key: cord-0807459-l2xolt2e
authors: Polok, Kamil; Fronczek, Jakub; van Heerden, Peter Vernon; Flaatten, Hans; Guidet, Bertrand; De Lange, Dylan W.; Fjølner, Jesper; Leaver, Susannah; Beil, Michael; Sviri, Sigal; Bruno, Raphael Romano; Wernly, Bernhard; Artigas, Antonio; Pinto, Bernardo Bollen; Schefold, Joerg C.; Studzińska, Dorota; Joannidis, Michael; Oeyen, Sandra; Marsh, Brian; Andersen, Finn H.; Moreno, Rui; Cecconi, Maurizio; Jung, Christian; Szczeklik, Wojciech
title: Association between tracheostomy timing and outcomes for critically ill COVID-19 patients aged ≥70 years: Prospective observational study in European intensive care units
date: 2021-11-29
journal: Br J Anaesth
DOI: 10.1016/j.bja.2021.11.027
sha: 678b9e8d9a3b524b3c2ac9ca3a55e1cb3e76b6f5
doc_id: 807459
cord_uid: l2xolt2e

BACKGROUND: Tracheostomy is performed in patients expected to require prolonged mechanical ventilation, but to date optimal timing of tracheostomy has not been established. The evidence concerning tracheostomy in COVID-19 patients is particularly scarce. We aimed to describe the relationship between early tracheostomy (≤10 days since intubation) and outcomes for patients with COVID-19. METHODS: This was a prospective cohort study performed in 152 centres across 16 countries from February to December 2020. We included patients aged ≥70 years with confirmed SARS-CoV2 infection admitted to the intensive care unit (ICU), requiring invasive mechanical ventilation. Multivariable analyses were performed to evaluate the association between early tracheostomy and clinical outcomes including three-month mortality, ICU length of stay and duration of mechanical ventilation. RESULTS: The final analysis included 1740 patients with a mean age of 74 years. Tracheostomy was performed in 461 (26.5%) patients. The tracheostomy rate varied across countries from 8.3% to 52.9%. Early tracheostomy was performed in 135 (29.3%) patients. There was no difference in three-month mortality between early and late tracheostomy in either our primary analysis (HR 0.96 [0.70 to 1.33]) or a secondary landmark analysis (HR 0.78 [0.57 to 1.06]). CONCLUSIONS: There is a wide variation across Europe in the timing of tracheostomy for critically ill patients with COVID-19. However, we found no evidence that early tracheostomy is associated with any effect on survival amongst older critically ill patients with COVID-19.

 There was wide variation between European countries in terms of both the number of older patients who receive tracheostomy, and the timing of the procedure.

 There was no association between the timing of tracheostomy and patient outcomes in this prospective observational study. 19) frequently causes respiratory failure and up to one in 20 affected patients requires admission to the Intensive Care Unit (ICU). [1] [2] [3] Increasing age, co-morbid disease and frailty, are all associated with poor patient outcomes. 4 5 There is limited data describing outcomes amongst older patients with COVID-19 treated in ICU and many aspects of the clinical management in this population remain unclear, including the optimal timing of tracheostomy. This issue is even more important considering the relation of frailty with not only increased need for tracheostomy, but also higher in-hospital mortality after tracheostomy among mechanically ventilated patients. 6 In patients who are expected to require prolonged mechanical ventilation, tracheostomy has several advantages, including reduced work of breathing, easier suctioning, reduced risk of accidental extubation, improved rehabilitation, oral hygiene and patient comfort. 7 To date, the optimal timing of tracheostomy has not been established. The evidence on mortality benefit from early tracheostomy is conflicting, with a significant variation in the direction and magnitude of effect between studies that assessed outcomes of patients requiring tracheostomy using different lengths of follow-up period. 8 Indications for tracheostomy in COVID-19 are similar to the general critically-ill population, but evidence about the riskbenefit ratio and the on optimal timing for this procedure is lacking.

As part of a multicentre, prospective observational study of elderly mechanically ventilated patients, we studied the rate and timing of tracheostomy amongst critically ill patients with confirmed COVID-19. Our aim was to explore associations between tracheostomy and timing and patient outcomes.

