13.1 Multiple Drug Allergies
Laura B. Hemmer
Allergy history is an integral part of preoperative assessment. Detailed and accurate history is particularly important in preparation for anesthesia when multiple medications and other agents are often given nearly simultaneously. Immune-mediated and nonimmune-mediated immediate hypersensitivity reactions are estimated to occur in 1 out of every 1,250 to 10,000 anesthetics (1
). Having a thorough allergy history allows the anesthesiologist caring for the patient on the day of surgery to prepare and simply confirm the allergies.
Some of the most challenging patients report allergies to multiple unrelated drugs. It can be difficult to identify true allergies and to identify potential allergic cross-reactivity between allergens with similar chemical structure. The term “multiple drug allergy syndrome” is used to define this problem. It is estimated that 1% to 5% of all medication-allergic patients have multiple drug allergy syndrome (2
). In addition, attributing potential cross-reactivity, when no potential exists, can make anesthetic plans needlessly complicated and perhaps distract from other concerns.
Allergology assessment before the procedure for patients with a history of perioperative severe immediate hypersensitivity reaction to an unknown agent is essential, if possible. This may avoid perioperative anaphylaxis (2
Neuromuscular blocking agents (NMBAs) are responsible for 50% to 70% of perioperative anaphylaxis in adults (1
). Since all NMBAs are quaternary ammonium compounds, cross-reactivity can be expected. However, negative skin-tested NMBAs may be safely administered after a history of anaphylaxis to a different NMBA
). Many common nonprescription agents, as well as neostigmine and morphine, contain ammonium ions that can cross-react with muscle relaxants and make anaphylaxis possible on the first exposure to a muscle relaxant (4
Antibiotics are responsible for the next most frequent number of perioperative anaphylaxis events (1
). Cross-reactivity between penicillin and cephalosporin is attributed to their shared B-lactam ring and attached side chains. Cross-reactivity has been found to be lower than was originally thought, particularly for second- and third-generation cephalosporins (2
). One should not administer penicillin or cephalosporins in a patient with a true penicillin IgE-mediated allergy. However, with approximately 10% of patients reporting penicillin “allergy,” many are excluded from first-line surgical antimicrobial prophylaxis with a cephalosporin (5
). Skin testing
rules out immediate hypersensitivity to penicillin in about 90% of patients with suspected/reported penicillin allergy (6
). Thus, the majority of patients currently excluded can safely receive cephalosporins. Penicillin antibiotics frequently can be associated with a delayed maculopapular rash, which is not IgE-mediated and does not require skin testing before cephalosporin administration (7
The overuse of antibiotics is of increasing concern, as evidenced recently by multiple organizations advocating for more appropriate use (8
). Preoperative anesthesia visits can play a substantial role in minimizing the use of inappropriate antibiotics for surgical prophylaxis. Some institutions address this issue by carefully avoiding documenting penicillin allergy when the patients only report side effects (e.g., gastrointestinal symptoms) and/or by developing processes to obtain same-day testing in allergy clinics when penicillin allergy is noted during the preoperative visit (11
Reported allergy to local anesthetics requires careful history taking, since true allergy is rare and symptoms can often be attributed to the epinephrine added to solutions (7
). When true local anesthetic allergy is suspected, it is important to note the specific agent to determine if it is an amide or ester. Substituting a local anesthetic of the opposite class, and avoiding added preservatives can avoid the need for more allergy investigation before anesthesia (4
It is necessary to obtain an allergy history that includes reactions to agents such as latex and foods. There may be cross-reactivity among these items and medicines or materials used perioperatively. Latex is a major cause of allergies during anesthesia, although the frequency of reactions to latex is dependent on local prevention policies within institutions. Widespread avoidance of latex products is frequently instituted (1
). Foods that cross-react with latex include mango, kiwi, avocado, passion fruit, banana, and chestnuts (4
Traditionally, there has been concern that egg, soy, and/or peanut allergic patients can be susceptible to anaphylaxis to propofol and this information has been incorporated in product leaflets in some countries. However, there is no evidence for this, and concern is now considered unfounded (12
