ABCDEF Bundle and Supportive ICU Care Practices for patients with COVID-19 infection: An international point prevalence study ~The ISIIC Study~

Although the number of patients with COVID-19 infection is increasing and concerns for their long-term disabilities are increasing, there is a lack of data about the delivery of the ABCDEF-bundle and supportive care in Intensive Care Units (ICUs). The aim of this study is to investigate the implementation of the ABCDEF-bundle and supportive care provided to patients with COVID-19 infections in ICUs. This was a world-wide two-day point prevalence study, on June 3 and July 1, 2020. A total of 212 ICUs in 38 countries (166 ICUs on Day 1 and 212 on Day 2) participated. Clinicians in each participating ICU completed web-based online surveys. The implementation rate for elements of the ABCDEF-bundle, other supportive ICU care measures and implementation associated structures were investigated. Data for 262 patients was collected during the two-day study. Of patients included, 124 (47.3%) underwent mechanical ventilation (MV) and 12 (4.6%) patients were treated with extracorporeal membrane oxygenation (ECMO). The proportion of patients with implementation of each element was: Element A (regular pain assessment) 45%; B (both spontaneous awakening and breathing trials) 28%; C (regular sedation assessment) 52%; D (regular delirium assessment) 38%; E (early mobility and exercise) 47%; and F (family engagement and empowerment) 16%. The implementation of element E for patients on MV was 16% and ECMO was 17%. Supportive care, such as providing protein throughout the ICU stay (under 1.2g/kg for more than 50% of the patients) and introduction of an ICU diary (25%) was inadequate. A higher implementation rate of elements A and D were recognized in ICUs with specic protocols for ICU care and lower numbers of ICU beds exclusively for patients with COVID-19 infection. Element E was implemented at a higher rate in ICUs with more ICU beds for patients with COVID-19 infection.


Introduction
It is clear that evidence-based and supportive Intensive Care Unit (ICU) care synchronized with treatment of the underlying disease should be the standard of care to prevent weakness and disabilities in patients after resolution of their critical illness [1][2][3]. The implementation of ICU care, along with the ABCDEF bundle [1], PADIS guideline [2], and nutrition guidelines [3,4], have been shown to be key elements for patients in ICUs not only to improve mortality and morbidity [5] but also to rehabilitate their functional abilities and health related quality of life [6]. A variety of guidelines recommend incorporation of these evidence-based approaches to ICU care into clinical practice [1][2][3], according to the local situation and available resources [7,8].
However, the novel coronavirus pandemic (SARS-CoV-2) rapidly changed ICU practice internationally [9]. Challenges include an inadequate number of beds to meet the staggering increase in the number of patients with COVID-19 infections [10] and unbalanced interprofessional staff resources to meet the demand [11]. These challenges may lead to patients not receiving the same quality of clinical care, resulting in poorer outcomes including increased mortality [12]. In addition to increased ICU mortality in patients with COVID-19 infections, recent evidence has highlighted the severe physical disabilities and prolonged symptoms during recovery from COVID-19 infection that limits patients' daily activities and quality of life after discharge from the hospital [13][14][15][16]. Thus, an enhanced recovery program which optimizes evidence-based ICU care and patient recovery is essential [15][16][17][18]. Although, many studies and guidelines propose a way to conduct ICU care including the ABCDEF bundle [19][20][21][22] and providing adequate nutrition [23,24] for patients with COVID-19 infections in this pandemic, data demonstrating implementation of these aspects of care in the ICU is insu cient. There are serious concerns regarding second waves in many countries, and these data are essential to improve future patient outcomes and minimize disabilities. Therefore, we conducted an international, internet-based, 2-day point prevalence survey, aiming to investigate the implementation of the ABCDEF-bundle, the PADIS guideline and other supportive care provided to patients with COVID-19 infections in ICUs, with consideration of the speci c ICU structure.

