Anaphylaxis: Implications of Monoclonal Antibody Use in Oncology

Mechanisms of Anaphylaxis and Illustration of Severity

Anaphylaxis may occur as an abrupt event during the course of other therapies; it has been examined systematically in only a few human studies. Two of these were investigations of venom immunotherapy—one conducted at Johns Hopkins University on the physiologic manifestations of anaphylaxis to stinging insects,[14] and the other in Australia on ant venom anaphylaxis.[15]

effectiveness of venom immunotherapy for the treatment of systemic allergic reactions to insect stings as judged by protection from a deliberate sting.[16] Patients in this study were divided into three categories: one group was treated with placebo, the second with immunization using whole insect body extracts, and a third with insect venom. At the end of the treatment protocol, all patients were subjected to an insect sting. The patients treated with venom were protected against allergic reactions after sting challenge, and this therapy was remarkably superior to placebo and whole-body extract treatment. In this study, 7 of 12 placebo patients and 7 of 11 whole-body extract–treated patients experienced systemic allergic reactions whereas only 1 of 18 patients immunized with venom experienced an acute allergic reaction.[16] Reactions after sting challenge in the 14 patients from the placebo and whole insect body extract–treated groups included urticaria in 11 patients and systemic anaphylaxis in 3 patients.

The courses of the reactions in two of the three patients with severe anaphylaxis from the Johns Hopkins immunotherapy study are shown in Figures 1 and 2.[14] Following the sting, patient 1 (Figure 1) complained of dizziness and nausea, and his systolic blood pressure sharply decreased from a baseline value of 140 mm Hg to approximately 60 mm Hg at 4 minutes. Placing the patient in the Trendelenburg position did not affect his blood pressure, but subcutaneous administration of epinephrine(Drug information on epinephrine) was associated with a return to baseline blood pressure during the next 2 to 3 minutes.

Figure 2 shows the course of anaphylaxis in a second, more severely affl icted patient.[14] No cutaneous manifestations were observed. Treatment was begun with a rapid infusion of physiologic saline and plasma protein fraction (human) 5%, USP (Plasmanate) immediately followed by intravenous administration of 0.5 mg epinephrine. Intravenous treatment with one unit of Plasmanate, 1 liter of saline, and a total of 2 mg of epinephrine did not effect improvement in the mean arterial pressure or pulse pressure during the initial 24 minutes. Subsequently, brief 1- to 2-minute rises in blood pressure occurred, associated with bolus administration of intravenous epinephrine. At 38 minutes, the mean arterial pressure was still 37 mm Hg, and a 2-minute infusion of norepinephrine(Drug information on norepinephrine) was administered followed by a rise in blood pressure to 100/45 mm Hg. Thereafter, the arterial pressure continued to rise, but neither it nor the pulse rate had returned to baseline levels during the first 90 minutes of anaphylaxis.

Although the patient denied chest pain, a 12-lead electrocardiogram revealed ST segment depression in leads 2, 3, and aVF. Frequent episodes of vomiting occurred during shock, usually associated with epinephrine injections. Although no obvious respiratory symptoms, such as tachypnea or wheezing, were observed, the PaO2 fell to 52 mm Hg during the anaphylactic reaction and only returned to 86 mm Hg 2 hours after the onset of anaphylaxis and its treatment. The total fl uid and epinephrine therapy administered consisted of 875 mL of Plasmanate (100 mL of Plasmanate contains 5 g of plasma protein, 88% albumin), 1.5 liters of normal saline, and 3.5 mg of epinephrine.

Patients 2 and 3 showed evidence of intravascular coagulation with decreases of factor V, factor VIII(Drug information on factor viii), and fibrinogen. These findings indicate that the clotting system is activated during severe anaphylaxis and have implications for the treatment of prolonged anaphylactic reactions.

Measurements of plasma histamine during anaphylaxis are shown in Figure 3.[14] The plasma histamine levels in normal individuals were less than 2 ng/mL, whereas in patients experiencing any insect sting with no symptoms or with only urticarial reactions, plasma histamine levels were 2 to 3 ng/mL. Figure 3 shows that plasma histamine levels were dramatically increased in the three patients experiencing severe anaphylaxis and appeared to correlate with the severity of the anaphylactic reaction.

For example, patient 1, with the mildest of the reactions, had a plasma histamine level of approximately 15 ng/mL, whereas patient 3 with the most severe anaphylactic reaction had a level of approximately 140 ng/mL. Note further that the levels of histamine in the patient with the most severe anaphylaxis were still approximately 80 ng/mL at 30 minutes and remained increased for at least 40 minutes.[14]

The Johns Hopkins study of severe anaphylaxis was conducted on a relatively small number of patients and without a defined clinical management protocol. The Australian study on ant sting anaphylaxis analyzed venom immunotherapy in patients with a history of systemic reactions to Myrmecia pilosula, the jack jumper ant responsible for 90% of ant venom anaphylaxis in southeastern Australia.[17] This study showed that venom immunotherapy is highly effective for the prevention of ant venom anaphylaxis. Allergic patients receiving venom immunotherapy were protected from reactions following a deliberate sting. None of the 23 patients had reactions. In contrast, 21 of 29 patients receiving placebo experienced reactions of varying severity but not hypotension, and 8 reactions were associated with hypotension, and thus severe anaphylaxis.

