Identification of Distinct Clinical Subphenotypes in Critically Ill Patients With COVID-19.

BACKGROUND: Subphenotypes have been identified in patients with sepsis and ARDS and are associated with different outcomes and responses to therapies. RESEARCH QUESTION: Can unique subphenotypes be identified among critically ill patients with COVID-19? STUDY DESIGN AND METHODS: Using data from a multicenter cohort study that enrolled critically ill patients with COVID-19 from 67 hospitals across the United States, we randomly divided centers into discovery and replication cohorts. We used latent class analysis independently in each cohort to identify subphenotypes based on clinical and laboratory variables. We then analyzed the associations of subphenotypes with 28-day mortality. RESULTS: Latent class analysis identified four subphenotypes (SP) with consistent characteristics across the discovery (45 centers; n = 2,188) and replication (22 centers; n = 1,112) cohorts. SP1 was characterized by shock, acidemia, and multiorgan dysfunction, including acute kidney injury treated with renal replacement therapy. SP2 was characterized by high C-reactive protein, early need for mechanical ventilation, and the highest rate of ARDS. SP3 showed the highest burden of chronic diseases, whereas SP4 demonstrated limited chronic disease burden and mild physiologic abnormalities. Twenty-eight-day mortality in the discovery cohort ranged from 20.6% (SP4) to 52.9% (SP1). Mortality across subphenotypes remained different after adjustment for demographics, comorbidities, organ dysfunction and illness severity, regional and hospital factors. Compared with SP4, the relative risks were as follows: SP1, 1.67 (95% CI, 1.36-2.03); SP2, 1.39 (95% CI, 1.17-1.65); and SP3, 1.39 (95% CI, 1.15-1.67). Findings were similar in the replication cohort. INTERPRETATION: We identified four subphenotypes of COVID-19 critical illness with distinct patterns of clinical and laboratory characteristics, comorbidity burden, and mortality.

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.

Multiorgan procurement is associated with a survival benefit after heart transplantation.

We assessed the impact of donor multiorgan procurement on survival following orthotopic heart transplantation (OHT). From the UNOS STAR database, we included all adult (≥18 Y) heart transplants (OHT) performed since 2000 and used donor IDs to determine how many other organs were procured from the same donor as the recipient's heart allograft (regardless of recipient). The Kaplan-Meier survival functions and risk-adjusted Cox proportional hazards regression models were computed to assess the association of multiorgan procurement with post-heart transplantation mortality. We included 40 336 OHT patients. Including the heart, the median number of donor organs procured was 3 (IQR, 3-4). Heart donors underwent liver procurement in 89.7%; kidney(s) in 98.1% (single 95%, bilateral 5%); lung(s) in 38.0% (single 28%, bilateral 72%); pancreas in 10.4%; and intestine in 1.6%. Following risk adjustment across 16 recipient- and donor-specific variables, an increasing number of organs procured were independently associated with reduced post-OHT mortality (HR 0.98, 95% CI 0.96-0.99, P = .025). Though no significant associations were found examining specific organ types, double lung procurement trended toward a protective effect (HR 0.96, 0.92-1.01, P = .086), with counts of non-lung organs procured still bordering on significance (HR 0.97, 95% CI 0.95-1.00, P = .067). These results likely reflect improved multiorgan donor quality.

Relationship of body mass index, serum creatine kinase, and acute kidney injury after severe trauma.

OBJECTIVES: Body mass index (BMI) is associated with acute kidney injury (AKI) after trauma, but underlying mechanisms are unclear. Body mass index correlates with both excess adiposity and increased muscle mass. Since the latter could predispose to severe rhabdomyolysis after trauma, we hypothesized that the BMI-AKI association may be partially explained by a direct relationship of BMI with serum creatine kinase (CK). METHODS: Prospective cohort study of 463 critically ill patients admitted to a level I trauma center from 2005 to 2015 with Injury Severity Score of >15 and serum CK measured in the first 7 days. We defined AKI by AKI Network creatinine criteria. We used simple linear regression to determine the association of BMI with peak CK and multivariable logistic regression to adjust the BMI-AKI association for peak CK and confounders. RESULTS: Median age was 43 years, 350 (76%) were male, 366 (79%) had blunt mechanism, and median Injury Severity Score was 24. Body mass index was associated with peak CK (R = 0.05, p < 0.001). Acute kidney injury developed in 148 patients (32%), and median time to peak CK was 29 hours (interquartile range, 15-56 hours) after presentation. Body mass index was significantly associated with AKI in multivariable models adjusted for age, race, sex, diabetes, injury mechanism and severity, and red blood cell transfusions (odds ratio [OR], 1.31 per 5 kg/m; 95% confidence interval [CI], 1.09-1.58; p = 0.004). Adding peak CK to the model partially attenuated the association of BMI with AKI (OR, 1.26 per 5 kg/m; 95% CI, 1.04-1.52; p = 0.018), and peak CK was also associated with AKI (OR, 1.19 per natural log; 95% CI, 1.00-1.41; p = 0.049). Peak CK remained associated with AKI when restricted to patients with values of <5,000 U/L (OR, 1.31 per natural log; 95% CI, 1.01-1.69; p = 0.043). CONCLUSION: Serum CK correlated with BMI and partially attenuated the association of BMI with AKI after major trauma, suggesting that excess muscle injury may contribute to the BMI-AKI association. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Obesity is Associated With Mortality and Complications After Trauma: A State-Wide Cohort Study.

