60-day survival of critically ill COVID-19 first comers


 Background: Germany reported sufficient intensive care unit (ICU) resources throughout the first wave of coronavirus disease 2019 (COVID-19). The treatment of critically ill COVID-19 patients without rationing may improve the outcome. We therefore analyzed resources allocated to critically ill COVID-19 patients and their outcomes. Methods: Retrospectively, we enrolled SARS-CoV2 PCR positive patients with respiratory failure from 03/08/2020 to 04/08/2020 and followed until 05/28/2020 in the university hospital of Freiburg, Germany. Results: Thirty-four COVID-19 patients were admitted to the ICU in the defined interval with medium age of 67±13 (31-86) years. 6/34 (17.6%) were female. All patients suffered from moderate or severe acute respiratory distress syndrome (ARDS), 91.2% of the patients were intubated and 23.5% required extracorporeal membrane oxygenation (ECMO). Proning was performed in 67.6%, renal replacement therapy (RRT) was required in 35.3%. 96% required more than 20 nursing hours per day. Mean ICU stay was 21±19 (1-81) days. 60-day survival of critically ill COVID-19 patients was 50.0% (17/34). Causes of death were multi-organ failure (52.9%), refractory ARDS (17.6%) and intracerebral hemorrhage (17.6%). Conclusions: Treatment of critically ill COVID-19 patients is protracted and resource intense. In a context without resources shortage, 50% of critically ill COVID-19 survived up to 60 days.


Background
Severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic encountered southwestern Germany in March 2020, causing relevant case numbers of the virus-related pneumonia . Clinical courses of critically ill patients with COVID-19 were characterized in international cohorts with mortality rates between 50 and 88% (including ongoing treatment cohorts). (1)(2)(3) The overall case fatality rates vary internationally (1-12%). Recently, reported case fatality rates in Germany remain lower than in neighboring countries. There are no convincing explanations for this phenomenon, whereas only limited data is available for critically ill patients in Europe and their outcomes. (3,4) Patients with severe pulmonary failure and adult respiratory distress syndrome (ARDS) are reported to require multiple organ replacement therapies, some of which have to be applied at the same time. As recently reported, severity of COVID-19 cases immensely increases the strain on staff and resources. (1) This retrospective study analyzes the rst cohort of patients on three intensive care units at a third-level treatment center in Freiburg, Germany. During the observation period the center never faced a shortage of human or technical resources for the treatment of those patients with ARDS caused by COVID-19. The present study focuses on the necessary resources for the treatment, the complications, and hospital survival.

Methods
We enrolled critically ill patients in case of PCR-con rmed SARS-CoV-2 infection and intensive care unit (ICU) admission due to pulmonary failure caused by COVID-19 from 03/08/2020 (date of ICU admission of our rst case) to 04/08/2020.

ARDS treatment
The ARDS treatment followed current guidelines and house-intern standard operating procedures for lung-protective ventilation, prone positioning and supportive therapies. (5) In case of hypoxia or hypercapnia in patients with lung-protective ventilation, ECMO was evaluated by an interdisciplinary team of at least one ECMO specialist, a registered nurses and a perfusionist following local standards.

Inclusion criteria
According to the local pandemic plan, COVID-19 patients were treated at different intensive care units (medical, and surgical). Patients were admitted to out hospital from the emergency room (ER), regular hospital wards, or from rst and secondary treatment centers. Our center serves as a reference and referral center for ARDS and ECMO offering a 24/7 ECMO retrieval service. All patients with proven SARS-CoV2 infection and severe respiratory failure requiring ICU therapy were included in the present study. The PCR tests were carried out from nasopharyngeal swabs or tracheal secretion. Patients with high clinical probability of COVID-19 but negative virology testing were excluded.

Endpoint de nition:
ARDS was classi ed according to the Berlin classi cation (6), Kidney injury according to the RIFLE de nition. All patients dismissed home were considered 60-day survivors in regards to this study. The cause of death was determined by clinical judgment of at least two intensivists part of this research project.