J o u r n a l P r e -p r o o f

COVIP was a prospective multicentre study which enrolled consecutive patients ≥ 70 years old admitted to ICU with COVID-19, confirmed with polymerase chain reaction (PCR) test (ClinicalTrials.gov, NCT04321265). The aim of this study was to describe short-term outcomes of older critically ill patients with COVID-19. The secondary aim of the study was to investigate factors associated with outcomes in this population with a particular focus on frailty. 5 9-11 This study was a part of very old intensive care patients (VIP) project (www.vipstudy.org) that had been endorsed by the European Society of Intensive Care Medicine (ESICM). Patients included in this substudy were recruited in 152 centres in 15

European countries and Israel from 12 February to 31 December 2020. The list of participating countries with numbers of centres and enrolled patients is available in Supplementary Table 1 . National study co-ordinators were responsible for local ethics approvals, supervision of patient recruitment and recruitment of ICUs. We were able to recruit patients without informed consent in some countries, while in the remaining countries informed consent was mandatory to include patients in the study (Supplementary Table 2) .

This sub-study of COVIP study included patients aged ≥70 years with confirmed SARS-CoV-2 infection admitted to the ICU and required invasive mechanical ventilation. Patients previously enrolled in the COVIP study were excluded. We aimed to recruit as many patients as possible in this observational study and no sample size calculation was performed. Each centre aimed to recruit at least 20 patients.

Data were collected using an online case report form (CRF). All dates were numbered sequentially from the date of ICU admission. We recorded baseline demographics and clinical characteristics of study participants. The definitions of evaluated comorbidities are summarised in Supplementary Appendix 1. We gathered information about tracheostomy including timing of the procedure in days since ICU admission. Early tracheostomy was defined as performed ≤10 days since the endotracheal intubation. This threshold was chosen by an international group of clinician-researchers within our study group. Sequential organfailure assessment (SOFA) score was calculated on admission. Frailty level prior to disease onset was evaluated using the 9-level clinical frailty scale (CFS), 12 13 and patients were categorised as fit (1-3 points), vulnerable (4 points) or frail (5-9 points). Patients were followed up until death or three months after ICU admission.

The primary outcome measure was all-cause mortality within 3 months after admission to the ICU. Secondary outcome measures were ICU length of stay and duration of mechanical ventilation. Information about outcomes were retrieved from the hospital administration system or by telephone follow-up.

Categorical variables were presented as numbers (percentage) and compared using Chi 2 test, while continuous variables were presented as medians with interquartile range and compared using Mann-Whitney test. Differences in crude survival between the groups were evaluated J o u r n a l P r e -p r o o f using the log-rank test. To account for immortal time bias we performed two complementary survival analyses. In the primary analysis patients were included in the survival analysis from the day of tracheostomy. We additionally performed a landmark analysis to account for selection bias. 14 In this analysis we excluded all patients who died or were weaned off the ventilator within the first 10 days after endotracheal intubation. Patients were divided into early and late groups, the latter including patients with late tracheostomy and those who were mechanically ventilated and never received tracheostomy. Proportional hazard Cox regression adjusting for age, sex, comorbidities, baseline CFS and SOFA scores was performed to assess the association between tracheostomy timing and three-month mortality in both analyses. A sensitivity analysis was performed using a multivariable model with tracheostomy timing as a continuous variable (number of days from intubation to tracheostomy) with restricted cubic splines (four knots located at the 5th, 35th, 65th and 95th percentiles of the distribution) allowing for non-linearity in the relationship between the timing of tracheostomy and mortality. All models satisfied the proportional hazard assumption. Differences between the groups in duration of mechanical ventilation and ICU length of stay were compared in both univariate analysis (Mann-Whitney test) and multivariable analysis performed using linear regression adjusting for age, gender, comorbidities, baseline CFS and SOFA scores. This was a complete case analysis; patients lost to follow-up were excluded. A two-sided p value < 0.05 was considered statistically significant. Statistical analyses were performed using R 3. Table 1 .

Tracheostomy was performed in 461 (26.5%) patients, a median of 14 days (IQR 9 to 20.5) from endotracheal intubation. Tracheostomy rate varied between the countries and ranged from 8.3% in Ireland to 52.9% in Denmark. The median interval between intubation and tracheostomy also varied across countries and was lowest for Ireland (3 days) Comparison of patients with tracheostomy and other invasively ventilated patients is presented in Table 1 .

