key: cord-0836969-3cmd180w authors: Forsberg, Gustaf; Berg, Sören; Divanoglou, Anestis; Levi, Richard; Ekqvist, David; Östholm Balkhed, Åse; Niward, Katarina title: Improved 60‐day survival but impaired general health in Swedish ICU‐COVID patients: An ambidirectional population‐based study date: 2022-03-14 journal: Acta Anaesthesiol Scand DOI: 10.1111/aas.14054 sha: 672961d3acddaaeeb362ca996b7c00672463d098 doc_id: 836969 cord_uid: 3cmd180w BACKGROUND: Survival among critically ill COVID‐19 patients varies between countries and time periods. Mortality rates up to 60% have been reported in intensive care units (ICUs). Standard‐of‐care has evolved throughout the pandemic. The purpose of the study was to explore management and mortality of COVID‐19 ICU‐patients during the first pandemic wave and assess their post‐ICU health status. METHODS: We conducted an exploratory observational ambidirectional population‐based study of ICU‐patients with COVID‐19 in a Swedish county during 1 March‐30 June 2020. Primary outcome was 60‐day mortality with secondary outcomes including treatments, complications, self‐reported general health and dyspnoea post‐discharge. Patients were consecutively divided into equal tertiles with cut‐offs on April 4 and April 20, 2020, to analyse time trends. RESULTS: One hundred patients, median age was 63 years, were included, and 60‐day mortality rate was 22%. Ninety‐one percent had moderate/severe ARDS and 88% required mechanical ventilation. In the first tertile of patients 60‐day mortality was 33%, declining to 15% and 18% in the following two. This reduction paralleled increased use of thromboprophylaxis, less steep rise of treated ICU‐patients per day and expanded ICU resources. Four months post‐discharge, 63% of survivors reported self‐assessed decline in general health retrospectively compared to prior COVID‐19. CONCLUSIONS: In this cohort, the initial 60‐day mortality quickly declined, despite continuous admittance of critically ill patients. This was parallel to adaptation to increased workload and more intense thromboembolic prophylaxis. A majority of survivors reported declined general health four months after discharge. Further studies on long‐term health status of ICU‐survivors are indicated. The study was approved by the Ethical Review Board in Sweden (2020-03888, 2020-02080 and 2020-03029, 2020-04443). In accordance with the ethics approval, and because the 4-month telephone follow-up was part of a clinical follow-up, a written informed consent was not required. The study was conducted within the county of Östergötland, Sweden. The county has a population of approximately 450,000 inhabitants and is served by three hospitals; a tertiary care university hospital with 400 beds and four ICUs, and two general hospitals, one with 241 beds and an ICU and the other with 76 beds. A total of 30 ICU beds were supported at the beginning of the pandemic. All COVID-19 patients admitted to an ICU within the county during the study period were included, and all hospitalized patients with symptoms of COVID-19 during the study period were tested for SARS-CoV-2 infection. We conducted an exploratory observational ambidirectional population-based study of patients with COVID-19 admitted to ICUs in a Swedish county during 1 March-30 June 2020. Clinical data were obtained retrospectively from hospital medical records and additional data were retrieved from the Swedish Intensive Care Registry. The primary outcome was 60-day mortality, with secondary outcomes including baseline characteristics, complications, treatments, and self-rated health. Clinical data, interventions, complications and 30-, 60-and 90-day mortality after ICU admission were registered as well as follow-up data for survivors at median four months postdischarge from hospital (telephone interview). To further analyse temporal changes, the study cohort was split into three tertiles with 33, 34 and 33 consecutively admitted patients to ICU, respectively. The time period for each tertile began on March 16, April 4, and April 20, 2020. No analysis of missing data was performed. Infection with SARS-CoV-2 was confirmed by a positive Real Time Polymerase Chain Reaction (RT-PCR) assay of nasopharyngeal swabs or a typical clinical picture together with a positive serological test detecting SARS-CoV-2 antibodies. Sixty-day mortality was defined as all-cause mortality within 60 days after admission to ICU. Expected 30-day mortality rate (EMR) was calculated using the Simplified Acute Physiology Score 3 (SAPS 3) score adapted to the Swedish setting. [7] [8] [9] The definition used for ARDS was the Berlin definition. 10 In a retrospective study of 100 consecutive Covid-19 ICU patients from one Swedish county, the overall 90-day mortality declined over time, but reduced self-reported quality of life was reported by most patients 4 months after discharge. telephone follow-up, dyspnoea was recorded according to the modified Medical Research Council (mMRC) dyspnoea scale. 