Key Points
- •
Most episodes of anaphylaxis occur in the community, not in healthcare settings. Food is by far the most common trigger. Concomitant asthma increases the risk of severe or fatal anaphylaxis.
- •
Diagnosis of anaphylaxis is based on recognition of symptoms and signs that occur suddenly (minutes to a few hours) after exposure to a known or likely trigger.
- •
Prompt treatment of anaphylaxis is essential: call for assistance, inject epinephrine IM in the mid-outer thigh, and place the patient supine or in a position of comfort. Provide oxygen, IV fluids, and other interventions as needed.
- •
Patients at risk of anaphylaxis should carry one or more epinephrine auto-injectors and a written, personalized, anaphylaxis emergency action plan, and wear medical ID.
- •
Anaphylaxis triggers should be confirmed and vigilantly avoided. Immunotherapy effectively prevents venom anaphylaxis. Regular follow-up and anaphylaxis education are important aspects of long-term management.
Introduction
The areas covered in this chapter on anaphylaxis in infants, children and teenagers include: epidemiology, patients at increased risk, mechanisms, triggers, diagnosis, treatment of the acute anaphylactic episode, and long-term management.
Anaphylaxis is defined as a serious generalized allergic or hypersensitivity reaction that is rapid in onset and might cause death. It typically occurs minutes to a few hours after exposure to the trigger and involves two or more body organ systems ( Box 58-1 ). The presence of hypotension or shock is not required in order to make the diagnosis. The term ‘anaphylactoid’ is no longer recommended for use.
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:
- 1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
- •
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, hypoxemia) *
* Another example is reduced peak expiratory flow.
- •
Reduced BP †
† Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2 × age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.
or associated symptoms of end-organ dysfunction (e.g. hypotonia [collapse], syncope, incontinence)
- •
- 2.
Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
- •
Involvement of the skin-mucosal tissue (e.g. generalized hives, itch-flush, swollen lips-tongue-uvula)
- •
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, hypoxemia) *
- •
Reduced BP † or associated symptoms (e.g. hypotonia [collapse], syncope, incontinence)
- •
Gastrointestinal symptoms (e.g. crampy abdominal pain, persistent vomiting)
- •
- 3.
Reduced BP † after exposure to a known allergen for that patient (minutes to several hours):
- •
Infants and children: low systolic BP † (age-specific) or greater than 30% decrease in systolic BP †
- •
Adults: systolic BP † or less than 90 mm Hg or greater than 30% decrease from that person’s baseline
- •
BP – Blood pressure.
Epidemiology
The rate of occurrence of anaphylaxis is increasing, yet under-diagnosis and under-coding remain a problem. In the general population, the incidence doubled from 21 per 100,000 person years in the 1980s to 49.8 per 100,000 person years in the 1990s, and the highest rate (70 per 100,000 person years) was reported in patients 0.8 to 19 years of age.
The hospitalization rate for anaphylaxis in patients under 20 years old increased more than 4-fold between 1990 and 2006, with peaks in the very young (0–4 years) and in teenagers. The incidence of emergency department (ED) visits and hospitalizations for anaphylaxis increased by 8.8% per year between 1993/4 and 2004/5, with a steep increase in hospitalizations for food-triggered anaphylaxis in children less than 5 years of age. The hospitalization rate for food-induced anaphylaxis more than doubled between 2000 and 2009, from 0.60 to 1.26 per 1,000 total hospitalizations, with corresponding increases in associated healthcare costs.
In addition to the increase in ED visits and hospitalizations, critical care unit admissions are also increasing; however, in hospitalized patients, the case fatality rate is low.
Most anaphylaxis fatalities occur in community settings. Indeed, most anaphylaxis episodes occur in such settings, where they predominate in boys and in atopic patients. Foods are by far the most common trigger, followed by insect stings and drugs.