This study prospectively evaluated treatment of anaphylaxis with intravenous adrenaline (epinephrine) and volume resuscitation.[15] Figure 4 shows the course and treatment of anaphylaxis in two patients. Patient 2 developed sudden visual loss, severe headache, and hypotension about 4 minutes after the sting challenge. Despite rapid infusion of 2 liters of normal saline over 5 minutes and adrenaline infusion (10 μg/mL, 5–15 μg/min), progressive bradycardia occurred and was treated with atropine(Drug information on atropine) 600 μg intravenously. The patient gradually improved over the following 5 to 10 minutes (Figure 4).

Patient 3 complained of a ‘‘lump in the throat’’ about 20 minutes after the sting challenge, followed 3 minutes later by unconsciousness, agonal respirations, and absent pulses. Adrenaline and saline infusions and atropine effectively restored normal vital signs. One hour after initiation of treatment, the adrenaline infusion was stopped; however, fl orid erythema developed with a fall in blood pressure and therapy was resumed. The patient subsequently recovered uneventfully.[15]

Treatment of Anaphylaxis

The essentials of anaphylaxis treatment have recently been reviewed [5,6,18] and are summarized in Table 3. Patients experiencing an acute anaphylactic reaction may say they feel odd or uncomfortable, or express a need to urinate or defecate. Such relatively nonspecific symptoms should be taken seriously and the patient evaluated by measuring blood pressure and pulse rate.

Once anaphylaxis is suspected, the patient’s airway, breathing, circulation, and level of consciousness should be assessed. If blood pressure is depressed, the patient should immediately be placed in the Trendelenburg position and an injection of epinephrine given intramuscularly into the lateral thigh muscle (vastus lateralis). A study of epinephrine plasma levels following intramuscular injection into the arm and into the leg compared to subcutaneous injection demonstrated the importance of injecting epinephrine into the lateral thigh muscle.[19] The typical dose of epinephrine is 0.3 mg and can be repeated every 5 to 15 minutes. While administration of intramuscular epinephrine will be sufficient treatment for many patients with anaphylaxis, failure of a prompt response should be quickly followed by establishing IV access for administration of normal saline and epinephrine.

For intravenous epinephrine administration, a concentration of 10 μg/mL (1:100,000), given by infusion and titrating the dose depending on the response and side effects, is the recommended treatment.[18] Figure 2 shows the need for frequent bolus dosing with intravenous epinephrine in patients with serious anaphylaxis. The use of continuous infusion provides the ability to titrate administration according to need (see legend to Figure 4). Normal saline should be given promptly, and rapid infusion of 1,000 mL over 1 to 3 minutes is recommended, repeating this dose as needed. Oxygen should be administered because of the known occurrence of hypoxia.

Studies in anesthetized ragweedsensitized dogs showed that epinephrine treatments by subcutaneous, intramuscular, and intravenous bolus were ineffective in preventing cardiovascular collapse. In contrast, a titrated intravenous infusion produced a sustained improvement.[20] It is important to keep in mind that overtreatment with epinephrine can lead to serious epinephrine toxicity, as manifested by tachycardia, hypertension, and the possibility of myocardial infarction and stroke.

The treatments discussed above and summarized in Table 3 are the critical elements of therapy. Other therapies, such as atropine administration, should be reserved for patients with bradycardia.[15] Therapies such as administration of antihistamines, including both blockers of the H₁ receptor and H₂ histamine receptors can be considered, although anaphylaxis is dependent on numerous mediators that are not affected by these medications. Administration of glucocorticoids is not a critical aspect of the treatment of anaphylaxis and should be considered only after all of the therapies described in Table 3 have been implemented.

Patients receiving beta-blockers have shown increased severity of anaphylaxis or resistance to treatment. Should a patient experiencing anaphylaxis also be taking beta-blockers, one should contemplate administration of glucagon(Drug information on glucagon), which is considered to activate adenylate cyclase independent of the beta receptor.[5] Patients taking glucagon may vomit, so precautions for protecting the airway should be taken. Biphasic Anaphylactic Reactions After treatment of the acute anaphylactic reaction, an observation period of at least 4 to 6 hours is recommended for mild to moderate reactions. For serious reactions, one should consider a more prolonged observation or hospitalization. The rationale for the prolonged observation is the occurrence of persisting manifestations of anaphylaxis once the effects of epinephrine have worn off. Another concern is a biphasic reaction. A biphasic anaphylactic reaction is any reaction occurring after complete resolution of immediate symptoms.

Various series have shown frequencies of biphasic reactions ranging from 3% to 20%.[6] Currently, no reliable clinical indicators identify patients at risk from a biphasic reaction, although a biphasic reaction may be more likely after an initial severe reaction and possibly more likely when epinephrine administration has been delayed.[21] The majority of the delayed reactions are mild and present with essentially the same features as the immediate reaction. The literature shows that delayed reactions have occurred within 24 hours. Patients at risk for a biphasic reaction or a delayed anaphylactic reaction should carry personal epinephrine injection devices and be instructed in their use.