Bates estimates that the annual additional costs associated with preventable adverse drug reactions occurring in a large tertiary care hospital were $2.8 million and that the costs associated with all adverse drug reactions were $5.6 million.22 Moreover, these estimates do not include costs of injuries to patients, malpractice costs, or the costs of less serious medication errors or admissions related to adverse drug reactions. These results suggest that hospitals can justify devoting additional resources to develop systems that reduce the number of preventable adverse drug reactions not only to improve patient care but also to reduce their related expenses.22

Detecting adverse drug reactions

All medications that are administered for therapeutic or diagnostic purposes are associated with unintended consequences. These events, when harmful, often are referred to as adverse drug reactions, and can include both predictable and unpredictable events. Premarketing trials frequently do not have sufficient power to reliably detect important adverse drug reactions, which may occur at rates of 1 in 10,000 or fewer drug exposures.25,26 Most premarketing trials may lack the follow-up necessary to detect adverse drug reactions following either related to the drug or delayed consequences associated with drug administration.26,27 Clinical trials often do not include certain patient populations where the drug may be potentially used in including pregnant women or children, although in recent years the FDA has encouraged companies for including these patient populations in their studies by extending patent time. The FDA approval of a new drug does not exclude the possibility of rare but serious adverse drug reactions.27 The severity of the adverse drug reactions and the availability of alternative effective treatments will alter what are considered tolerable adverse drug reactions.28

Adverse drug reactions can be classified as either 1) events that occur rarely in the population; or as 2)events that represent an increased frequency over a relatively common rate in the general population.27 Other important factors to consider include the occurrence of the reaction relative to the time of exposure. Both the frequency of the event, rare or relatively common, and the timing of the event relative to drug use influence the likelihood of detecting the adverse drug reaction with different surveillance methods. Different methods have been used to identify previously unknown harmful outcomes that may be attributable to the use of medications. These methods include premarketing clinical trials, postapproval spontaneous case reports, aggregate population-based data sources, computerized collections of data from organized medical care programs, and postmarketing studies.27,29 Case reports will be considered separately because they are often the method by which adverse drug reactions can be first noted.

Case Reports

Case reports are important to consider for detecting adverse drug reactions. One of the first methods to detect the potential for a pharmacologic agent to produce serious adverse drug reactions have been noted first in case reports.30,31 Brewer suggests that unusual or rare events that occur during initial drug use are more likely to be detected by case reports than increases in common events or events that occur remotely in time from the medication use.27 In a comparison of post-marketing cohort studies with spontaneous reporting for detecting adverse drug reactions, Rossi reported that in three different phase 4 clinical studies of a pharmacologic agent, no adverse drug reactions were detected.32 During this time, there were spontaneous reports of new adverse drug reactions for two of the three drugs. Case reports require only the suspicion that an adverse event may be related to the prior use of a drug and some mechanism for alerting others.27

FDA reporting mechanisms: MEDWATCH

To improve the detection of previously unknown serious adverse drug reactions and knowledge about regulatory actions taken in response to reporting of these events, Dr. Kessler and the FDA introduced the MEDWATCH program in June 1993. The FDA has assumed the responsibility for assuring the safety and efficacy of all regulated marketed medical products including drugs, biologics, medical and radiation-emitting devices, and special nutritional products (e.g., medical foods, dietary supplements and infant formulas). The FDA encourages health professionals to monitor for and report serious adverse events and product problems to FDA either directly or via the manufacturer are integral to this process. MedWatch, the FDA Medical Products Reporting Program, is an initiative designed both to educate all health professionals about the critical importance of being aware of, monitoring for, and reporting adverse events and problems to FDA and/or the manufacturer and; to ensure that new safety information is rapidly communicated to the medical community thereby improving patient care.

