Massive Air Embolism Following Necrotizing Pancreatitis and COVID-19 Infection—The Role of Postmortem Computed Tomography

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the COVID-19 pandemic raised important questions about workplace exposures to the virus, including postmortem exposures. The complexity of COVID-19 disease and its numerous unanticipated complications made autopsy even more vital in determining the pathophysiology of the disease. Performing traditional autopsy, however, carries risk of exposure. The following report describes an unusual case in which a patient diagnosed with COVID-19 and necrotizing pancreatitis underwent postmortem computed tomography (PMCT) prior to limited traditional autopsy and was unexpectedly found via PMCT to have large and diffuse venous air emboli and a new peripancreatic hematoma. In this case, not only did PMCT play a crucial role in determining the cause of death but also it allowed for a limited autopsy, thereby reducing the exposure to SARS-CoV-2 and associated risk to the autopsy staff and pathologists.

Introduction

Postmortem computed tomography (PMCT), otherwise known as virtual autopsy or “virtopsy,” has become increasingly useful in medicolegal investigation and the evaluation of natural sudden death (1). It has the potential to reduce numbers of high-risk medicolegal autopsies, particularly in patients with HIV and hepatitis C, thus reducing the exposure of infectious agents to pathology staff (2). During the COVID-19 epidemic, autopsy became more important to investigate the pathophysiology of the disease and its numerous unanticipated complications; however, many sites suspended their performance, largely due to exposure risks (3 -5). As such, PMCT may be a particularly effective tool to allow for a limited autopsy in cases where exposure to a highly infectious agent, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may occur. In the following case, supplementation of PMCT to limited autopsy in a patient diagnosed with COVID-19 and necrotizing pancreatitis revealed a massive venous air embolism, a rare complication of necrotizing pancreatitis.

Case Description

A 68-year-old male with a history of localized prostate cancer and hyperlipidemia presented to the emergency room (ER) with acute abdominal pain. Two days prior, he was diagnosed with COVID-19 after a confirmed workplace exposure and subsequent development of mild flu-like illness symptoms. On presentation to the ER, he demonstrated a normal temperature and normal oxygen saturation. Labs showed markedly elevated lipase, liver function tests, and inflammatory markers ( Table 1 ). Computed tomography (CT) scan showed peripancreatic edema, gas and fluid collection, consistent with necrotizing pancreatitis. Treatment included intravenous fluids, antibiotics, and pain control and initially his symptoms and inflammatory markers improved. During his hospitalization, his oxygen requirements increased, and he underwent a course of dexamethasone and remdesivir for COVID-19. Nine days into his hospitalization, he was thought to have recovered from his COVID-19 illness. Approximately three weeks after hospitalization, fever recurred, and inflammatory markers started to rise again ( Table 1 ). Repeat CT scan showed enlarged areas of peripancreatic necrosis with air collections consistent with superinfection. The advanced endoscopic gastroenterology team performed direct endoscopic necrosectomy after placing an endoscopic ultrasound (EUS) guided cystogastrostomy stent, a standard of care treatment for infected pancreatic necrosis. Although no histological specimens or cultures were obtained during the procedure, EUS demonstrated heterogeneous debris containing a large acute necrotic fluid collection with gas shadows adjacent to the gastric body, consistent with unorganized acute necrotic collection with superinfection. A metal stent was deployed across stomach wall to empty the fluid collection seen on imaging. A voluminous amount (∼ 400 cc) of foul-smelling purulent fluid was suctioned from the necroma following stent placement, accompanied by necrotic solid chunks of debris. Although improving overall, his hospital course was complicated by melena and Clostridium difficile colitis for which he received blood transfusions and oral vancomycin, respectively. Inflammatory markers remained high despite improvement in symptoms and tolerance of oral feeding. Approximately five weeks after hospitalization, he was found unresponsive in the early morning with bloody oral secretions, despite appearing well two hours prior. Cardiopulmonary resuscitation (CPR) was initiated, and his first cardiac rhythm was asystole. A mechanical chest compression device (MCCD) was correctly placed, but despite maximum effort he was pronounced dead after 30 minutes of resuscitation. An autopsy was ordered to evaluate the cause of unexplained sudden death.

