Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: A retrospective single-centre study.

Post-intensive care unit (ICU) sequelae, including physical and mental health problems, are relatively unexplored. Characteristics commonly used to predict outcome lack prognostic value when it comes to long-term physical recovery. Therefore, the objective of this study was to assess the incidence of non-recovery in long-stay ICU-patients. In this single-centre study, retrospective data of adults with an ICU stay >48 hours who visited the specialized post-ICU clinic, and completed the Dutch RAND 36-item Short Form questionnaire at 3 and 12 months post-ICU, were retrieved from electronic patient records. In cases where physical functioning scores at 12 months were below reference values, patients were allocated to the physical non-recovery (NR) group. Significantly different baseline and (post-)ICU-characteristics were assessed for correlations with physical recovery at 12 months post-ICU. Of 250 patients, 110 (44%) fulfilled the criteria for the NR-group. Neither the severity of illness, type of admission, nor presence of sepsis did not differ between groups. However, NR-patients had a higher age, were more often female, and had a higher incidence of co-morbidities. Shorter LOS ICU, lower incidence of medical comorbidities, and better physical performance at 3 months were significantly correlated with 1-year physical recovery. Comorbidities and reduced physical functioning at 3 months were identified as independent risk-factors for long-term physical non-recovery. In conclusion, a substantial proportion of long-stay ICU-patients who visited the standard care post-ICU clinic did not fulfil the criteria for full physical recovery at 12 months post-ICU. Commonly used ICU-characteristics, such as severity of illness, do not have sufficient prognostic value when it comes to long-term recovery of health-related quality of life.

Introduction

Over the past decades, both hospital mortality and long-term mortality of intensive care unit (ICU) patients have declined [1, 2]. However, post-ICU recovery has been shown to be complex and eminently heterogeneous. Clinical evaluations of recovery after ICU-admission commonly focus on mortality and on the ability to perform basic activities of daily living (ADL). Indeed, ADL-performance seems to be a strong indicator of self-efficacy at the moment of ICU or hospital discharge and is often used to identify short-term care needs [3]. However, these outcomes may be poor estimates of long-term prognosis. Thus, this short-term focus on recovery often does not equate the impact of critical illness in the long run.

Long-term recovery after critical illness is often characterised by a range of physical and mental impairments, e.g. ICU-acquired weakness, cognitive decline, and emotional distress, among others [4, 5]. It is commonly known that persistence of impaired physical health interferes with successful rehabilitation, which is an important issue for ICU-patients and their family. Pre-ICU physical health, demographic factors and disease aetiology influence physical recovery to some extent [6]. Still, ICU-admission and the highly specialized treatment that comes with it seem to play an equal role in the aetiology of long-term non-recovery. The finding that patients with a prolonged length of stay (LOS) are specifically burdened with long-term health problems illustrates the importance of this major life event as a separate risk factor for non-recovery [7].

To fill this deficiency in prognostic power, recent developments have been focused on health-related quality of life (HRQoL) as an indicator for long term recovery [8]. HRQoL-measurements encompass an integrative approach to physical, mental and social health of ICU-survivors. More specifically, both reduced physical health and being (partially) disabled have been shown to directly reflect on long-term HRQoL after ICU-discharge [9, 10]. To develop interventions which would improve HRQoL, specific target groups and risk factors with prognostic value regarding long-term non-recovery need to be determined. However, previous literature has often reported heterogenic results and were characterized by an overrepresentation of elective surgical ICU-patients, due to the ability to perform baseline tests [11]. Furthermore, loss to follow-up is a serious limitation concerning the implications of results [12]. These disadvantages make the generalization of previously obtained findings troublesome.

In conclusion, characteristics commonly used to predict outcome in ICU-patients lack sufficient prognostic value when it comes to long-term physical recovery. The paucity of predictors makes the identification of subgroups which fail to recover problematic. An integrative assessment of HRQoL has the potential to unravel the complexity of non-recovery in ICU-survivors. In this study we aimed to assess the patient-reported incidence of non-recovery in long-stay ICU-patients. Furthermore, factors in relation to various points in time (from baseline to 3 months post ICU-discharge) were considered for long-term (1 year) non-recovery.