The purpose of the MedWatch program is to enhance the effectiveness of postmarketing surveillance of medical products as they are used in clinical practice and to rapidly identify significant health hazards associated with these products.33 The program has four goals: 1.) To increase awareness of drug and device-induced disease; 2.) To clarify what should (and should not) be reported to the agency; 3.) To make it easier to report by operating a single system for health professionals to report adverse events and product problems to the agency; and 4.) To provide regular feedback to the health care community about safety issues involving medical products.33 The program is intended to encourage health care professionals to report serious adverse events suspected to be caused by drugs, medical devices, special nutritional products, and other products regulated by the FDA. Serious events are those that lead to death, hospitalization, significant or permanent disability, or congenital anomaly or require medical or surgical intervention to prevent 1 of these events.27,33 Physicians may report adverse drug reactions by telephone, fax, or mail or through the FDA's MEDWATCH Internet site. You can also connect to this site via the link on After the introduction of MEDWATCH, reporting of adverse drug reactions to the FDA increased because of improved reporting by pharmacists.34 Unfortunately, adverse drug reactions are underreported by physicians to either manufacturers or the FDA. 35

Surveillance Systems: Post-marketing Studies

Post-marketing cohort studies to detect unknown adverse drug reactions have been considered disappointing.30,32 Brewer has suggested spontaneous reports will likely remain the most efficient way to detect rare adverse events that occur temporally with drug use. Post-marketing cohort studies may be able to define adverse drug reactions that are relatively common and occur with increased frequency in patients exposed to a drug.

Meta-analysis of adverse drug reactions

When multiple clinical trials have been performed, studies may either combine data especially as a meta-analysis as a means to detect adverse drug reactions. However, these methods may vary in their ability to detect adverse outcomes.27 The FDA evaluates information from multiple sources, including pre-marketing studies, post-marketing clinical trials, observational studies, and case reports to determine if a drug is safe.25 Meta-analysis is the quantitative analysis of two or more independent studies to increase the potential data base to investigate additional effects when assessing drug safety.36 Although meta-analysis are used as a method for determining the effectiveness of therapies, the use of meta-analysis to assess safety remains limited to date.37 Meta-analysis are used to increase the statistical power when for comparing outcomes, or assessing outcomes in subgroups.27

For adverse events that are occur temporally with initial use of a drug, case-control studies have been the most effective method for assigning causality of adverse outcomes to a therapy that are otherwise unpredictable based on known toxicology studies, the structure or function of the medication, or use history of similar agents.27 In contrast, national voluntary reporting systems, post-marketing surveillance schemes, and hospital surveillance systems have contributed less in these situations to concluding that the cause of the adverse event was an adverse drug reaction.30 Although the association between adverse events and drug exposure evaluated by using randomized, controlled clinical trials would provide the best data for evaluating the potential for adverse drug reactions, the evidence necessary for the FDA to undertake regulatory action is often less than that derived from a clinical trial and can be fairly limited to a series of potential case reports.27,38

Brewer has suggested that to look for previously undescribed adverse drug reactions requires looking at the most commonly used drugs and the most significant adverse outcomes.27 A second option would be to look for adverse drug reactions that might be predicted based on the profile of adverse effects for the medication.27

Life threatening adverse drug reactions: anaphylaxis

When a foreign substance (antigen) is re-introduced into a sensitized individual, it binds to IgE antibodies and initiates anaphylaxis.1 Prior exposure to the antigen or to a substance of similar structure is required to produce sensitization, although an allergic history if usually unknown to the patient. On reexposure, the binding of the antigen to bridge two immunospecific IgE antibodies located on the surfaces of mast cells and basophils liberates a complex series of inflammatory molecules that produce acute cardiopulmonary dysfunction.1 The liberated mediators produce a symptom complex of bronchospasm and upper airway edema in the respiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria in the cutaneus system. Cardiovascular collapse during anaphylaxis results from the effects of multiple mediators on the heart and peripheral vasculature.1