Data management
The data collection was carried out till 05/28/2020. We extracted patient related data from our hospital data systems and documentation from transferring hospitals. The local ethics committee approved the study protocol (Ethik-Kommission der Albert-Ludwigs-Universität Freiburg le number 234/20). Hospital survival was de ned as discharge from the ICU on a step-down unit / regular ward or hospital discharge.
Non-survivors and ICU-survivors were compared with chi-square test and univariate ANOVA. Patients with ongoing therapies were excluded from testing differences. We performed analyses with SPSS, version 26 (IBM, NYC, USA) and Prism, version 8 (GraphPad, San Diego, USA) and a p-value of <0.05 was considered statistically signi cant

Baseline characteristics and comorbidities
During the observation period, 34 COVID-19 patients with pulmonary failure were admitted and treated on the ICU. Medium age was 67±13 years, 6 (17.6%) were female.
The medical history of the patients comprised overweight (76.5%), hypertension (52.9%), diabetes (25.3%) and cardiac diseases (23.5% coronary artery disease, 17.6% valve operation or chronic heart failure heart). The number of patients with chronic respiratory precondition was low (Table 1).
Simpli ed Acute Physiology Score (SAPS) II score was signi cantly higher in non-survivors compared to survivors (50±7 vs. 42±14; p=0.037). No other signi cant differences in comorbidities were found.
Assessment of symptoms, vitals on admission, virologic ndings, microbiological ndings, the laboratory measures and imaging are presented in the supplemental material (Table S1).

ICU resources and management
Length of ICU treatment in non-survivors was 17±7 (2-72) days, patients discharged from ICU were treated 25±22 (1-81) days ( Table 2). The dates of arrival, cumulative therapies and outcomes of individual patients are displayed in gure 1.
Half of our patients suffered from moderate, half of severe ARDS. Intubation was performed in 91.2% of the cases, prior to the intubation in 10 patients (29.4%) nasal high ow (NHF) and / or non-invasive ventilation (NIV) was applied.
Three patients (8.8%) were exclusively managed with NHF / NIV. On average, patients were on invasive mechanical ventilation (IMV) for 19±21 (0-79) days. Positive end-expiratory pressure (PEEP) levels were high during the three rst treatment days on average 12.5±3 (7-18) mbar. Spontaneous breathing on the ventilator was performed in 73.5% in the rst 24 hours. Weaning from the respirator was successfully completed in 12 cases before ICU discharge, 5 patients went to a weaning unit.
Proning was performed in 67.6%. If proning was not indicated, alternative strategies were incomplete prone positioning (135°), pilot´s seat positioning or the use of a rotational bed. Thus, 88.2% of our patients underwent daily therapeutic positioning maneuvers.
The initial antiviral treatment followed house-intern expert consensus and was a combination of hydrochloroquine and lopinavir/ritonavir (70.6%) and later on a hydrochloroquine only treatment (23.5%).
Five patients received tocilizumab (14.7%). Additional information is presented in the supplements (Table  S2).
Resource intense multi-organ replacement ICU treatment was measured in nursing hours using Inpuls®categories in 25 patients. A time investment of > 20 hours per day was necessary in 96.0% of our patients and required a 1:1 nurse-patient ratio. Additional information is presented in the supplements. The cumulative therapies are displayed in gure 2.

Outcomes and complications
At the end of the follow up, exactly half of our patients were dead, the other half was discharged from ICU, including 5 transferals to weaning units (4 in-house transferals). More than half of the survivors were able to be discharged home (58.8%), 2 went on a rehabilitation therapy without oxygen supply. On average the survival since admission was 60±8 days (51-81 days).
Nine (52.9%) patients died because of untreatable multi-organ failure as the main cause of death in the cohort. Three (21.4%) patients died because of refractory ARDS. Notably, 3/17 (17.6%) patients died of fatal intracerebral hemorrhage. Because of SARS-CoV-2 PCR positivity organ donation was impossible in these patients. Two (11.8%) patients did not continue therapy because of "do not resuscitate" (DNR) orders and received palliative treatment. No medical autopsies were carried out in this cohort (Table 3).