Materials and methods

Study population

This retrospective, single-centre study was performed in a tertiary teaching hospital with a closed-format ICU. Local protocol dictates that all ICU-patients with an LOS ICU ≥48 hours receive an invitation for the specialized post-ICU clinic at 3 months after ICU-discharge. In line with this protocol, patients fill in an HRQoL-questionnaire and return it before their visit. At 12 months, patients repeat the questionnaire and return by mail. Data from all patients admitted to the ICU between 2012 and 2018 who completed and returned the questionnaire were retrieved for this study. Data of patients who did not survive until the 1 year follow-up, were lost to follow-up, or who did not complete the physical functioning (PF) domain of the questionnaire were excluded from analysis (Fig 1).

Fig 1

Flowchart of retrieved study data.

Ethical considerations

Due to the retrospective nature of this study, a local ethical committee determined this study was eligible to be assessed as a nWMO-research project (Regionale Toetsingscommissie Patiëntgebonden Onderzoek, Leeuwarden, The Netherlands; nWMO-number: nWMO 358). The need for informed consent was waived by the ethical committee as the patient-record data was analyzed anonymously.

Data collection

In the specialized post-ICU clinic, the Dutch translation of the RAND-36 item Health Survey (RAND-36), which is very similar to the Medical Outcome Study Short-Form-36 (MOS SF-36), was used to evaluate HRQoL [13]. This questionnaire consisted of nine subscales used to assess physical functioning, social functioning, role limitations due to physical or emotional problems, mental health, energy/fatigue, pain, general health perception, and experienced changes in health during the past four weeks. In each subscale, a score was given from 0 to 100, in which higher scores represented better HRQoL. Effectiveness, validity and reliability of the RAND-36 have been tested repeatedly in both the general population and numerous patient groups, including ICU-patients [14].

According to standard protocol, PF-domain scores of the RAND-36 were collected at 3 and 12 months after ICU-discharge. These scores were compared to a reference value of healthy individuals aged 65 to 75. A margin was taken into account, resulting in a reference value PF-domain score of 65 [13]. All patients with a PF-domain score below 65 were considered as part of the non-recovery (NR)-group [median score: 35 [20-50]). Simultaneously, patients with a PF-domain score equal or above 65 were assigned to the recovery (R)-group (median score: 85 [75-95]). Baseline characteristics and usual care data were collected from electronic patient files. Three patients did not complete all questions of the PF-domain of the RAND-36 and were subsequently excluded from analysis.

Standard care data on physical functioning were retrieved from electronic patient files (for overview, see Table 1). Functional status, muscle strength, walking distance, mobility, and balance were taken into account. Functional status, i.e. ADL-performance, at discharge and 3 months after ICU-admission, was assessed using the Barthel Index Score (BIS), a 10-item survey with a score range of 0–20 points [15]. Hand grip strength of the right hand (kg), also at discharge and 3 months after ICU-admission, was measured using a handheld dynamometer and transformed to a score relative to an age-adjusted reference value [16]. Mobility was tested using the Morton Mobility Index (MMI) score at discharge and 3 months after ICU-admission [17]. This survey consisted of 15 items with a score range of 0–19 points which were transformed to a relative score from 0–100 percent. Additionally, walking distance and balance were measured at the specialized post-ICU clinic at 3 months after ICU-discharge using the 14-item Berg Balance Scale (BBS), with a score range of 0–56 and the 6-minute walking test (6-MWT), which measured the distance (m) walked in 6 minutes relative to an age-adjusted reference value (%) [18, 19]. In all physical tests a higher score indicated a better outcome. After retrieval, all data were coded and processed in accordance with the General Data Protection Regulation.

Table 1

Timeline of standard care data collection.

ICU-admission	Sex, Age, APACHE III-score, Comorbidities, Admission type, Diagnosis 'Sepsis', Diagnosis 'After CPR'
ICU-discharge	LOS ICU, Days of mechanical ventilation, Need for renal replacement therapy, Barthel Index Score, Hand grip strength (right hand), Morton Mobility Index score
3 month visit post-ICU outpatient clinic	Barthel Index Score, Hand grip strength, Morton Mobility Index score, 6-Minute Walking Test score, Berg Balance Scale, RAND-36 physical functioning subscale score
12 month follow up	RAND-36 physical functioning subscale score