Incidence and risk of anaphylactic reactions

The incidence of anaphylactic reactions during surgery and in critically ill patients has been suggested to be increasing.1 Most of the information regarding anaphylactic reactions to drugs administered during anesthesia and in the intensive care units in the United States is from case reports and, to a lesser extent, retrospective studies. Their relative propensity to produce an allergic reaction is therefore not reflected in these reports. Protamine is the only drug that has been studied in a relatively large series for the incidence of anaphylaxis.39,40 Reactions to drug additives/preservatives and muscle relaxants may be more frequently reported because these drugs are most often administered.1

The agents most likely to be implicated in causing anaphylactic reactions during anesthesia or in the intensive care unit in 2000 are antibiotics, blood products, drug additives/preservatives, muscle relaxants, and proteins (latex and protamine), although a variety of parenterally administered drugs and agents have been reported to cause anaphylactic/anaphylactoid reactions.1 The increasing reported incidence of anaphylactic reactions to muscle relaxants appears to reflect their ability to either release histamine and/or produce false positive wheal and flare responses during skin testing.

Even if the risk of a life threatening anaphylactic reaction is small, if the drug is administered to millions of patients, the actual number of patients developing anaphylaxis is important to consider. This is particularly important for latex sensitive patients, or as we view new pharmacologic or different preparations of drugs are introduced into practice. One important example of this is propofol. The original formulation of propofol was solubilized in Cremophor, a solvent with a known increased risk of producing adverse drug reactions, and was changed to intralipid to avoid this potential adverse response.1 The new generic form of propofol now contains a sulfiting agent that was not tested in clinical trials. One important factor to consider is the clinical manifestations of actual allergic reactions often may be mistakenly attributed to predictable adverse drug reactions and may often go unreported. Most anesthetic agents including propofol cause hypotension and dose-related vasodilation by direct and indirect mechanisms.1 Bronchospasm may occur during laryngoscopy and intubation under light planes of anesthesia.1 Clinicians may easily confuse true allergic reactions with known drug effects.1 Although some agents are more frequently responsible for anaphylactic reactions than others, any drug can cause an allergic, potentially fatal reaction.1 The agents most likely to produce anaphylaxis will be reviewed. Latex and blood products, although they are not drugs, will be considered because they are important to consider as causes for anaphylaxis in the hospitalized patient.


Intravenous antibiotics are an important cause of anaphylaxis and adverse reactions as previously reviewed.6,22 Like penicillins, cephalosporins possess a beta-lactam ring, but the five-membered thiazolidine ring is replaced by the six-membered dihydrothiazine ring.1 Vancomycin can produce life-threatening anaphylactoid reactions after rapid intravenous administration in humans, and should be administered slowly and as a dilute solution to avoid this complication.1 Any parenterally administered antibiotic can potentially produce anaphylaxis.1

Blood products

Although blood is not a pharmacologic agent, it represents an important cause of life-threatening hypersensitivity reactions. Blood products include whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, fibrin glue, gamma globulin, platelets, and represent a variety of potential cellular and humoral antigens that are administered.1 Even several milliliters of plasma present in packed red blood cells contain sufficient numbers of donor leukoagglutinin antibodies to produce transfusion-related acute lung injury.41 Platelets can also produce life threatening reactions via multiple mechanisms, including the infusion of cytokines generated by the inflammatory cells in platelets during storage. Multiple mechanisms are responsible for producing anaphylaxis or other hypersensitivity reactions following transfusion of allogeneic blood.1

