key: cord-0942295-3sdtpqur
authors: Mir, Tanveer; Attique, Hassan Bin; Sattar, Yasar; Regmi, Neelambuj; Khan, Muhammad Shayan; Youns, Haris; Qayoom, Basharat; Jerger, Michael T.; Alraies, M. Chadi
title: Does Pulmonary Embolism In Critically Ill COVID-19 Patients Worsen The In-Hospital Mortality: A Meta-Analysis
date: 2020-11-25
journal: Cardiovasc Revasc Med
DOI: 10.1016/j.carrev.2020.11.024
sha: 9d680a2aabd865618b9c891752db8820a015643b
doc_id: 942295
cord_uid: 3sdtpqur

Background Mortality in critically ill COVID (coronavirus disease) patients secondary to pulmonary embolism (PE) has conflicting data. We aim to evaluate the mortality outcomes of critically ill patients with and without PE (WPE). Methods Three studies were identified after a digital database search on PE in ICU (intensive care unit) patients until September 2020. The primary outcome was mortality. Outcomes were compared using a random method odds ratio and confidence interval of 95%. Results A total of 439 patients were included in the study. Diabetes, hypertension, and renal replacement requirement had no statistically significant association between PE and WPE, p=0.39, p=0.23, and p=0.29 respectively. The study revealed that males have higher odds of PE, OR-1.98, 95%CI-1.01-3.89; p=0.05. In-hospital mortality results were comparable between PE and WPE after subgroup analysis and correction of heterogeneity, p=0.25. Conclusion PE in critically ill COVID patients had similar in-hospital mortality outcomes as WPE patients. The findings are only hypotheses generated from observational studies and need future randomized, prospective clinical trials for a definitive conclusion.

 Our study compares the largest sample size between PE and WPE COVID patients admitted to ICU.

 Our analysis demonstrated that critically ill COVID patients admitted to ICU had comparable mortality with and without PE.

 Comorbidities like hypertension, diabetes have no association with PE.

 Renal replacement requirements were similar in critically ill COVID patients whose illness was complicated by PE.

Coronavirus, the pandemic infected worldwide with clinical presentations from asymptomatic cases to severe respiratory distress, multi-organ dysfunction, and death(1). Respiratory distress secondary to COVID-19 in critically ill patients is multifactorial. The pulmonary causes of respiratory distress in a critically ill patient can be secondary to acute respiratory distress syndrome (ARDS) or ventilation-perfusion mismatch in lungs (2, 3) . Cardiac causes of hypoxia, from pulmonary edema, can be secondary to multiple coronaviruses-related cardiac injuries including myocarditis, patients are at a high risk of venous thromboembolism, including pulmonary embolism, which can worsen ventilation-perfusion mismatch and hence hypoxia. The prevalence of pulmonary embolism in critically ill patients has been reported from 15% to 28.57%.

COVID being a procoagulant state, cases of venous thromboembolism have been reported even if the patients were on prophylactic or therapeutic anticoagulation. A meta-analysis by Hasan et al. reported a prevalence of venous thromboembolism in critically ill patients of 31% and the patients were either on prophylactic or therapeutic anticoagulation (6) . The prevalence of PE in critically ill COVID patients has been reported higher than COVID patients not admitted to intensive care units (7) . There are conflicting results on mortality in critically ill COVID patients with and without pulmonary embolism. Since pulmonary embolism has a high prevalence in critically ill COVID patients and PE would worsen hypoxia in such critically ill patients with COVID ARDS, we aimed to do a database search to evaluate the pulmonary embolism outcomes and association of any comorbidity with PE in critically ill COVID patients admitted to ICU.

The included studies recruited a total of 439 patients: (PE 82 and WPE 357 

The overall mortality was with higher Odds for PE than WPE (OR=1.54) with p<0.05, however, without statistical significance; 95%CI= 0.36-6.61, and heterogeneity of the test was 75%. A subgroup analysis was done given high heterogeneity. After excluding J o u r n a l P r e -p r o o f Journal Pre-proof Contou Figure 5 .

The publication bias was illustrated graphically with funnel plotting. The vertical axis of the plot used standard error to estimate the sample size of the study, plotting large population studies on top and smaller at the bottom. The horizontal spread reflected the power and effect size of the included studies. On visual assessment, our funnel plot was symmetrical, indicating that the limited scatter was due to sampling variation and not publication bias; Figure 6 .