Patients at Increased Risk of Severe Anaphylaxis
Severity of concomitant atopic diseases is a predictor of life-threatening anaphylactic episodes. Persistent asthma, especially if not optimally controlled, is an important risk factor for fatal anaphylaxis. Urticaria pigmentosa with extensive (>90%) involvement of the skin or blistering increases the risk of anaphylaxis in infants and children. Concurrent use of antihypertensive medications such as beta-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors potentially makes anaphylaxis more severe. Additionally, infants, teenagers and pregnant teens can be uniquely vulnerable in anaphylactic episodes because of issues with under-recognition and under-treatment.
Co-factors that can amplify anaphylaxis include exercise, ethanol, NSAIDs (nonsteroidal antiinflammatory drugs), colds or other acute infections, fever, perimenstrual status and emotional stress. Some amplification mechanisms are better understood than others; for example, exercise, ethanol and NSAIDs increase food allergen bioavailability from the gastrointestinal tract, and acute viral infections decrease the mast cell activation threshold.
Pathologic Mechanisms in Anaphylaxis
In the pediatric population, anaphylaxis typically involves IgE specific to food, venom or other allergen, high-affinity IgE receptors (FcεR1 receptors), mast cells and basophils and release of mediators of inflammation. These include preformed histamine and tryptase, and newly generated mediators such as platelet-activating factor, leukotrienes, prostaglandins, cytokines and chemokines ( Figure 58-1 ).
Recruitment of other inflammatory pathways has been reported. These include activation of the complement cascade leading to formation of C3a, activation of the coagulation pathway, and activation of the kallikrein-kinin system pathway with kinin formation. Direct activation of mast cells by physical factors such as exercise, exposure to cold water or cold air, or ingestion of medications such as opioids can also trigger anaphylaxis.
IgG-mediated anaphylaxis is reported after administration of high molecular weight dextran or monoclonal antibodies such as infliximab.
Triggers
In the pediatric population, food is by far the most common trigger of anaphylaxis. Milk, egg, peanut, tree nuts such as cashew, crustacean shellfish such as shrimp, and finned fish are the predominant food triggers in many geographic areas, while sesame, wheat and peach predominate in others. The relative importance of food triggers also differs with age; for example, in infants, milk, egg and peanut are the common concerns ( Box 58-2 ).
Allergen Triggers (IgE-Dependent Immunologic Mechanisms)
Foods, e.g. milk, egg, peanut, tree nut, finned fish, crustacean shellfish, soy, and wheat
Food additives, e.g. spices, colorants, vegetable gums, and contaminants
Stinging insects: Hymenoptera species, e.g. bees, yellow jackets, wasps, hornets and ants
Medications, e.g. penicillins, cephalosporins and other antibiotics, ibuprofen and other NSAIDs, and chemotherapeutic agents
Biologic agents, e.g. monoclonal antibodies, and allergens (challenge tests, allergen-specific immunotherapy)
Natural rubber latex
Inhalants (rare), e.g. horse dander, and grass pollen
Uncommon triggers *
* In the pediatric population, uncommon triggers include vaccines to prevent infectious disease.
Novel allergens
Direct Mast Cell Activators
Physical factors
Exercise †
† With or without co-triggers/co-factors such as foods, ethanol, NSAIDs, cold water or cold air.
Cold water or cold air
Heat
Sunlight/ultraviolet radiation
Medications, e.g. opioids
IDIOPATHIC ANAPHYLAXIS ‡
‡ Idiopathic anaphylaxis is uncommon in children. The possibility of a novel trigger or a mast cell activation syndrome should be ruled out.
NSAIDs – Nonsteroidal antiinflammatory drugs.
Potential food triggers include hidden, substituted, cross-reacting or cross-contacting foods, additives such as spices and colorants, novel food allergens (for example, red meats containing the carbohydrate allergen galactose-α-1,3,-galactose), contaminants such as storage mites in flour, and food parasites such as the live nematode Anisakis simplex in fish. Rarely, anaphylaxis is triggered by skin contact from food as such, vomited food, or inhalation of odors or cooking vapors, e.g. from fish.
Other anaphylaxis triggers include venom from stinging insects such as bees, yellow jackets, wasps, hornets and ants, and less commonly, saliva from biting insects such as mosquitoes, caterpillars and ticks.
