Anaphylaxis

Background

Portier and Richet first coined the term anaphylaxis in 1902 when a second vaccinating dose of sea anemone toxin caused a dog's death. The response was the opposite of prophylaxis and thus was referred to as anaphylaxis, meaning without protection.

Anaphylaxis is an acute systemic reaction caused by the release of mediators from mast cells and basophils. More than one organ system should be involved for the reaction to be considered anaphylaxis. The most common organ systems involved include the cutaneous, respiratory, cardiovascular, and gastrointestinal systems.

The phrase anaphylactic reaction usually refers to a type I hypersensitivity reaction with mast cell and basophil degranulation mediated by antigen binding of specific immunoglobulin E (IgE). The term anaphylactoid reaction refers instead to a non–IgE-mediated mechanism of mast cell/basophil activation. The term anaphylaxis refers to the physiologic events due to either mechanism.

Pathophysiology

When mast cells and basophils degranulate, whether by IgE- or non–IgE-mediated mechanisms, preformed histamine and newly generated leukotrienes and prostaglandins are released. The physiologic responses to these mediators include smooth muscle spasm in the respiratory and gastrointestinal tract, vasodilation, increased vascular permeability, and stimulation of sensory nerve endings. These physiologic events lead to the classic symptoms of anaphylaxis: flushing; urticaria; pruritus; bronchospasm; and abdominal cramping with nausea, vomiting, and diarrhea. Hypotension and shock can result from intravascular volume loss, vasodilation, and myocardial dysfunction. Increased vascular permeability can result in a shift of 50% of vascular volume to the extravascular space within 10 minutes.

Additional mediators activate other pathways of inflammation: the neutral proteases, tryptase and chymase; proteoglycans such as heparin and chondroitin sulfate; and chemokines and cytokines. These mediators can activate the kinin system, the complement cascade, and coagulation pathways. Working together, these inflammatory pathways recruit other inflammatory cells, including eosinophils and lymphocytes, resulting in prolonged, biphasic, and/or intensified reactions.

Despite the potential contribution of multiple mediators, histamine infusion alone is sufficient to produce most of the symptoms of anaphylaxis. Histamine mediates its effects through activation of histamine 1 (H1) and histamine 2 (H2) receptors. Vasodilation is mediated by both H1 receptors and H2 receptors. H2 receptors exert a direct effect on vascular smooth muscle, whereas H1 receptors stimulate endothelial cells to produce nitric oxide. Cardiac effects of histamine are largely mediated through H2 receptors. H1 receptors are primarily responsible for extravascular smooth muscle contraction (eg, bronchial tree, gastrointestinal tract). Both H1 receptors and H2 receptors mediate glandular hypersecretion.

Frequency

United States

The true incidence is unknown. Moneret-Vautrin et al recently reviewed the published literature and stated that severe anaphylaxis affects at least 1-3 persons per 10,000 population. Neugut et al estimated that 1-15% of the US population are at risk of experiencing an anaphylactic or anaphylactoid reaction. They estimated that the rate of actual anaphylaxis to food was 0.0004%, 0.7-10% for penicillin, 0.22-1% for radiocontrast media (RCM), and 0.5-5% after insect stings.

A population-based study from Olmsted County, Minnesota, detected an average annual incidence of anaphylaxis of 21 cases per 100,000 person-years. Ingestion of a suspect food was the cause in 36% of cases; a medication, allergy immunotherapy, or a diagnostic agent was the cause in 17% of cases; and an insect sting was the cause in 15% of cases. Thirty-two percent of cases were considered idiopathic. Episodes of anaphylaxis occurred more frequently in the summer months of July through September, which is attributable to insect stings.

In a study of patients referred to an allergy practice in Memphis, Tennessee, food was the cause of anaphylaxis in 34% of patients, medications in 20%, and exercise in 7% (insect sting anaphylaxis was excluded from the study). The cause of anaphylaxis was undetermined in 37% of patients. A separate study estimated the number of cases of idiopathic anaphylaxis in the United States to be 20,000-47,000 cases per year (approximately 8-19 episodes per 100,000 person-years).

International

Geographic location is not thought to exert a major effect on incidence. Two European studies detected a lower average annual incidence than found in the Olmsted County study (3.2 cases of anaphylactic shock per 100,000 person-years in Denmark; 9.8 cases of out-of-hospital anaphylaxis per 100,000 person-years in Munich, Germany). Rates in Europe range from 1-3 cases per 10,000. Simons and colleagues examined the rate of epinephrine prescriptions for a population of 1.15 million patients in Manitoba, Canada, and found that 0.95% of this population was prescribed epinephrine, an indicator of perceived risk that future anaphylaxis may occur.