Our study revealed a higher prevalence of pulmonary embolism in male patients admitted with severe COVID to ICU. The study did not reveal any association between comorbidities like diabetes, hypertension with pulmonary embolism, p=0.39, and p=0.23 respectively. The requirement for renal replacement therapy was comparable between the two groups, p=0.29. Interestingly the pulmonary embolism did not result in the overall worsening of mortality in critically ill COVID patients who had PE than patients who did not had a pulmonary embolism (p=0.25). The major limitation of all these studies was the inclusion of the smaller scale population and being relatively underpowered to assess the mortality outcomes in critically ill patients with PE.

COVID is a hypercoagulable state caused by vascular endothelial damage (10) . All patients included in this meta-analysis were on antithrombotics, either prophylactic or therapeutic. Venous thromboembolism was reported in patients despite being on antithrombotics, however, rates were less in patients on higher doses of antithrombotics (2, 8, 9) . Klok heparin (5000 U twice to three times per day) in patients with creatinine clearance < 30 mL/min (12) . Anticoagulation forum has recommended high dose venous thromboprophylaxis for critically ill patients ( LMWH 40 mg SC twice daily, LMWH 0.5 mg/kg subcutaneous twice daily, heparin 7500 SC three times daily, or low-intensity heparin infusion (13) . Currently, there are no randomized controlled trials on in-hospital outcomes of with and without PE in critically ill COVID patients. However, randomized trials on the evaluation of the appropriate anticoagulation in COVID critically ill patients are under study which could better explain the prophylactic and therapeutic anticoagulation guidelines for critically ill COVID patients.

Our study is constrained by the limitations of the included studies. A significant barrier was our inability to perform a stratified subgroup analysis based on the different selection criteria. The inherent heterogeneity in the observational and posthoc data limits our ability to draw definitive conclusions about the outcomes and associations of PE in critically ill COVID patients. The predictive odds of all the components could not be calculated due to insufficient reporting of the stratified event rates. Forest plot comparing mortality outcomes for PE and WPE. The results were comparable between the two groups. 

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Higher Intensity Thromboprophylaxis Regimens and Pulmonary Embolism in Critically Ill Coronavirus Disease 2019 Patients

COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome

COVID-19 cardiovascular epidemiology, cellular pathogenesis, clinical manifestations and management

Acute Pulmonary Embolism: Focus on the Clinical Picture

Venous thromboembolism in critically ill COVID-19 patients receiving prophylactic or therapeutic anticoagulation: a systematic review and meta-analysis

Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence

Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study

Factors Associated With Pulmonary Embolism Among Coronavirus Disease 2019 Acute Respiratory Distress Syndrome: A Multicenter Study Among 375 Patients

COVID-19 is, in the end, an endothelial disease

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum

 Tanveer Mir contributed to concept and design of the manuscript including the acquisition, analysis and interpretation of data as primary and corresponding author. TM also revised the work critically including the final version and agreed to be accountable for all aspects of the work.  Hassan Bin Attique had substantial contributions to the conception or design of the work, provided the majority of images and drafted the work critically including the final version and agreed to be accountable for all aspects of the work. Also he had a major contribution in evaluation of quality of the studies included in the meta-analysis.  Yasar Sattar contributed to the analysis of cases including drafting the work for important intellectual content and final approval and agreed to be accountable for all aspects of the work.  Neelambuj Regmi had significant contribution to the concept, the acquisition, analysis and interpretation of data for the work, drafted the work including the images and revised the final version of the manuscript to be published and agreed to be accountable for all aspects of the work.  Muhammad Shayan Khan had substantial contributions to the conception or design of the work, provided the majority of images and drafted the work critically including the final version and agreed to be accountable for all aspects of the work.  Haris Youns had substantial contributions to the conception or design of the work, provided the majority of images and drafted the work critically including the final version and agreed to be accountable for all aspects of the work.  Basharat Qayoom contributed to the analysis of cases including drafting the work for important intellectual content and final approval and agreed to be accountable for all aspects of the work.  Michael T. Jerger contributed to the analysis of cases including drafting the work for important intellectual content and final approval and agreed to be accountable for all aspects of the work. He mentored during the whole process.  M Chadi Alraies had significant contribution to the concept, the acquisition, analysis and interpretation of data for the work, drafted the work including the images and revised the final version of the manuscript to be published and agreed to be accountable for all aspects of the work. He mentored during the whole process as lead mentor.J o u r n a l P r e -p r o o f