BACKGROUND: With rising obesity rates in the United States, knowledge of obesity's impact on trauma outcomes is essential to providing high-quality care. The interaction between body mass and outcomes is unclear, with existing literature demonstrating conflicting results. We hypothesized that in a broad cohort of trauma patients, obesity would be associated with in-hospital mortality. MATERIALS AND METHODS: We conducted a retrospective cohort study using the 2014-2015 Pennsylvania Trauma Outcomes Study (PTOS) registry, a state-wide registry to which all accredited Pennsylvania trauma centers are required to report. We included nonburn adult trauma patients admitted to level I and II centers. Because PTOS lacks height data, weight thresholds of 111.75 kg for men and 95.05 kg for women were used, which correspond to BMI = 30 kg/m2 at the 99th height percentile in the United States. We tested the association of obesity with in-hospital mortality using logistic regression to adjust for confounders. RESULTS: We included 46,329 patients in a complete case analysis. In univariate logistic regression analysis, injury mechanism, presence of a complication, age, sex, need for blood transfusion, Revised Trauma Score, and Injury Severity Score were associated with mortality. On multivariate analysis, including these factors, obesity was significantly associated with mortality (odds ratio 1.36, 95% confidence interval 1.10-1.69). Respiratory, thromboembolic, and infectious complications, as defined by PTOS, were more common in obese patients. CONCLUSIONS: After adjusting for patient and injury characteristics, obesity is associated with increased mortality following trauma. This information may help resolve previous conflicting evidence and guide providers in caring for the obese patient.

Association of Histopathologic Phenotype of Periampullary Adenocarcinomas With Survival.

Importance: Patients with periampullary adenocarcinomas have widely variable survival. These cancers are traditionally categorized by their anatomic location of origin, namely, the duodenum, ampulla, distal common bile duct (CBD), or head of the pancreas. However, they can be alternatively subdivided histopathologically into intestinal or pancreaticobiliary (PB) types, which may more accurately estimate prognosis. Objectives: To identify factors associated with survival in patients with periampullary adenocarcinomas and to compare survival between those having intestinal-type or PB-type cancers originating from the duodenum, ampulla, or distal CBD with those having pancreatic ductal adenocarcinoma (PDAC). Design, Setting, and Participants: This study was a retrospective analysis of medical records in a prospectively maintained database. Three pathologists separately evaluated histopathologic phenotypes at a university-based tertiary referral center. Study participants were all patients (N = 510) who underwent pancreatoduodenectomy for adenocarcinoma between January 1995 and December 2014. Main Outcome and Measure: Overall survival. Results: This study identified 510 patients (mean [SD] age, 66.1 [10.9] years; 245 female [48%]) who underwent pancreatoduodenectomy for adenocarcinomas: 13 duodenal, 110 ampullary, 43 distal CBD, and 344 PDAC. The median overall survival was 61.2 (interquartile range [IQR], 22.0-111.0), 70.4 (IQR, 26.7-147.7), 40.6 (IQR, 15.2-59.6), and 31.4 (IQR, 17.3-86.3) months for patients with cancers of the duodenum, ampulla, distal CBD, or pancreas, respectively (P = .01), indicating a significant difference between the 4 tumor anatomic locations. Most duodenal (61.5% [8 of 13]) and ampullary (51.8% [57 of 110]) cancers were intestinal type, and most distal CBD tumors were PB type (86.0% [37 of 43]). Those with intestinal-type duodenal, ampullary, or distal CBD adenocarcinomas had longer median overall survival than those with PB type (71.7 vs 33.3 months, P = .02) or PDAC (31.4 months, P = .003). There was no survival difference between PB-type cancers and PDAC (33.3 vs 31.4 months, P = .66). On multivariable analysis, histologic grade (hazard ratio [HR], 1.98; 95% CI, 1.56-2.52; P < .001), histopathologic phenotype (HR, 1.75; 95% CI, 1.16-2.64; P = .008), and nodal status (HR, 1.45; 95% CI, 1.12-1.87; P = .05) were significantly associated with survival, while anatomic location was not. Conclusions and Relevance: Histopathologic phenotype is a better prognosticator of survival in patients with periampullary adenocarcinomas than tumor anatomic location. Those with PB-type duodenal, ampullary, or distal CBD adenocarcinomas have survival similar to those with PDAC.

Left atrial-esophageal fistula repair after radiofrequency catheter ablation for atrial fibrillation.

Left atrial-esophageal fistula (LAEF) is a rare complication of radiofrequency ablation (RFA) procedures undertaken for atrial fibrillation (AF). This complication is associated with significant morbidity and mortality. Currently, there is no clear consensus on the appropriate management strategy. We report a case of a LAEF that developed in a patient 2 weeks after RFA for medication refractory AF. The patient underwent successful repair of the fistula through a left posterolateral thoracotomy, wherein the esophageal and atrial lesions were repaired primarily with an intercostal muscle flap and bovine pericardial patch to reinforce and prevent recurrence.