). This is because the highly purified egg lecithin and refined soy oil used in propofol either are not the allergic determinant, or no longer possess enough of the allergenic proteins to produce a reaction. Crossreactivity between soy and peanuts was the concern for peanut allergy and propofol avoidance, but, since soy is not contraindicated, there is no restriction with peanut allergy either (2
). Egg allergy is not a contraindication to use of the colloid albumin, since the principal egg protein is distinct from human albumin. There is no reported cross-reactivity among colloids, so reported allergy to one colloid does not prevent substitution of another colloid (4
Concern over iodine allergy and perioperative medications is similarly unfounded. The allergenic determinants of fish and shellfish are chemically distinct from iodine, so there is no need to modify the anesthetic plan with “iodine allergy.” Patients with a shellfish allergy do not need to avoid the common topical antiseptic povidone iodine unless they have had a hypersensitivity reaction to povidone iodine (2
). Similarly, the allergenic determinant of iodinated contrast agents is not iodine, so these can be used safely (2
). The various iodinated contrast agents share a similar structure, so skin testing should be performed to identify safe contrast agents after an IgE-mediated reaction to one contrast agent (2
Theoretically, patients with a history of fish allergies or vasectomies can develop a hypersensitivity to protamine sulfate which is used to reverse the anticoagulant effects of heparin. However, no clinical reactions have been reported in these cases, and protamine is not prohibited (2
With modern emphasis on multimodal approaches to pain management, NSAIDs have gained use in the perioperative setting (1
). A step-wise approach to diagnosis of hypersensitivity to NSAIDs is recommended, and usually includes drug provocation testing with the suspected culprit agent or with alternative agents (13
Patients with multiple drug allergies can undergo uneventful, safe anesthetics with careful planning (14
). Appropriate preoperative allergy evaluation is critical to prevent immediate hypersensitivity reactions under anesthesia. When a history of anaphylaxis during a prior anesthetic is reported, appropriate follow-up includes obtaining documentation of the event if available, allergy referral if not previously done, and appropriate documentation of the allergy in the patient’s record (4
1. Mertes PM, Demoly P, Malinovsky JM. Hypersensitivity reactions in the anesthesia setting/allergic reactions to anesthetics. Curr Opin Allergy Clin Immunol. 2012;12:361-368.
2. Dewachter P, Mouton-Faivre C, Castells MC, et al. Anesthesia in the patient with multiple drug allergies: are all allergies the same? Curr Opin Anaesthesiol. 2011;24:320-325.
3. Asero R. Multiple drug allergy syndrome: a distinct clinical entity. Curr Allergy Rep. 2001;1:18-22.
4. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg. 2003;97:1381-1395.
5. Solensky R, Earl HS, Gruchalla RS. Clinical approach to penicillin-allergic patients: a survey. Ann Allergy Asthma Immunol. 2000;84:329-333.
6. Lang DM. The malady of penicillin allergy. Ann Allergy Asthma Immunol. 2016;116:269-270.
7. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.
11. Park M, Markus P, Matesic D, et al. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol. 2006;97:681-687.
12. Asserhøj LL, Mosbech H, Krøigaard M, et al. No evidence for contraindications to the use of propofol in adults allergic to egg, soy or peanut. Br J Anaesth. 2016. 116(1):77-82.
13. Kowalski ML, Makowska JS, Blanca M, et al. Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs): classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA. Allergy. 2011;66:818-829.
14. Kulkarni SJ, Kelkar VP, Nayak PP. Anesthesia in a patient with multiple allergies. J Anaesthesiol Clin Pharmacol. 2014;30(3):433-434.
13.2 Dyspnea and Poor Exercise Tolerance
Dyspnea is a common symptom reported by patients as the limitation to physical exertion. It is a subjective discomfort of breathing with physiologic, psychological, social, and environmental contributing factors (1
). Dyspnea is a nonspecific symptom associated with a multitude of conditions. Some of these conditions are associated with significant perioperative risk, especially if a major surgery is planned. Dyspnea may be the only, or the most prominent complaint of patients with pulmonary or cardiac disease, metabolic conditions, or simply deconditioning. Inability to meet a metabolic demand during ADLs predicts an inability to meet the demands of illnesses or surgery. Healthy individuals will have dyspnea when engaging in vigorous activities with more physically fit persons having less shortness of breath at any given workload than sedentary ones.
