Anaphylaxis to Tissue Plasminogen Activator in the Treatment of Pulmonary Embolism: A Case Report of Mixed Shock Management

Acute pulmonary embolism (PE) impairs gas exchange and pulmonary circulation, which can progress to acute right ventricular failure, obstructive shock, and death. Pulmonary embolism is one of the leading causes of cardiovascular mortality, and the reported annual incidence rates are between 39 and 115 per 100 000 population.1 Because of the severity and fast onset of pulmonary embolism, many patients die suddenly or within hours of an acute PE. Early recognition and treatment are paramount to avoiding death associated with PE.2Classification of PE severity guides therapeutic approaches and prognostic evaluation. The 2019 European Society of Cardiology (ESC) guidelines provide severity classifications based on hemodynamic stability, right ventricle (RV) dysfunction, positive cardiac enzymes (troponin), and Pulmonary Embolism Severity Index (PESI) scoring.2 The PESI scoring system consists of 11 parameters, including patient characteristics and vital signs, to stratify patients with a PE into 5 severity classes based on clinical parameters to determine the risk of 30-day mortality in order to guide treatment decisions.3 The higher the PESI score, the higher the risk associated with the PE. A PESI score of less than or equal to 65 indicates very low risk (class I), a PESI score of 66 to 85 indicates low risk (class II), a PESI score of 86 to 105 indicates intermediate risk (class III), a PESI score of 106 of 125 indicates high risk (class IV), and a PESI score of greater than 125 indicates very high risk (class V). The simplified PESI (sPESI) uses fewer criteria (age, history of cancer or chronic obstructive pulmonary disease, heart rate, systolic blood pressure, and oxygen saturation) to score PE severity. Each criterion is worth 1 point; 0 points indicates low risk, whereas 1 or more points indicate high risk.4The ESC guidelines classify PE severity and the risk of early (in-hospital or 30-day) death as high, intermediate-high, intermediate-low, or low.2 Patients with low risk have a PESI class of I or II or an sPESI score of 0; those with intermediate-low risk include patients with an elevated PESI score with or without RV dysfunction or an elevated troponin level; patients with intermediate-high risk include those with elevated PESI scores with both RV dysfunction and an elevated troponin level; and high-risk patients are those with hemodynamic instability.The ESC guidelines recommend that patients who are classified as high risk be treated with reperfusion therapy, usually with systemic alteplase, a recombinant tissue plasminogen activator (tPA).2 Alteplase is a thrombolytic agent that cleaves plasminogen to form plasmin, an enzyme involved in the degradation of fibrin clots.5Although alteplase is structurally identical to endogenous tPA, several cases of anaphylaxis to tPA have been reported.6 Anaphylaxis is an immune-mediated response that can rapidly progress to anaphylactic shock. Since a patient with PE classified as high risk can experience obstructive shock, anaphylactic shock can potentially be difficult to recognize initially in this patient population. It is essential for clinicians to differentiate these shock states in order to appropriately treat patients.This article describes a patient who experienced anaphylactic shock to alteplase during treatment for a high-risk PE and the management of a mixed distributive and obstructive shock state within the role of the acute care nurse practitioner (ACNP) in a cardiac critical care team.A 72-year-old male presented with shortness of breath and hypoxia. He was normotensive and mildly tachycardiac with a heart rate of 100 to 105 beats per minute. His oxygen saturation was 94% at rest while receiving high-flow nasal cannula therapy (100%/40 L); with exertion, his oxygen saturation level dropped to 86%. Imaging confirmed a saddle PE with large thromboembolism burden and extension into all lung lobes (see Figure 1 and Figure 2). The PE was believed to have resulted from a recent hospitalization for necrotizing fasciitis in the right foot that was treated by amputation below the knee, leaving the patient using a wheelchair for mobility. He developed deep vein thrombosis (DVT) in his left leg during that initial hospital stay and was discharged on apixaban 5 mg twice daily after completing the initial loading regimen of 10 mg twice daily for 7 days. He denied any history of bleeding or clotting disorders and stated he had been adherent to his medications, confirmed to have been filled at the pharmacy. Ultrasonography revealed an extensive left lower extremity DVT from the proximal femoral through calf veins, which had significantly progressed from his previous hospital stay. Current laboratory results compared with initial results showed a lactate level of 1.0 mmol/L (an improvement from 2.1 mmol/L), high-sensitivity cardiac troponin test results of 32 ng/L to 71 ng/L, and an N-terminal pro–brain natriuretic peptide test result of 36 pg/mL. A transthoracic echocardiogram (TTE) revealed significant RV strain with a positive McConnell’s sign. McConnell’s sign is a distinct echocardiographic finding that would lead to a high suspicion