Drug additives/preservatives

Anaphylactic or other adverse reactions to parenteral medications may be caused by additives, including sulfites and parabens, that are used as preservatives in parenteral solutions.1 Any parenterally administered agent may produce a life-threatening allergic reaction because of preservatives that may be included in the solution and should be considered whenever evaluating patients with anaphylaxis.1
Sulfiting agents are widely used as preservatives and antioxidants in solutions of medication 1,42,43 Sulfiting agents include sulfur dioxide, sodium or potassium sulfite, bisulfite, and metabisulfite. The FDA allows the addition of sulfites to foods and drugs.44 Allergic reactions to sulfites can develop from exposure to oral or parenteral sulfites.44-52 Exposure to oral sulfites typically occurs from ingestion of foods and beverages that contain sulfites, such as beer, wine, and salads at salad bars. In allergic patients who ingest sulfites, pH changes occur, generating sulfur dioxide and producing bronchospasm, coughing, or asthma.53 Of more concern to intensivists are allergic reactions to the parenteral administration of agents containing sulfites. With intravenous administration of such agents, inflammatory cells, including connective tissue mast cells, mucosal mast cells in the perivascular spaces, and basophils, are exposed to antigens, which include drug additives. These cells are the key initial players in anaphylaxis. Sulfites are contained in certain agents used in critically ill patients. The problem we face as clinicians is a lack of data on the incidence and risk of hypersensitivity reactions to intravenous sulfites. The incidence of these adverse responses because they have never been well studied for parenteral agents. Patients with multiple drug allergies and those with reactive airway disease are potentially at a greater risk for an allergic response to sulfite-containing solutions.1,42

Parabens are preservatives included in multidose vials of local anesthetics that can produce hypersensitivity reactions1,42 They are aliphatic esters of parahydroxybenzoic acid and include methylethyl, propyl, and butyl parabens. Sodium benzoate, structurally related to the parabens, may cross-react.


Although latex is not a pharmacologic agent, it represents an environmental agent often implicated as an important cause of anaphylaxis and will be considered.1 Health care workers, children with spina bifida and urogenital abnormalities, and certain food allergies have also been recognized as individuals at increased risk for anaphylaxis to latex.54-59 Brown reported a 24% incidence of irritant or contact dermatitis and a 12.5% incidence of latex-specific IgE positivity in Anesthesiologists.60 Of this group, 10% were clinically asymptomatic although IgE positive. A history of atopy was also a significant risk factor for latex sensitization. Brown suggests these individuals are in their early stages of sensitization and perhaps, by avoiding latex exposure, their progression to symptomatic disease can be prevented.60 Patients allergic to bananas, avocados, and kiwis have also been reported to have antibodies that cross react with latex.55,60,61 Multiple attempts are being made to reduce latex exposure to both Healthcare workers and patients. If latex allergy occurs, then strict avoidance of latex from gloves and other sources needs to be considered, following recommendations as reported by Holzman.62 Because latex is such a ubiquitous environmental antigen, this represents a daunting task. Despite the recognition of latex anaphylaxis, multiple other agents including antibiotics, induction agents, muscle relaxants, non-steroidal anti-inflammatory drugs, protamine, colloid volume expanders, and blood products represent additional etiologic agents often responsible for anaphylaxis in surgical patients.1


Diabetic patients receiving protamine containing insulin as neutral protamine Hagedorn (NPH) or protamine insulin have a 10-30 fold increased risk for anaphylactic reactions to protamine when used for heparin reversal.1 The incidence of anaphylaxis to protamine is 0.6-2% in this patient population. 39,40 Because protamine is often administered concomitantly with blood products, protamine is often implicated as the causative agent in adverse reactions, especially in cardiac surgical patients. Platelet and other allogeneic blood transfusions can produce a series of adverse reactions via multiple mechanisms, and blood products have a greater potential for allergic reactions compared to protamine.1 Although antigen avoidance is one of the most important considerations in preventing anaphylaxis, this is not always possible, especially with certain agents where alternatives are not available. Protamine is an important example of where alternatives are under investigation, but not currently available.1

Management of the allergic patient

Patients with an allergic history have been suggested to have an increased risk for anaphylaxis.1 There appears to be a greater risk of anaphylaxis in patients with an allergic history or atopy receiving an intravenous anesthetic. In 85 patients LaForest evaluated for reactions, 46% noted a history of allergy or atopy.63 In the first North American study, Moscicki and coworkers reported the incidence of atopy in 27 patients evaluated for anaphylaxis was 44.4%; the reported incidence of atopy in the U.S. population was 5% to 22%.64 Although this group of patients represents an increased risk, Fisher and coworkers believe it is not sufficient to make pretreatment a reasonable prophylactic maneuver.63