Statistical analysis

All data were extracted from the electronic patient files and transferred to a coded data file in January, 2019. Variables were summarised as median [interquartile range, IQR] and number (percentage) for continuous or categorical variables, respectively. At baseline, ICU-discharge, and 3 months after ICU-discharge, characteristics were compared between the R-group and NR-group using either the Mann-Whitney U test or the 2-sided Pearson Chi-Square test, as appropriate. Variables with a clinically relevant difference (p≤0.25) were considered for further analysis. A sample size-appropriate selection of these variables was made using both clinical experience and relevant literature regarding their already known effect on recovery and outcome. This selection was assessed for significant correlations with recovery, i.e. reaching the age-adjusted reference value. Spearman's rank correlation coefficient (rho) was computed and tested for significance. Finally, a binomial regression analysis was used to identify independent risk factors at ICU-discharge for non-recovery. Throughout the analysis, a 2-sided p-value of 0.05 was considered statistically significant. All statistical analyses were conducted using SPSS Statistics for Windows, Version 24.0 (IBM, Chicago, IL, USA).

Before conducting a multivariate analysis, data were inspected for missing values. The main reason for missing data was related to the delayed implementation of physical functioning measurement in the ICU and in the specialised post-ICU clinic. Variables with ten percent or more missing values were supplemented using multiple imputations (S1 Table). The assumption was made that the majority of the missing data was missing completely at random, as this was mainly caused by a delayed implementation of the physical measurements. Five imputed datasets were created using predictive mean matching in order to correct for non-normality. Binomial regression analysis was applied using the backward elimination enter method.

Results

Identification of R-group and NR-group

A total of 250 patients visited the standard care post-ICU clinic at 3 months after ICU-discharge and completed the PF-domain of the RAND-36 questionnaire at 3 and 12 months. PF-domain scores at 12 months were compared to age-adjusted reference values [13]; median age was 67 [58-74]. Concurrently, 110 patients (44%) were assigned to the NR-group (PF-subscale score at 12 months: 35 [20-50]) and 140 (56%) to the R-group (PF-subscale score at 12 months: 85 [75-95]). In a univariate analysis, NR-patients had a significantly lower PF-domain score at 3 months compared to the R-patients (PF-subscale score at 3 months: 38 [25-55], 75 [60-85], respectively. p < 0.001). Additionally, PF did not change significantly over time in the NR-group. Contrarily, PF-domain scores of R-patients were higher at 3 months after discharge and increased significantly over time (p < 0.001) (Fig 2).

Fig 2

Median and 10-90th percentile of physical functioning domain score (RAND-36) of R- and NR-patients at 3 and 12 months after ICU-admission.

*** p<0.001.

Baseline: & ICU-characteristics

Further univariate comparison of baseline characteristics comparing NR- to R-patients revealed significant differences in demographic factors, comorbidities, disease aetiology, and ICU-morbidity. NR-patients had a higher age (p <0.05), were more often of the female sex (p < 0.05), and had a higher incidence of co-morbidities (i.e. presence of pre-existing comorbidities; p < 0.001). Furthermore, NR-patients had a longer LOS ICU, more days on mechanical ventilation, and a higher incidence of renal replacement therapy (p <0.05). However, patients in the R-group there was a higher incidence of cardiopulmonary resuscitation as primary reason for ICU-admission (p < 0.05). There were no differences in severity of illness score (APACHE III), admission type, and presence of sepsis (Table 2A).