Medication triggers include penicillins, cephalosporins and other antibiotics, NSAIDs such as ibuprofen, and antineoplastic agents. Contaminants in medications, including traces of food, can also trigger anaphylaxis. Peri-operative anaphylaxis can be triggered by antibiotics or by neuromuscular blockers/muscle relaxants such as suxamethonium, but any inhaled, injected or topically applied agent can be implicated, including antiseptics such as chlorhexidine.
Natural rubber latex in medical equipment and supplies can trigger anaphylaxis in healthcare settings, and latex found in some infant pacifiers, bottle nipples, teethers, toys, balloons, sports equipment including balls and racquet handles, and condoms can trigger it in community settings.
Other potential triggers include biologic agents such as the monoclonal antibodies infliximab and omalizumab, allergen skin tests (especially intradermal tests), allergen challenge tests, and allergen immunotherapy by any route.
Vaccines that protect against infectious diseases seldom trigger anaphylaxis. If they do, the culprit is usually an excipient (such as gelatin, yeast, dextran, polysorbate-80), egg (influenza and yellow fever vaccines), neomycin or polymyxin B, not the microbial content.
In exercise-induced anaphylaxis, common co-triggers/co-factors include foods (wheat, shrimp, celery), NSAIDs, ethanol, and concurrent exposure to cold water or cold air, which can also trigger anaphylaxis independently of exercise.
Idiopathic anaphylaxis is uncommon in infants, children and teenagers (see also Idiopathic Anaphylaxis, pages 534 and 535 , and Box 58-6 ).
Diagnosis
In the pediatric population, diagnosis of anaphylaxis depends almost entirely on the history and physical findings.
Clinical Diagnosis
Diagnosis of anaphylaxis is based on recognition of the sudden onset of characteristic symptoms and signs within minutes to hours after exposure to a known or likely trigger or activity ( Figure 58-2 ). Clinical criteria for diagnosis have been developed and validated as an instrument for rapid assessment of patients who present with a possible diagnosis of anaphylaxis in EDs and other medical settings, or those who present to their primary care physician after the acute event, and for use in epidemiologic studies ( Box 58-1 ). These criteria have high sensitivity for identification of anaphylaxis, good specificity and a high negative predictive value.
Anaphylaxis is under-reported in the pediatric population, especially in infants. First episodes might not be recognized as such, especially if symptoms are mild and/or transient. Skin involvement (itching, flushing, generalized urticaria and/or angioedema) is helpful in making the diagnosis; however, it is absent or unrecognized in 10% to 20% of anaphylactic episodes and can be missed if itching is absent, if a partial skin examination is performed or if an H 1 antihistamine has been given. Patients with dysphonia, dyspnea or shock might not be able to describe their symptoms. Anaphylaxis might not be recognized as such in an asthmatic with acute respiratory symptoms if concomitant symptoms such as itching, vomiting or dizziness are not reported. Lack of recognition or delayed recognition of anaphylaxis due to patient or caregiver depression or substance abuse might also be relevant.
In infants, a high index of suspicion is needed in order to diagnose anaphylaxis. They cannot describe their symptoms, and some of their signs can be difficult to interpret because they also occur in healthy babies ( Table 58-1 ). A typical presentation includes skin signs such as generalized urticaria, gastrointestinal signs such as persistent vomiting, and/or respiratory symptoms and signs. Hypotension is often undocumented, for example in settings where infant-size blood pressure cuffs are unavailable.