Table 1.

Lab Values at Different Time Points During the Hospitalization.

	Normal values	Day 1	Day 9	Day 14	Day 26
Lipase (U/L)	11-55	>3000	170
Triglycerides (mg/mL)	<150	75
Ferritin (ng/mL)	30-400	1384
Procalcitonin (ng/mL)	<0.25	28.9	2.53
C reactive protein (mg/L)	<10	88.6	217.9		265
Alkaline phosphatase (U/L)	9-122	143	119	110	285
Alanine aminotransferase (U/L)	9-59	421	53	33	21
Aspartate aminotransferase (U/L)	10-35	371	49	51	39
D-Dimer (mg/L)	< 0.68	2.03	12.31		7.46
White blood cell count (x 1000/µL)	4-10	15.9	28.8	18.7	35

Prior to autopsy, the patient underwent whole-body CT (Discovery 570c NM/CT, GE Healthcare; 120 kV, 500 mA and with 0.625 mm slice thickness) just under 48 hours postmortem. PMCT demonstrated pneumatosis intestinalis, portal venous gas, intraperitoneal free air, and extensive air throughout the venous system filling the vena cava, coronary sinus, and both right heart chambers. Diffuse air was seen throughout the soft tissues and veins of the upper thorax, neck, extremities, and head. In the abdomen, ascites and distended gallbladder were similar to the most recent antemortem study. The peripancreatic necrotic collection was seen in the lesser sac abutting the distal pancreatic body and tail. Two pigtail catheters (from prior cystogastrotomy) terminating in necrotic collection were visualized. A new hematoma was observed layering next to the cystogastrostomy stent and air-filled veins, likely representing the entry point of the air into the venous system and source of the hematoma (Figure 1).

Figure 1:

Postmortem CT images in coronal view and 3D reconstructed image of air-filled right heart. A, Extensive intravenous air (shown in black) was observed. The superior vena cava and right atrium are filled with air (white arrow), furthermore a valve is clearly visible in the air filled internal jugular vein (yellow arrow). B, Intracardiac air is seen within the right heart, including the right atrium and right pulmonary trunk (white arrow). Intragastric air is visible (yellow arrow), together with intraperitoneal free air (blue arrow) with vascular opening into one of the gastric veins (red arrow). C, A hematoma (red arrows) was visible with layering next to the necrosectomy tube (yellow arrow), a finding that was not present on the premortem CT scan. D, 3D reconstructed image of the air-filled right heart. The atrium (white arrow), right ventricle (yellow), and pulmonary valve (blue arrow) are clearly visible.

Limited autopsy (included the chest cavity and limited abdominal organs, but excluding the complete exenteration of small and large bowel, trachea, and the genitourinary system) was performed as the postmortem COVID-19 sample was positive. The lungs were grossly and microscopically normal, but bilateral serous pleural effusions were present (measuring 950 mL on the left and 120 mL on the right). A large, serous peritoneal effusion was found (1500 mL) and an additional 500 mL of hemorrhagic and liquefactive necrosis of the omentum. A portion of the pancreas near the spleen was identified and recovered; although this was histologically normal, much of the solid debris that was evacuated from this area and histologically assessed represented organizing thrombus. There was extensive saponification and inflammation of the identifiable pancreas and other abdominal serosal surfaces. The necrosectomy tube port was positioned in the posterior gastric wall at the cardia with the inner plastic stents extending through the port into the necrosis bed (Figure 2). The other half of the tube was free-floating in the peritoneum. A peripancreatic mass was identified and confirmed upon sectioning and microscopy to be a hematoma (Figure 3). The transverse colon adjacent to the pancreas was discolored and demonstrated chronic inflammation microscopically. Postmortem findings of the gallbladder included wall-thickening and fibrin deposition, and there was a dense mixed inflammatory infiltrate of lymphocytes, plasma cells, and macrophages, consistent with chronic cholecystitis. The cause of death was determined to be necrotizing pancreatitis leading to extensive hemorrhage and massive venous air embolization, resulting in sudden cardiovascular collapse.