Table 2

A. Baseline—& ICU-characteristics, B. 3-months post-ICU admission measurements.

Characteristics	All, n = 250	NR, n = 110 (44.0%)	R, n = 140 (56.0%)	p-value
A.
Demographic factors
Female, n (%)	94 (37.6)	49 (44.5)	45 (32.1)	.044 *
Age	67 [58–74]	68 [60–76]	66 [57–72]	.016 *
APACHE III	79 [59–98]	76 [60–98]	82 [56–99]	.565
Comorbidities
Comorbidities, n (%)	114 (45.6)	67 (60.9)	47 (33.6)	< .001 ***
Aetiology
Admission, n (%)
Medical	131 (52.4)	55 (50.0)	76 (54.3)	.433
Elective surgical	43 (17.2)	17 (15.5)	26 (18.6)
Acute surgical	76 (30.4)	38 (34.5)	38 (27.1)
Sepsis, n (%)	82 (32.8)	40 (36.4)	42 (30.0)	.287
CPR, n (%)	49 (19.6)	15 (13.6)	34 (24.3)	.035 *
ICU morbidity
LOS ICU	11 [6–20]	12 [7–26]	10 [5–18]	.011 *
Mechanical ventilation (days)	6 [3–12]	7 [4–19]	5 [3–9]	.035 *
Renal replacement therapy (CVVH)	50 (20.0)	30 (27.3)	20 (14.3)	.010 *
B.
PF, at ICU-discharge
BIS (0–20)	11 [6–16]	8 [5–13]	14 [8–17]	.001 **
Hand grip strength right (%)	57.30 [40.00–85.26]	48.99 [31.60–69.28]	68.16 [47.31–92.10]	.006 **
MMI (0–100)	30 [20–44]	30 [20–42]	30 [29–45]	.128
PF, 3 months after ICU-admission
BIS (0–20)	20 [20–20]	20 [18–20]	20 [20–20]	< .001 ***
MMI (0–100)	85 [74–85]	74 [62–85]	85 [85–100]	< .001 ***
6-MWT (%)	86.00 [68.75–97.00]	76.00 [62.00–88.00]	92.00 [80.00–103.00]	< .001 ***
BBS (0–56)	53 [49–56]	49 [44–54]	55 [52–56]	< .001 ***
Hand grip strength right (%)	96.15 [81.15–116.80]	89.59 [70.70–105.00]	100.89 [86.81–122.12]	< .001 ***

Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CPR, cardiopulmonary resuscitation; LOS ICU, Length of stay Intensive Care Unit; CVVH, Continuous Veno-Venous Hemofiltration; BIS, Barthel index score; MMI, Morton Mobility Index; 6-MWT, 6-minute walk test; BBS, Berg balance scale.

Physical functioning at discharge and 3 months after ICU-admission

NR-patients performed worse on physical functioning compared to R-patients at ICU-discharge with regards to functional status (p < 0.01) and muscle strength (p < 0.01). These differences persisted 3 months after ICU-admission (p < 0.001). Furthermore, NR-patients performed worse on walking distance, mobility and balance tests compared to R-patients 3 months after ICU-admission (p < 0.001). No significant difference in mobility was found between these patient groups at ICU-discharge (Table 2B).

Correlations with recovery

Spearman’s rank order correlation was computed in order to assess the correlation of recovery measures with those upon baseline-, ICU-discharge- and 33 month post-ICU-measures, i.e. reaching the age-adjusted reference value of the PF-domain score at 12 months after ICU-admission (Fig 3). The incidence of medical comorbidities at ICU-admission was weakly negatively correlated with recovery (rs = -.27, p < .001). Of the measures taken at ICU-discharge, LOS ICU, physical performance (i.e. BIS), and hand grip strength were weakly positively correlated with recovery (rs = .06, p < .05, rs = .25, p < .001, rs = .29, p < .01, respectively). Physical performance and hand grip strength at 3 months after discharge were also weakly positively correlated with recovery (rs = .33, rs = .27, p < .001). Additionally, walking distance (6-MWT), mobility (MMI), balance (BBS), and PF-domain score at 3 months after ICU-admission were moderately positively correlated with recovery (rs = .40, rs = .37, rs = .43, rs = .60, p < .001, respectively). It is of note that there was no significant correlation of either baseline APACHE III or mobility scores at ICU-discharge with recovery.

Fig 3

Pairwise correlations with recovery at 12 months after ICU-admission.

Significant correlations visualised in black.

Independent risk-factors

Finally, the independent predictive value of commonly used baseline characteristics and measures for physical functioning at 3 months after ICU-admission was assessed. A binary logistic regression was performed to ascertain the effects of LOS ICU, the APACHE III score, the incidence of medical comorbidities at baseline, as well as walking distance, mobility, balance, hand grip strength and physical functioning at 3 months after ICU-admission on the likelihood of recovery of physical functioning at 12 months after ICU-admission. Patients with pre-existing comorbidities may be less likely to improve in physical functioning after 12 months (original data: OR .620, CI .279–1.377; p = .241, corrected for missing values: OR .380 CI .197-.734; p = .004). A higher balance testing score at 3 months after admission was associated with an increased chance of recovery of physical functioning (original data: OR 1.105 CI 1.025- .192; p = .009, corrected for missing values: OR 1.066 CI 1.005–1.132; p = .034). Finally, a higher RAND-36 physical functioning subscale score at 3 months after ICU-admission increases the likelihood of recovery at 12 months (original data: OR 1.058 CI 1.037–1.080; p < .001, corrected for missing values: OR 1.052 CI 1.036–1.069; p < .001). The logistic regression model was statistically significant (original data: χ2(3) = 79.1, p < .001). The model explained 50.0% (Nagelkerke R2 original data) of the variance in recovery of physical functioning and correctly classified 78.2% of cases.