| Anaphylaxis Symptoms that Infants Cannot Describe | Anaphylaxis Signs that May be Difficult to Interpret/Unhelpful in Infants, and Why | Anaphylaxis Signs in Infants |
|---|---|---|
| GENERAL | ||
| Feeling of warmth, weakness, anxiety, apprehension, impending doom | Behavioral changes such as persistent crying, fussing, clinging, irritability, fright | |
| SKIN/MUCOUS MEMBRANES | ||
| Itching of lips, tongue, palate, uvula, ears, throat, nose, eyes, etc.; mouth tingling or metallic taste | Flushing (may also occur with fever, hyperthermia or crying spells) | Sudden onset of generalized hives (potentially difficult to discern in infants with acute atopic dermatitis; scratching and excoriations will be absent in young infants); also, angioedema (face, tongue, oropharynx) |
| RESPIRATORY | ||
| Throat tightness; chest tightness; shortness of breath | Hoarseness, dysphonia (common after a crying spell); drooling/increased secretions (common in teething infants) | Sudden onset of coughing, stridor, wheezing, dyspnea, apnea, cyanosis |
| GASTROINTESTINAL | ||
| Dysphagia, nausea, abdominal pain/cramping | Drooling, spitting up/regurgitation (common after feeds), loose stools (normal in infants, especially if breastfed); colicky abdominal pain | Sudden onset of persistent vomiting |
| CARDIOVASCULAR | ||
| Feeling faint or dizzy (pre-syncope), confusion, blurred vision, difficulty in hearing | Hypotension (need appropriate size blood pressure cuff; low systolic blood pressure for infants is defined as less than 70 mm Hg from 1 month to 1 year, and less than (70 mm Hg + [2 × age]) in years in the first and second years of life; tachycardia, defined as greater than 120–130 beats per minute from 3 months to 2 years, inclusive; loss of bowel and bladder control (ubiquitous in infants) | Weak pulse, arrhythmia, diaphoresis/sweating, collapse/unconsciousness |
| CENTRAL NERVOUS SYSTEM | ||
| Headache | Behavioral changes (see above), drowsiness, somnolence (common in infants after feeding) | Sudden onset of lethargy, hypotonia, unresponsiveness or seizures |
Differential Diagnosis
The differential diagnosis of anaphylaxis in infants includes age-unique entities ( Box 58-3 ). The differential diagnosis of anaphylaxis in children and teens includes common entities such as acute generalized hives associated with viral infection, acute asthma, syncope (faint), anxiety or panic attack, and aspiration of a foreign body. It also includes less common entities such as excess histamine syndromes (e.g. mast cell activation syndromes, ruptured or leaking hydatid cyst); restaurant (post-prandial) syndromes (e.g. food poisoning, scombroid poisoning); and nonorganic diseases (e.g. vocal cord dysfunction, Munchausen syndrome or Munchausen syndrome by proxy). Flush syndromes are rare in the pediatric population except for nonallergic red man syndrome triggered by vancomycin. Seizures and stroke and other forms of shock (septic, hypovolemic or cardiogenic) should also be considered in the differential diagnosis.
Skin
Acute episode of urticaria, urticaria pigmentosa/mast cell activation syndrome, hereditary angioedema
Respiratory (Upper or Lower Respiratory Tract)
Acute onset of symptoms due to obstruction, which can be congenital (e.g. laryngeal web, vascular ring, malacias) or acquired (e.g. aspiration of foreign body *
* Peanuts and tree nuts are commonly associated with both foreign body inhalation and anaphylaxis.
, croup, bronchiolitis, asthma); asphyxiation/suffocation, breath-holdingGastrointestinal Tract
Acute onset of symptoms due to obstruction, which can be congenital (e.g. pyloric stenosis, malrotation) or acquired (e.g. intussusception), food protein-induced enterocolitis syndrome with an acute presentation
Cardiovascular System
Apparent life-threatening event/sudden infant death syndrome; different forms of shock: septic, hypovolemic, cardiogenic, distributive (other than anaphylaxis)
Central Nervous System
Seizure, postictal state, stroke, trauma, child abuse, increased intracranial pressure
Other, Including
Metabolic disorders
Infectious diseases: pertussis, gastroenteritis, meningitis
Ingestion of: drug overdose, poison or toxin (e.g. food, chemical, plant)
Munchausen syndrome by proxy (Meadow’s syndrome)
Laboratory Tests to Support the Clinical Diagnosis
In the pediatric population, laboratory tests ( Figure 58-2 ) are seldom helpful in confirming the clinical diagnosis of anaphylaxis. The most widely used test, measurement of serum or plasma total tryptase levels, takes several hours to perform and is not available on an emergency basis. Even in blood samples obtained promptly (between 15 minutes and 3 hours) after symptom onset, tryptase levels are seldom elevated in children and in food-induced anaphylaxis. Lack of availability of tryptase measurements is not a barrier to prompt clinical diagnosis of anaphylaxis. A tryptase level in the normal reference range cannot be used to refute the clinical diagnosis of anaphylaxis. Initial treatment of anaphylaxis should never be delayed in order to obtain a blood sample for tryptase measurement.