15, 16 They were also asked to rate their general health status at the time on a five-point Likert scale from very good to very bad, similar to the general question regarding overall health in the WHO health survey, 17 and to estimate their general health on the same scale prior to COVID-19. The questionnaire was part of a clinical follow-up, with a primary focus to identify long term rehabilitation needs, with specific focus on cognition, physical functioning and activity level, described further in a publication by Divanoglou et al. 18 For the purposes of this study questions regarding self-rated general health and dyspnoea are included for analysis. Out of 113 patients with COVID-19 admitted to ICU during the study period, 10 (8.8%) patients were excluded as COVID-19 was not the reason for admission and another 3 (2.7%) patients as they were transferred to another county ( Figure 1 ). Among the 100 patients included in the analyses, 98 (98%) were confirmed SARS-CoV-2 PCR positive and 2% were included based on a typical clinical picture in combination with a positive serological test. The median age was 63 years and 75 (75%) were male ( Table 1) . The most frequent comorbidities were hypertension (53%), diabetes mellitus (29%), and ischemic heart disease (18%). On admission to ICU, median SOFAscore was 4. Most of the patients had moderate or severe ARDS (91%) and 88% required mechanical ventilation. Limitation of the level of care, that is, withholding ventilator support, dialysis or cardiopulmonary resuscitation was decided for 18 patients during their time in the ICU. Mortality rates at 30, 60 and 90 days after admission to ICU were 19% (95% CI: 11%-27%), 22% (95% CI: 14%-30%) and 23% (95% CI: 15%-31%) respectively. The 60-day mortality rate was 4% among the 25 patients with no underlying comorbidity compared to 28% among patients with comorbidity (p < .05). Fifteen patients were immediately transferred from the emergency room to the ICU and their 60-day mortality was 40% (6/15), that is, twice the mortality rate observed among the patients not in need of immediate ICU treatment (19%, 16/85, p < .05) ( Table 2) . At 60 days after ICU admission, 6% of patients were still in the ICU. The 22 non-survivors were significantly older (median age 70 vs. 61 years, p < .05, Table 1 ) and suffered more ICU complications (95% versus 67%, p < .05). Septic shock and acute kidney injury/failure were significantly more frequent among non-survivors than survivors (59% vs. 18% and 82% vs. 42% respectively p < .05) ( Figure 2 ). Ventilator-associated pneumonia was confirmed in 18% of mechanically ventilated patients (16/88) and suspected in another 32% (28/88). Blood types A or AB were present in 42% of survivors and in 53% of non-survivors. Among non-survivors, the decision to withhold or withdraw treatment was made in 59% (13/22); in more than half (7/13) the decision to withdraw was made due to prolonged invasive mechanical ventilation (median 20.5 days in ICU) with poor predicted prognosis. At four months post-discharge, 39% (24/62) rated their general health as good or very good, compared to a rating of 85% prior to COVID-19 as recalled ( Alive at 60 day followup (n=78 (78%)) Lost to 4 month followup, 5-point Likert scale (n=16 (21%)) and mMRC (n=14 (18%)) Follow-up at 4 months using 5-point likert scale (n=62 (79%)) and mMRC (n=64 (82%)) Deceased at 60 day follow-up (n= 22 (22%)) severe ARDS and 10/23 had no comorbidity. In the subgroup whose general health had declined at least two points, the median age was 59 years, 14/21 were male and median time in hospital was 37 days of which 14 days were on mechanical ventilation, all had moderate or severe ARDS, and 7/21 had no comorbidity. At four months postdischarge, 39% (25/64) of the survivors experienced limitations related to breathing (≥2 points on mMRC scale, Figure 4 ). In addition to antibiotics, the specific treatments given in the ICU were high-dose LMWH (83%), corticosteroid equivalent to 6 mg dexamethasone (17%), and hydroxychloroquine (19%) ( Table 3) . Twenty-seven (27%) patients received continuous renal replacement therapy. On admission to hospital, non-survivors had significantly Self-rated general health before COVID-19 Self-rated general health at follow-up (~4 months) A decline in 60-day mortality was observed over the three tertiles from 33% (95% CI: 24%-42%) to 15% (95% CI: 8%-22%), and 18% (95% CI: 11%-26%) respectively (p=NS) ( Table 4 ). Thirty-day mortality showed a similar pattern (30%, 15% and 12%, Figure 5 ). Median EMR was 14% in the first tertile, 10% in the second and 12% in the last tertile ( Figure 5) . Table 3 ). The use of high-dose LMWH increased significantly in the second and third tertile compared to the first (from 59% to 94% in the last two tertiles, p < .05) ( Figure 5 , Table 4 ), but did not differ between survivors and non-survivors ( Table 3) . Median D-dimer on admission to hospital among patients subsequently admitted to the ICU in the first tertile was significantly higher than in the second and third tertiles (0.63 vs. 0.48 and 0.19, p < .05), but there was no significant difference in thromboembolic events between the three groups. This ambidirectional population-based study presents an in-depth In the present study there was a reduction in 60-day mortality from a high level of 33% during the first tertile falling to 15% and 18% in the following two, with similar 30-day mortality at 30%, 15% and 12% respectively. Although not statistically significant, this reflects the declines in mortality rate recently reported from other centres. In a large observational study, there was a gradual decline in 60day mortality for all ICU-treated COVID-19 patients in Sweden from 36% in March to 21% post-wave (July-September) 2020. 