Discussion

In this retrospective study, a substantial proportion of patients (44%) who visited the standard care post-ICU clinic did not fulfil criteria for full physical recovery at 12 months after ICU-admission. We identified impaired physical functioning at 3 months (assessed as decreased balance and RAND-36 physical functioning subscale scores), as well as the presence of comorbidities at baseline as independent risk factors associated with non-recovery at 12 months. Thus, prediction of further (non-)recovery can only be made with reasonable accuracy 3 months after admission. In contrast, LOS ICU, duration of mechanical ventilation, and renal replacement therapy lost significance in our multivariate model. Moreover, well-established risk factors for hospital mortality, including APACHE III, as well as medical admission type and presence of sepsis, were equal in patients with and without full physical recovery at 12 months.

The observed percentage of patients in de NR-group was in line with previous literature. In general, comparison with the existing literature is hampered by differences in HRQoL-scales used, a focus on specific subgroups, and limited follow-up time in small study populations [20]. In a comparable Dutch general long-stay ICU population, SF-36-derived functional status one year post-ICU was limited in 54 percent of patients, as compared to an age-adjusted reference population [7]. Even in a substantially younger Norwegian mixed-ICU population, the majority of patients did not return to the age-adjusted physical functioning SF-36-score at one year post-ICU [21]. In a large cohort of long-stay ICU-patients with sepsis as the primary reason for ICU-admission, the mean SF-36 physical functioning at 12 months was 41 ± 35 percent [22]. Furthermore, in a small subset of acute respiratory distress syndrome (ARDS) survivors, 43 percent had self-reported functional limitations 12 months after ICU-admission [23]. The overall picture that emerges from these data is that a substantial amount of patients do not recover to the fullest extent.

Our data confirmed the presence of comorbidities as an independent risk-factor for the absence of full physical recovery, as reported by others [24]. However, in contrast to the general perception that severity of illness score and age are risk-factors for reduced HRQoL as well, the APACHE III score and age were not independently associated in our multivariate model [25]. In a general ICU-population with a median APACHE II score of 11, HRQoL after one year was not different either between patients with high and low Sequential Organ Failure Assessment (SOFA) scores [26]. In contrast, in a large cohort of patients with pneumonia and/or sepsis, the Simplified Acute Physiology Score (SAPS) II was an independent predictor for reduced HRQoL. However, this effect was completely attributable to the difference between Q1 (lowest SAPS-score) and the rest of the group, whereas there was no significant difference between Q2 to Q4. Furthermore, the presence of sepsis and age were not independently associated with HRQoL in this study, which is similar to the results in the present study [27]. In a recent retrospective study, several multivariate models were constructed to assess influential factors on one-year HRQoL, expressed as the EQ-5D derived utility index. Although the APACHE II and SOFA score, as well as age, were independently associated, the authors underlined that the models at best explained 20–40 percent of the variability in utility index score [6]. The limitations of the available predictive models for outcome are generally well-recognised, since they are designed to predict hospital mortality instead of long-term outcome and HRQoL [28].

The most important distinction between previous models and our approach was related to the inclusion of HRQoL and physical status data at 3 months, which was done in order to predict HRQoL one year post-ICU. At first glance, it might be confusing to incorporate baseline characteristics from the moment of ICU-admission as well as post-ICU parameters. However, the results of the present study justify the notion that the net result of long-term outcome is not only determined by the severity of illness but also by the individual response of the patient to the insult. According to the Nagelkerke R2, not only was our model able to explain 50 percent of the variability in physical functioning recovery, it also rendered the majority of baseline characteristics statistically insignificant. An additional explanation for the substantial goodness-of-fit lies in the bivariate distinction between patients who fully recover versus those who do not. This division seems to closely match the diversity in HRQoL-scores which occurs during recovery after critical illness.