Design and Setting
This was a worldwide two-day point prevalence study of evidence-based ICU care for critically ill patients in ICUs with COVID-19 infections, which was approved by the ethics committee of the Saiseikai Utsunomiya Hospital (2020-07) as the central institution, registered in UMIN (ID: 000046103), and followed

Baseline patient characteristics
There were 135 and 127 patients in ICUs on the rst and second survey dates respectively (Table 2), with equal distribution of age groups. Most patients were male (68%). Racial mix included mostly and Asian (45%) and white (39%). The median ICU length of stay was 9  days. Of a total of 262 patients, 47.3% (n = 124) patients underwent MV and 4.6% (n = 12) patients were treated with ECMO. There was no statistically signi cant difference between the rst and second survey days for these characteristics, except for the use of MV (p < 0.001), the number of patients who underwent prone positioning (p = 0.002), and its duration (p < 0.05) ( Table 2).

Implementation of the ABCDEF bundle
Implementation of the ABCDEF bundle was primarily by intensivists (58%), followed by nurses and a multidisciplinary/-professional team ( Table 3). The implementation of each element of the bundle is shown in Fig. 1 and Table 3. Among the different patient groups, there were signi cant differences in implementation of elements A, C, D, and E. The implementation rates included: element A, regular pain assessment, (45%); element B, both spontaneous awakening and breathing trials, (28%); element C, regular sedation assessment, (52%); element D, regular delirium assessment, (38%); element E, early mobility and exercise, (47%); element F, family engagement and empowerment, (16%). The details associated with implementation of each element are shown in Supplemental Table 6. Most patients undergoing MV and ECMO were managed with a target for pain control and sedation by using of fentanyl and benzodiazepines. The Numerical Rating Scale, Critical-care Pain Observation Tool, and Behavioral Pain Scale were used as Pain assessment tools, the Richmond Agitation-Sedation Scale for sedation assessment, and the Confusion Assessment Method for ICU to monitor delirium. The most common reason why spontaneous awakening trials (Element B) were not performed was respiratory instability, followed by the absence of a protocol. Overall, 11% of patients were diagnosed with delirium. Non-pharmacological interventions, such as orientation, optimizing sleep conditions, and mobilization, were more frequently performed than pharmacological interventions to control delirium. While 75% of the patients without MV or ECMO could mobilize to the level of standing, the implementation of element E for the patients on MV or ECMO was less than 20%. The mobility level increased gradually over during the ICU stay, while the median level in patients undergoing MV remained IMS 0, the level of passive exercise in bed (Fig. 2). The barriers preventing increased mobility to sitting at the edge of the bed or higher were primarily respiratory factors, such as desaturation or an excessive respiratory rate, followed by consciousness factors. The involvement of intensivists in mobilization (20%) was less frequent than nurses (60%) or physiotherapists (56%). The cycle-ergometer and electrical neuromuscular stimulation were rarely used. Electronic devices, using a monitor to facilitate meetings, were used for 40% of the patients. The full implementation of all elements of the ABCDEF bundle was achieved for only 1% of the patients (Supplemental Table 7).

Implementation of other supportive ICU care
Most patients, even while undergoing MV or ECMO, received nutrition therapy with 1000-2000 kcal/day as their total energy intake via feeding tube or oral intake (Table 3). Protein greater than 1.2 g/kg/day was supplied to less than 50% of patients at any time during the ICU stay (Fig. 2). The implementation of sleep assessment, ICU diary and physical restraints were 33%, 25%, and 20% respectively. About half of the patients received either non-pharmacological or pharmacological interventions to promote sleep (Supplemental Table 8).

