Intensive Care Resources and 60-Day Survival of Critically-Ill COVID-19 Patients

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 ICU resources allocated to COVID-19 patients with respiratory failure and their outcomes. Methods: Retrospectively, we enrolled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (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: In the defined interval, 34 COVID-19 patients were admitted to the ICU with median age of 67±13 (31-86) years. Six of 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%. Ninety-six percent required more than 20 nursing hours per day. Mean ICU stay was 21±19 (1-81) days. Sixty-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 COVID-19 with respiratory failure survived up to 60 days.

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 first 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 and 60-day survival.
This article was previously posted to the Research Square preprint server 2020, August 02.

Materials And Methods
We enrolled critically ill patients in case of polymerase chain reaction (PCR)-confirmed 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 first case) to 04/08/2020.

Inclusion criteria
According to the local pandemic plan, COVID-19 patients were treated at different ICUs (medical and surgical). Patients were admitted to the ICU from the emergency room (ER), regular hospital wards, or from first and secondary treatment centers. Our center serves as a reference and referral center for ARDS and veno-venous extracorporeal membrance oxygenation (ECMO) offering a 24/7 ECMO retrieval service. All patients with proven SARS-CoV-2 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.
Patients with do not resuscitate (DNR) orders not excluding ICU therapy for respiratory failure (ventilation, prone positioning) were included. We adhered to their wish if patients did prefer to not continue ICU therapy.

Pre-ICU treatment
Patient management prior to ICU was outlined in in-house standard operating procedures related to COVID-19. It included hygiene concepts, laboratory work-up, lung-ultrasound, radiology imaging, volume therapy, perioperative management, discharge requirements, and anti-infective recommendations. During the first wave of the pandemic all guidelines were rapidly implemented and shared with transferring hospitals to align therapies.
If patients were transferred from other hospitals, we collected patients reports to minimize the loss of information.

ARDS treatment
The ARDS treatment followed current guidelines and house-intern standard operating procedures for lungprotective ventilation, prone positioning and supportive therapies [6,7].
In our center attempts with non-invasive ventilation were carried out with high-flow nasal cannula (HFNC) or non-invasive ventilation (NIV) prior to invasive mechanical ventilation (IMV).
At this point of time, steroids next to relaxation or recruitment maneuvers were not standard therapy in ARDS in our center; these strategies remained a case-by-case decision and were rarely used in early ARDS. Steroid therapies have been implemented later on.
In case of persistent hypoxia or hypercapnia in patients with lung-protective ventilation after employment of all conservative strategies, ECMO was evaluated by an interdisciplinary team of at least one ECMO specialist, a registered nurse, and a perfusionist following local standards. (Relative) exclusion criteria were ventilation over seven days without lung protection, acute intracerebral hemorrhage, severe comorbidities (metastatic cancer), severe thrombocytopenia, coagulopathy, and advanced age (no cut-off).
For the ECMO circuit we cannulated bifemoral or jugular with a dual lumen cannula. Applied systems were Stöckert Centrifugal Pump Console (SCPC) (LivaNova, Munich, Germany) or the Cardiohelp-System (Maquet, Rastatt, Germany) with customized tubing sets and oxygenators. We primed the sets with 700 ml electrolyte solution and 5000 IE of unfractionated heparin.

Nursing hours
Nursing hours were calculated on a representative day for the patients and cumulative for one representative medical ICU (14-bed) based on the Inpuls® Intensivpflege-und Leistungserfassungssystem, intensive care nursing and activity recording system (Inpuls®, Heidelberg, Germany

Endpoint definition
ARDS was classified according to the Berlin classification [8]. Acute kidney injury was diagnosed according to the RIFLE definition and supported by RRT if necessary [9,10]. Frailty was clinically judged according to the modified Rockwood Clinical Frailty Score if meeting the 5th category or higher [11]. All patients dismissed home or to a rehabilitation unit were considered 60-day survivors in regards to this study (if ICU and following hospital stay were shorter than 60 days). The cause of death was determined by clinical judgment of at least two intensivists (participants of this research project).

Data management
The data collection was carried out till 05/28/2020 for the patients admitted between 08/03/2020 until 08/04/2020. Patients admitted later were not included in the analysis. We extracted patient related data from our hospital data systems and documentation from transferring hospitals.

