Acute Respiratory Distress Syndrome Following Anaphylactic Shock—“A Deadly Duel”—Case Report and Literature Review

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Introduction
Anaphylaxis, a relatively common life threatening medical emergency, is known to cause acute respiratory distress syndrome (ARDS). Similarly, the treatment of choice in anaphylactic shock, epinephrine, is also implicated in non-cardiogenic pulmonary oedema and ARDS, although the latter is rare and associated with supratherapeutic doses in general. The possible mechanisms of the pulmonary oedema in each of these instances are discussed in detail in this paper. Special emphasis is given to the management of both anaphylaxis-based and adrenaline induced pulmonary oedema. It is important to note that high index of suspicion and early diagnosis are paramount in avoiding any acute or long-lasting effects following such an episode. The necessity of preventing iatrogenic drug administration errors is also discussed.

Case Presentation
A 58-year-old diabetic woman for twelve years was managed in the surgical ward of our institution for lower limb cellulitis. Sensitivity test for crystalline penicillin was positive. She was started on Meropenum 500 mg IV as per local protocol. Her blood and tissue cultures were negative. Cellulitis was settling by day 05. The next day, the patient was accidentally injected with parenteral penicillin due to a nursing error. Soon after, her BP crashed to 76/30 with a tachycardia of 140 and a peripheral saturation of 86%. Examination revealed clear lung bases with no stridor. Immediate working diagnosis of anaphylaxis was made and IM epinephrine (1:1000) 0.5 mg to the anterolateral thigh and intravenous crystalloid 10 ml/kg bolus was administered while monitoring vitals. She was haemodynamically stable following 6 cycles of epinephrine and transferred to the ICU. Inward chest X-ray, ECG and echocardiogram revealed no abnormalities. ABG obtained in the 1st hour was normal (pH 7.37, PaO 2 96 mmHg, PaCO 2 34 mmHg, lactate 1.6 mmol/dl, FiO 2 0.4). Blood for serum tryptase was collected although testing was not done due to the unavailability of the reagents.

Discussion
The multisystem involvement with the propensity for organ dysfunction could lead to serious morbidity and mortality in anaphylaxis. A significant number of patients who develop lower airway respiratory symptoms may ultimately develop acute respiratory distress syndrome (ARDS).
There are varying clinical disorders which may lead to ARDS, although the pathogenesis in anaphylaxis is considered to be a widespread inflammatory injury to lung endothelium and epithelium causing marked rise in permeability, permitting exudation into alveoli. [1] The resulting injury further promotes the inflammatory cascade leading to extensive injury to lung parenchyma precipitating respiratory insufficiency. Anaphylaxis due to morphine which is secondarily complicated by ARDS is previously reported by Tobi, et al. (2018) [2] in a 16 year old patient who underwent an orchidopexy under spinal anaesthesia supplemented by intravenous morphine. He developed a biphasic reaction attributed later to morphine, which was complicated by severe ARDS. The patient was intubated and ventilated for few days but recovered completely. The ARDS in this particular case had occurred immediately following anaphylactic shock.
In our patient, intravenous penicillin injection resulted in anaphylactic shock (managed with a relatively low cumulative dose of intramuscular epinephrine) and subsequent ARDS. Several animal studies have shown that the onset of pulmonary edema can be as early as one hour or less [3] although signs of ARDS were apparent after about 4 hours in our patient. She had stable haemodynamics thus was managed with non-invasive ventilation and Oxygen therapy in the Intensive care and made a slow but steady recovery. With regard to the mechanisms of ARDS in anaphylaxis, it could be either by direct injury to the lung parenchyma or secondary to effects of systemic mediators on the lung, released during anaphylaxis. Out of the indirect causes of ARDS in anaphylaxis, the commonest is sepsis leading up to 40% of cases [4]. Varying degrees of ARDS (2012) has demonstrated that pulmonary edema ensues more rapidly with α rather than β adrenergic stimulation. [3] This suggests that a patient who is on β blocking agents may be at elevated risk of developing pulmonary edema due to unopposed α action of epinephrine. Systemic hypotension following the initial hypertension is characteristically reported in literature as the "diphasic response of epinephrine" [12]. This is assumed to be due to prolonged stimulation of β adrenoceptors after the cessation of α adrenoceptor stimulation subsequent to the catabolism of exogenous epinephrine below a certain plasma threshold level which may be propagated by the release of epinephrine first taken up by the nerve endings. This could be treated with intravenous crystalloids and if warranted, with inotropes, along with strict monitoring of fluid balance.
High flow oxygen combined with positive pressure ventilation is the first line therapy in ARDS. [9] The elevated pressures in broncho-alveolar system counteract the pressure in pulmonary capillaries and minimize transudation. [13] Non-invasive ventilation (NIV) could be beneficial to patients with haemodynamic stability and mild to moderate degrees or even severe ARDS where a favourable response to NIV is witnessed. Mechanical ventilation following endotracheal intubation is opted in cases of associated multi-organ dysfunction or severe, refractory cases of ARDS. Historically the use of morphine has been established in the treatment of pulmonary edema. Alleviation of anxiety dampening the sympathetic over activity, overall reduction in metabolic rate and reduced venous pressure rendering less workload on the heart, reduced suction effect on the lungs due to central depressor effects are the possible pharmacodynamics of morphine. [9] Aim of diuretics in non-cardiogenic pulmonary edema is to promote a rapid diuresis and remove excess fluids. Rarely this could be adequate as standalone therapy [9]. Ersoz and Finestone (1971) proposed the  [10] although this is no longer practiced.
Error in drug administration is a well-known cause for increased in-patient morbidity and mortality. Adhering to the "five rights" and developing local protocols are indispensable in minimizing these errors. Using more than one identifier such as name with initials, age or guardian's name would be decisive in avoiding possible misidentification of patients as was the case in our patient.
Last but not least, we suggest that additional safety measures such as, displaying a sign board, educating the patient or caregiver to notify any allergies and proper handing over, particularly of allergy history should be followed specifically in developing countries where digital patient management systems are unavailable.

Conclusion
Anaphylaxis is notorious for its animosity in both the rapidity of onset and poorer outcomes in cases of delayed treatment. The definitive treatment for anaphylaxis and epinephrine could also lead to life threatening complications such as flash pulmonary edema and ARDS. Thus, monitoring a post anaphylactic shock patient in a high dependency unit is highly advisable. Anaphylaxis in hospitalized patients is almost always due to erroneous drug administration.
Proper patient identification using several identifiers, following the "five rights" and adhering to local protocols are pivotal in avoiding these errors.