Association between ICU structure and implementation of the ABCDEF bundle
In ICUs with protocols for pain and sedation management, more patients received elements A and C, while fewer patients received element E in the ICU with the protocol for mobilization/rehabilitation (Table 4). Daily multidisciplinary rounds and a 1:1 nurse to patient ratio did not improve the rate of implementation of the bundle and nutrition therapy. With a 1:2 nurse to patient ratio, elements D, E, and nutrition therapy were more frequently implemented. As more ICU beds were assigned exclusively to patients with COVID-19 infections, elements A and D were less frequently implemented, whereas element E and nutrition therapy were more frequently implemented. There was no ICU structure which lead to the implementation of elements B and F. The presence of dedicated physiotherapists and ability of physiotherapists to enter the rooms of patients with COVID-19 infections did not improve the implementation of element E. The number of visiting hours was limited in both patients who received element F and those who did not. (Supplemental Table 9).

Discussion
This worldwide two-day point prevalence study demonstrated an overall low rate of implementation of the ABCDEF bundle, inadequate protein intake, and rare use of ICU diaries for patients with COVID-19 infections. This study also showed better implementation of evidence-based and supportive ICU care in ICUs using speci c protocols and with a de ned number of ICU beds exclusively assigned to patients with COVID-19 infections. Structural elements such as daily multidisciplinary/-professional rounds and a 1:1 nurse to patient ratio, did not lead to greater implementation.
The delivery of elements of the bundle to patients with COVID-19 infections was lower than that shown in nationwide and international prevalence surveys conducted before the pandemic (Supplemental Table 10) [5,28]. The ABCDEF bundle is a strong evidence-based approach to ICU care that prevents ICU patients from developing physical, cognitive, and mental disabilities, termed the post-intensive care syndrome (PICS) [29], which has long lasting effects even after intensive care and hospital discharge. Many studies have suggested that each element of the bundle has its own role to prevent PICS [1,5,6,8] and synchronized implementation would provide further bene ts [30]. Despite ongoing research about the speci c outcomes of patients who survive COVID-19 infections (NCT04360538, NCT04508712), it is likely that these patients have problems similar to survivors of other critical illnesses. The ndings of this study call for urgent efforts to incorporate the ABCDEF bundle of care into routine clinical practice, especially as many countries are dealing with serious concerns for a second wave of COVID-19 infections. The serious disabilities and persistent symptoms after COVID-19 infection [13][14][15][16] raise serious concerns about the long-term outcomes associated with PICS induced by COVID-19 infection [17,18].
Relatively high rates of implementation for elements A, C, and D for patients undergoing MV might re ect the need for intense management of pain, sedation, agitation, and delirium to stabilize symptoms induced by COVID-19 infection, such as strong spontaneous breathing and coughing [31,32], and to prevent exacerbation of pulmonary injury by self-in icted lung injury [33][34][35][36]. This study also shows a relatively low prevalence of delirium potentially because of deep sedation with the use of benzodiazepines. This could also affect the implementation and intensity of mobilization.
As previously reported [37,38], MV and ECMO were major barriers to implementation of element E for patients with COVID-19 infections. The complicated pathophysiology of the pulmonary illness with two different phases of acute lung injury caused by COVID-19 infection, which need different ventilation strategies to avoid exacerbation of lung injury [33][34][35][36], could limit aggressive mobilization of patients. The variety of neurological complications, such as weakness and fatigue after the acute phase of the disease, often reported as complications associated with COVID-19 infections recently [13][14][15][16]39] and recognized as barriers to mobilization, could also inhibit the implementation of element E. More research is needed to develop the most e cient approach to early rehabilitation of patients with COVID-19 infections and a high risk for developing PICS.
This study showed that energy via enteral nutrition was provided to most of patients, while the protein intake did not reach the target level at any time during the ICU stay. Although many guidelines and statements, including those speci cally related to COVID-19 infection, recommended nutrition therapy to provide adequate energy and protein to preserve skeletal muscle and function [3,4], the protein intake did not often reach the target (1.2 g/kg/day) after or even before the pandemic. The failure to provide su cient protein and the absence of nutritionists under strict infection regulations might hinder providing enough protein.
