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Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia
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Page 1: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Adverse Drug Reactions

Jerrold H. Levy, MD

Professor of Anesthesiology

Emory University School of Medicine

Director of Cardiothoracic Anesthesiology

Emory Healthcare

Atlanta, Georgia

Page 2: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Introduction• Any drug can cause an ADR• Perioperatively, multiple agents are

administered• Occult antigens pose major

problems (ie, latex, additives)• Fatal ADRs leading cause of death • ADR costs may lead to an additional

$1.56-$4 billion/yr in US

Page 3: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Incidence of Reactions

• 5% adults in US are allergic to • >1 drugs • 30% of medical inpatients develop

an ADR• 3% of all hospital admissions are

due to ADRs• Risk of an allergic reaction is

approximately 1-3% for most drugs

Page 4: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

WHO Definition of ADRs

Any noxious, unintended, undesired effect of a drug which occurs at doses used for prophylaxis, diagnosis, or therapy, excluding therapeutic failures, intentional and accidental overdose and drug abuse, and does not include AEs due to errors in drug administration.

Page 5: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

PREDICTABLE REACTIONS

• Dose dependent

• Related to drug’s actions

• Occur in normal patients

• 80% of adverse effects

Page 6: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

PREDICTABLE REACTIONS

• Overdosage or toxicity

• Side effects

• Secondary/Indirect effects

• Drug interactions

Page 7: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

UNPREDICTABLE REACTIONS

• Dose-independent

• Not related to drug’s actions

• Related to immune response (allergy)

Page 8: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Safety and Pharmaceutical Agents

•Safety and efficacy must be shown for a drug to be FDA approved

•Costs also drive considerations of how drugs are used in clinical practice or approved by regulatory agencies

•Generic drugs can be approved without rigorous testing required of new drugs tested in clinical studies

Page 9: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Safety and Pharmaceutical Agents (2)

• Costs also determine the use of pharmaceutical agents.

• Clinicians may accept the lack of safety data when one agent is significantly cheaper to use.

• Safety data incurs significant costs• Significant costs are associated with

severe ADRs when they occur

Page 10: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

ADR Prevention Study (JAMA 1995;274;29,35, NEJM 1991:324;377)

• Rate of ADRs 6.5/100 admissions• 28% ADRs were preventable and

serious• ADRs increase LOS 1.9 days and

increase hospital costs $1939 (not including costs of injuries)

• The annual national cost of drug-related M&M is enormous

Page 11: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Costs associated with ADRs (JAMA 1997; 277: 307-311)

• Prospective study to compare LOS and total charges

• 247 ADRs in 204 patients• 57% significant, 30% serious, 12%

life-threatening, and 1% fatal• Nonpreventable ADRs: analgesics

(30%), antibiotics (30%), oncologic agents (8%), and sedatives (7%)

Page 12: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Costs associated with ADRs (JAMA 1997; 277: 307-311) (2)

• The largest % preventable ADRs were caused by analgesics (29%), sedatives (10%), antibiotics (9%), and antipsychotics (7%)

• Allergic complications occurred in 7% of patients, and cardiovascular complications in 16%

Page 13: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Costs associated with ADRs (JAMA 1997; 277: 307-311) (3)

• An ADR was associated with $2,595 of additional costs not including the costs of injuries

• Annual ADR costs for the two Harvard hospitals = $5.6 million

• Estimated preventable ADR costs are in the billions

Page 14: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Detecting ADRs

• Clinical trials often do not include certain patient populations where the drug may be potentially used, including pregnant women or children, although recently the FDA has encouraged companies to study these patient populations by extending patent time

Page 15: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Detecting ADRs (2)

• Premarketing trials frequently do not have sufficient power to reliably detect important ADRs, which may occur at rates of 1 in 10,000 or fewer drug exposures

• FDA drug approval does not exclude the possibility of rare but serious ADRs

Page 16: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

ADR detection methods

• Premarketing clinical trials• Post approval spontaneous case

reports• Aggregate population-based data

sources• Computerized data collections• Postmarketing studies• Case reports

Page 17: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Case ReportsOne of the methods to detect the potential for a pharmacologic agent to produce serious ADRs have been noted first in case reports. Unusual or rare events that occur during initial drug use are more likely to be detected by case reports (JAMA 1999:281;824)

Page 18: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

FDA Reporting Mechanisms: MEDWATCH

• To improve the detection of previously unknown serious ADRs and knowledge about regulatory actions taken in response to reporting of these events, FDA introduced MEDWATCH in 1993

Page 19: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

FDA Reporting Mechanisms: MEDWATCH (2)

• FDA encourages health professionals to monitor for and report serious adverse events and product problems to FDA

Page 20: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

MedWatch Program (3)

• MedWatch is designed to educate health professionals about the critical importance of being aware of, monitoring for, and reporting adverse events and problems to FDA

Page 21: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

MedWatch Program (4)

• Designed 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.