Evidently, future studies incorporating physical functioning at 3 months after ICU-discharge are urgently needed. In addition, it is necessary to identify factors and sub-groups not only at 12 and 3 months but also at ICU-discharge, in order to potentially facilitate multidisciplinary aftercare programs which aim to improve long-term HRQoL as early as possible.

Limitations

Even though these findings may contribute to a further understanding of the large diversity in recovery after critical illness, there were several limitations to our study to keep in mind. First of all, the retrospective, single centre design clearly limited the potential to generalise results. The patient population per hospital can be highly diverse, especially in critical care. With regards to our physical functioning data, there was a high amount of missing data due to loss to follow up. Furthermore, our study design lacked baseline measurements of HRQoL, identical to other studies regarding acute ICU patients. Henceforth, methods in order to resemble baseline measurements should be considered, such as proxy measurements [29]. Additionally, to take into account the pre-admission frailty of patients admitted to the ICU-ward would strengthen results.

Additionally, this study reports on the physical recovery of patients who were willing and/or are able to visit the post-ICU outpatient clinic at 3 and complete the questionnaires at 12 months after ICU-discharge. Consequently, the recovery of patients who were unable to conduct the previous is unknown. It should be noted that most patients lost to follow-up indicated an overwhelming amount of appointments with health-care professionals as the main reason to decline the post-ICU clinic invitation, rather than inability to attend due to physical or mental health problems. Future studies might be able to limit the number of lost to follow-up measurements by conducting proxy or measurements via telephone. Additionally, due to the retrospective nature of this study and the limited financial resources of the standard care post-ICU clinic, no in-person physical tests were conducted at 12 months after discharge. This would have improved the robustness of the data and should be taken into account in future studies regarding this subject.

Conclusions

A significant amount of ICU-patients do not recover in physical functioning 1 year after ICU-admission. Pre-existing comorbidities and limited physical functioning at 3 months after ICU-admission predict such a lack of long-term physical recovery. Future studies are needed to define subgroups of ICU-patients in need of a timely, multidisciplinary and personalised aftercare program in order to improve long-term health-related quality of life in critical illness survivors.

Percentage of missing values and medians of the original and imputed dataset.

(DOCX)

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7 Sep 2020

PONE-D-20-21277

Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-center study

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Reviewer #1: I applaud the authors for investigating a noteworthy issue that, up until recent, has received little scientific attention. The overall findings are not surprising given the results of other studies assessing similar long-term outcomes among ICU patients. While the study is credible, it lacks the methodological prowess to create results that build upon existing literature.

I am unsure why objective, in-person physical function data was collected at discharge and 3 months, but not at 12 months. The robustness of the data would have been increased if the authors hadn’t relied solely on self-report at 12 months.

Also, the sample size would have been improved if some sort of proxy measure was taken to reflect physical function and recovery of those unable to return to the clinic. For instance, the SF-36 could have been completed over the phone.

Did the authors have any contact with the participants between the 3 and 12 month period? If so, this should be outlined in the the methods. If not, perhaps this would have helped decrease loss to follow-up over the course of the study.

The way the authors have the methods written makes it difficult to keep track of what measures were collected when. A diagram illustrating some sort of timeline (ie admission, discharge, 3-months, 12-months) along with the measures collected at each time point would be helpful.

Again, the overall aim of this study is worthwhile; however, the study holds substantial methodological limitations that make it worthy of publication.

Reviewer #2: In their manuscript “Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-center study” the authors report on recovery/non-recovery of ICU survivors and explore the role of potential risk factors. The data presented are interesting and can advance knowledge in the area. However, some points need to be further addressed.

1. The title of the study does not sound to be in line with aim (lines 101-102, to identify risk factors for long-term non-recovery at various time points from baseline to three months post-ICU discharge) and, in part, conclusions. The authors might consider rephrasing.

2. What was the hypothesis to contact this study?

3. The aim may better get rephrased to suggest that factors in relation to various time points (from baseline to three months post ICU-discharge) were considered for long-term (1 year) non-recovery.

4. Line 107. ‘were invited’ may be more appropriate than ‘are invited’.

5. Lines 133-134. Pls consider defining NR and R-group.

6. Results, #3.1. Pls consider also reporting PF values at 12 months for both groups, as this is a major variable to report.