Survival analysis was performed in 450 patients with tracheostomy and known tracheostomy timing and survival status at 3 months since the admission to the ICU. The three-month mortality in the analysed subgroup was 50.4% (227/450). We found no difference in three-month mortality between early (defined as performed ≤10 days since the endotracheal intubation) and late tracheostomy groups (49.5% vs. 52.6%, log-rank p=0.9). A multivariable analysis did not demonstrate any effect of tracheostomy timing on three-month mortality (HR 0.96, 95%CI 0.70 to 1.33). Similarly, the landmark analysis revealed similar findings (HR 0.78, 95%CI 0.57 to 1.06). Adjusted survival rate curves are presented in Figure   3 . Detailed results of survival analysis in both primary and landmark analyses are summarised in Table 2 

In this prospective observational study including more than 2000 mechanically ventilated patients with confirmed COVID-19 aged ≥70 years, there was wide variation in tracheostomy rate and timing across participating countries. We did not find evidence that tracheostomy was associated with any advantage in terms of three-month mortality, ICU length of stay or duration of mechanical ventilation.

Even though tracheostomy was introduced to the ICUs in the 1950s, uncertainties around the procedure remain, particularly regarding indications for tracheostomy and optimal timing. 15 16 There is a lack of high-quality evidence to define the optimal use of tracheostomy in COVID- 19 patients and concerns about the safety of medical personnel during this aerosol-generating procedure. 17 Initial guidelines recommended that tracheostomy should be preferably performed only in patients with a negative SARS-CoV-2 swab test, 18 but it has been subsequently suggested delaying tracheostomy beyond 14 days from the initial diagnosis may decrease the risk of transmitting the disease to healthcare workers. 18 19 Current guidelines issued by the American College of Chest Physicians state that tracheostomy is indicated in patients with COVID-19 in whom prolonged mechanical ventilation is expected, without the requirement to routinely test for SARS-CoV2 prior to the procedure. 20 We did not identify any temporal trends in the use of tracheostomy through the course of the pandemic. It is however possible that tracheostomy may have been performed more frequently when the number of hospitalised COVID-19 patients was lower.

Tracheostomy is performed in approximately 13% of patients with acute respiratory distress syndrome, making it one of the most common airway-related procedures in ICU. 21 In this study tracheostomy was performed in around one quarter of mechanically ventilated patients, J o u r n a l P r e -p r o o f which is consistent with previous reports of tracheostomy rates among critically-ill COVID-19 patients, which range from 16.4% to 53.0%. 22 Another interesting observation is a large variation of tracheostomy practices across the countries included in our study, as the frequency of tracheostomy ranged from 8.3% in Ireland to 52.9% in Denmark. The variation in tracheostomy timing was even greater. Similar analyses in the pre-COVID-19 era also suggested significant differences in tracheostomy practices around the world. 21 Importantly, non-random selection of participating ICUs could have influenced this observation as the approach to tracheostomy may vary between both hospitals and countries. 23 In the majority of clinical scenarios tracheostomy is considered in patients who have survived the acute phase of the disease and show signs of improvement, therefore giving hope for a positive outcome. 15 It is therefore not surprising that our analysis showed that patients who underwent tracheostomy have a higher survival rate compared to the remaining mechanically ventilated patients. This also corroborates the results of a recently published meta-analysis suggesting that mortality is much lower amongst those COVID-19 patients who do receive a tracheostomy. 24 Although the topic has been widely studied, the optimal timing of tracheostomy has not yet been established. There is no consensus definition for early tracheostomy, with cut-off points ranging from <4 days to ≤21 days. Observational studies are inherently prone to unmeasured confounding, while randomised trials are hindered by a high proportion of patients allocated to the late tracheostomy group who ultimately do not require the procedure. To account for both immortal time and selection bias we performed two separate and complementary analyses, including landmark analysis. We have attempted to model this effect in our landmark analysis excluding patients who died or who were weaned from ventilation within 10 days from intubation, and may therefore not have been candidates for tracheostomy.

Patients were divided into early and non-early tracheostomy group with the latter including J o u r n a l P r e -p r o o f patients who did and did not undergo tracheostomy, providing a similar population to those included in intention-to-treat analyses in randomised trials. 14 25 Both survival analyses confirmed a lack of association between the timing of tracheostomy and three-month survival for critically ill patients with COVID-19. The findings of meta-analyses including RCTs performed before the COVID-19 pandemic suggest that early tracheostomy is associated with a lower mortality amongst patients who require prolonged mechanical ventilation. 8 26 However, the evidence base for patients with COVID-19 consists solely of observational data.