25 Western reports showed similar falls in mortality among critically ill patients during the first wave, from initial 42%-44% to 19%-25% in May 2020. 23, 26 The reason for this decline in mortality is still unknown but likely multifactorial. There was no apparent difference in patient No novel effective drugs were introduced for COVID-19 treatment during the first wave. The RECOVERY study report on reduction of mortality by steroid treatment was not released until mid-June 2020. 28 The risk for thromboembolic events was quickly recognized with aggressive thromboprophylaxis being instituted later in the first wave. In a meta-analysis by Malas and co-workers, 29 the overall incidence of venous thromboembolism amongst COVID-19 ICU treated patients was 31% (95% CI: 23%-39%) compared to 14% (95% CI: 7%-21%) in the present study. Limited use of high-dose thromboprophylaxis as well as a trend towards more frequent decisions to limit level of care on the ICU (Table 4 ) may have contributed to the higher mortality observed in the beginning of the first wave. Studies have suggested that blood types A and AB are associated with increased COVID-19 mortality. 30 In this ICU cohort, blood type distribution was comparable to the general population in Sweden 31 with no significant difference between survivors and non-survivors. Poor self-rated general health was seen in most ICU survivors four months after discharge. Despite 85% of followed-up survivors recalling their health as being good or very good prior to COVID-19, decline in self-rated general health, all had ARDS, more ventilator days, and longer hospital stay. This is consistent with a study by Taboada and co-workers, reporting an association between deterioration in HRQoL and duration of mechanical ventilation and length of hospital stay. 34 While HRQoL and self-rated general health are not equals, the latter can be seen as part of the former as evident from the short-form health survey (SF-36), where the first question addresses self-rated general health. 35 Given that self-rated general health has been found to be a strong predictor of healthcare demand, 36 our findings indicate that a considerable subgroup of ICU COVID-19 survivors require long-term support regarding both general health as well as dyspnoea, as a large proportion of this cohort's survivors also experienced limitations in breathing at follow-up. Dyspnoea after COVID-19 is described in several reports. 37, 38 There are however reports indicating that the degree of dyspnoea post hospitalization related to COVID-19 is independent of whether the patient was admitted to the ICU or not. 39, 40 A limitation of the present study is the small sample size. Patient recollection of pre-COVID-19 general health assessment entails a risk of bias in overestimating the level of health before ICU and is regarded as a major limitation. Another limitation is that only survivors were possible to include for follow-up, with lack of pre-morbid data on self-rated health for deceased patients. Furthermore, in addition to the 22 deceased patients another group of 14 patients in the study cohort did not participate in the telephone interview 4-month post-discharge. Study strengths are found in the rigorous data extraction. In the cohort of all ICU-treated COVID-19 patients in the county during the first months of the pandemic, the initially high 60-day mortality quickly declined, despite a continuing admittance of critically ill patients. This fall in mortality, without any change in case mix, was in parallel with successful adaptation to increased workload, less steep increase in patients treated in the ICU and implementation of gained knowledge of this new disease entity, where thromboembolic complications is a major pathogenetic mechanism. Four months post-discharge a large proportion of surviving patients reported a decline in retrospectively self-assessed general health and symptoms of impaired respiratory function. Swedish Intensive Care Registry. This work was supported by ALF grants from the Region of Östergötland, Sweden. The authors declare that they have no conflict of interest. All authors contributed to the study design and had access to the data. GF entered and organized data, KN, and SB conducted all statistical analysis. All authors contributed to data acquisition, interpretation and manuscript writing. All authors read and approved the final manuscript. 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