Figure 2:

Tissues samples from the gastrointestinal block 72 hours after formalin fixation. A, Whole upper gastrointestinal system block (posterior view). Extensive saponification of the omentum is visible along with evidence of liquefactive necrosis of the lesser sac of the omentum and portions of the pancreas. Part of the necrosectomy tube was loose in the abdominal cavity (not shown). B, Close up view of the necrosectomy opening from the posterior stomach wall at the cardia.

Figure 3:

Tissues samples 72 hours after formalin fixation. Gross histological view of a 12.5 × 6.0 × 3.5 cm mass in the abdomen, in peripancreatic location. Histologically this was classified as a large, organized hematoma. (A) Anterior view and (B) transverse view of the hematoma recovered from the abdominal cavity.

Discussion

Venous air embolism—occurring when gas enters the systemic venous circulation—most commonly occurs secondary to manipulation of central lines, surgery, trauma, intravenous infusion, pacemaker placement, or positive pressure ventilation (6 -8). However, physiologic factors, such as hydrostatic gradient favoring the spontaneous entry of air into the vasculature and the incision of noncollapsing veins (i.e., gastric, epiploic), can facilitate air emboli (6). Once gas enters the venous circulation, it travels to the heart and lungs resulting in gas exchange interference, cardiac arrhythmia, pulmonary hypertension, right ventricular strain, and cardiac failure if the emboli are severe and persistent (6). While the sudden introduction of over 50 mL of air is likely to result in acute cor pulmonale and/or asystole, injection of approximately 100 to 500 mL of air into human circulation is lethal (6). Treatment includes aggressive CPR, 100% oxygen support (for which mechanical ventilation is often required), volume expansion, and inotropic support (9). Hyperbaric oxygen therapy and central venous catheter placement for evacuation of intravascular air have also been described (9). Air embolism is difficult to diagnose at autopsy without significant pretest probability and requires filling the pericardium with water and assessing for air leakage after puncture of the right atrium (10). This procedure is operator dependent and has poor sensitivity; therefore postmortem CT is considered the gold standard for diagnosis of air embolism at autopsy.

Several potential causes of this patient’s extensive venous air emboli were considered. First, air may have entered the circulation via erosion through an adjacent vein (likely the gastroepiploic veins), likely secondary to extensive necrotizing pancreatitis with superinfection of necrotic collections and pneumoperitoneum. The PMCT confirmed the new hematoma near the cystogastrostomy site and demonstrated air filled veins likely representing the entry of the air into the venous system (Figure 1). While iatrogenic etiology was considered, the patient did not have a central line and had expired early morning without a recent infusion through his peripheral intravenous line, making this unlikely. A potential alternate mechanism for air embolism was massive bowel necrosis, given the findings of pancreatic necrosis, omental necrosis, inflamed bowel, and pneumatosis intestinalis. The combination of autopsy findings of chronic cholecystitis and extensive saponification and inflammation of the identifiable pancreas together with antemortem imaging findings and procedure reports, however, suggest the mechanism to be more consistent with necrotizing pancreatitis. While resuscitation with MCCD may also have contributed to the distribution of the air, it is less likely to be the inciting factor in this case as the mediastinum showed no significant trauma and the patient’s lungs were relatively intact. Air embolus after the use of MCCD is a rare complication and is most often seen with concurrent thoracic and abdominal trauma, which was not seen in this patient (11). Another possibility is that the gas seen on postmortem imaging was due to postmortem gas production, but this is unlikely as the patient underwent scanning less than 48 hours after death and the body was stored in a cool morgue (2-4 °C). Furthermore, the fact that the intravascular air was limited to the venous system makes postmortem gas production even less likely. There was some air in the soft tissues in the chest and neck, likely secondary to retrograde dispersion of the intravenous air due to the CPR provided by the MCCD. No subcutaneous air was seen in the abdomen or extremities. Such localization of subcutaneous emphysema would be atypical for postmortem gas production. The intra-abdominal gas distribution, location, and amount were similar compared to an antemortem CT scan obtained 10 days prior to death.