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, six (17.6%) were female (
Baseline characteristics are displayed for all patients, non-survivors and survivors. Data are n (%) or mean with standard deviation and range. Student´s t-test or Fisher´s exact test was performed to derive p-values.
a DNR, no not resuscitate order was assessed prior to ICU admission and did not exclude ICU therapy for respiratory failure (ventilation, prone positioning). Patients not willing to receive ICU therapy were primarily not transferred to our unit.
b Other cardiac condition: valve operation or chronic heart failure.
c Frailty was clinically judged; clinical frailty scale (CFS) which is a modification of the Canadian frailty scale by Rockwood [11]. If a category of 5 or higher was met (help needed for daily life activities), we categorized the patient as frail.
73.5% of the patients were privately insured with no difference between survivors and non-survivors. DNR order was given in five cases not excluding ventilation therapy for respiratory failure.
Preeminently, 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). The number of patients with chronic respiratory precondition was low. Frailty occurred more often in the non-survivor group (35.3% vs. 5.9%; p=0.085). No significant differences were found between the two groups relating to the comorbidities.
Assessment of symptoms, vitals on admission, virologic findings, microbiological findings, the laboratory measures, and imaging are presented in Table 2
ICU resources and therapy are displayed for all patients, non-survivors and survivors. Data are n (%) or mean with standard deviation and range. Student´s t-test or Fisher´s exact test was performed to derive p-values.
a Therapeutic positioning maneuvers included complete proning, incomplete proning (135°), pilot´s seat positioning or the use of a rotational bed.
b Acute kidney injury is defined by the RIFLE definition [9].
Attempts for non-invasive management (NIV or HFNC) before intubation were carried out in 38.2%.
Prone positioning was performed in 67.6%. If prone positioning 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. Initially, antiviral treatment was applied to almost all patients (97.1%), but not continued later on, when it was proven not to be effective.
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 (  To present the cumulative resources during the pandemic on the ICU, we depicted the dates of arrival, organ replacement therapies per patient and outcomes on day 60 ( Figure 1).

COVID-19 Patients
Date of admission, clinical course and outcomes at day 60 are depicted for each patient from the first admission on 03/08/2020 until 05/28/2020.
Days with non-invasive ventilation (non-invasive oxygen support; green), invasive ventilation (blue) and additional extracorporeal membrane oxygenation (ECMO; orange) are displayed.
The cumulative therapies of our units are displayed in Figure 2.

FIGURE 3: Nursing Burden in the First Wave of the COVID-19 Pandemic on a Medical ICU
Inpuls® data show intensive care nursing and activity recording for an exemplary 14-bed medical ICU. Categories 1 and 2 (K1-2) include monitoring patients, categories 3-6 (K3-6) include intensive care patients with ascending maintenance effort, severity of disease, and resource application. Data is presented over the months January to June 2019 (baseline) and 2020 (first wave of the COVID-19 pandemic). In April the whole burden of the first wave of the COVID-19 pandemic is depicted as patients are categorized 100% in K3-6, whereas in 2019 representative values for this ICU are displayed with averagely 90% of the patients in K3-6.
Whereas in 2019 representative values for this ICU are displayed with averagely 90% of the patients in K3-6 (intensive care patients with ascending maintenance effort, severity of disease, and resource application), in April 2020 patients are categorized exclusively (100%) in K3-6.

Outcomes and complications
At the end of the follow-up, exactly half of our patients were deceased, the other half was discharged from ICU, including five transferals to weaning units (four in-house transferals). More than half of the survivors were able to be discharged home (58.8%), two went on a rehabilitation therapy without oxygen supply. On average the followed-up survival since admission was 60±8 days (51-81 days).
The clinical course was complicated by pneumothorax or pneumomediastinum in six (17.6%) cases. Furthermore, five (14.7%) patients exhibited non-fatal pulmonary embolism/thrombosis in segmental and sub-segmental lung arteries. Superinfections during treatment in 18 (52.9%) cases were dominated by Serratia marcescens (33.3%). Aspergillus fumigatus superinfection was detected in two (11.1%) patients (Table 6).  c Transferals to weaning units included four transferals to an incorporated weaning unit and one transferal to an external weaning unit.
Intracerebral hemorrhage was significantly more often recorded in non-survivors (p=0.044).
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, as they were not willing to undergo re-intubation and received palliative treatment. No medical autopsies were carried out in this cohort.