In young infants, interpretation of tryptase levels presents additional complexities, because baseline tryptase levels are elevated due to an increased mast cell burden in the developing immune system. At age 3 months, median baseline tryptase levels are reported as 14.2 ± 10.2 µg/L in atopic infants and 6.1 ± 3.54 µg/L in healthy infants. Levels gradually decline, and by age 9 to 12 months, they reach those found in older infants and young children.
Plasma histamine levels and 24-hour urine levels of histamine and its metabolite, N -methylhistamine, are measured in some clinical laboratories. Other mast cell mediators such as platelet-activating factor are measured only in research laboratories.
Treatment of the Acute Anaphylactic Episode
The essentials of prompt initial anaphylaxis treatment are outlined in Box 58-4 . It is important to have a printed protocol that is posted and rehearsed regularly, to have the essential medications, supplies and equipment for emergency treatment readily available, and to pre-designate staff responsibilities. Remove any suspected relevant trigger. Rapidly assess the patient’s airway, breathing, circulation, skin and body weight (mass). Simultaneously, call to request help from a resuscitation team in a healthcare setting or from emergency medical services (EMS) in a community setting, inject epinephrine promptly, and place the patient supine or semi-reclining in a position of comfort.
Have a printed, posted emergency protocol for recognition and treatment of anaphylaxis, and rehearse it regularly
Rapidly assess airway, breathing, circulation, skin and weight (body mass)
Call for help: emergency medical services (e.g. 9-1-1) in community settings, or resuscitation team in healthcare settings *
* Simultaneous steps: call for help, inject epinephrine and position the patient.
Inject epinephrine (adrenaline) intramuscularly in the mid-outer thigh in a dose of 0.01 mg/kg (up to a maximum dose of 0.15 mg in an infant, 0.3 mg in a child, or 0.5 mg in a teenager); if there is minimal or no response, it can be repeated several times at 5–15 minute intervals * †
† The epinephrine solution for intramuscular injection is 1 mg/mL (1 : 1,000).
‡
‡ Patients with anaphylaxis refractory to intramuscular injection of epinephrine and fluid resuscitation should preferably be transferred to the care of an emergency medicine team with the training, experience and equipment to provide skilled management of the airway and ventilation, and to provide optimal shock management by administering vasopressors safely through an infusion pump, with frequent dose titrations based on continuous electronic monitoring of cardiac rate and function and blood pressure, and monitoring of oxygenation using pulse oximetry.
Place the patient supine (or in a position of comfort if dyspneic or vomiting) and elevate the lower extremities * ; the patient should not suddenly sit up or stand and should not walk or run
When indicated:
Administer high-flow oxygen (8–10 L/minute) by face mask
Give nebulized albuterol (salbutamol), 1.25–2.5 mg every 20 minutes or continuously to relieve bronchospasm that persists despite epinephrine injection
Give IV fluids (child: 0.9% [isotonic] saline, up to 10–20 mL/kg in the first 5–10 minutes §
§ Titrate the rate of volume expansion to the cardiac rate and blood pressure; monitor for volume overload; in many pediatric emergency departments, hand-held ultrasound units are now used to monitor for and prevent volume verload.
; teen: 0.9% [isotonic] saline, 1–2 liters rapidly (5–10 mL/kg in the first 5 minutes) §
Start cardiopulmonary resuscitation
Start continuous electronic monitoring of cardiac rate and function, blood pressure, respiratory rate, and monitor oxygen saturation (by pulse oximetry) ‖
‖ If continuous monitoring is not available, monitor vital signs every 1–5 minutes.