Protocol-driven nutrition strategies focusing on providing enriched protein, high-protein enteral formulas (> 20%) [40], and sometimes the addition of aminoacid parenteral nutrients in case of digestive complications of COVID-19 infection [41], must be considered.
The ICU diary is used to supplement the patient's memory in the ICU, and helps mitigate anxiety, depression, and post-traumatic stress disorder [42]. Just 20% of ICUs provided diaries, which is low compared to ICUs from Scandinavia [43]. In order to introduce ICU diaries while considering limitations imposed by serious infections, a novel strategy, such as electrical ICU diaries shared online or video based ICU diaries, might be bene cial [44].
The introduction of protocols, especially for pain and sedation management, could provide an ICU with a systematic and resource-conserving approach that would facilitate delivery of evidence-based ICU care [5,8,11]. However, these results show that a protocol for mobilization did not facilitate implementation of element E possibly because of the several complicated mechanisms of lung injury and different ventilation strategy in the various phases of the illness [33][34][35][36]. A mobilization protocol for other patient populations might apply to patients with COVID-19 infections. In this setting, the aggressive involvement of intensivists, which was lower in this study, and a specialized mobilization program for patients with COVID-19 infections, considering the severity and phases of the lung injury, might facilitate the delivery of safe and e cient rehabilitation with appropriate considerations of risk [45]. Incorporating the dedicated use of ergometers and electrical muscle stimulation into the protocol may also promote rehabilitation.
Controlling the number of ICU beds might allow adjusting the workload of the staff appropriately [46,47]. Although more ICU beds for patients with COVID-19 infections may increase the burden and responsibility of medical staff making it di cult to implement evidence-based and supportive ICU care, as seen in the poor levels of implementation of elements A and D, it could be lead to greater implementation of element E and nutrition. Assigning more beds, or centralization, could bene t patients by providing multidisciplinary/-professional and structured interventions by trained and experienced staff [48,49]. The effectiveness of centralization according to the local resources and sta ng capacity under a standardized or specialized protocol should be investigated.
Daily multidisciplinary/-professional rounds and a 1:1 nurse to patient ratio, which were regarded as important aspects of care [19], might consume excessive time and resources in an ICU. Optimizing distribution of resources according to the clinical needs might be key factors for the implementation of evidencebased and supportive ICU care.
This study has acknowledged strengths and limitations. Although data were collected from many countries around the world, including locations considered to be COVID-19 infection "hotspots", the relative proportion of data from Japan could introduce bias and limit the generalizability of the results to ICUs in other countries. The limited number of patients also limits applying the results in other ICUs. Second, surveys were conducted at two time points, one month apart, to include more data. However, as evidence and recommendations for the care of patients with COVID-19 infection has been changing, the policies for ICU care might have changed. For example, an increased number of patients receiving prone positioning on the second survey and the decrease in its duration may be partially due to a recent paper which showed the positive effect of short-term prone positioning [50].

Declarations
Ethics approval and consent to participate: The study protocol was approved by the Ethics Committee of the Saiseikai Utsunomiya Hospital (No 2020-07). The ethics committee con rmed that the informed consent from the patient was waived because of the nature of this study.

Consent for publication: Not applicable
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests: The authors declare that they have no competing interests for the submitted work. There are several potential con icts of interests for some authors outside of this submitted study. KN reports personal fees from Abbott Laboratory, Nestle, TERUMO, GETINGE, Asahi Kasei Pharma, Ono Pharmaceutical, Japan Blood Products Organization, Nihon Pharmaceutical, Otsuka Pharmaceutical, P zer, Toray, and Baxter, and grants from Asahi Kasei Pharma outside the submitted work. HK receive a salary from Japanese Society for Early Mobilization (Non-pro t Society) as a chair (full time) outside the submitted work. EWE reports grants from VA/NIH, personal fees from P zer, Orion, Lilly, personal fees from Masimo, grants from kohler, outside the submitted work. IS reports personal fees from Abbott Laboratory, Teijin Pharma, Nestle and Nihon Pharmaceutical. NO reports grants from Asahi Kasei Pharma, Ono