The cause of the patient’s pancreatitis was thought to be secondary to gallstones; however, no gallstones were found in the common bile duct, pancreatic duct, or major duodenal ampulla antemortem. Additionally, the patient triglycerides were normal and he had denied alcohol use. Despite these findings, the presence of histological evidence of an inflammatory reaction in the pancreas confirms antemortem pancreatic inflammation. There is a theoretical possibility that the SARS-CoV-2 virus can cause endothelial damage as the pancreas has the SARS-CoV-2 receptors; however, no definitive association has been found. Although some retrospective and case–control studies found a higher proportion of idiopathic pancreatitis within the COVID-19 patient population, the diagnosis of pancreatitis in these studies was often made based on abnormal lab values without—or with very limited—corroborative imaging, raising the possibility that the actual cause of the pancreatitis went undetected (12). There is, however, clear evidence that patients with acute pancreatitis and coexistent COVID-19 infection are at risk for severe acute pancreatitis, worse clinical outcomes, prolonged hospital stay, and high 30 day mortality (13). In this patient, the lack of lung disease apart from pleural effusions makes it less likely that COVID-19 infection played a significant role in this particular patient’s cause of death.

It is known that patients can persistently test positive with polymerase chain reaction tests for COVID-19 for extended periods after recovery; however, it is very rare that the virus can be cultured after day 10 from symptom onset in this patient population. Current recommendations are to ease isolation requirements if the patient is asymptomatic and did not require hospitalization (14). Due to the fact that he tested positive (even postmortem), had underlying illness, and was hospitalized, this patient remained in COVID-19 isolation throughout his hospitalization and, as such, his autopsy was performed under COVID-19 restrictions.

Conclusion

This patient developed necrotizing pancreatitis leading to hemorrhage and air embolization into the venous system, ultimately causing sudden cardiovascular collapse and death. The air embolization was due to a combination of factors, including acute necrotizing pancreatitis with superinfection of necrotic collections, pneumoperitoneum, and recent cystogastrostomy/necrosectomy. It is important to note that, had PMCT not been performed, detection of diffuse air emboli via traditional autopsy would have been unlikely: in this case, radiologic-pathologic correlation was vital for accurate cause of death determination. Virtopsy was also beneficial in that it allowed a limited autopsy, thereby reducing the exposure of autopsy staff to SARS-CoV-2.

AUTHORS

Inga Melvinsdottir MD, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, School of Medicine; Yale Translational Research Imaging Center, Department of Internal Medicine, Yale University, School of Medicine

Roles: A, B, C, D, E, 6

Nadia Solomon MD, MSc, MA, Department of Radiology and Biomedical Imaging, Yale University, School of Medicine

Roles: B, C, D, E, 6

Roxanne Wadia MD, Department of Pathology, Yale University School of Medicine

Roles: B, C, D, E, 6

Thiruvengadam Muniraj MD, FRCP, Department of Gastroenterology, Yale University School of Medicine

Roles: B, C, D, E, 6

Steffen Huber MD, Department of Radiology and Biomedical Imaging, Yale University, School of Medicine

Roles: B, C, D, E, 6

Albert J. Sinusas MD, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, School of Medicine; Yale Translational Research Imaging Center, Department of Internal Medicine, Yale University, School of Medicine; Department of Radiology and Biomedical Imaging, Yale University, School of Medicine

Roles: A, B, C, D, E, 1, 3, 4, 6