key: cord-0806043-2i9k6yoe
authors: Hayanga, J. W. Awori; Kakuturu, Jahnavi; Dhamija, Ankit; Asad, Fatima; McCarthy, Paul; Sappington, Penny; Badhwar, Vinay
title: Cannulate, Extubate, Ambulate approach for Extracorporeal Membrane Oxygenation for COVID-19
date: 2022-03-11
journal: J Thorac Cardiovasc Surg
DOI: 10.1016/j.jtcvs.2022.02.049
sha: 80fc475e94be45eccdfb826483a54b68f1a9e8ac
doc_id: 806043
cord_uid: 2i9k6yoe

OBJECTIVE We compared outcomes in patients with severe COVID-19 versus non-COVID-19-related acute respiratory distress syndrome (ARDS) managed using a dynamic, goal-driven approach to venovenous (VV) extracorporeal membrane oxygenation (ECMO). METHODS We performed a retrospective, single-center analysis of our institutional ECMO registry using data from 2017 to 2021. We used Kaplan-Meier plots, Cox proportional hazard models, and propensity score analyses to evaluate the association among COVID-19 status (COVID-19-related ARDS vs. non-COVID-19 ARDS) and survival to decannulation, discharge, tracheostomy, and extubation. We also conducted subgroup analyses to compare outcomes with the use of extracorporeal cytoreductive techniques (Cytosorb and plasmapheresis). RESULTS The sample comprised 128 patients, 50 with COVID-19 and 78 with non-COVID-19 ARDS. Advancing age was associated with decreased probability of survival to decannulation (p = 0.04). Compared to the non-COVID-19 ARDS group, patients with COVID-19 had a greater probability of survival to extubation (p < 0.01) and comparable survival to discharge (p = 0.14). CONCLUSION Patients with COVID-19 managed on ECMO had comparable outcomes as patients with non-COVID ARDS. A strategy of early extubation and ambulation may be a safe and effective strategy to improve outcomes and survival, even for patients with severe COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) COVID-19 86 pandemic has been the greatest healthcare event of this generation. It has had a broad 87 sweeping impact on the global health and economy. 1 The intention to ambulate 88 critically ill patients creates a "pervasive progressive culture of mobility" that influences 89 sedation practices, pulmonary toilet practices and drug dosing. It is potent mitigation 90 against critical illness polyneuropathy. Indeed, as early as extracorporeal membrane 91 oxygenation (ECMO) Day 1, we seek to decrease sedation and wake the patient with a 92 view to extubation or early tracheostomy. This provides the cue to directing our 93 rehabilitative efforts towards ambulation and perpetuates the programmatic mantra of 94 "cannulate, extubate, ambulate." 95

To further mitigate the excess mortality borne by the pandemic, we modified our 96 approach to extracorporeal support. We adjusted our algorithms and expectations in 97 response to dynamic, often scarce, resources, personnel, and therapeutics. Our and time-to-event outcomes using Kaplan-Meier plots. We investigated predictors 166 contributing to each outcome using Cox proportional hazards models. 18 We present 167 results for the original numeric variables and their categorized version, to improve 168 clinical interpretation. We categorized age into under 24 (young adults), between 25 and 169 59 (adults), and above 60 (older adults). 19 We categorized BMI as 30 and above 170 (obese) and below 30 (non-obese). 20 We also split the risk scores using cut-offs 171 associated with a poor prognosis (Table 2) . 15 Within the Cox proportional hazards 172 models, we considered death as a censored event, thus mitigating an immortal survival 173 bias. 21 We present our results as hazard ratios (HR) with 95% confidence intervals (CI) 174 and deemed them significant when confidence intervals did not cross the value of 1.0. 175 Propensity score analysis: We evaluated outcome differences between COVID-19 176 vs. non-COVID-19 ARDS patients, using the data balanced through inverse probability 177 weighting (IPW). 22 We evaluated balance regarding the covariates described above. 23 178

Our propensity score analysis included missing data as a separate variable category, 179 assigning a weight for missing variables. Once we achieved covariate balance, we used 180

Cox proportional hazards models to evaluated outcome differences between the two 181 groups as described above. 182 Figure 1) . 198

Compared to the other cohort, COVID-19 patients presented a significantly higher 199 probability of survival to extubation alive (HR: 2.17, 95% CI: 1.28 -3.67, p < 0.01), and Figure 3) . 208 J o u r n a l P r e -p r o o f