The majority of patients will have one of the three broad categories as their cause of dyspnea: cardiovascular, pulmonary, or miscellaneous (Fig. 13.1
). And, more than one condition can exist together. Most patients with chronic dyspnea of unclear etiology have one of five diagnoses: asthma, chronic obstructive pulmonary disease (COPD
), interstitial lung disease, deconditioning, or cardiac dysfunction. Miscellaneous conditions account for the rest. Nocturnal dyspnea is more specific than exertional dyspnea for heart failure. Asthma can be associated with dyspnea during sleep but does not improve with upright posture. Common cardiac causes of dyspnea are heart failure including diastolic dysfunction, valvular or ischemic disease. In addition intracardiac shunts or constrictive pericarditis can present as dyspnea. Dyspnea at rest or with minimal exertion is indicative of true disease, and of more concern if anxiety is not causative. Functional causes of dyspnea all have worsening dyspnea with exertion. Dyspnea can be caused by an increased work of breathing due to failure of the cardiopulmonary system to move oxygen from the atmosphere to the blood. Dyspnea can be due to insufficient hemoglobin to carry oxygen to the tissues. Neuromuscular conditions may limit the ability to breathe. Dyspnea can be a symptom of chronic thromboembolic disease. Some conditions may stimulate pulmonary vascular or interstitial receptors which trigger dyspnea, often out of proportion to the degree of either hypoxia or hypercarbia. Dyspnea due to deconditioning is often described as heavy breathing rather than feeling an increased work of breathing. And, often with careful questioning one can determine that patients are actually fatigued rather than truly dyspneic.
The clinical examination (history and physical findings) can limit the possibilities and guide diagnostic studies (Fig. 13.1
). The history and physical examination leads to accurate diagnoses in two-thirds of cases (2
). Risk factors for medical conditions such as tobacco use or family history of premature coronary artery disease along with symptoms such as orthopnea or findings on examination like wheezing or edema direct next steps. Associated symptoms such as cough, chest pain, peripheral edema, or muscle weakness focus the differential diagnoses. Certain phrases that patients use may suggest specific conditions. Patients with heart failure are more likely to complain of suffocation, those with COPD
feel that “they cannot take a deep breath,” asthmatics may say it feels “tight,” and deconditioned patients have a sense of heavy breathing (3
). On examination
auscultation of the lungs and heart is essential but observation for clubbing, peripheral edema, jugular venous distension, kyphoscoliosis, or muscle weakness is important.
Figure 13.1 Differential diagnosis and diagnostic approach to evaluate dyspnea.
Initial testing usually involves an electrocardiogram (ECG
), hemoglobin, BNP
, thyroid function tests, chest radiograph, spirometry, and oximetry (resting and after walking several feet). Specialized testing is directed by the initial test results. A normal BNP
is highly predictive of a low risk of cardiac disease as the cause of dyspnea and predicts a low risk of perioperative major adverse events (5
). Most dyspneic patients with heart failure have BNP
values exceeding 400 pg/mL; BNP
levels between 100 and 400 pg/mL in a dyspneic patient raise
suspicion of compensated left ventricular dysfunction, pulmonary embolism, or cor pulmonale. Higher BNP
levels occur with severe reduction in ejection fraction or decompensated heart failure.
An echocardiogram is warranted for further evaluation of dyspnea of unknown origin or those with risk factors for or symptoms of heart failure, pulmonary hypertension or for a patient with a history of heart failure with worsening dyspnea or other clinical changes. Individuals >50 years of age with symptoms of dyspnea and an auscultated murmur warrant an echocardiogram. The classic symptoms associated with aortic stenosis are chest pain, presyncope or syncope, and dyspnea. Dyspnea is an early but often overlooked symptom, and 75% of symptomatic patients die within 3 years without valve replacement (7
). Pulmonary function tests (PFTs) are discussed in Chapter 4.11
. In addition to usual spirometry to measure airflow, measurement of diffusing capacity and flow volume loops may be helpful. The role of PFTs may be for diagnosis (“is dyspnea caused by lung disease or heart failure?”) or to guide management (“can dyspnea or wheezing be improved further?”), but not as a risk assessment tool or to deny a beneficial procedure. Cardiopulmonary exercise testing (CPET
) may be more useful than traditional PFTs (8
). A 6-minute walk test or simple stair climbing is a useful first screen and if favorable predicts lower risk. Computed tomography (CT) scans and CPET
are rarely necessary but can be useful if the above tests are not diagnostic (10
) (see Chapter 2.4
). CT can show interstitial lung disease or emphysema not seen on chest radiographs. CPET
may be useful if more sophisticated evaluation is needed. However, occasionally patients present in the preoperative period with a history of symptoms (chest pain or dyspnea with exertion) consistent with ischemia and meet independent criteria for evaluation with stress testing.