Pretreatment for allergic reactions with antihistamines and/or corticosteroids may not prevent true anaphylactic reactions.1 Most of the literature on pretreatment is from studies evaluating patients with previous radiocontrast media reactions that are non-immunologic mechanisms.1 Although attempts to pretreat patients for anaphylaxis to latex are growing in clinical practice, there is no data to support this as an effective preventative measure. Avoiding the inciting antigen is the most effective method to prevent anaphylaxis.1


Any drug administered in the hospitalized patient has the potential to produce some form of adverse drug reaction. There are significant untoward risks, costs, and increased hospital stays associated with adverse drug reactions. It would be ideal if physicians could prevent anaphylaxis, the most life threatening form of an adverse drug reaction. Certain patients may be at an increased risk for adverse reactions, and certain procedures or drugs are more often implicated in producing reactions than others. Patients with a history of allergy, atopy, or asthma have been suggested to be at an increased risk. In addition, antibiotics, blood products, drug preservatives (ie, sulfites and methyparabens) and polypeptides (ie, aprotinin, latex, and protamine) may be associated with a higher incidence of reactions. Hopefully, the future will help us develop specific tests and new therapeutic methods to prevent or treat life threatening adverse drug reactions when they occur. In the meantime, antigen or drug avoidance whenever possible is still the best method to avoid an adverse drug reaction.

Visit the site On the site is a link to the Food and Drug Administration MedWatch for information on adverse drug reactions and reporting, additional information regarding updated abstracts and a treatment plan for anaphylaxis.


1. Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, Second Edition. Stoneham, Butterworth-Heinemann, 1992
2. Lazarou J, Omeranz B, Corey P: Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200-5
3. Classen D, Pestotnik S, Evans R, Burke J: Computerized surveillance of adverse drug events in hospital patients. JAMA 1991; 266: 2847-2851
4. Classen D, Pestonik S, Evans R, Lloyd J, Burke J: Adverse drug events in hospitalized patients: excess length of stay, extra costs, and attributable mortality. JAMA 1997; 277: 301-306
5. Bates D, Leape L, Petrycki S: Incidence and preventability of adverse drug events in hospitalized adults. J Gen Intern Med 1993; 8: 289-294
6. Bates D, Cullen D, Laird N: Incidence of adverse drug events and potential adverse drug events: implication for prevention. JAMA 1995; 274: 29-34
7. De Swarte R: Drug allergy - problems and strategies. J Allergy Clin Immunol 1984; 74: 209-221
8. Miller R: Hospital admissions due to adverse drug reactions: a report from the Boston Collaborative Drug Surveillance Program. Arch Intern Med. 1974; 134: 219-223
9. Program BCDS: Drug-induced anaphylaxis: a cooperative study. JAMA 1973; 224: 613-615
10. Armstrong B, Dinan B, Jick H: Drug-related deaths among medical inpatients. JAMA 1977; 237: 879-881
11. deShazo R, Kemp S: Allergic reactions to drugs and biologic agents. JAMA 1997; 278: 1895-1906
12. Borda I, Slone D, Jick H: Assessment of adverse reactions within a drug surveillance program. JAMA 1968; 205: 99-101
13. Organization WH: International Drug Monitoring: The role of the hospital. Geneva, Switzerland, 1996
14. Porter J, Jick H: Drug-induced anaphylaxis, convulsions, deafness, and extrapyramidal symptoms. Lancet 1977 1977; 1: 587
15. Levy J: Hemostatic agents and their safety. J Cardiothorac Anesth 1999; 13(Suppl 1): 6-11
16. Leape L, Brennan T, Laird N: The nature of adverse events in hospitalized patients: results from the Harvard Medical Practice Study II. N Engl J Med 1991; 324: 377-384
17. Leape L, Bates D, Cullen D: Systemes analysis of adverse drug events. JAMA 1995; 274: 35-43
18. Koska M: Drug errors: dangerous, costly, and avoidable. Hospitals 1989; 63: 24
19. Korin J: Cost implications of malpractice and adverse events. Hosp Formulary 1993; 28: 59-61
20. Evans R, Classen D, Horn S, Bass S, Burke J: Preventing adverse drug events in hospitalized patients. Ann Pharmacother 1994; 28: 523-527
21. Commissioners NAoI: Medical Malpractice Closed Claims 1975-1978, . Brookfield, Wis, National Association of Insurance Commissioners, 1980
22. Bates D, Spell N, Cullen D, Burdick E, Laird N, Petersen L, Small S, Sweitzer B, Leape L: The costs of adverse drug events in hospitalized patients. JAMA 1997; 277: 307-311
23. Johnson J, Bootman J: Drug-related morbidity and mortality: a cost-of-illness midel. Arch INtern Med 1995; 155: 1949-1956
24. Association AH: Hospital Statistics, . Chicago, IL, American Hospital Association, 1993
25. Anello C, O'Neill R: Does research synthesis have a place in drug regulatory policy? synopsis of issues: assessment of safety and postmarketing surveillance. Clin Res Reg Aff 1996; 13: 13-21
26. Sills J, Tanner A, Milstein J: Food and Drug Administration monitoring of adverse drug reactions. Am J Hosp pharm 1986; 43: 2764-2770
27. Brewer T, Colditz G: Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999; 281: 824-829
28. Enas G, Goldstein D: Defining, monitoring and combining safety information in clinical trials. Stat. Med 1995; 14: 1099-1111
29. Strom B: Postmarketing survillance and other epidemiologic uses of drug prescription data in the United States. Ann Ist Super Sanita 1991; 27: 235-237
30. Venning G: Identification of adverse reactions to new drugs, IV: verification of suspected adverse reactions. BMJ 1983; 286: 544-547
31. Venulet J: Establishing requirements for the use of terms for reporting adverse drug reactions. Int J Clin Pharm REs 1992; 12: 61-64
32. Rossi A, Knapp D, Anello C: Discovery of adverse drug reactions: a comparison of selected phase IV studies with spontaneous reporting methods. JAMA 1983; 249: 2226-2228
33. Kessler D: Introducing MEDWATCH: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993; 269: 2765-2768
34. Piazza-Hepp T, Kennedy D: Reporting of adverse events to MEDWATCH. Am J Health Syst Pharm 1995; 52: 1436-1439
35. Scott H, Thacher-rEnshaw A, Rosenbaum S: Physician reporting of adverse drug reactions: results of the Rhode Island adverse drug reaction reporting project. JAMA 1990; 263: 1785-1788