Mortality/Morbidity

• Fatalities from anaphylaxis are infrequent but not rare. Estimates range from 0.65-2% of patients with anaphylaxis. The case-fatality rate from the Olmsted County study was 0.65%. Severe reactions to penicillin occur with a frequency of 1-5 cases per 10,000 patient courses, with fatalities in 1 case per 50,000-100,000 courses. Insect stings cause 25-50 deaths per year. Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital and are estimated to cause 125 deaths per year in the United States. Anaphylactoid reactions to RCM were estimated to have caused 500 deaths in 1982, although this number has likely decreased because of increased awareness and the use of pretreatment regimens and/or lower osmolar agents for patients with a history of RCM reaction.

• In the United Kingdom, one half of fatal anaphylaxis episodes have an iatrogenic cause (ie, anesthesia, antibiotics, or radiocontrast), while foods and insect stings each account for a quarter of the fatal episodes.

• The most common causes of death are cardiovascular collapse and laryngeal edema.

Race

• Race has no known effect on the risk of anaphylaxis.

Sex

• In the Olmsted County study, men and women were equally affected.

• The Memphis study showed a slight female predominance.

• Earlier studies have suggested that episodes of anaphylaxis to intravenous muscle relaxants, aspirin, and latex are more common in women, while insect sting anaphylaxis is more common in men. These sex discrepancies are likely a function of exposure frequency.

Age

• Anaphylaxis can occur at any age. In the Olmsted County study, the age range was 6 months to 89 years. The mean age was 29 ±19 years. The Memphis study had an age range of 12-75 years, with a mean of 38 years.

• Simons and colleagues noted the highest frequency of prescriptions for epinephrine in boys aged 12-17 months (5.3%). The rate was 1.4% for those younger than 17 years, 0.9% for those aged 17-64 years, and 0.3% for those aged 65 years or older.

• Severe food allergy is more common in children than in adults. However, since severe food allergy often persists into adulthood, the frequency in adults may be rising.

• Anaphylaxis to RCM, insect stings, and anesthetics has been reported to be more common in adults than in children. Whether this is a function of exposure frequency or increased sensitivity is unclear.

Other risk factors:

• Atopy is risk factor. In the Olmsted County study, 53% of the patients with anaphylaxis had a history of atopic diseases (eg, allergic rhinitis, asthma, atopic dermatitis). The Memphis study detected atopy in 37% of the patients. Other studies have shown atopy to be a risk factor for anaphylaxis from foods, exercise-induced anaphylaxis, idiopathic anaphylaxis, radiocontrast reactions, and latex reactions. Underlying atopy does not appear to be a risk factor for reactions to penicillin or insect stings.

• Route and timing of administration affect anaphylactic potential. The oral route of administration is less likely to cause a reaction, and the reaction is usually less severe, although fatal reactions occur following ingestions of foods by someone who is allergic. The longer the interval between exposures, the less likely an anaphylactic (IgE-mediated) reaction will recur. This is thought to be due to catabolism and decreased synthesis of specific IgE over time. This does not appear to be the case for anaphylactoid reactions.

• Asthma is a risk factor for fatal outcomes.

• Delay in administration of epinephrine is also a risk factor for fatal outcomes.

Treatment

Medical Care

Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Basic equipment and medication should be readily available in the physician's office. Lieberman et al have recently described this in great detail.

• For the initial assessment, check the airway closely and secure as needed. Assess the level of consciousness and obtain blood pressure, pulse, and oximetry values.

• Place the patient in the supine position, and begin supplemental oxygen.

• Remove the source of the antigen if possible (eg, stinger after bee sting).

• A tourniquet applied to the extremity with the antigen source can retard antigen exposure to the systemic circulation. Release the tourniquet every 5 minutes, and do not leave it in place for longer than 30 minutes.

• Administer intramuscular epinephrine into a different extremity immediately. Epinephrine maintains the blood pressure, antagonizes the effects of the released mediators, and inhibits further release of mediators from mast cells and basophils. Physicians are sometimes reluctant to administer epinephrine for fear of adverse effects. However, epinephrine is usually well tolerated and is lifesaving. Anaphylactic deaths correlate with a delay in the administration of epinephrine. The initial dose can be repeated as necessary, depending on the response.