Discussion
We present a 60-day follow-up of our rst critically ill COVID-19 patients due to pulmonary failure in southwestern Germany. The age and common comorbidities were similar to international cohorts. (1)(2)(3)7) In our cohort, 60-day survival was 50.0%. Importantly, the majority of our survivors were able to return into their former lives.
This is similar to the case-fatality rate of 49.0% reported for "critical cases" in a large Wuhan registry (8) and much lower than suggested by early reports in the COVID-19 pandemic for patients with severe pulmonary failure.(2,3) Importantly, we present data with a long follow-up. In other registries a very small number of patients actually could return to normal life.(2,3) Therefore, we can report a sounder estimate of prognosis of COVID-19 patients.
As Germany did not experience a shortage of ICU resources, it is not surprising that in our cohort, ICU therapy lasted longer than reported in other registries. (1,9) Also, more resources were allocated to patients in this registry including multiple organ replacement therapies -ECMO therapies (1) and renal replacement therapy was required more often than reported in other cohorts from Wuhan or New York.(1-3) Another German registry similar rates of ECMO and renal replacement therapy. (3) We are the rst to report an estimate on the enormous amounts of nursing hours required for treating these patients.
As for cause of death, only 17.6% died from refractory respiratory failure. Data of 92 COVID-19 associated deaths states ARDS as the main complication followed by myocardial injury, liver and kidney injury and multiple organ failure. (10) In pandemic conditions, resource shortages might necessitate rapid decisions regarding futility compared to normal conditions. Survival rate in the present study is lower than described for a general ARDS population (60-day survival 68% (11)). When considering, that ARDS mortality is lower in tertiary hospitals than in hospitals of rst and second treatment level (12), the high mortality found in this registry might suggest a signi cant case-fatality rate of COIVD-19 patients requiring ICU therapy. According to the SAPS II score, our cohort had a relatively high predicted risk of death (over 40%), which is higher than in cohorts characterized beforehand. Also, many patients treated on our ICU were transferred for severe pulmonary failure and ECMO evaluation. Therefore, considering the small patient numbers and the lack of a control group, we cannot compare mortality of COVID-19 patents with ARDS to other ARDS patients.
As stated by Klok et al. the incidence of thrombotic complications is up to 31% in COVID-19 patients on the ICU.(4) The notable rate of 14.7% non-fatal pulmonary artery thrombosis is in line with their ndings. Further studies concentrated on autopsies and con rmed a high rate of thrombembolic events.(13) At the moment the underlying mechanism for the coagulopathy leading to pulmonary artery thrombosis and cerebral bleeding, which were leading causes of the complications in this cohort, is unknown. Nevertheless, the coagulopathic state in COVID-19 does not only seem to lead to thrombotic events as documented, but also to a relevant rate of bleedings. In the cohort ve intracerebral hemorrhages occurred, three being fatal.

Limitations:
First, the case number is limited and the data has to be veri ed by larger cohorts and longer follow-up intervals. Second, the cohort is a selected one as the university hospital of Freiburg is a tertiary center. The center has a large number of patient allocations from primary or secondary treatment centers because of evaluation of ECMO therapy or limited resources in the other centers.

Conclusions
Caring for critically ill COVID-19 patients requires an immense amount of organ replacement therapies, nursing hours and ICU days. The 60-days survival is 50% in a German tertiary treatment center despite full resources. High mortality in COVID-19 might be disease-speci c rather than caused by resource shortage. Availability of data and materials: The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests: The authors declare that they have no competing interests or con ict of interests.
Funding: This research did not receive any speci c grant from funding agencies in the public, commercial, or non-for-pro t sectors. The article processing charge was funded by the Baden-Wuerttemberg Ministry of Science, Research and Art and University of Freiburg in the funding program Open Access Publishing.
Authors' contributions: CNL concepted and designed the study, performed data acquisition, interpretation of the data, drafted and revised the manuscript. VZ concepted and performed data acquisition and revised the manuscript. BS was a major contributor in analysis, interpretation of the data, writing the manuscript. BH contributed in interpretation of the data and revising the manuscript. SU contributed in interpretation of the data and revising the manuscript. PB contributed in interpretation of the data and revising the manuscript. TB contributed in interpretation of the data and revising the manuscript. DD contributed in interpretation of the data and revising the manuscript. CMB contributed in interpretation of the data and revising the manuscript. TW contributed in interpretation of the data and revising the manuscript. DLS concepted and designed the study, created the artwork, contributed in interpretation of the data and revising the manuscript. All authors read and approved the nal manuscript.