Clinical characteristics and post-intensive care outcomes of COVID-19 pneumonia.

Background: COVID-19 can result in a severe viral pneumonia, with high reported mortality rates in patients requiring mechanical ventilation. There is controversy as to whether established therapeutic approaches to acute respiratory distress syndrome are optimal in this condition, and numerous novel therapies have been used, often outside the context of randomised trials. In addition, longer term quality of life outcomes associated with COVID-19 are as yet unknown. The aim of this case series is to describe demographic, physiological and outcome data of patients with COVID-19 admitted to our intensive care units who were treated according to evidence-based guidelines for acute respiratory distress syndrome. Methods: We retrospectively reviewed the records of all patients admitted to intensive care units in our institution with COVID-19 between March and June, 2020. Physiological and laboratory data were recorded at baseline and daily until intensive care discharge or death. Quality of life was assessed at a virtual post-intensive care follow-up clinic around 10 weeks after ICU discharge. Results: 45 patients with COVID-19 were included, 37 (82.2%) of whom were male, with a mean age of 55 years. 42 (93.3%) of this cohort met criteria for acute respiratory distress syndrome at time of admission. Clinical management was consistent with evidence based institutional guidelines introduced for acute respiratory distress syndrome. Median length of intensive care stay was 14 days. The intensive care mortality rate was 8.9%. Functional and psychological morbidity post intensive care was signicant: 45.2% of respondents had at least moderate impairment of mobility and 35.5% described at least moderate symptoms of anxiety or depression at the time of follow up. Conclusions : This case series demonstrates low mortality in a cohort of patients treated according to an established evidence-based approach for acute respiratory distress syndrome. However, COVID-19 survivors have a marked functional and psychological morbidity impacting quality of life following ICU admission. The therapeutic goal in the future will be to achieve similar survival outcomes while minimizing the signicant morbidity associated with COVID-19 related critical care admission.

45.2% of respondents had at least moderate impairment of mobility and 35.5% described at least moderate symptoms of anxiety or depression at the time of follow up.
Conclusions : This case series demonstrates low mortality in a cohort of patients treated according to an established evidence-based approach for acute respiratory distress syndrome. However,  survivors have a marked functional and psychological morbidity impacting quality of life following ICU admission. The therapeutic goal in the future will be to achieve similar survival outcomes while minimizing the signi cant morbidity associated with COVID-19 related critical care admission.

Background
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the novel betacorona virus that causes coronavirus disease 2019 (COVID-19) (1,2). A minority of patients develop a severe viral pneumonia precipitating acute respiratory distress syndrome (ARDS), multi-organ failure and death (3,4). The mortality of patients requiring admission to Intensive Care Units (ICUs) is high, reported at between 26% and 50% worldwide (4,5,6,7). Prompted by this, numerous therapies have been used on a compassionate basis in the absence of robust evidence, including antivirals and immune modulators, with mixed results (8,9). Furthermore, it has been suggested that COVID-19 pneumonia represents a su ciently novel disease entity that standard evidence-based approaches to ARDS are not applicable or even deleterious (10,11,12). This retrospective case series describes clinical and physiological features, treatment strategies, and clinical and functional outcomes for patients with COVID-19 admitted to Intensive Care Units in the Belfast Health and Social Care Trust between 1st March and 1st June 2020 and treated according to evidence-based guidelines for ARDS (13).

Population and Setting
All patients admitted to Intensive Care Units within Belfast Health and Social Care Trust with a primary diagnosis of COVID-19 from March 1 to June 1, 2020 were included in this case series. COVID-19 infection was de ned by a positive result on reverse transcriptase polymerase chain reaction (RT-PCR) assay together with a compatible clinical history.
Clinical management and investigations were at the discretion of the treating clinical team according to an institutional guideline (available online, additional le 1) which utilized a standard evidence-based approach to ARDS including low tidal volume ventilation and conservative uid management (13). The use of novel therapies outside the context of clinical trials was actively discouraged. The exception to this approach was anticoagulation. Patients were initially treated with low molecular weight heparin according to a standard institutional guideline for venous thromboembolism prophylaxis. Due to frequent and recurrent thrombosis of continuous renal replacement therapy lters despite regional citrate anticoagulation, however, dosing was increased using an algorithm based on patient weight, brinogen level, renal function and anti-Xa levels.