• Intramuscular administration of epinephrine results in higher and more rapid maximum plasma concentrations of epinephrine compared with the subcutaneous route in both rabbit animal models and a small number of children.

• Antihistamine therapy is considered adjunctive to epinephrine. Administer both an H1 blocker and an H2 blocker because studies have shown the combination to be superior to an H1 blocker alone in relieving the histamine-mediated symptoms. Diphenhydramine and ranitidine are an appropriate combination.

• Establish intravenous access for (1) the administration of adjunctive medications and (2) the administration of intravenous fluids to maintain blood pressure, if needed.

• Racemic epinephrine via a nebulizer can be used to reduce laryngeal swelling but does not replace intramuscular administration of epinephrine.

• Treat bronchospasm that has not responded to subcutaneous epinephrine with inhaled beta2-adrenergic agonists such as albuterol.

• Corticosteroids do not have an immediate effect on anaphylaxis; however, administer them early to prevent a potential late-phase reaction (biphasic anaphylaxis).

• Maintaining proper blood pressure is important in the treatment of anaphylactic reactions.
• • Hypotension is often the most difficult manifestation of anaphylaxis to treat.

  • Persons with protracted hypotension must be monitored in an intensive care unit setting.

  • Because hypotension in anaphylaxis is due to a dramatic shift of intravascular volume, the fundamental treatment intervention (after epinephrine) is aggressive intravenous fluid administration. Large volumes of crystalloid may be required, potentially exceeding 5 L. The exact amount should be individualized, based on blood pressure recovery and urine output. In severe cases, invasive monitoring of central venous pressure and cardiac output may be required.

  • Pressors may also be needed to support blood pressure. Intravenous epinephrine (1:10,000 preparation) can be administered as a continuous infusion, especially when the response to intramuscular or subcutaneous epinephrine (1:1000) is poor. Dopamine infusion can also be used.

  • Military antishock trousers have also been used successfully to maintain blood pressure in persons with anaphylaxis.

  • Patients with anaphylaxis who are taking a beta-adrenergic blocking agent (eg, for hypertension, migraine prophylaxis) can have refractory anaphylaxis that is poorly responsive to standard measures. Glucagon is the drug of choice in this situation. It has both inotropic effects and chronotropic effects on the heart by increasing intracellular levels of cyclic adenosine 3,'5'-monophosphate, independent of the beta-adrenergic receptors.

• Respiratory compromise in the acute setting (ie, respiratory failure) mandates endotracheal intubation. If the endotracheal tube cannot be passed because of severe laryngeal edema, tracheotomy is required.

• For vascular collapse, depending on severity, refractory hypotension may require placement of an invasive cardiovascular monitor (Swan-Ganz catheter) and arterial line.

• Treatment of cardiopulmonary arrest is discussed elsewhere.

• Anti-IgE (omalizumab) complexes circulating (but not receptor-bound) IgE and keeps it from binding to its receptors. It does not remove IgE bound to receptors and takes several months to have a substantial effect. It is not to be used in an acute setting.

Surgical Care

This is limited to the possible need for surgical airway intervention.

Consultations

• Most patients with an episode of anaphylaxis should be referred to an allergist/immunologist for further evaluation and treatment. Despite the logic of this recommendation, the Olmsted County study demonstrated that only 52% of patients were referred for such a consultation.

• In the case of severe anaphylaxis requiring admission to the intensive care unit, an intensivist should be consulted.

• Prophylaxis for intravenous RCM involves prednisone (or hydrocortisone), diphenhydramine, ranitidine (or another type 2 antihistamine), with or without ephedrine, and/or the use of a different contrast agent.
• • Administer prednisone (50 mg PO) or hydrocortisone (200 mg IV) at 12, 6, and 1 hour before the radiocontrast procedure.

  • Administer diphenhydramine (50 mg PO/IV) and ranitidine (150 mg PO or 50 mg IV) with or without ephedrine (25 mg PO) 1 hour before the procedure. Ephedrine should not be used in patients with hypertension, CAD, older patients with a strong family history of CAD, arrhythmia, thyrotoxicosis, monoamine oxidase inhibitor use, or porphyria.

  • Consider using a contrast agent with lower osmolarity.

