key: cord-0720595-s3sd6xx8
authors: Damodaran, Srinath; Joshi, Shreedhar S.; Kumar, Sunil; Natarajan, Pooja; Patangi, Sanjay Orathi; Kumaran, Thiruthani
title: COVID Convalescence- A boon or bane in cardiac surgery?..: A “second hit” hypothesis.
date: 2020-10-17
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2020.10.021
sha: 0eea53c3f5ccc2dbaefd97daf3a1ed3e5faa07c5
doc_id: 720595
cord_uid: s3sd6xx8

COVID-19 pandemic continues to affect healthcare services. As elective cardiac surgical services resume back to normal, clinicians will encounter COVID-19 recovered patients for cardiac surgery. The hyper-immune pathophysiology of COVID-19 and exposure to inflammation of cardiac surgery, cardiopulmonary bypass, mechanical ventilation, blood transfusion, and perioperative infections could lead to exacerbated responses exemplified by systemic inflammatory response syndrome and cascade to multi-organ dysfunction syndromes. We present a case of a coronary artery disease undergoing off-pump coronary artery bypass surgery after the institutional protocol of two COVID-19 RT-PCR tests were reported negative. Intraoperatively, unexplained hypoxemia was observed, which warranted CPB support to complete the grafting. At multiple attempts of failed weaning, IABP and high inotropes helped to wean. The patient had a stormy postoperative course with low oxygenation, bleeding, low cardiac output syndrome, rhabdomyolysis of lower limb muscles, requiring multiple blood and blood product transfusion, and renal replacement therapy. Despite the corrective measures, severe hyperkalemia, and cardiac arrest ensued. IgG antibodies to the SARS-CoV-2 virus were tested considering the unexplained hypoxemia. A ‘convalescent COVID-19’ patient with ‘first hit’ at primary infection, encountering a ‘second hit’ of surgery and perioperative insults might result in a hyper-immune response. This ‘second hit’ hypothesis should be considered when COVID-19 convalescent (COVID-19 disease symptomatic or asymptomatic) patients undergo cardiac surgery and present with unusual complications.

COVID-19 pandemic continues to affect healthcare services. As elective cardiac surgical services resume back to normal, clinicians will encounter COVID-19 recovered patients for cardiac surgery. The hyper-immune pathophysiology of COVID-19 and exposure to inflammation of cardiac surgery, cardiopulmonary bypass, mechanical ventilation, blood transfusion, and perioperative infections could lead to exacerbated responses exemplified by systemic inflammatory response syndrome and cascade to multi-organ dysfunction syndromes. We present a case of a coronary artery disease undergoing off-pump coronary artery bypass surgery after the institutional protocol of two COVID-19 RT-PCR tests were reported negative. Intraoperatively, unexplained hypoxemia was observed, which warranted CPB support to complete the grafting. At multiple attempts of failed weaning, IABP and high inotropes helped to wean. The patient had a stormy postoperative course with low oxygenation, bleeding, low cardiac output syndrome, rhabdomyolysis of lower limb muscles, requiring multiple blood and blood product transfusion, and renal replacement therapy.

Despite the corrective measures, severe hyperkalemia, and cardiac arrest ensued. IgG antibodies to the SARS-CoV-2 virus were tested considering the unexplained hypoxemia. A 'convalescent COVID-19' patient with 'first hit' at primary infection, encountering a 'second hit' of surgery and perioperative insults might result in a hyper-immune response. This 'second hit' hypothesis should be considered when COVID-19 convalescent (COVID-19 disease symptomatic or asymptomatic) patients undergo cardiac surgery and present with unusual complications.

A 62-year-old male with coronary artery disease was scheduled for elective coronary artery bypass grafting (CABG). He was a long-term diabetic and hypertensive on regular medications. The preoperative evaluation of other organ systems was unremarkable. Investigations of renal function, liver function, chest X-ray, and coagulation parameters were within normal limits. However, the blood count revealed lymphopenia that had no clinical correlation. Echocardiography demonstrated normal functionality but coronary angiography showed significant triple vessel disease. As per institutional protocol, screening was done twice prior to surgery for Severe Acute Respiratory Distress Syndrome Coronavirus-2 (SARS-CoV-2) by reverse-transcriptase polymerase chain reaction (RT-PCR) test. These tests were done 7 days apart with a negative report for Coronavirus disease (COVID-19) in both instances. A high-resolution computer tomography (HRCT) scan of the chest was performed that revealed nothing overt. He was retained in hospital-based quarantine isolation for the waiting period of the RT-PCR testing and then subsequently transferred to the cardiac unit on the eve of scheduled off-pump CABG surgery.

On transfer to the operating room, his baseline vitals recordings were unremarkable with an oxygen saturation of 97% on room air. Under local anesthesia, an invasive radial arterial blood pressure monitoring line was inserted and arterial blood gas (ABG) analysis at this stage was normal.