of a PE that includes RV dysfunction, akinesis of the mid free wall, and normal motion of the apex.6The multidisciplinary PE team, which included critical care cardiology and interventional cardiology, created a treatment plan to continue the heparin infusion since the patient initially exhibited mild improvement in oxygenation. However, the patient began to exhibit signs of worsening hypoxemia with any movement, and the team decided to administer tPA. On the basis of his sPESI score of 2 (≥ 1), his new RV dysfunction (with RV enlargement seen on echocardiogram and computed tomography), significant hypoxemia, and proximal DVT, he was deemed to be at high risk for mortality. His PESI score of 132 (class V) indicated very high risk, and his hemodynamic instability indicated high risk according to the ESC guidelines.After discussion between the critical care pharmacist and the multidisciplinary team, the patient was given 50 mg intravenous (IV) tPA. At the end of the infusion, he was noted to have suddenly worsening hypotension. He was given small IV boluses of epinephrine 200 µg twice, 1 L of lactated Ringer solution, and an epinephrine infusion. His blood pressure stabilized when he received only 0.01 µg/kg/min of IV epinephrine. He remained hypoxic, and the team decided to administer another 50 mg IV of tPA with a 10 mg IV bolus, followed by the remainder of the infusion (40 mg) over 2 hours.Upon receiving the 10 mg IV bolus, the patient suddenly became more hypotensive. It was presumed that he was experiencing an allergic reaction and was given diphenhydramine 25 mg IV, famotidine 20 mg IV, and methylprednisolone 125 mg IV. He was given 1 L of lactated Ringer solution and multiple vasopressor medications including epinephrine, norepinephrine, and vasopressin. His lactate level was elevated. Repeat TTEs during this time revealed a functional RV and decreased RV size, although the RV remained enlarged, and his left ventricle remained hyperdynamic. His oxygen saturation level improved significantly with thrombolysis.On physical examination, the patient was warmer, indicating better perfusion. The team considered the patient a candidate for extracorporeal membrane oxygenation (ECMO) to support the RV and oxygenation; however, adequate perfusion was maintained with vasoactive medications, and ECMO was not needed. The patient eventually received methylene blue 1 mg/kg for refractory anaphylaxis and vasoplegic shock, a sodium bicarbonate infusion for severe metabolic acidosis, and ongoing fluid resuscitation. By the next day, he was off all vasoactive medication infusions and reported resolution of his shortness of breath while on room air by hospital day 2. He was discharged home on hospital day 4 with a prescription for rivaroxaban 15 mg twice daily for 21 days followed by 20 mg daily for 3 months. He was switched from apixaban to rivaroxaban given his PE occurrence while taking apixaban. A TTE on the day of discharge demonstrated greatly improved RV function and continued normal left ventricular ejection fraction (55%-60%).Anaphylactic shock is classified as a distributive shock state and has the hallmark characteristic of profound systemic vasodilation. Conversely, PE with shock is classified as obstructive shock, resulting in reduced cardiac output and oxygen delivery due to an alteration in ventricular filling or emptying. The most common subtype of obstructive shock is from venous thromboembolism and PE. It is rare to have a case involving mixed distributive and obstructive shock, and the hemodynamics of both require complex management. In this case, the patient required both intravascular volume to support the preload needs of obstructive shock and vasoactive medications to increase systemic vascular resistance and counteract the profound systemic vasodilation. To our knowledge, there are no other known case reports of mixed obstructive and distributive shock due to anaphylaxis to tPA in the setting of a PE.The overall incidence of anaphylaxis in the United States is estimated to be up to 2%, with drug-induced anaphylaxis likely underrecognized and therefore undertreated.7,8 However, the leading risk for anaphylaxis in adults is medications.9 Anaphylaxis is a listed side effect of tPA, with an occurrence of 1.9% to 5.1% from case reports of tPA administration for ischemic stroke.10,11 There is no documented incidence of anaphylaxis after tPA administration in the setting of PE.Initial treatment of anaphylaxis consists of close monitoring of cardiovascular and respiratory function due to the potential for collapse of either system. Guideline recommendations for treatment of anaphylaxis center around early identification and first-line medications such as epinephrine.9,12,13 Organizational guidelines have recognized that few anaphylaxis medication options exist with adequate supporting evidence to be considered first-line therapies. The National Center for Medical Service Administration grades anaphylaxis by use of a set of adapted diagnostic criteria from the American National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network to best determine appropriate treatment with a GRADE (grading of recommendations, assessment, development, and evaluation) of I through IV for severity.14 Early identification