**4. Signs and Symptoms**

Anaphylaxis causes a generalized systemic reaction affecting multiple organ systems, symptoms involving the skin occur in 80–90% of cases, respiratory tract in 70%, GI in 45%, CV in 45%, and CNS involvement in 15% [50, 51]. The cardiovascular and respiratory systems are the principal shock organs in fatal anaphylaxis. Death occurs in most often due to shock or acute respiratory distress, but DIC and epinephrine overdose have also been cited as cause of death [26, 52–55]. Most fatal cases of anaphylaxis due to medication or venoms are a result of shock, in food related anaphylaxis respiratory involvement is the main cause of death although shock is still possible [26, 56].

Anaphylaxis develops rapidly with symptoms developing in minutes. Biphasic reactions, where symptoms resolve and then reappear later occurs around 20% of the time [57]. A systematic review of biphasic reactions found the medium time between resolution of initial symptoms and onset of delayed symptoms to be 11 h, with a range of 0.2–72 h [58].

#### **4.1 Cardiovascular changes**

Cardiovascular manifestations of anaphylaxis develop due to direct and indirect effects of mediators on the vasculature and heart. Increased vascular permeability causes rapid fluid extravasation, with up to 35% of plasma volume shift occurring

in a matter of minutes [59, 60]. Vascular smooth muscle relaxation causes vasodilation and a rapid decrease in SVR [61, 62]. Rapid drop in measured CVP suggests that venodilation plays a major as well. The combined effects as extravasation and venodilation cause significant reduction in preload. This can be severe enough to cause Empty ventricle syndrome, has been documented in autopsies of patients who died from anaphylaxis [63].

Arrhythmias and myocardial infarction can also be seen in anaphylaxis. Arrhythmias may develop due to the combined direct effect of mediators, and hemodynamic changes previously described. Myocardial infarctions seen in anaphylaxis may be due to decreased venous return and direct effects of mediators on coronary arteries causing vasospasm or disruption of atherosclerotic plaques [64, 65].

Compensatory response to these changes includes rise in heart rate, ejection fraction, and cardiac index [61, 62]. Although Tachycardia is typical in anaphylaxis, although bradycardia may be seen as well. Bradycardia occurs due to a compensatory *Bezold-Jarisch* reflex, and has been found to have lower mortality rates when compared to cases of anaphylactic shock with tachycardia [66, 67]. Atropine therefore should not be administered, as it would counteract this protective effect and may increase mortality [68].

#### **4.2 Respiratory changes**

The entire respiratory tract can be affected in anaphylaxis, involving the upper airway and/or lower airway [69]. Upper airway symptoms develop due to fluid extravasation causing mucosal edema [70]. Some symptoms of upper airway involvement include angioedema, stridor, dysphagia, and rhinorrhea [50, 71]. Lower airway obstruction occurs due to mucosal edema, bronchospasm, and mucous plugging [70]. Oxygen saturation may decrease secondary to respiratory effects of anaphylaxis limiting airflow. When there is diffuse lower respiratory tract involvement, decreased oxygen saturation can persist despite endotracheal intubation [72]. When PaO2 is adequate, tissue oxygenation can still be compromised causing anaerobic metabolism. In one study on rats, tissue oxygenation of muscle decreased faster in anaphylaxis compared to nicardipine induced hypotension. The anaphylactic group also showed a greater increase in lactate and lactate-pyruvate ratio indicating depletion of intracellular energy storage [73].

#### **4.3 Mucocutaneous, gastrointestinal, and neurologic changes**

Mucocutaneous symptoms (e.g. flushing, pruritus, angioedema, and urticaria) are common in anaphylaxis, however in cases of shock cutaneous symptoms are often absent. Vasodilation and increased vasculature permeability leads to flushing and angioedema [74]. In addition to vascular changes, urticaria develops due inflammatory cell infiltration and neuropeptide release from sensory nerves [75]. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal pain [76]. These symptoms are likely due to intestinal smooth muscle contraction and alterations in water and electrolyte absorption [77, 78]. Neurologic changes are mostly secondary to hypotension and decreased perfusion and may manifest as dizziness, confusion, syncope/presyncope, or headache [50]. More serious effects including seizure and stroke may also be seen but are rare [74, 79].
