c



 
Jerrold H. Levy, MD
Professor of Anesthesiology
Emory University School of Medicine
Director of Cardiothoracic Anesthesiology
Emory Healthcare
Atlanta, Georgia
 r  
 Any drug can cause an ADR
 Perioperatively, multiple agents
are administered
 ccult antigens pose major
problems (ie, latex, additives)

atal ADRs leading cause of death
 ADR costs may lead to an
additional $1.56-$4 billion/yr in US
 r  
 
 5% adults in US are allergic to
 1 drugs
 % of medical inpatients develop
an ADR
 % of all hospital admissions are
due to ADRs
 Risk of an allergic reaction is
approximately 1-% for most drugs
 :
   c 
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.
PREDICTABLE REACTI S

 Dose dependent
 Related to drug¶s actions
 ccur in normal patients
 % of adverse effects
PREDICTABLE REACTI S

 verdosage or toxicity
 Side effects
 Secondary/Indirect effects
 Drug interactions
 UPREDICTABLE
REACTI S
 Dose-independent
 ot related to drug¶s actions
 Related to immune response
(allergy)
Safety and Pharmaceutical Agents
Safety and efficacy must be shown for
a drug to be
DA 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
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
c 
  
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 Rate of ADRs 6.5/1 admissions

 2% ADRs were preventable and
serious
 ADRs increase L S 1.9 days and
increase hospital costs $199 (not
including costs of injuries)
 The annual national cost of drug-
related M&M is enormous
 ë

 $ %c 
cc"&'#
 Prospective study to compare L S
and total charges
 247 ADRs in 24 patients
 57% significant, % serious, 12%
life-threatening, and 1% fatal
 onpreventable ADRs: analgesics
(%), antibiotics (%), oncologic
agents (%), and sedatives (7%)
 ë

 $ %c 
cc"&'##

 The largest % preventable ADRs

were caused by analgesics (29%),
sedatives (1%), antibiotics (9%),
and antipsychotics (7%)
 Allergic complications occurred in
7% of patients, and cardiovascular
complications in 16%
 ë

 $ %c 
cc"&'##
 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
  c 
 Clinical trials often do not include
certain patient populations where
the drug may be potentially used,
including pregnant women or
children, although recently the

DA has encouraged companies
to study these patient populations
by extending patent time
  c #
 Premarketing trials frequently do
not have sufficient power to
reliably detect important ADRs,
which may occur at rates of 1 in
1, or fewer drug exposures

DA drug approval does not
exclude the possibility of rare but
serious ADRs
 c   (% 
 Premarketing clinical trials
 Post approval spontaneous case
reports
 Aggregate population-based data
sources
 Computerized data collections
 Postmarketing studies
 Case reports
 ë
 )
ne 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 1999:21;24)
hc ) %
 ("
!:c*ë
 To improve the detection of
previously unknown serious ADRs
and knowledge about regulatory
actions taken in response to
reporting of these events,
DA
introduced MEDWATCH in 199
 hc ) %
 ("
!:c*ë #

DA encourages health
professionals to monitor for and
report serious adverse events and
product problems to
DA
  :
%
(#
 MedWatch is designed to
educate health professionals
about the critical importance of
being aware of, monitoring for,
and reporting adverse events
and problems to
DA
  :
%
(#
 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.
  :
%
(#
 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
r 
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)%,
 
 
 1 in 2,5-5, 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
 +c
)%,
- #
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.
 +c
)%,
- #
 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
 +c
)%,
- #
 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
c( (), 
 
) )



)%,
- 
 Antibiotics
 Blood products
 Drug additives/preservatives
 Muscle relaxants
 Proteins (latex and protamine)
 c .  

 Penicillin and cephalosporins

 ancomycin
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 r((,., 
 h . ,
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/



 Includes sulfites and parabens,
used as preservatives in parenteral
solutions
 Additives/preservatives that may
be included in I drugs should be
considered in the etiology of occult
anaphylaxis
 c 
/


#
 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
 c 
/


#
 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
 +
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-c,,

 Allergy to bananas, avocados,

kiwis, mangos
 Healthcare workers
 Children with urogenital
abnormalities, spina bifida
0
-c,, c% , 
 24% incidence irritant/contact
dermatitis
 12.5% incidence of latex-specific
anti-IgE
 1% were clinically asymptomatic
although IgE positive
Ò





0
-c,, c% , 
 Atopy was a risk factor for
sensitization
 Brown suggests by avoiding latex
exposure, progression to
symptomatic disease may be
prevented
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 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 (La
orest)
 44.4% atopy in pt with anaphylaxis
(compared to 5- 22%) (Moscicki)
 4c 5
 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
 4c 5#
 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
adversereactions.com