36. Halvorsen K, Burdick E, Colditz G, Frazier H, Mosteller F: Combining results from independent investigatoin; meta-analysis in clinical reseasrch. NEJM Books 1992: 413-426
37. Lau J, Antman E, Jimenez-Silva J, Kupelnick B, Mosteller F: Cumulatie meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992; 327: 248-254
38. Auriche M, Loupi E: Does proof of casualty ever exist in pharmacovigilance? Drug Safety 1993; 9: 230-235
39. Levy JH, Zaidan JR, Faraj B: Prospective evaluation of risk of protamine reactions in patients with NPH insulin-dependent diabetes. Anesth Analg 1986; 65: 739-742
40. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weintraub WS: Evaluation of patients at risk for protamine reactions. J Thorac Cardiovasc Surg 1989; 98: 200-204
41. Popovsky M, Moore S: Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985; 25: 573-577
42. Simon R: Adverse reactions to drug additives. J Allergy Clin Immunol 1984; 74: 623-630
43. Simon R, Green L, Stevenson D: The incidence of sulfite sensitivity in an asthmatic population. J Allergy Clin Immunol 1982; 69: 118.
44. Hosen H: Provocative testing for sulfite sensitivity in clinical allergy. Journ Asthma 1986; 23: 145-147
45. Bonneau J: Contact allergy to sulfites: contact allergens, sources of exposure, and clinical profile. Allergie Immunologie 1994; 26: 324-326
46. Boxer M, Bush R, Harris K, Patterson R, Pruzansky J, WH Y: The laboratory evaluation of IgE antibody to metabisulfites in patients skin test positive to metabisulfites. J Allergy Clin Immunol 1988; 82: 622-626
47. Jamieson D, Guill M, Wray B, May J: Metabisulfite sensitivity: case report and review of the literature. Ann Allergy 1985; 54: 115-121
48. Lodi A, Chiarelli G, Mancini L, Crosti C: Contact allergy to sodium sulfite contained in an antifungal preparation. Contact Dermatitis 1993; 97: 29
49. Sainte-Laudy J, Vallon C, Guerin J: Enhanced human basophil activation and histamine release by IL3 priming: application to sulfite allergy diagnosis. Inflammation Research 1995; 44 Suppl 1: S3-4
50. Schwartz H, Sher T: Bisulfite sensitivity manifesting as allergy to local dental anesthesia. J Allergy Clin Immunol 1985; 75: 525-527
51. Torun M, Bayhan A, Yentur G: Response of allergic and normal persons to sulfiting agents in wine: determination of thiosulfate excretion in urine. Clinical Chemistry 1989; 35: 1792-1793
52. Vena G, Foti C, Angelini G: Sulfite contact allergy. Contact Dermatitis 1994; 31: 172-175
53. Wuthrich B: Adverse reactions to food additives. Ann Allergy 1993; 71: 379-384
54. Arellano R, Bradley J, Sussman G: Prevalence of latex sensitization among hospital physicians occupationally exposed to latex gloves. Anesthesiology 1992; 77: 905-908
55. Blanco C, Carrillo T, Castillo R, Quiralte J, M C: Latex allergy: Clinical features and cross-reactivity with fruits. Ann Allergy 1994; 73: 309-314
56. Carillo T, Cuevas M, Munoz T, Hinojosa M, Moneo I: Contact urticaria and rhinitis from latex surgical gloves. Contact Dermatitis 1986; 15: 69-72
57. Gerber AC, Jorg W, Zbinden S, Seger RA, Dangel PH: Severe intraoperative anaphylaxis to surgical gloves: Latex allergy, an unfamiliar condition. Anesthesiology 1989; 71: 800-802
58. Holzman R: Latex allergy: an emerging operating room problem. Anesth Analg 1993; 76
59. Moneret-Vautrin DA, Laxenaire MC, Bavoux F: Allergic shock to latex and ethhylene oxide during surgery for spina bifida. Anesthesiology 1990; 73: 556-58
60. Brown R, Schauble J, Hamilton R: Prevalence of latex allergy among anesthesiologists: Identification of sensitized but asymptomatic individuals. Anesthesiology 1998; 89: 292-299
61. Lavaud F, Prevost A, Cossart C, Guerin L, Bernard J, S K: Allergy to latex, avocado, pear, and banana: Evidence for a 30 kd antigen in immunoblotting. J Allergy Clin Immunol 1995; 95: 557-564
62. Holzman R, Sethna N: A "latex-safe" environment prevents allergic reactions in latex-allergic patients, International Latex Conference: Sensitivity to Latex in Medical Devices. Baltimore, MD, FDA-Center for Devices and Radiological Health, 1992
63. LaForest M, More D, Fisher M: Predisposing factors in anaphylactoid reactions to anaesthetic drugs in an Australian population: the role of allergy, atopy and previous anaesthesia. Anaesth Intensive Care 1980; 8: 454-459
64. Moscicki R, Sockin S, Corsello B, Ostro M, Bloch K: Anaphylaxis during induction of general anesthesia: subsequent evaluation and management. J Allergy Clin Immunol 1990; 86: 325-332

(Copyright 1999. Modified and reprinted with permission by the McMahon Publishing Group and