• Desensitization procedures can be used for a medication allergy.
• • Published protocols exist for desensitization to various medications. Consult an allergist/immunologist skilled in desensitization procedures to perform these protocols. The patient should usually be in an intensive care unit setting with intravenous access and epinephrine and parenteral diphenhydramine at the bedside. Obtain informed consent prior to the procedure. Anaphylactic reactions that may result in death is a potential complication of this procedure.

  • A typical desensitization protocol for beta-lactam antibiotics involves starting at a dose that is 6-7 logs below the usual therapeutic dose and increasing the dose by 1 log every 20-30 minutes.

• Pretreatment protocols do not work for IgE-mediated anaphylaxis.

• Patients should be given epinephrine autoinjectors and should be instructed in the use of the device. Good evidence suggests that physicians underprescribe epinephrine and that patients (or their parents) fail to use epinephrine as quickly as possible.

Diet

The only dietary consideration is the future avoidance of a suspect or culprit food.

Activity

Once the acute episode of anaphylaxis has resolved, no activity limitations are necessary, with the rare exception of exercise-induced anaphylaxis.

Medication

The primary medication for acute anaphylaxis is epinephrine. All other therapies are adjunctive, including antihistamines, corticosteroids, and albuterol. Dopamine may be required to maintain blood pressure, and glucagon can be used in patients taking beta-blockers who have refractory anaphylaxis.

Drug Category: Adrenergic agonists

These agents help maintain blood pressure, antagonize effects of released mediators, and prevent further release of mediators.

Drug Name	Epinephrine (Adrenalin, EpiPen, EpiPen Jr)
Description	DOC for treating anaphylaxis. Has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.
Adult Dose	0.3-0.5 mL (0.3-0.5 mg) of 1:1000 solution IM; administer fraction of total dose (0.1-0.2 mL) at site of antigenic exposure, if accessible, and 0.3 mL into different extremity (thigh muscle is preferable); repeat prn, depending on response 1-2 mL (0.1-0.2 mg) of 1:10,000 preparation (0.1 mg/mL) IV q5-20min prn or continuous IV infusion of 2-10 mcg/min for more critical situations
Pediatric Dose	0.01 mg/kg IM prn 2 mcg/min IV infusion
Contraindications	No absolute contraindications in life-threatening anaphylaxis; documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; during labor (may delay second stage of labor)
Interactions	Beta-blockers antagonize physiologic effects; increases toxicity of alpha-blocking agents and halogenated inhalational anesthetics; TCAs and MAOIs potentiate effects; digoxin potentiates arrhythmogenic effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in elderly persons and those with prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, or cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias; adverse effects include anxiety, headache, palpitations, and hypertension

Drug Category: Antihistamines

These agents block effects of released histamine at H1 receptor, thereby treating flushing, urticarial lesions, vasodilation, and smooth muscle contraction in bronchial tree and GI tract.

Drug Name	Diphenhydramine (Benadryl)
Description	Widely available with a long history of efficacy and relative safety. FDA indication for anaphylaxis. IV administration provides faster onset of action.
Adult Dose	10-50 mg IV/IM q4h prn; IV rate not to exceed 25 mg/min; not to exceed 400 mg/d 25-50 mg PO q6-8h prn; not to exceed 400 mg/d
Pediatric Dose	12.5-25 mg PO tid/qid or 5 mg/kg/d or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d 5 mg/kg/d IV/IM or 150 mg/m2/d divided qid; IV rate not to exceed 25 mg/min; daily dose not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; concurrent use of MAOIs
Interactions	Potentiates effect of alcohol and other CNS depressants (eg, hypnotics, sedatives, tranquilizers); MAOIs prolong and intensify anticholinergic effects of antihistamines
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in breastfeeding and newborns secondary to risk of convulsions and death in the baby; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; adverse effects include drowsiness, reduced mental alertness, and xerostomia

Drug Category: Histamine2-receptor antagonists

These agents block effects of released histamine at H2 receptors, thereby treating vasodilation, possibly some cardiac effects, and glandular hypersecretion. H2 blockers with H1 blockers have additive benefit over H1 blockers alone in treating anaphylaxis. Ranitidine (Zantac) probably preferred over cimetidine (Tagamet) in anaphylaxis in light of the risk for hypotension with rapidly infused cimetidine and the multiple, complex drug interactions with cimetidine. Famotidine (Pepcid) IV is another good alternative.