Data collection and de nitions
Data collection comprised a comprehensive retrospective review of electronic and paper-based notes.
Baseline demographic details were noted for all patients and comorbidities were de ned using the Charlson Comorbidity Index (14). Acute Physiology And Chronic Health Evaluation (APACHE) II scores were calculated based on the initial 24 hours of ICU admission (15). ARDS was de ned according to the Berlin criteria (16).
For the rst 24 hours, ventilatory parameters were matched to corresponding arterial blood gases. On subsequent days, all data were collected at 0800 hours. Sequential Organ Failure Assessment (SOFA) scores were calculated daily (17): for the purposes of calculating the neurological component, presedation Glasgow Coma Scale was assumed to be 15 for all intubated patients.

Data recording and outcomes
All data were recorded in Microsoft Excel (Microsoft, 2020). Statistical analysis was performed on Microsoft Excel or Graphpad Prism software v8.0 software. Early outcomes included ICU and hospital mortality, duration of mechanical ventilation, and ICU and hospital length of stay. Surviving patients were invited to attend a virtual follow-up clinic at 6-8 weeks following hospital discharge as part of routine clinical care. Prior to attending the clinic, patients were asked to complete online questionnaires to assess quality of life and functional status (EQ-5D-L) (18).
To give context and for comparison, demographic, clinical and outcome data generated were presented alongside data from (i) data from a critically-ill COVID-19 cohort within the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme, a long-standing national clinical audit of patient outcomes from adult critical care units in England, Wales and Northern Ireland (up to date as of 24/07/2020) (19) and (ii) data from the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNGSAFE) study, a recent large worldwide cohort study of patients with ARDS (20).

Ethics
The Belfast Health and Social Care Trust Research and Development department deemed this work not to require research ethics approval.

Baseline Characteristics
Over the period March 1st to June 1st, 45 patients met criteria for inclusion. Baseline demographic and clinical characteristics are summarized in Table 1. The majority of patients (N = 32, 76.1%) had received non-invasive Continuous Positive Airway Pressure (CPAP) at ward level prior to ICU admission, and 43 of 45 patients (95.6%) underwent invasive mechanical ventilation within the rst 24 hours of ICU admission: the remaining 2 patients were not intubated.   Table 2. Mean PF ratio in the rst 24 hours of presentation to ICU was 183.2 mmHg. All patients had bilateral in ltrates on chest radiograph at time of referral, and 42 patients (93.3%) met Berlin criteria for ARDS, predominantly of moderate severity.  In the rst 24 hours of ICU admission, the mean PEEP applied was 11.9 cmH 2 0 and a mean estimated driving pressure of 12.2 cmH 2 0 was required to achieve average tidal volume of 6.7 ml/kg of ideal body weight. Mean dynamic compliance of patients was 40.4 ml/cmH 2 0 (additional le 1). Sequential PF ratios for the cohort appeared relatively static for the rst 10 days of admission, with sustained improvements evident between days 10 and 14 (Fig. 1).
Therapeutic modalities used are shown in Table 3. No patients received extra-corporeal membrane oxygenation (ECMO). One patient who was deemed unsuitable for ECMO was treated with airway pressure release ventilation as a rescue measure and survived.  Quality of life outcome data were available for 31 patients at mean of 65 days following ICU discharge (Table 4). 14 patients (45.2%) described at least a moderate problem with their mobility and 11 patients (35.5%) reported moderate to severe problems with anxiety and depression following ICU discharge.