7. Results, #3.4. This section refers to correlations of various variables with PF-score at 12 months; however, it seems to be written as referring in between-group comparisons (already done in #3.2.). Pls consider rephrasing. Also, at lines 218, 222 the authors mention tendency but report significant p values. Pls clarify.

8. Figure 3. Nice figure to graphically represent r coefficients.

9. Results, #3.5. The authors might include a table to report values (OR, CI, p) for all variables employed in the regression model. Also, what is meant by “pooled results”? Are they results corrected for missing values?

10. Both last paragraph of discussion (lines 302-315) and #5 refer to study limitations. What is the reason for separating? Pls clarify.

11. Conclusions, lines 327-330. This phrase might be more appropriate to include in discussion than conclusions, as it refers to future studies.

12. The authors might consider including in discussion a comment on the necessity to identify factors and sub-groups not only at 3 months after but also at hospital discharge to potentially facilitate rehabilitation interventions as early as possible.

Reviewer #3: Review:

Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-center study

Corresponding Author: Lise Frieda Elisabeth Beumeler

General:

I thank the authors for the opportunity to read their manuscript “Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-center study”. The authors investigated the post-intensive care recovery with a survey assessed by patients (Dutch-RAND 36-item Short Form).

1. I am very concerned about the study design. What is “retrospective” in this study? Study design sound more like an observational study. Which leads to the question “How did the study get submitted to the ethics committee”. As a retrospective study? Which does not correspond to the real study design. It seems questionable that an ethic committee waived the need for informed consent of an observational study. Even, when patient-related data were used and study-related procedures were used (Hand Grip strength, 6-MWT and BBS at discharge from ICU AND 3 month post-discharge). Please provide the correspondence to your local ethic committee including the study protocol (translated in English).

As it can be assumed that the study was submitted to the ethics committee as "retrospective", which does not correspond to the real study design. Please clarify this.

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Reviewer #1: No

Reviewer #2: Yes: Eleftherios Karatzanos PhD

Reviewer #3: No

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19 Oct 2020

Dear academic editor and reviewers,

The authors would like to thank the reviewers for their elaborate and helpful comments regarding our submitted manuscript. The manuscript has been edited to address their concerns.

Please find the revised manuscript and related documents enclosed in this resubmission. The authors thank you again for your careful consideration.

Academic editor’s response:

1. The authors thank the editor for providing information regarding PLOS ONE’s style requirements. The manuscript and all additional files are adjusted accordingly.

2. The date upon which the authors accessed the clinical data sources in this study was added to the Methods section.

3. After careful revision of the data the authors agree with the editor to make the minimal anonymized data set necessary to replicate our study findings accessible through “Beumeler, L.F.E. (2020). Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-centre study [Data set]. Zenodo. http://doi.org/10.5281/zenodo.4091035”. We thank the editor in advance for updating our Data Availability statement on our behalf.

4. The duplicate of our ethics statement has been removed from the manuscript. According to the response of the editor, it now only appears in the Methods section of the manuscript.

5. The appropriate captions for our supporting information file is added at the end of our manuscript and the in-text citation is updated.

Comments to the Author

The authors thank the reviewers for their elaborate response to the questions regarding the manuscript and their useful feedback. To adhere to the information provided by the questions regarding the integrity and language of the manuscript, the procedural text is clarified and the whole manuscript is assessed by a professional English language expert.

Comments to reviewer 1

The authors thank reviewer 1 for acknowledging the importance of the investigation of this issue. We agree with reviewer 1 regarding the complimentary nature of our findings. There have indeed been similar findings in other studies regarding long-term outcomes among ICU patients. However, differences in patient characteristics, ICU treatment methods, and after care facilities make it relevant to investigate these trajectories within a Dutch tertiary teaching hospital, as opposed to for instance a academic hospital (in The Netherlands or abroad). Furthermore, tertiary teaching hospitals may even treat more patients and also less complex cases compared to an academic hospital, which supports the relevance of the above. In our opinion it therefore adds insights to build upon within the development of locally applicable, personalised after care programs.

We thank reviewer 1 for addressing the confusion related to the lack of in-person follow up in physical functioning data at 12 months. We agree that inclusion of these measurements would greatly improve the robustness of the data. Due to the retrospective nature of this study, we were unable to obtain these data thus far. To clarify this issue, we added this limitation of the study to our manuscript. In an upcoming prospective study, we include several in-person follow up visits within the first year after discharge to overcome this issue.