of anaphylaxis and prompt treatment with epinephrine are the current first-line recommendations by the World Allergy Organization, with emphasis on removing any triggers and ensuring stability for the patient’s airway, breathing, and circulation.12 Although dosing of epinephrine can vary, intramuscular epinephrine has shown benefit in reversing the detrimental effects of anaphylactic shock with lower side effects compared with other routes of administration.12 Additional therapies such as antihistamine and glucocorticoids are considered second line due to limited evidence for their use; therefore they should be considered after use of epinephrine in the treatment of anaphylaxis.12Epinephrine is a nonselective adrenergic agonist that rapidly increases vascular resistance and cardiac output while reversing bronchoconstriction associated with anaphylaxis.9 Epinephrine is the first-line medication for GRADE II to IV anaphylaxis. Intramuscular administration is the preferred route for GRADE II and III reactions due to ease of administration and decreased side effects; however intravenous administration can be considered for GRADE IV reactions with impending cardiac collapse in a controlled setting.9 The dosing recommendation for intramuscular (IM) epinephrine is 0.01 mg/kg, with a maximum of 0.5 mg for adults and 0.3 mg for children; dosing can be repeated every 5 to 15 minutes as needed.13 Intravenous epinephrine is typically dosed as either 0.05 or 0.1 mg intermittent boluses repeated every 3 minutes as needed.13 Risks of intravenous epinephrine include hypertension and ventricular arrhythmias; therefore patients should be closely monitored after its administration. For refractory anaphylaxis, an epinephrine infusion can be initiated to further relieve ongoing symptoms.15 The intravenous infusion is initiated at 0.1 µg/kg/min and titrated to response as needed.13Antihistamines work on the histamine receptors to antagonize the release of histamine and relieve pruritis, flushing, and urticaria, but they do not relieve the cardiovascular or respiratory symptoms associated with anaphylaxis.16 The onset of action and mechanism of antihistamines make this class of medications unsuitable for sole treatment of acute anaphylaxis.16 H1 receptor antagonists and H2 receptor antagonists are used as adjunct therapy to epinephrine for additional symptom control of anaphylaxis.17Glucocorticoids bind to the glucocorticoid receptors on cell membranes to inhibit gene expression and production of new inflammatory mediators.9 Glucocorticoids are commonly administered in anaphylaxis, but there is limited evidence for acute benefit. Use of glucocorticoids have benefit in preventing protracted symptoms and biphasic reactions, but evidence has shown glucocorticoids should not be used prior to or in place of epinephrine for anaphylaxis.9Methylene blue inhibits the effects of nitric oxide synthase and blocks formation of cyclic guanosine monophosphate to reduce vasorelaxation.18 This mechanism is theorized to be beneficial as a synergistic effect with epinephrine in severe cases of anaphylactic shock.19 The use of methylene blue to treat patients experiencing vasoplegia in anaphylaxis refractory to epinephrine treatment is based on case reports and extrapolations from other indications and types of shock.15The ability to recognize mixed shock states and knowledge of appropriate use of vasoactive and inotropic medications to manage patients is an established clinical competency for providers subspecializing in critical care cardiology.20 Acute care nurse practitioners play an important role on the cardiac intensive care team to improve patient outcomes when they are working at their highest level of expertise in training, certification, and competencies.21,22A patient presenting with mixed shock physiology poses significant challenges to the clinician in order to identify and treat the condition appropriately. Compounding the difficulty in these situations is the paucity of evidence-based guidelines to assist with management of patients with mixed shock states. The critical care ACNP must recognize the circulatory shock and interpret hemodynamics to provide immediate appropriate interventions and prevent patient deterioration. Furthermore, as shock states can rapidly convert to another type of shock, frequent reassessment is critical. Vigilant monitoring for adverse effects of therapeutic interventions is pivotal to improving patient outcomes. The ACNP must remain current with available guideline updates such as updated epinephrine dosing and route of administration to treat anaphylaxis.9Mixed shock states can be extremely difficult to recognize in real time due to competing and complex changes in hemodynamics. In this case report, the multidisciplinary team was able to recognize distributive shock from anaphylaxis to tPA, which was concurrent with obstructive shock from a PE. The incidence of anaphylaxis from tPA is likely underrecognized; due to the rapid progression to anaphylactic shock, practicing clinicians should be aware of this potential complication in the setting of PE. The ACNP working in cardiac critical care must maintain competency in the recognition and management of mixed shock states to improve patient outcomes.