Induction of anesthesia was accomplished with a standardized narcotic, benzodiazepine, and muscle relaxant-based technique. Subsequently, he was intubated with an appropriately sized endotracheal tube (ETT). Following confirmation of the ETT position, the patient was connected to the anesthesia care station. Controlled ventilation with volume-controlled mode was chosen with a tidal volume of 8mL/kg. This generated a peak airway pressure of under 25 cm H 2 O. Adequacy of ventilation parameters was verified by ABG. Heparin was instituted in a dose of 400 IU/kg to facilitate grafting and monitored with activated clotting time (ACT). Left internal mammary artery to left anterior descending artery (LAD) anastomosis was completed uneventfully. However, during verticalization for the obtuse marginal artery (OM) grafting, the attending anesthesiologist observed significant desaturation. Common causes of desaturation were evaluated that included checking of the ventilator and circuits, ET tube, pulse oximetry probe position, and end-tidal carbon dioxide monitoring. Both pleural cavities were opened by the surgeon revealing adequate lung expansion.

The fraction of inspired oxygen (FiO 2 ) was increased to 1, ETT suctioning was done to clear out secretions, positive end-expiratory pressure (PEEP) was increased to 8 cm H 2 O. A repeat ABG showed marginal improvement of the arterial partial pressure of oxygen (PaO 2 ) ( Table 1) . Transesophageal echocardiography (TOE) was performed to rule out intracardiac shunts, PFO (Patent foramen ovale) causing right to left shunt, severe TR (Tricuspid regurgitation), new-onset mitral regurgitation (MR), right ventricular (RV) and left ventricular (LV) dysfunction and acute pulmonary embolism (APE). Grafting to OM was performed on a beating heart. Considering the low PaO 2 :FiO 2 ratio, a decision was taken to establish on cardiopulmonary bypass (CPB) to graft the posterior descending artery (PDA). An attempt to separate from CPB resulted in hypoxia, worsening hemodynamics, and ventricular fibrillation (VF). CPB was re-established and the heart was defibrillated. The grafts when examined appeared to be functioning well, and in the absence of any mechanical or metabolic cause of instability, a decision was taken to put in additional vein grafts to the distal LAD and OM vessels. A second attempt to wean off CPB was unsuccessful due to low cardiac output and low PaO 2 . An intra-aortic balloon pump (IABP) was inserted in the right femoral artery to augment cardiac function. After a further 45-minute rest on CPB, the patient was successfully weaned off. The sternum was left open with a retractor in situ due to borderline hemodynamics and high vasoactive support (epinephrine 0.1 µg/kg/min, norepinephrine 0.1 µg/kg/min, Levosimendan 0.1 µg/kg/min). A pulmonary artery catheter was floated that revealed a normal pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), and cardiac index (CI). The patient was transferred to the intensive care unit (ICU) with a PaO 2 :FiO 2 ratio of 170 mm Hg and a CI of 2.3 L/min/m 2 . Hematuria was noticed.

In the ICU, the patient was established on a controlled mode of ventilation with a FiO 2 of 100% and a PEEP of 15 cm H 2 O. His vital parameters stabilized over a few hours to a modest dose of vasoactive support (epinephrine 0.05 µg/kg/min and Levosimendan 0.05 µg/kg/min) and an IABP. Inhaled nitric oxide was commenced in a dose of 40 PPM to counter borderline PaO 2, but did not significantly improve oxygenation. The serial ABG during the perioperative period is depicted in Table 1 An arterial doppler study revealed poor flow in both the lower limbs. The hyperkalemic state and metabolic acidosis continued to worsen on RRT that culminated in a cardiac arrest that could not be revived. Extracorporeal membrane oxygenation was considered but not offered given the patient's advanced critical state with no reversibility quotient.

We report this case to highlight the perioperative complications encountered in managing a convalescent COVID-19 patient during elective cardiac surgery. Asymptomatic COVID-19 disease continues to be a predominant presentation in patients infected with SARS-CoV-2. Elective cardiac surgical services have resumed function with perioperative protocols aimed at minimizing risk to the healthcare professional and providing safety to patients from acquiring COVID-19 during their hospital stay. Varied protocols exist depending on endemic factors and the prevalence of the disease. Screening with RT-PCR for SARS-CoV-2 is an integral part of the preoperative workup.

Testing for antibodies as a screening modality has been reviewed without any conclusion. 1 The patient in context was cleared for active COVID-19 disease by two negative RT-PCR tests as per institutional protocol. But the perioperative unexplained hypoxemia, excessive bleeding, and raised D-dimer values triggered IgG antibody testing for SARS-CoV-2. The presence of these antibodies ratified the diagnosis of convalescence of COVID-19 disease.

