All incidents took place during general anesthesia for major surgery. They all have in common that causes of shock, other than anaphylaxis stemming from the respective drug, could be excluded with great probability.
A 63-yr-old woman with a history of cervix carcinoma was scheduled for major hepatic resection due to metastasis. She had no allergies in her medical history. She was taking no regular medication apart from oral aspirin 100 mg. At the start of surgery, her vital signs were stable, with sinus rhythm (SR) 62/min and mean arterial blood pressure (MAP) 91 mm Hg (Table 2). As requested by the surgeon, aprotinin 1 million IU in 100 mL normal saline was infused at a rate of 3.3 mL/min without a test injection. Twenty minutes later, her hemodynamic function deteriorated rapidly: SR 130/min, MAP 30 mm Hg. An anaphylactic reaction to aprotinin was suspected, and the infusion was stopped. Resuscitation was started with epinephrine (cumulative dose 1 mg), methylprednisolone 1000 mg, infusion of 2000 mL crystalloids, 1000 mL 6% hydroxyethylstarch (molecular weight [MW] 130,000 D), and vasopressor support with norepinephrine 0.44 μg · kg−1 · min−1. With these measures, a MAP of 55 mm Hg was achieved (Table 2). A transesophageal echocardiography excluded other reasons for hemodynamic deterioration. After 2 U of vasopressin, hemodynamic function quickly stabilized, and norepinephrine was reduced to 0.044 μg · kg−1 · min−1, which resulted in SR 81/min and MAP 79 mm Hg (Table 2). Surgery was continued and terminated 4 h later without any further adverse events.
A 53-yr-old man was scheduled for major liver re-resection due to colon carcinoma. During the first liver resection, the patient had received aprotinin. There were no reports of drug or food allergies. He was taking no regular medication. Induction of general anesthesia and surgery were uneventful until the administration of the test dose of aprotinin (1 mL). Thereafter, his hemodynamic function deteriorated rapidly (Table 2): SR 160/min, MAP 30 mm Hg. Anaphylaxis due to aprotinin was suspected. Resuscitation was started with epinephrine (1 mg), methylprednisolone (1000 mg), 1500 mL crystalloid fluid, 1000 mL hydroxyethylstarch 10% MW 200,000 D, and norepinephrine (0.5 μg · kg−1 · min−1). Because hemodynamic function could not be stabilized, two units of vasopressin were administered. Subsequently, norepinephrine was reduced to 0.1 μg · kg−1 · min−1 (heart rate [HR] 84/min, MAP 75 mm Hg). Liver resection was completed 3 h later without further incidents.
A 58-yr-old man with a medical history of arterial hypertension, insulin-dependent diabetes mellitus, obesity, and vascular occlusive disease was scheduled for vascular surgery. General anesthesia and surgery were uneventful until an infusion of 1000 mg of metamizol. Within 5 min, the patient became severely hypotensive (MAP 30 mm Hg, HR 160/min), and bronchospasm and generalized erythema developed. His lungs were ventilated with 100% O2, and he was given epinephrine (total, 400 μg), methylprednisolone (1000 mg), and 1000 mL crystalloid fluids. The patient then became pulseless. Chest compressions were initiated, and epinephrine (1 mg) was given, accompanied by a norepinephrine infusion (0.4 μg · kg−1 · min−1), resulting in ventricular tachycardia (HR >200/min). Vasopressin (5 U) stabilized his hemodynamic function almost immediately: SR was restored (110/min), and MAP increased to 75 mm Hg. Thirty minutes later, the patient was tracheally extubated and he made an uneventful recovery.
A 47-yr-old man was scheduled for posterior lumbar intervertebral fusion. His medical history was unremarkable, and there were no reports of allergies. At the end of an uneventful surgical procedure, he received an infusion of metamizol (2000 mg). About 10 min later, the patient suffered cardiac arrest, accompanied by bronchospasm and generalized erythema. Chest compressions were started, and epinephrine (total, 3 mg), methylprednisolone (1000 mg), dimitenden (8 mg), ranitidine (50 mg), lidocaine (100 mg), and norepinephrine (0.75 μg · kg−1 · min−1) were injected. His MAP (30 mm Hg) was only restored after 5 U vasopressin. Two additional doses of vasopressin (5 U) were required to stabilize his hemodynamic function at SR 85/min, MAP 70 mm Hg on norepinephrine 0.04 μg · kg−1 · min−1.
During craniotomy for evacuation of an intracerebral hematoma, hemodynamic function of a 73-yr-old man remained stable. On completion of surgery, the patient received an infusion of metamizol (1000 mg). Shortly thereafter, the norepinephrine infusion had to be increased from 0.1 to 0.8 μg · kg−1 · min−1, and the metamizol infusion was stopped; however, his MAP decreased to 25 mm Hg. Epinephrine (total, 1.6 mg), methylprednisolone (1000 mg), as well as histamine H1 and H2 blocker were administered without restoring normal hemodynamic function. After 8 U of vasopressin, his hemodynamic function stabilized to a MAP of 90 mm Hg at a HR of 80/min with minimal norepinephrine support (0.1 μg · kg−1 · min−1).