Intensive care resources and 60-day survival
We present a 60-day follow-up of our first 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]12]. In our cohort, 60-day survival was 50.0%. Importantly, the majority of our survivors were able to return to their former lives.
This is similar to the case-fatality rate of 49.0% reported for "critical cases" in a large Wuhan registry [13] 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].
To characterize the non-survivor and possible determinants of mortality at 60 days, we analyzed the mode of death. Data on mode of death for in-hospital mortality were presented beforehand [5]. Thus, respiratory failure remained eminent in three cases. All other patients seemed to have overcome respiratory failure but died from overwhelming complications or multiorgan-failure. Interestingly, three patients died from intracerebral hemorrhage and were studied in a subsequent analysis [14]. ICU therapy withdrawal was due to DNR orders in two patients (no re-intubation preferred) -not decisively influencing the high mortality in our opinion. Patients not willing to receive ICU therapy were primarily not transferred to our unit. If patients developed the wish to not continue ICU therapy, we adhered to their wish.
Data of 92 COVID-19-associated deaths states ARDS as the main complication followed by myocardial injury, liver injury, kidney injury, and multiple organ failure [15]. 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%) [16]. When considering that ARDS mortality is lower in tertiary hospitals than in hospitals of first and second treatment level [17], the high mortality found in this registry might suggest a significant case-fatality rate of COVID-19 patients requiring ICU therapy. According to the severity scores (SOFA and SAPS II score), our cohort had a relatively high predicted risk of death (over 40%), which is higher than in cohorts characterized beforehand.
Finally, we do not know if unlimited resource allocation affects mortality. We can only suggest that reported very high death rates in the first weeks of the pandemic might result from a shortage of resources and a collapsing health system.
But, no matter what kind of resources you apply, death rates seem to stay about 50% in a very critical ICU cohort. This further depicts the potential harm of the virus and possible devastating course of COVID-19.
Other general determinants of mortality are age, comorbidities, multi-organ failure, and complications. The latter are often due to a hypercoagulable state during the infection. 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% nonfatal pulmonary artery thrombosis is in line with their findings. Further studies concentrated on autopsies and confirmed a high rate of thromboembolic events [18]. At the moment, the underlying mechanism for the coagulopathy leading to pulmonary artery thrombosis and cerebral hemorrhage, which were leading causes of the complications in this cohort, is unknown.
As Germany did not experience a shortage of ICU resources, it is not surprising that in our cohort ICU therapy lasted longer than reported as in other registries [1,19]. Not knowing the course of the disease, we ran through long therapies with our patients -partly being surprised by their recovery capacities after weeklong efforts and stagnation.
Also, more resources were allocated to patients in this registry including multiple organ replacement therapies -ECMO therapies and RRT were required more often than reported in other cohorts from Wuhan or New York [1,2]. Another German registry depicts similar rates of ECMO and RRT [3].
Our hospital never faced a personal or machine shortage (including ventilators, dialysis machines or ECMO systems). Staffing acquirements were calculated by the Inpuls® category and met with 2:1 (patient:nurse) or in extreme cases 1:1 (patient:nurse) staffing. We are the first to report an estimate on the enormous amounts of nursing hours required for treating every patient and the burden for a whole ICU unit during the first wave of the COVID-19 pandemic.
If resource allocation was appropriate remains unknown. The long courses of disease and late possible recoveries suggest not to limit ICU therapies to a certain time span or compare to other virus or bacterial pneumonia.
This might be even more difficult if facing a resource shortage. Concepts of resource allocation should be discussed interdisciplinary according to current recommendations and local conditions/obligations [20].

Limitations
The case number is limited and the data has to be verified by larger cohorts and longer follow-up intervals. Further, the cohort is a selected one as the university hospital of Freiburg is a tertiary center. Therefore, generalizability for other settings is limited. 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. For comparability patients´ severity scores should be regarded e.g., SOFA Score.
Moreover, our study misses further information about patients´ socioeconomic status. To hint at income level, we included the health insurance status. In Germany private health insurance is only allowed after reaching a certain yearly income level (e.g., 62.550 Euro in 2020).
Also, as many patients were transferred from other hospitals a loss of information is not excludable in therapies prior to ICU.
Finally, 60-day mortality was incomplete followed if patients were discharged home earlier. Further, followup was not assessed by functional state and questionnaires on quality of life.

Conclusions
Caring for critically ill COVID-19 patients requires an immense amount of organ replacement therapies, nursing hours and ICU days. The 60-day survival is 50% in a German tertiary treatment center despite full resources. High mortality in COVID-19 might be disease-specific rather than caused by resource shortage.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study. Ethik-Kommission der Albert-Ludwigs-Universität Freiburg im Breisgau issued approval 234/20. The local ethics committee approved the study protocol; verbal or written consent was deemed unnecessary (Ethik-Kommission der Albert-Ludwigs-Universität Freiburg im Breisgau 234/20). . Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: 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. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.