Discussion
In this case series, we describe the cohort of critically ill patients with COVID-19 admitted to ICU for acute hypoxemic respiratory failure in our institution. Almost all ful lled Berlin criteria (16) for moderate to severe ARDS and were managed according to standard evidence-based approaches for ARDS with low mortality.
Physiological parameters were consistent with previous studies in ARDS: in particular, respiratory system compliance was reduced to a comparable degree to other cohorts of patients with ARDS (5,7,23). Our use of dynamic, rather than static, measures of lung compliance likely represents an over-estimation. Few patients exhibited the proposed 'L' phenotype with near normal compliance (12) (additional le 1).
The most striking clinical feature of this cohort was prolonged in ammation and hypoxemia, which were associated with prolonged mechanical ventilation and ICU stay, and with considerable post-discharge morbidity.
The ICU mortality rate of 8.9% is substantially lower than that previously reported, albeit our cohort is small. At the time of submission, the reported mortality for patients with COVID-19 in ICUs in England, Wales and Northern Ireland was 39.9% (19), which is consistent with other series thus far (5, 7) and similar to the published 34% mortality for a cohort of patients with all-cause ARDS (20). The reasons for the lower mortality observed in our cohort are not entirely clear. Our patients were slightly younger and appear to have had less severe systemic derangement at time of presentation than those included in other cohorts (19). Nevertheless, the majority of our cohort had failed CPAP by the time of ICU admission and almost all were mechanically ventilated within 24 hours. Baseline respiratory physiology is comparable both with ICNARC and LUNGSAFE cohorts (19,20). Furthermore a comparable proportion of patients required renal replacement therapy to those in the published ICNARC report (31.1% vs 26.6%) (20).
Other factors which may have contributed to the low mortality rate in this cohort include the relatively late epidemiological surge of COVID-19 in our region. This allowed su cient opportunity for adequate resource allocation to ICUs, introduction of institutional guidelines, and staff training. Heterogeneity of clinical management was minimized and there was a high level of adherence to evidence-based guidelines for ARDS (13). Critical care capacity was never exceeded and predicted rationing of ICU resources was never required.
Neuromuscular blockade was used in the majority of patients, for a mean duration of 4.9 days, longer than has previously been tested within the con nes of clinical trials (24,25), and likely re ective of prolonged hypoxemia. Prone positioning was widely used within our cohort, often repeatedly, with a mean 39.1% increase in PF ratio immediately post proning (additional le 1). This magnitude of therapeutic effect is comparable to that published previously in ARDS (23).
Post-discharge quality of life data were available for just over two thirds of our cohort, with all respondents reporting a problem in at least one dimension of mobility, self-care, usual activities, pain/discomfort and anxiety/depression post-ICU discharge. 45.2% of patients had at least moderate issues with mobility and 61.3% had moderate to severe problems participating in previous activities. These results are comparable to those published previously for outcomes after all cause ICU admission (28). Anxiety and depression were at least a moderate problem with 35.5% of responders; a feature well documented in post-ARDS survivors. The incidence in this cohort is congruent with previous reported rates (29). These data illustrate the major burden on rehabilitation services which will follow the COVID-19 pandemic, and the clear need for evidence-based approaches to management of the post-intensive care syndrome (29).
The complex pathophysiology and heterogenous disease spectrum associated with COVID-19 mean there is an ongoing urgent need for investigation of novel therapies such as antivirals and immune modulating agents. While clear bene t has emerged for some (30,31), our data support our belief that evidencebased supportive measures as re ned over decades of research into ARDS remain key to the critical care management of COVID-19.

Conclusion
COVID-19 pneumonia results in clinically similar respiratory physiology to that previously described for ARDS. In our cohort, we demonstrated that strict adherence to evidence-based ARDS treatment can be associated with good outcomes without the use of novel therapies. The burden of the disease extends much longer than the initial ICU admission and the challenge of future critical care management of COVID-19 will be to minimize the considerable resource burden and morbidity, while achieving similar or better survival outcomes. Availability of data and materials: All data generated and/or analysed during this study are available from the corresponding author on reasonable request. The data are not publicly available due to containing information that could compromise patient privacy.

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