A 43-yr-old woman with chronic pancreatitis was scheduled for Whipple’s procedure. Her medical history was unremarkable. Two hours after the start of combined general and epidural anesthesia, the patient was given a gelatin infusion. When 200 mL were infused, her hemodynamic function collapsed (MAP 30 mm Hg, HR increased to 95/min). There was no bronchospasm and no cutaneous reaction. The gelatin infusion was stopped immediately. Epinephrine (3 × 100 μg) was injected along with methylprednisolone (1000 mg), and 1000 mL crystalloids and 250 mL 7.2% sodium chloride/6% hydroxyethylstarch MW 200,000 D were infused rapidly. Norepinephrine was infused (1.2 μg · kg−1 · min−1) along with a further bolus of epinephrine (500 μg). After 2 U of vasopressin, her hemodynamic function stabilized quickly to MAP 65 mm Hg, SR 60/min at a norepinephrine infusion rate of 0.07 μg · kg−1 · min−1.
Pharaoh Menes’ death in 2600 BC after a wasp sting is renowned as the first report of anaphylaxis.6 However, not all Egyptologists followed this “translation” of hieroglyphs on two ebony plates.7 Instead, this account must be seen as one of the first of many anecdotes about anaphylaxis. Even today, data about the incidence and severity of anaphylaxis are limited; the estimated incidence during anesthesia ranges between 1 in 10,000 and 1 in 20,000 anesthesia cases.8
Anaphylactic shock occurring during anesthesia is lethal in about 3%–10% of cases, even in previously healthy individuals,9–11 with neuromuscular blocking drugs being responsible for more than half of these events.12 Metamizol, aprotinin, and gelatin, the drugs presumed to have caused the anaphylactic reactions in our cases, are known for their anaphylactic potential as well, with the incidence of aprotinin anaphylaxis after re-exposure reported to be 3%–17%.13,14
Anaphylactic shock is associated with systemic vasodilation and increased vascular permeability, causing a mixed distributive-hypovolemic shock pattern.15,16 Circulating blood volume may decrease by as much as 35% within 10 min because of extravasation resulting in poor venous return, hypotension, tissue hypoperfusion, and cellular anoxia.1,17
Epinephrine has been considered useful in the treatment of anaphylaxis since 1925.18 Retrospective analyses have indicated that epinephrine and fluid resuscitation are effective treatments for anaphylaxis occurring during anesthesia.17 Injection of epinephrine counteracts the systemic vasodilation and inhibits further release of anaphylactic mediators from mast and basophil cells.19–23 Luckily, most episodes of anaphylaxis respond to treatment with a single dose of epinephrine. However, evidence in the literature suggests that a poor outcome during anaphylactic shock is associated with late administration of epinephrine.2,24
There is not a great deal of evidence in the literature, however. In 2005, the American Heart Association conceded that their guidelines for treatment of anaphylaxis consisted of “therapies that are commonly used and widely accepted but are based more on consensus than evidence.”3 When little or no evidence is available, recommendations based on clinical experience and physiological rationale should be considered. Our cases demonstrate clearly that vasopressin may help if circulatory function deteriorates quickly despite adequate standard treatment.
Sympathetic excess, either therapeutic or due to endogenous release, frequently results in hemodynamically significant tachycardia. This itself can result in myocardial or cerebrovascular ischemia, decreased cardiac output, or degeneration into ventricular dysrhythmias, even in the absence of coronary artery disease.25 This scenario is exemplified by our third case, in which loss of SR occurred immediately after repeated injection of epinephrine.
Patients receiving β-blockers, such as our index patient (case 0),5 may not respond adequately to epinephrine.3,9,12,26 Regardless of the undesired effects associated with epinephrine (e.g., increased myocardial oxygen consumption, ventricular arrhythmias, and myocardial dysfunction), even high doses are recommended as first-line treatment of severe anaphylactic shock, along with aggressive intravascular volume expansion. This is followed by antihistamines and steroids and cardiopulmonary resuscitation if needed.
A significant issue faced by clinicians is how to proceed if epinephrine and fluid resuscitation are unsuccessful, or excessive use of these interventions is not suitable. In case of profound hypotension, a decision needs to be made promptly. The available evidence, although largely anecdotal, is compelling and favors an empirical addition of a potent vasoconstrictor bolus to resuscitate patients with severe anaphylaxis. Drugs successfully used have included norepinephrine,27 the α1-agonists methoxamine,28 and metaraminol,29 and the pituitary hormone vasopressin.5,30 Our cases clearly demonstrate the immediate positive effect of vasopressin in restoring normal hemodynamic function.