A recently published meta-analysis, including 203 patients with COVID-19 from three studies, did not show mortality benefit from early tracheostomy. 27 Our sensitivity analysis with timing of tracheostomy evaluated as a non-linear continuous variable did not indicate any association between tracheostomy timing and three-month mortality. However, this observation may be affected by the improved outcomes for patients who survive the immediate phase of COVID-19 within the first few days of ICU admission. It was important to undertake this sensitivity analysis because any definition of early versus late tracheostomy will inevitably be an arbitrary choice. This approach dichotomizes the dataset leading to loss of information and an increased risk of bias. We therefore encourage readers to take all the complementary analyses into consideration while drawing conclusions from this study. In our opinion this sensitivity analysis suggests that it is unlikely that the threshold selected in our study affected the conclusions in a meaningful way. However, the need remains to create a uniform definition of early tracheostomy to facilitate the research in this area.

With regards to the effect of tracheostomy timing on the duration of mechanical ventilation and duration of ICU stay, the existing evidence suggests that early tracheostomy increases the number of ventilator-free days and reduces the duration of ICU stay. 8 26 The primary analysis in our study showed that patients in the early tracheostomy group experienced shorter ICU J o u r n a l P r e -p r o o f stays and spent fewer hours on mechanical ventilation. However, this observation is subject to bias in the primary mortality analysis population. We undertook a landmark analysis to accounts for this source bias, the findings of which suggest there is no effect of tracheostomy timing and ICU stay or duration mechanical ventilation after adjustment for potential confounders. While a meta-analysis of previous studies including critically ill COVID-19 patients suggest that early tracheostomy is associated with a shorter ICU stay, these findings are limited by low patient numbers and the same source of bias described above. 24 28 The main strength of our study is a large cohort of prospectively recruited patients with COVID-19 who underwent tracheostomy which significantly improves the quality of available evidence. Our study also has some limitations. The interpretation of observational studies evaluating timing of tracheostomy are inherently susceptible to immortal time bias and confounding. We aimed to minimise bias by including two complementary survival analyses.

Our results cannot easily be generalised to the wider population of COVID-19 patients because the COVIP study only enrolled patients aged ≥70 years. The low numbers of patients enrolled in some countries may result in a poor reflection of national tracheostomy practices.

The consensus cut-off of ≤10 days that we used to define an early tracheostomy is by default arbitrary. At the same time, using a single threshold allowed us to emulate a clinical trial scenario in landmark analysis. To avoid missing relevant signals, we performed a sensitivity analysis where number of days to tracheostomy was treated as a continuous variable. Finally, we were not able to explore the effect of several factors which may also alter patients outcomes including decannulation, sedation, time to mobilisation, incidence of delirium and discharge destination. 

Critical Care Utilization for the COVID-19

Early Experience and Forecast During an Emergency Response

Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention

Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area

Population risk factors for severe disease and mortality in COVID-19: A global systematic review and meta-analysis

The impact of frailty on survival in elderly intensive care patients with COVID-19: the COVIP study

Frailty and invasive mechanical ventilation: association with outcomes, extubation failure, and tracheostomy

Management of tracheostomies in the intensive care unit: a scoping review

Early versus late tracheostomy for critically ill patients

Lactate is associated with mortality in very old intensive care patients suffering from COVID-19: results from an international observational study of 2860 patients

Inhibitors of the renin-angiotensin-aldosterone system and COVID-19 in critically ill elderly patients

A new multi-national network studying very old intensive care patients

A global clinical measure of fitness and frailty in elderly people

Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: Results of a multicenter, prospective study

Analysis of survival by tumor response

Tracheotomy in the intensive care unit: guidelines from a French expert panel

Tracheotomy: Historical review

Clinical evidence based review and recommendations of aerosol generating medical procedures in otolaryngology -head and neck surgery during the COVID-19 pandemic

Systematic review of international guidelines for tracheostomy in COVID-19 patients

Tracheostomy During the COVID-19

Pandemic: Comparison of International Perioperative Care Protocols and Practices in 26 Countries

Use of Tracheostomy During the COVID-19 Pandemic: American College of Chest Physicians/American Association for Bronchology and Interventional Pulmonology/Association of Interventional Pulmonology Program Directors Expert Panel Report

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Assessment of the harms and potential benefits of tracheostomy in COVID-19 patients: Narrative review of outcomes and recommendations

Indications, Timing, and Techniques of Tracheostomy in 152 French ICUs

Association of Tracheostomy With Outcomes in Patients With

Transmission Among Health Care Professionals: A Systematic Review and Metaanalysis

Effect of early tracheostomy in mechanically ventilated patients

Timing of tracheotomy in ICU patients: A systematic review of randomized controlled trials

Systematic review and metaanalysis of tracheostomy outcomes in covid-19 patients

team QEHBC-19 airway. Safety and 30-day outcomes of tracheostomy for COVID-19: a prospective observational cohort study