Drug Name	Ranitidine (Zantac)
Description	H2 antagonist, which, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.
Adult Dose	50 mg/dose IV/IM q6-8h IV bolus administration: Dilute 50 mg in 20 mL NS (concentration of 2.5 mg/mL), inject at rate not >4 mL/min (5 min) Alternatively, 150 mg PO bid; not to exceed 600 mg/d
Pediatric Dose	<12>12 years: 1.25-2.5 mg/kg/dose PO q12h; not to exceed 300 mg/d 0.75-1.5 mg/kg/dose IV/IM q6-8h; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; if CrCl is <50>5 d may cause ALT elevations; case reports suggest ranitidine may precipitate acute porphyria

Drug Category: Bronchodilators

These agents stimulate beta2-adrenergic receptors in bronchial smooth muscle, causing bronchodilation.

Drug Name	Albuterol (Proventil, Ventolin)
Description	Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.
Adult Dose	Nebulizer: 2.5-5 mg q4-6h in 2-5 mL sterile NS or water; to make solution, dilute 0.5 mL (2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS (more frequent administration can be used for severe bronchospasm) MDI: 1-2 puffs q4-6h; more frequent administration can be used for severe bronchospasm
Pediatric Dose	Nebulizer <5>5 years: Administer as in adults MDI <12>12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents; may exacerbate diuretic-induced hypokalemia; may decrease digoxin levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular disorders (eg, coronary artery disease, cardiac arrhythmias, severe hypertension), hyperthyroidism, diabetes mellitus, and seizure disorder; adverse effects include tremor and mild tachycardia

Drug Category: Corticosteroids

Bind to the intracellular glucocorticoid receptors in inflammatory cells with multiple downstream immunomodulating effects. Glucocorticoids ameliorate delayed effects of anaphylaxis.

Drug Name	Methylprednisolone (Solu-Medrol)
Description	May help prevent late-phase allergic reactions (biphasic anaphylaxis). No immediate effects.
Adult Dose	Loading: 125-250 mg IV over several min Maintenance: 0.25-1 mg/kg/dose IV q6h for up to 5 d
Pediatric Dose	Loading: 2 mg/kg IV Maintenance: Administer as in adults
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics; concomitant use with NSAIDs increases risk of peptic ulcer
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use (most are unlikely with short-term use for acute anaphylaxis)

Drug Category: Positive inotropic agents

These agents help maintain blood pressure independent of adrenergic receptors by increasing intracellular levels of cyclic AMP. In addition, stimulate release of endogenous catecholamines.

Drug Name	Glucagon (GlucaGen)
Description	DOC for severe anaphylaxis in patients taking beta-blockers (should be used in addition to epinephrine, not as a substitute). Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Exerts opposite effects of insulin on blood glucose. Elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources, such as proteins and fats (gluconeogenesis). Increases hydrolysis of glycogen to glucose (glycogenolysis) in liver in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Also increases force of contraction in heart and has a relaxant effect on GI tract. Dose used for anaphylaxis is higher than usual dose of 1 mg (1 U) IV/IM/SC used to treat hypoglycemia.
Adult Dose	1-5 mg IV bolus, followed by infusion of 5-15 mcg/min titrated against blood pressure
Pediatric Dose	Hypoglycemia <20>20 kg: 1 mg (1 U) IV/IM/SC Anaphylaxis: May need higher doses
Contraindications	Documented hypersensitivity; pheochromocytoma
Interactions	Effects of anticoagulants may be enhanced (although onset may be delayed); monitor prothrombin activity for signs of bleeding in patients receiving anticoagulants and adjust dose accordingly
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse effects include nausea, vomiting, sudden and marked increase in blood pressure in patients with pheochromocytoma, and severe rebound hypoglycemia in patients with insulinoma

Drug Category: Vasopressors

These agents are useful as adjunctive therapy to IV fluids to treat refractory hypotension from anaphylaxis.

Drug Name	Dopamine (Intropin)
Description	Considered DOC for anaphylaxis-induced refractory hypotension. Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and peripheral vasoconstriction produced by higher doses. More than 50% of patients are satisfactorily maintained on doses <20>
Adult Dose	2-5 mcg/kg/min IV; after initiating therapy, increase dose by 1-4 mcg/kg/min q10-30min until optimal response obtained; not to exceed 50 mcg/kg/min
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; pheochromocytoma; ventricular fibrillation
Interactions	Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure closely during infusion; prior to infusion, correct hypovolemia; monitoring central venous pressure or left ventricular filling pressure may be helpful for detecting and treating hypovolemia; extravasation can cause necrosis of surrounding tissue, which is treated with phentolamine injected at the site