Dyspnea can be quantified using an instrument such as the Modified Medical Research Council (MMRC
) dyspnea scale (Table 13.1
) or the modified Borg Scale (Table 13.2
TABLE 13.1 Modified Medical Research Council (MMRC) Dyspnea Scale
Only breathless with strenuous exercise
Short of breath when walking up a small hill or hurrying on level ground
Breathlessness causes patient to walk slower than others on level ground or need to stop to breathe
Need to stop to breathe after walking 100 yards or a few minutes on level ground
Too breathless to leave home or breathless when dressing
Adapted from Fletcher CM, Elmes PC, Fairbairn MB, et al. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J. 1959;2:257-266.
TABLE 13.2 Modified Borg Scale
Intensity of Dyspnea or Fatigue
Very, very slight
Very, very severe
1. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185:435-452.
2. Pratter MR, Curley FJ, Dubois J, et al. Cause and evaluation of chronic dyspnea in a pulmonary disease clinic. Arch Intern Med. 1989;149:2277-2282.
3. Scano G, Stendardi L, Grazzini M. Understanding dyspnoea by its language. Eur Respir J. 2005;25:380-385.
4. Ambrosino N, Serradori M. Determining the cause of dyspnoea: linguistic and biological descriptors. Chron Respir Dis. 2006;3:117-122.
5. Lurati Buse GA, Koller MT, Burkhart C, et al. The predictive value of preoperative natriuretic peptide concentrations in adults undergoing surgery: a systematic review and meta-analysis. Anesth Analg. 2011;112:1019-1033.
6. Payne CJ, Gibson SC, Bryce G, et al. B-type natriuretic peptide predicts long-term survival after major non-cardiac surgery. Br J Anaesth. 2011;107:144-149.
7. Carabello BA. Introduction to aortic stenosis. Circ Res. 2013;113:179-185.
8. Bernstein WK. Pulmonary function testing. Curr Opin Anaesthesiol. 2012;25:11-16.
9. Martinez FJ, Stanopoulos I, Acero R, et al. Graded comprehensive cardiopulmonary exercise testing in the evaluation of dyspnea unexplained by routine evaluation. Chest. 1994;105:168-174.
10. Hennis PJ, Meale PM, Grocott MP. Cardiopulmonary exercise testing for the evaluation of perioperative risk in non-cardiopulmonary surgery. Postgrad Med J. 2011;87: 550-557.
13.3 Refusal of Blood/Jehovah’s Witness
David M. Rothenberg
Recent data suggest that approximately 16 million people worldwide refuse transfusion of blood or blood products citing religious, moral, social, or personal beliefs, or for medical reasons (1
Understanding blood refusal is most pertinent in caring for patients who are members of the Jehovah’s Witness (JW) faith. JWs number more than 7.5 million and are represented in more than 240 countries or territories. JWs actively seek medical treatment when ill, but adamantly refuse blood transfusions, in opposition to the recommendation of healthcare providers, as the administration of blood or blood components is in conflict with their scriptural commands, and sentences them to eternal damnation.
There is diversity in how JW patients interpret or apply their credence, and there are individual practices in acceptance of various blood product components (Table 13.3
); therefore it is essential for clinicians to identify each patient’s personal beliefs. Even in the absence of a defined group doctrine, patients have a right to refuse blood transfusion based on their wishes and convictions. When caring for patients who refuse blood transfusions, practitioners take into account the ethical aspects of medical practice; the need for informed consent and proper advanced directives; the acuity of care; and the age of the patient.