The primary role of vasopressin is fluid homeostasis. The strongest release stimuli are increasing plasma osmolarity and severe hypovolemia.31 When osmolarity of the extracellular fluid increases, the plasma concentration of vasopressin increases only moderately. However, vasopressin synthesis in the hypothalamus and secretion from the posterior pituitary gland are also controlled by the sympathetic nervous system; i.e., the baroreflex, so that, regardless of extracellular osmolarity, vasopressin will be secreted if cardiovascular stability is threatened (e.g., hypotension, hypovolemia). Indeed, during the initial phase of profound hypotension and shock, the plasma vasopressin concentration can reach extremely high levels, e.g., 100–500 pg/mL. In the late phase of septic and hemorrhagic shock, approximately 1/10th of maximal plasma concentrations have been measured.32
The precise mechanism of the vasopressor action induced by vasopressin remains unclear. In vasoplegic shock states, vasopressin restores vascular tone by at least four mechanisms: (1) activation of V1 receptors (previously called V1a) that mediate vasoconstriction via Gq protein activation of phospholipase C, (2) the ability to close adenosine triphosphate-sensitive K channels while activation of adenosine triphosphate-sensitive K channels produces cellular hyperpolarization resulting in vasodilatation, (3) modulation of nitric oxide, and (4) enhancement of adrenergic and other vasoconstrictor drugs.33,34 In addition, vasopressin could act during anaphylactic shock as an “anti-inflammatory drug” by antagonizing the effects of nitric oxide. During anaphylactic shock, distribution in vasoactive action of vasopressin seems to be optimal: vasoconstriction in skin, skeletal muscle, intestine and fat, with relatively less constriction of coronary and renal vasculature, and cerebral vasodilation.35,36
In hemodynamically compromised patients, circulatory homeostasis is disrupted by factors that primarily diminish venous return or those that impair compensatory responses, which restore cardiac preload.37 It has been estimated that an 80% reduction in splanchnic blood flow, e.g., from 1500 to 300 mL/min, would increase MAP by 32 mm Hg when cardiac output is 5 L/min, but only by 6 mm Hg when cardiac output is 25 L/min. Thus, the effect of translocated volume on MAP is only marginal when there is low resistance to flow, as in anaphylactic shock.38,39
Considering this pathomechanism, a potent vasopressor such as vasopressin is needed. Hemodynamic measurements in our cases 1 and 2 confirmed an immediate effect of vasopressin on systemic vascular resistance (+200%) when epinephrine and norepinephrine had failed.
Infusion of vasopressin in patients with advanced vasodilatory shock after surgery did not appear to compromise cutaneous microcirculation.40 In a recent study, reduction in regional flow in the superior mesenteric artery and microcirculatory blood flow in the upper gastrointestinal tract of septic pigs receiving low-dose vasopressin (0.06 U · kg−1 · h−1) suggest compromised mucosal blood flow.38 This could possibly contribute to gut mucosal barrier dysfunction and subsequent multiple organ failure. However, in both studies, vasopressin was infused continuously, whereas our experiences are based on administration of a few small bolus doses during a short time (total dose, 0.03–0.11 U/kg body weight). Mobilization and redistribution of splanchnic blood flow/volume by vasopressin, a hormone with a plasma half-life of about 10 to 35 min,39 seems to restore cardiac preload immediately. Assuming that the anaphylactic reaction can be stopped and coronary and cerebral perfusion pressures can be maintained, there will only be a short-term reduction in microcirculatory blood flow.
Cases 4 and 5 needed far more vasopressor support than the other patients (Table 1). Both received H1 and H2 antagonists in the hope of lessening the severity of anaphylaxis. However, like β-adrenergic drugs, histamine increases myocardial contractility by increasing myocardial levels of cAMP.41 In a rat model, pretreatment with H1-receptor blockade, with or without concurrent H2-receptor blockade, worsened hypotension and decreased survival time.42 In anaphylactic shock, the need for more extensive vasopressor support should be expected in patients receiving β-blockers or those who received H1 and H2 antagonists.
In our opinion, there are three principal therapeutic principles in the treatment of anaphylactic shock:
1. Termination of mast cell degranulation and interruption of the mediator-related vicious cycle.
2. Pharmacological modulation of vascular tone (e.g., reduction of peripheral blood flow demands).
3. Intravascular volume replacement.
Appropriate measures are
1. Discontinuation of the causative agent and administration of epinephrine,
2. Administration of vasopressin, and
3. Reasonable administration of IV fluids.
We advocate that our recommendations regarding the management of anaphylactic shock be incorporated in the upcoming guidelines for cardiopulmonary resuscitation and emergency cardiovascular care.
The authors thank Don Bredle, PhD (Professor for Kinesiology, Department of Kinesiology, University of WI-Eau Claire, WI), for his helpful suggestions in the preparation of this article.
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© 2008 International Anesthesia Research Society
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