In the current global COVID-19 pandemic, patients presenting for elective cardiac surgery can feature in the symptomatic/ asymptomatic spectrum. Recently recovered COVID-19 patients have cardiac myocardial inflammation, myocardial edema, fibrosis, and RV dysfunction. 2 is a prothrombotic state with reports of venous, arterial, and catheter-related thrombosis. APE continues to be the most common thrombotic manifestation of COVID-19. Lower limb ischemia and rhabdomyolysis is a potential complication of IABP initiated ischemia complicated by a prothrombotic state. Cross-links between inflammation and prothrombotic state are evident by laboratory markers of raised D-dimers, fibrinogen, factor VIII, von Willebrand factor, and decreased antithrombin levels. 8 The exacerbation of inflammatory cascade in recovered COVID-19 patients undergoing surgery in convalescence can be explained by a 'first and second hit' theory. The contained inflammation in the primary disease (first hit) can be exacerbated by stimuli of mechanical ventilation, infection, stasis, thrombosis, bleeding, ischemia, hypoxia, blood transfusions, transfusion-related acute lung injury (TRALI) (second hit) and cause a second uncontrolled inflammatory cascade culminating in a multiple organ dysfunction syndromes. 9 In such scenarios, avoiding the second hit by reducing inflammation with lung-protective strategies, thrombo-prophylaxis, early prone ventilation in the postoperative period, anti-fibrinolytic therapy and peripheral vascular screening are evolving concepts. 9 In the current clinical setting with the presence of IgG antibodies for SARS-CoV-2 and two preoperative negative RT-PCR, we postulated a convalescent phase of a recent past COVID-19 asymptomatic disease in our patient. RT-PCR continues to be the gold standard for diagnosing COVID-19 to date. False-negative results vary from 2 -29% across the globe owing to factors related to viral load, sampling techniques, and timing of testing in the disease course. Pretest probability is the clinical likelihood of a person having COVID-19 depending on local COVID-19 prevalence, SARS-CoV-2 exposure history, and symptoms. Pretest probability helps validate the result of RT-PCR or guide further testing. Repeat testing is known to overcome the limitations in RT-PCR sensitivity, but it should be at the discretion of the treating team. 10 Institutional protocol with testing RT-PCR twice 7 days apart to rule out false-negative results was followed. With seroprevalence of 0.22 to 47% across the population, the use of antibodies for testing as a routine preoperative screening protocol is far from being cost-effective. [11] [12] [13] But, using antibodies to test inconclusive RT-PCR and Rt-PCR not correlating with the clinical scenario is recommended, as was performed in the present scenario ins the post-operative period. 14 ELISA for antibodies specific to SARS-CoV-2 were performed and resulted positive for IgG in the present case. There are seven types of human coronavirus infections including SARS-Cov_2, SARS-CoV, MERS-CoV. Cross-reactivity of antibodies across the SARS virus family does exist, but the small number of patients infected per year and the younger age population affected more with the low pathogenicity SARS virus make it clinically less likely for this cross-reactivity to affect the decision making in COVID-19 pandemic. 11 The first episode of desaturation and hypoxemia was possibly an exacerbated inflammation due to mechanical ventilation (second hit) potentiated by altered hemodynamics during the verticalization of heart, MR, worsening diastolic function, increased PCWP, and subsequent pulmonary venous congestion. 9 The pulmonary Micro CLOTS pathophysiology evolved extensively during the case with the lowest recorded PaO 2 :FiO 2 ratio of 70mmHg. Cardiac dysfunction secondary to residual COVID-19 is speculative unless preoperative CMRI defines myocardial inflammation. Limb ischemia and rhabdomyolysis is an extension of the prothrombotic state complicated by IABP insertion and high dose vasopressor. 15 Thrombotic microangiopathy (TMA) was observed to be disproportionately high in COVID-19 patients even in those not hospitalized. TMA is characterized by low platelet count, elevated D-dimer, and LDH levels. 16 These laboratory values are difficult to interpret in settings of cardiac surgery and CPB but a preoperative assay might alert the clinician. The role of perioperative dexamethasone in cardiac surgery is not outlined in this setting. The benefits of plasma exchange on CPB and plasma adsorbent filtration on RRT are yet to be ascertained in the perioperative cardiac surgical patient.

To conclude, convalescent COVID-19 patients will increasingly present for elective cardiac surgical procedures in the near future. They pose a higher risk in the perioperative phase. Negating the 'second hit' by avoiding CPB, ventilation-associated lung injury, postoperative infection states and TRALI is not always feasible. These cases could very easily 'snowball' into high resource utilization with a low success rate. Routine testing of IgG antibodies preoperatively, prophylactic steroid therapy, and re-stratifying surgical techniques are debatable options. Extended evaluation of the heart (CMRI), pulmonary function testing, and coagulation testing (D-dimer and TEG) can be of help in COVID -19 recovered patients for perioperative risk stratification. By default, in the current COVID-19 pandemic, the patient manifesting a severe perioperative inflammatory response should trigger a suspicion of COVID-19 even though they were deemed negative pre-operatively by RT-PCR. It is prudent to outline these risks while consenting patients for surgery as the pathophysiological manifestations of the COVID-19 disease process during the convalescence phase continues to evolve with no cardiac risk stratification scoring system in place to encompass this scenario. OM -Obtuse marginal artery; POD -post-operative day; CPB -cardiopulmonary bypass; PaO 2arterial partial pressure of oxygen; RRT -renal replacement therapy; FiO 2 -fraction of inspired oxygen concentration; PEEP -positive end-expiratory pressure; T0-T7 -timeline.

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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