Page 22: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

MedWatch Program (5)• To increase awareness of drug and

device-induced disease• To clarify what should (and should

not) be reported to the agency• To facilitate reporting by operating a

single system for health professionals to report AEs and product problems

• To provide regular feedback to the health care community about safety issues involving medical products

Page 23: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Incidence and risk of perioperative anaphylactic reactions

• 1 in 2,500-5,000 patients• Incidence of perioperative

anaphylactic reactions has been suggested to be increasing

• Most of the information in the US is from case reports and, to a lesser extent, retrospective studies

Page 24: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Risk of Anaphylaxis (1)

Even if the risk of an anaphylactic reaction is small, if the drug is administered to millions, the actual number of reactions is important to consider. This is important for latex sensitive pts, or as we examine new pharmacologic or different preparations of drugs that are introduced into practice.

Page 25: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Risk of Anaphylaxis (2)

• Propofol was first solubilized in Cremophor, a solvent with a known risk of ADRs; changed to intralipid

• Generic form of propofol contains a sulfiting agent not tested in clinical trials

• Clinical manifestations of true allergic reactions often may be mistakenly attributed to predictable ADRs and may often go unreported

Page 26: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Risk of Anaphylaxis (3)

• Anesthetic agents including propofol cause hypotension and dose-related vasodilation by direct and indirect mechanisms

• Bronchospasm may occur during laryngoscopy and intubation under light planes of anesthesia

• Clinicians may confuse true allergic reactions with known drug effects

Page 27: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Agents most often implicated in perioperative anaphylaxis

• Antibiotics• Blood products• Drug additives/preservatives• Muscle relaxants• Proteins (latex and protamine)

Page 28: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Antibiotics

• Penicillin and cephalosporins

• Vancomycin

Page 29: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Blood Products

• Whole blood, RBCs

• Platelets

• FFP, cryoprecipitate

• Immunoglobulins

• Fibrin glue

Page 30: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Drug Additives/Preservatives

• Includes sulfites and parabens, used as preservatives in parenteral solutions

• Additives/preservatives that may be included in IV drugs should be considered in the etiology of occult anaphylaxis

Page 31: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Drug Additives/Preservatives(2)

• In allergic patients who ingest sulfites, gastric pH generates sulfur dioxide producing bronchospasm, coughing, or asthma

• The problem we face as clinicians is a lack of data on the incidence and risk of hypersensitivity reactions to intravenous sulfites

Page 32: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Drug Additives/Preservatives (3)

• 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

Page 33: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Risk factors for Latex Allergy

• Allergy to bananas, avocados, kiwis, mangos

• Healthcare workers

• Children with urogenital abnormalities, spina bifida

Page 34: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Latex Allergy in Anesthesiologists

• 24% incidence irritant/contact dermatitis

• 12.5% incidence of latex-specific anti-IgE

• 10% were clinically asymptomatic although IgE positive

Brown RH: Anesthesiology 1998;89:287

Page 35: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Latex Allergy in Anesthesiologists

• Atopy was a risk factor for sensitization

• Brown suggests by avoiding latex exposure, progression to symptomatic disease may be prevented

Brown RH: Anesthesiology 1998;89:287

Page 36: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Protamine• Isolated from salmon sperm• Complex set of ADRs• 0.6-2% reactions in NPH

diabetics• Multiple mechanisms for

reactions

Page 37: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

Management of the Allergic Patient

• Greater risk of anaphylaxis in pts with an allergic history or atopy receiving an iv anesthetic

• 46% pt with anaphylaxis had a history of allergy or atopy (LaForest)

• 44.4% atopy in pt with anaphylaxis (compared to 5- 22%) (Moscicki)

Page 38: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

SUMMARY

• Any drug can produce some form of ADR

• Significant untoward risks, costs, and increased hospital stays associated with ADRs

• Allergy, atopy, or asthma pts have been suggested to be at an increased risk

Page 39: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

SUMMARY (2)

• Antibiotics, blood products, drug preservatives (sulfites and methylparabens) and polypeptides (ie, aprotinin, latex, and protamine) may be associated with a higher incidence of reactions

• Drug avoidance whenever possible is still the best method to avoid an ADR

Page 40: Adverse Drug Reactions Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Director of Cardiothoracic Anesthesiology Emory.

adversereactions.com


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