Consider second-line medications ¶
¶ These second-line medications do not replace epinephrine.
:
methylprednisolone IV, 1–2 mg/kg/day (single dose)
H 1 antihistamines such as cetirizine by mouth, 0.25 mg/kg to a maximum of 10 mg, or diphenhydramine IV, 1 mg/kg (to a maximum of 50 mg) to relieve itch/hives persisting despite epinephrine injection
Epinephrine (Adrenaline)
Epinephrine has life-saving α 1 -adrenergic vasoconstrictor effects that prevent and relieve airway obstruction, hypotension and shock, and life-saving β 2 -adrenergic effects, including bronchodilation and suppression of mediator release from mast cells and basophils ( Box 58-4 , Table 58-2 ).
| Medications | Epinephrine * | β 2 -Adrenergic Agonist | H 1 Antihistamine † | Glucocorticoid |
|---|---|---|---|---|
| Pharmacologic effects | At α 1 -receptor ↑ vasoconstriction ↑ peripheral vascular resistance ↑ blood pressure ↓ mucosal edema, e.g. in larynx At β 1 receptor ↑ heart rate ↑ force of cardiac contraction At β 2 receptor ↓ release of mediators ↑ bronchodilation | At β 2 receptor ↑ bronchodilation | At H 1 receptor ↓ itch (skin, mucous membranes) ↓ hives and flushing | At glucocorticoid receptor Given to prevent or diminish the late-phase response and biphasic, multiphasic or protracted symptoms associated with ongoing mediator release |
| Potential adverse effects when given in standard doses | Transient anxiety, pallor, restlessness, tremor, palpitations, headache, dizziness | Tremor, tachycardia, dizziness, jitteriness | First-generation H 1 antihistamines sedate, impair cognitive function, and cause other adverse effects | Adverse effects are unlikely after 1 or 2 doses |
| Current recommendations | Treatment of first choice | In addition to epinephrine, an inhaled bronchodilator, e.g. albuterol (salbutamol) can be given for bronchospasm | Not life-saving; in addition to epinephrine can be given for relief of itching and hives, if needed; not for initial or sole treatment | Not life-saving; in addition to epinephrine , can be given for the reasons stated above; not for initial or sole treatment |
* Epinephrine by IM injection in the mid-outer thigh is the initial treatment of choice in healthcare settings and in community settings.
† Cetirizine 0.25 mg/kg to a maximum of 10 mg by mouth; for intravenous use, diphenhydramine 1 mg/kg, maximum 50 mg.
Epinephrine should be promptly injected intramuscularly in the mid-outer thigh (vastus lateralis muscle) to achieve peak plasma and tissue concentrations rapidly. The epinephrine dose is 0.01 mg/kg IM for first aid treatment (maximum 0.15 mg in an infant; maximum 0.3 mg in a child; maximum 0.5 mg in a teenager). It needs to be injected before anaphylaxis progresses to severe respiratory or cardiac symptoms. If indicated, it can be repeated several times at 5–15 minute intervals. Failure to inject it promptly increases the risk of hypoxic-ischemic encephalopathy and death. There is no absolute contraindication to epinephrine treatment ( Box 58-4 ).
The severity of an anaphylactic episode can differ from one patient to another, and in the same patient from one episode to another. At the onset, it is impossible to predict whether the patient will respond promptly to treatment, die within minutes or recover spontaneously due to endogenous secretion of epinephrine, angiotensin II and endothelin I.
Rates of epinephrine injection in anaphylaxis are improving in some pediatric emergency departments. In one study that included prospective data collection, 79% of all pediatric patients with anaphylaxis (and 100% of those with severe anaphylaxis) received epinephrine injections as initial treatment.