Age was significantly associated with time to decannulation and discharge alive 210 (discharge HR: 0.97, 95% CI: 0.95 -0.99, p < 0.01) ( Table 6 ). Patients older than 60 211 years had a lower probability of survival to decannulation (HR: 0.43; 95% CI: 0.20 -212 0.96, p = 0.04) and discharge (HR: 0.23, 95% CI: 0.07 -0.80, p = 0.02). The PRESET 213 score was also associated with the time to extubation alive (HR: 0.85, 95% CI: 0.77, 214 0.95, p < 0.01), and patients with a PRESET score above 5 presented decreased 215 survival to extubation (they were extubated later than the patients with a lower score, 216 HR: 0.43, 95% CI: 0.27 -0.68, p < 0.01). Patients with an APACHE score above 23 and 217 those with a SOFA score above 10 had decreased survival to extubation alive than 218 patients with lower APACHE and SOFA scores (p < 0.05). This was also true for 219 patients with a Murray score above 3 who had decreased survival to decannulation (HR: 220 0.50, 95% CI: 0.33 -0.78, p < 0.01) than those with lower scores. Lastly, patients who 221

were transported from greater distances from the hospital had a higher probability of 222 undergoing tracheostomy (HR: 1.00, 95% CI: 1.00 -1.01, p < 0.01) ( Table 6) . 223

Supplementary Figure 4 presents Kaplan-Meier plots for the association between BMI 224 and time-to-event outcomes. Most patients with a BMI above 30 extubated before 225 decannulation (36.40% vs. 64.80%). However, this difference was not statistically 226 significant (p = 0.13). 227

A total of 25 patients in the COVID group received Cytosorb therapy, while 25 COVID-229 differences between the two groups (Table 7, Supplementary Tables 10 -12 and  231 Supplementary Figures 5 and 6) . We explored the impact of an early extubation and ambulation protocol in combination 251 with a modified approach to candidacy. The outcomes were comparable in patients 252 with COVID and those achieved in non-COVID ARDS. Application of this strategy in 253 patients with COVID-19 appears to not only be safe, but our approximate survival rate 254 of 70% is significantly higher than the ELSO benchmark for COVID ECMO of 52%. 25 Having cannulated the patient, we sought, as a matter of routine, to limit the duration of 286 mechanical ventilation. To accomplish this, we adjusted our ventilatory strategy to 287 accommodate patients of high BMI, a common comorbidity. Prior to the pandemic, we 288 defaulted to protective settings of 4-6ml/kg tidal volume, FiO2 30%, PEEP 10, pressure 289 support 10, and respiratory rate of 10 with a view to limiting plateau pressure to less 290 than 30cmH2O. With growing experience, however, we concluded that this approach 291 was not universally applicable, particularly in the context of obesity. As such, we 292 modified the strategy and adjusted ventilatory settings based on esophageal manometry 293 and made changes in response to varying mechanics that were, in turn, influenced by 294 body mass and variations in intrathoracic pressure secondary to the weight exerted on 295 the chest by body fat and tissue. patients with either cannulation strategy by firmly securing the cannulas and tubing 308 using silk sutures and adhesive securement devices. Admittedly, our approach to 309 extubation and early ambulation is in stark contrast to the ethos in programs more 310 accustomed to patients laying comatose for the duration of the ECMO course. Ours, 311 however, is not a novel strategy specific to the pandemic and indeed it has been our 312 practice cultivated over several years and which proffered the very experience that 313 permitted extrapolation to the COVID population. 314

We limited candidacy among the super-obese to BMI less than 48 in view of the 316 difficulty in achieving adequate flows in these patients, who typically require 5-7L/min. 317

Cannulation in these patients often requires multiple people to retract the pannus and 318 rolls of adipose tissue that frequently obscure the cannulation sites and raise the 319 complexity of acquiring access to deeply situated vessels. High BMI, nonetheless, is 320 somewhat of a paradox in extracorporeal support. It has been demonstrated to be 321 protective in some circumstances. 28-30 Indeed within the calculus of mortality using the 322 PRESERVE scoring system, a high BMI is protective, proffering a value of -2 in the 323 scoring system in which the higher the score, the higher the risk of death. 28-30 As such, 324 rigorous studies are required to better elucidate the relationship between BMI and 325 survival in extracorporeal support. Regarding candidacy, our results identify a 326 dichotomy in survival in patients with age >60, SOFA >10, APACHE >23, PRESET >5, 327

and Murray >3. The composite use of these risk severity scores has allowed us greater 328 insight into candidacy, selection and may likely form the basis of an absolute 329

contraindication once it has been tested more rigorously. In our experience, therefore, 330 BMI alone did not constitute a contraindication. CytoSorb complemented our programmatic approach to cytokine reduction in patients 334 with virulent inflammatory illness for which we had hitherto relied only on plasma 335 exchange techniques. As such, the third deviation from the norm was our approach to 336 the use of cytokine reduction techniques in which we adopted a threshold ferritin level of 337 1000 and D-dimer of 3000 as an indication for cytokine reduction therapy. 31 We 338 excluded the use of IL-6 as a criterion for therapy because estimating this marker 339 requires sending blood to an outside institution and precludes the timely titration of 

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Monoclonal Antibodies for Prevention and 441 Treatment of COVID-19

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