Treatment of Anaphylactic Shock: Where Is the Evidence?

In this issue of Anesth Analg, Dr. Schummer et al. present six patients with anaphylactic shock who experienced severe cardiovascular failure that was barely responsive to conventional fluid and catecholamine therapy, but promptly improved after arginine vasopressin (AVP) therapy.1 The case presentations are convincing and leave little doubt that the patients suffered from anaphylactic shock, and that they would have improved as rapidly with a therapy other than AVP. As suggested by the authors, it is unlikely that evidence-based medicine-derived criteria are useful tools to determine an effective therapy for anaphylaxis and anaphylactic shock. Because allergic symptoms can vary in their quality and extent and virtually all cases of anaphylactic shock occur unpredictably, it will be difficult to conduct prospective, randomized, controlled trials for this condition. To summarize the clinical evidence for therapeutic interventions recommended by the European Resuscitation Council for the treatment of anaphylaxis and anaphylactic shock,2 we have performed a concise literature review. Medline was searched for clinical studies using the search terms “anaphylaxis” and “anaphylactic shock” together with “antihistamine,” “glucocorticoids/corticoids,” “epinephrine,” or “fluids.” Where possible, the evidence was graded as suggested by the Oxford Centre for Evidence-based Medicine3 (Table 1). Only studies with clinical study end points were classified; articles revealing exclusively in vitro or animal data were not graded.Table 1: Levels of Evidence as Suggested by the Centre for Evidence Based Medicine3Table 2 displays the results of our Medline search. Although several entries were found for single treatments, most were case reports, expert opinions, or reviews. Conclusively, the current evidence for the treatment of anaphylaxis and anaphylactic shock can simply be deemed insufficient, as shown here:Table 2: Results of the Medline Search on Drug Therapy in Anaphylaxis/Anaphylactic Shock Antihistamines—Level C. However, there is Level A evidence that the combination of H1 and H2 antihistamines is more effective in the resolution of allergic cutaneous syndromes than H1 antagonists alone, Epinephrine—Level C, Corticoids—Level D, and Fluids—Level D Accordingly, a critical appraisal of the literature for the treatment of anaphylaxis with antihistamines performed by the Cochrane Study Group also could not identify a study that satisfied the inclusion criteria.4 When the study by Schummer et al. is added to the current literature, the evidence for the use of AVP in severe anaphylactic shock could be similarly graded as Level C. For the aforementioned reasons, evidence-based medicine seems to be an inappropriate scientific instrument for determining the best treatment for patients suffering from anaphylaxis or anaphylactic shock. Considering these points, the question raised by Schummer et al. should not be “Is AVP better than epinephrine?” but rather “Can AVP be beneficial for selected patients with severe anaphylaxis?” As shown by the authors in these six cases, we have to answer the latter question with “obviously, yes!” Critics may well argue that because no control group was present, it is possible that just as many would have survived if conventional therapy had simply been continued. This is true and cannot be excluded; however, it can be claimed that more and higher epinephrine dosages could have been administered in most cases. This may have not only improved cardiovascular function but also decreased histamine liberation. Nonetheless, the clinical scenarios presented pointed much more to an imminent cardiovascular collapse after prolonged unsuccessful standard shock therapy. Furthermore, all patients experienced excessive vasodilatation as the main pathophysiologic feature of shock. A vasopressor such as AVP can only be expected to be helpful if a critical degree of vasodilatation has occurred. Contrary to what the authors suggest, it would be wrong to inject AVP simply for the sake of maintaining arterial blood pressure, e.g., if myocardial dysfunction is the main component of hemodynamic dysfunction. Although this is rare and difficult to diagnose,5,6 the presence of chronic heart failure must always alert the attending physician that the patient may be threatened by a low cardiac output syndrome in acute stress situations such as severe anaphylaxis. What could be the potential benefits of using additional AVP instead of excessively increasing catecholamine vasopressors? Because of its non-adrenergic properties, AVP can dramatically reduce high and potentially toxic catecholamine dosages in advanced vasodilatory shock states.7 This resulted in a significantly lower incidence of new-onset tachyarrhythmias during supplementary AVP infusion,8 and may also translate into a survival benefit in some patients with septic shock.9 Whether AVP has other specific advantages in the treatment of anaphylaxis, as has been shown for epinephrine,6,10 it needs to be evaluated in future animal and in vitro studies. Preliminary evidence suggests that AVP is even more effective in reversing histamine-induced vasodilation in vitro than epinephrine.11 Although AVP should be used at the discretion of each attending physician assessing the clinical situation, the choice of the AVP dosage must be based on the experience of other authors. Basically, both bolus injections and continuous AVP infusions have been used. Bolus injections usually result in immediate hemodynamic changes and seem to be clearly indicated in severe cases of cardiovascular instability, which cannot be controlled by other measures. An injection of about 4 IU for a 70 kg adult (0.06 IU/kg), as suggested by Schummer et al., is a good recommendation. Alternatively, 10 IU of AVP diluted in 10 mL of normal saline may be titrated to clinical responses. Nonetheless, it needs to be considered that adverse reactions, particularly coronary vasoconstriction and decreases of cardiac output, have been reported after bolus injections of AVP at variable dosages.12 Therefore, a continuous infusion of AVP as a supplementary vasopressor drug is a safer option, but also requires that the patient’s circulation can be controlled with fluid resuscitation and catecholamine therapy. In this case, recommendations based on AVP infusion in patients with advanced vasodilatory shock should be adopted. Although the Surviving Sepsis Campaign guidelines recommend an AVP dosage of 0.03-0.04 IU/min,13 a recent study suggested that 0.067 IU/min (4 IU/h) is more effective in stabilizing hemodynamic function in severe shock states than 0.033 IU/min (2 IU/h).14 In conclusion, the case series by Schummer et al. shows that the use of AVP may be effective and potentially lifesaving in selected patients with severe anaphylaxis. When treating anaphylactic shock, physicians need to keep in mind that the clinical evidence for recommended therapies is as limited as the data favoring AVP. Thus, they should base their decisions on both the clinical situation and comprehensive knowledge of the pharmacologic background of their interventions.