Fewer than 20% of pediatric patients with food-induced anaphylaxis treated with epinephrine receive a second dose, either because of failure to respond to the initial dose or because of biphasic anaphylaxis, defined as recurrence of symptoms hours after resolution of the initial symptoms, despite no further exposure to the trigger.
In a retrospective review of ED patients with anaphylaxis, most of whom were children, 17% of those who received one epinephrine injection required one or more additional injections; however, the need for subsequent injections did not correlate with obesity or overweight status. In some patients, the heights and weights used for body mass index calculations were estimated, not measured during the ED visit.
Epinephrine seldom causes serious adverse events in the pediatric population. In patients of all ages, IM epinephrine is 10 times safer than an IV bolus dose of epinephrine. IV injection can be associated with delayed epinephrine administration due to difficult venous access, and with overdose due, for example, to overly rapid infusion or use of a 1 : 1,000 epinephrine solution that has not been appropriately diluted 10-fold or 100-fold. Unless cardiopulmonary arrest is imminent or has occurred, IV epinephrine should be given by physicians skilled in vasopressor administration through an infusion pump with dose titration based on the clinical information obtained by continuous electronic monitoring of blood pressure and cardiac rate and function. Reasons for failure to inject epinephrine promptly and reasons for occasional apparent failure of response to epinephrine injections are listed in Box 58-5 .
Why Healthcare Professionals Fail to Inject Epinephrine Promptly
Lack of recognition of anaphylaxis symptoms/failure to diagnose anaphylaxis
Episode appears mild, or there is a history of previous mild episode(s) *
* Subsequent anaphylaxis episodes can be more severe, less severe or similar in severity.
Inappropriate concern about transient mild pharmacologic effects of epinephrine, e.g. tremor
Lack of awareness that serious adverse effects are nearly always attributable to epinephrine overdose or to IV administration, especially IV bolus, rapid IV infusion or IV infusion of a 1 : 1,000 epinephrine solution instead of an appropriately diluted solution (1 : 10,000 or 1 : 100,000 concentrations)
Why Patients and Caregivers Fail to Inject Epinephrine Promptly
Lack of recognition of anaphylaxis symptoms/failure to diagnose anaphylaxis
Episode appears mild, or there is a history of previous mild episode(s) *
H 1 antihistamine or asthma puffer is used initially instead, relieving early warning signs such as itch and cough, respectively
Prescription for epinephrine autoinjectors (EAIs) not provided by physician
Prescription for EAIs provided but not filled at pharmacy (e.g. if not affordable)
Patients do not carry EAIs consistently (due to size and bulk, or ‘don’t think they’ll need it’)
Patients and caregivers are afraid to use EAIs (fear of making an error when giving the injection, or a bad outcome)
Patients and caregivers are concerned about injury from EAIs
Competence in using EAIs is associated with regular allergy clinic visits; it decreases as time elapses from first EAI instruction; regular re-training is needed
Difficulty in understanding how to use EAIs (15% of mothers with no EAI experience could not fire an EAI immediately after a one-on-one demonstration)
Errors in EAI use can occur despite education, possibly related to the design of some EAIs
Why Patients Occasionally Fail to Respond to Epinephrine Injection
Delayed recognition of anaphylaxis symptoms; delayed diagnosis
Error in diagnosis: problem being treated (e.g. foreign body inhalation) is not anaphylaxis
Rapid progression of anaphylaxis †
† Median times to respiratory or cardiac arrest are 5 minutes in iatrogenic anaphylaxis, 15 minutes in stinging insect venom anaphylaxis, and 30 minutes in food anaphylaxis; however, regardless of the trigger, respiratory or cardiac arrest can occur within 1 minute in anaphylaxis.
Epinephrine † :
injected too late, dose too low on mg/kg basis, dose too low because epinephrine solution has degraded (e.g. past the expiration date, stored in a hot place, etc.)
injection route or site not optimal; dose took too long to be absorbed
patient suddenly sits up or walks or runs, leading to the empty ventricle syndrome
concurrent use of certain medications, e.g. β-adrenergic blockers
Other Life-Saving Measures
Supplemental oxygen should be administered by face mask at a flow rate of 8–10 L/minute to patients receiving repeated doses of epinephrine, and those with moderate or severe respiratory symptoms or concomitant asthma.