MEDICAL PRACTICE IS GUIDED BY FOUR FUNDAMENTAL ETHICAL PRINCIPLES
Autonomy and Self-determination
In order to exercise the right of autonomy, patients must have the ability to make decisions, to understand the nature of procedures, risks, benefits, and alternatives. Physicians assess capacity
during a clinical encounter, whereas competency
can only be proclaimed by a court of law (2
While most JWs who follow the Watch Tower Bible and Tract Society (WTS
) doctrine refuse transfusions of blood and its components, a distinct subset identifies with The Association of Jehovah’s Witnesses for the Reform of Blood (AJWRB
), and questions the biblical basis for the prohibition. These proponents for acceptance of blood claim that JW patients are controlled and penalized by the WTS
, and while they do not promote the acceptance of certain blood components versus others, they encourage JW patients to seek scientific information and make lifesaving choices for themselves and their families, and persuade physicians to have meaningful interactions with JW patients and promote “noninterventional paternalism.” (3
When treating patients who refuse blood transfusions, practitioners must address the following questions:
Does the patient have the appropriate decision-making capacity?
Have all the risks, benefits, and alternatives been explained?
Is the patient free of coercion and able to make decisions in accordance with their own values?
Is the patient able to communicate consistent choices regarding decisions?
A private and confidential conversation between patient and the treating physicians is necessary, so the JW patient has the opportunity to express his/her preferences regarding blood transfusion, without friends or family members to influence his/her decision. Patients should clearly define what fractions of blood (e.g., cryoprecipitate, recombinant factors, albumin) are acceptable. (Table 13.3
). Strict confidentiality
must be ensured if the patient confides that they are secretly willing to accept blood in extremis. Patients have to decide if any of the information communicated to physicians can be disclosed to family members or church elders in case they become incapacitated.
TABLE 13.3 Type of Blood Product or Procedure to Discuss With JW patient
Type of Blood Product or Procedure
Most erythropoietin is albumincoated and is a personal decision; darbepoetin contains no albumin
Recombinant factor VII
Not made from blood, although some may still object
If kept in continuous circuit
Acute normovolemic hemodilution
If kept in continuous circuit
Cardiopulmonary or venovenous bypass
If kept in continuous circuit
If kept in continuous circuit
Stored autologous blood
Not in continuous circuit
Organ and bone marrow transplant
pRBCs, packed red blood cells
2015 ASA Syllabus on Ethics. Edited by Barbara G Jericho and Jeffrey S Jacobs, Asahq.org, American Society of Anesthesiologists, www.asahq.org/resources/ethics-and-professionalism
The principle of beneficence states that it is the physician’s duty to act in the patient’s best interest. Therefore physicians must offer the best care available within the constraints of the patient’s wishes, including appropriate planning or referrals to more experienced providers. Withholding blood transfusion is an act of beneficence for a faithful JW patient; some physicians feel that withholding life-saving blood transfusions violates the ethical principle of beneficence, regardless of a patient’s wishes. In nonemergency situations, medical providers have the right to defer care and to refer the patient to another medical provider or center with expertise in caring for patients who refuse transfusions. In the United States, the respect for patients’ autonomy surpasses the principle of beneficence.
The principle of do no harm is challenging to interpret in the setting of withholding blood transfusion. Although a provider may believe that allowing a bleeding patient to die by not transfusing is clearly causing harm, a devout JW’s belief in the loss of eternal salvation and resultant disassociation from their family and church from the receipt of a blood transfusion may be of greater harm.
Social and Distributive Justice
This ethical principle assesses the fair distribution of risks, benefits and cost in medical care. Distributive justice does not play a major role during routine surgical cases, but it becomes paramount when dealing with patients who, for example, refuse transfusions and are scheduled to undergo solid organ transplantation. The availability of solid organs for transplantation is limited, and such a resource may be wasted if a patient whose clinical status requires a blood transfusion refuses such treatment. However, by carefully selecting appropriate candidates, solid organ transplantation is performed with excellent results in many centers specialized in the care of JW patients.
INFORMED CONSENT, ADVANCED DIRECTIVES, AND SURROGATE DECISION MAKERS
After discussions with the JW patient, physicians should clearly document in the medical record the alternatives to transfusion, including blood conservation techniques, and risks associated with the omission of transfusion. The JW patient should sign a Refusal of Blood Products
form (see Fig. 13.2
), and indicate on a form similar to Table 13.3
which blood components and blood conservation
techniques (e.g., cardiopulmonary bypass, cell saver, hemodialysis) are not acceptable.
Figure 13.2 Refusal of blood products. (Courtesy of David M. Rothenberg, MD.)
In addition, depending on the jurisdiction, a surrogate may be required to witness and sign the form as well (4
). Before patients undergo procedures associated with a high incidence of hemorrhage, end-of-life decisions need to be addressed.
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