Isotonic (0.9%) saline is preferred for IV fluid resuscitation in anaphylaxis ( Box 58-4 ). A Cochrane review of randomized controlled trials (RCT) of IV fluid resuscitation in more than 20,000 critically ill patients (including infants and children) with distributive shock found that administration of colloids such as hetastarch or albumin conferred no survival advantage over crystalloids such as 0.9% saline.
For patients with cardiopulmonary arrest, in addition to rescue breathing at a rate of 15–20 breaths/minute, CPR guidelines now emphasize chest compressions at a rate of at least 100/minute and a depth of 4 cm in infants and 5 cm in children. In teens, they should be performed at a rate of 100–120/minute and a depth of 5–6 cm. Interruptions should be minimized ( Box 58-4 ).
Second-Line Medications
H 1 antihistamines, H 2 antihistamines, glucocorticoids and β 2 -adrenergic agonists are second-line medications in anaphylaxis and should not be substituted for epinephrine in initial treatment or given as the only treatment because they do not prevent or relieve life-threatening laryngeal edema, hypotension or shock ( Box 58-4 , Table 58-2 ).
In a Cochrane systematic review, no high-quality evidence from RCTs was found to support the use of H 1 antihistamines in the treatment of anaphylaxis. H 1 antihistamines relieve itching, urticaria, flushing and angioedema, but do not relieve life-threatening respiratory or cardiovascular symptoms. Onset of action of an oral liquid formulation of cetirizine takes 30 minutes for relief of itch and 40 minutes for relief of hives. Impairing, nonsedating H 1 antihistamines can interfere with recognition of anaphylaxis symptoms ( Box 58-4 , Table 58-2 ).
In another systematic review, no high-quality evidence from RCTs was found to support H 2 antihistamine use in anaphylaxis. If given in addition to H 1 antihistamines, they provide slightly increased relief of hives and flushing, but they do not relieve itching or life-threatening respiratory or cardiovascular symptoms.
In other Cochrane systematic reviews, no high-quality evidence from RCTs has been found to support glucocorticoid use in anaphylaxis treatment. These medications do not relieve acute symptoms and signs. Based on limited evidence, they are given to prevent biphasic anaphylaxis symptoms, which are reported to occur in 6% of pediatric patients with anaphylaxis. As their onset of action through transcription of genes encoding pro-inflammatory proteins is relatively slow (hours, not minutes), corticosteroids are good candidates for investigation in RCTs ( Box 58-4 , Table 58-2 ).
An inhaled β 2 -adrenergic agonist such as albuterol (salbutamol) can be given to patients with wheezing that persists after epinephrine injection ( Box 58-4 , Table 58-2 ).
Refractory Anaphylaxis
Patients with anaphylaxis refractory to epinephrine, supplemental oxygen and IV fluids should, if possible, be transferred to the care of a specialist team for ventilatory and inotropic support and continuous electronic monitoring of blood pressure, cardiac rate and function, and respiratory rate and oxygenation (by using pulse oximetry). Where continuous electronic monitoring and pulse oximetry are not available, vital signs should be measured at frequent regular intervals (every 1–5 minutes). Based on case reports in adults, methylene blue infusion is life-saving in anaphylaxis refractory to conventional treatment; however, there are no pediatric studies.
Observation and Monitoring
Duration of observation and monitoring in healthcare settings should be individualized; for example, patients with moderate or severe respiratory or cardiovascular symptoms require monitoring for at least 6 to 8 hours. Recommendations for safe observation periods are supported by the finding that mediators measured at intervals during anaphylaxis peak at different times, and some mediators such as histamine, tryptase, IL-6 and IL-10 correlate with delayed deterioration. At discharge, patients should be equipped with an anaphylaxis emergency action plan listing common symptoms, given (or prescribed) an EAI, with information about when, why and how to use it, and instructed to seek follow-up care ( Box 58-4 ).
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