Secondly, we agree with reviewer 1 that proxy measures or telephonic interviews regarding the questionnaires could have improved the sample size by reducing the number of patients lost to follow ups. To clarify, the standard care outpatient clinic always requests the patient to complete and return the questionnaire even if they are unable or unwilling to visit the clinic. This study aims to contribute to improving standard care practices in the recovery phase. However, regular follow up visits are still not common practice. Due to the retrospective nature of this study we were unable to improve this. This also applies to the idea regarding more regular follow up contact between patients and the workers in the clinic. Reviewer 1’s suggestion will be added to the manuscript as a recommendation for future studies.

Thirdly, we value reviewer 1’s comment regarding the possible difficulty readers may experience regarding keeping track of what measures were collected when. To clarify this process, we have added a timeline-table along with the measures collected at each time point, as suggested. We hope this makes the associated text easier to read.

Finally, we value the effort reviewer 1 has made to help us improve the manuscript and clarify essential matters regarding our study methodology.

Comments to reviewer 2

The authors thank reviewer 2 for their elaborate feedback on our manuscript. Below the points mentioned by reviewer 2 will be discussed to clarify the questions that arose while reading through the manuscript.

1. We agree with reviewer 2 that the title does not completely encompass the aim of this study. As mentioned in the objectives, we investigated the incidence of non-recovery in long-stay ICU-patients and identified risk-factors for non-recovery. We see that this might lead to some confusion. Concordantly, we adjusted the manuscript to clarify this issue.

2. This retrospective patient-data study was designed to be exploratory.. The purpose of the study was to explore the area of recovery in physical functioning after long-term ICU-admission in our specific patient-group more thoroughly in order to develop hypotheses that can be tested in our future research.

3. We thank reviewer 2 for their suggestion regarding rephrasing the aim of our study. The suggestion is added to the manuscript.

4. The suggested rephrasing has been adopted in the manuscript.

5. In line 133-134 the NR and R-group are written out fully. Also, the physical functioning subscale score medians with IQR are added to suffice in the request made by reviewer 2.

6. Physical functioning subscale scores at 12 and 3 months are clarified in the 3.1 result section.

7. We agree with reviewer 2 regarding the need to rephrase the results of the analyses for correlations with recovery at 12 months. This paragraph has been rephrased to better display the nature of these results.

8. We thank reviewer 2 for the compliment regarding Figure 3.

9. Regarding the results in 3.5, reviewer 2 suggests to include a table reporting values of the multivariate analysis. Although we agree with the need to display results in an orderly fashion, we prefer to textually report these results. However, we do agree with the raised question about the ‘pooled results’. Using this terminology might be confusing to the reader. Indeed, they entail the results corrected for missing values. Consequently, this is adjusted in the manuscript.

10. Reviewer 2 correctly points out that the last paragraph of the discussion should be included within the limitations. This is corrected in the manuscript.

11. +12 Following reviewer 2’s suggestions regarding the conclusions of this study, a short paragraph is added in the discussion section.

Comments to reviewer 3

The authors thank reviewer 3 for their effort to carefully review our manuscript. Additionally, we appreciate that reviewer 3 openly and clearly shares their concerns about the ethical considerations of this study. Following the comments, it is clear to us that the explanation of the study design is articulate enough. To make sure other readers do not have a similar reaction to this manuscript, several adjustments have been made to clarify the retrospective nature of this study. We guarantee this study is retrospective and think a more extensive explanation can mitigate reviewer 3’s concerns. All data used in this study was collected within our standard care after care clinic, by our ICU-nurses. This data was collected to facilitate proper after care, as the nurses and intensivists use the results in their consult with the patient and the correspondence that is send to the general practitioner and, in case of referral, to a physical therapist/psychologist/rehabilitation specialist. For instance, the hand grip strength, walking test score, and balance and mobility results are communicated to the physical therapist to give an idea of the current physical status of the patient. These data were all recorded within our patient-data-system. Before the start of this study, a study protocol was send to our local medical ethical committee (Regionale Toetsingscommissie Patiëntgebonden Onderzoek, Leeuwarden, The Netherlands; nWMO-number: nWMO 358). This ethical committee concluded our study protocol was indeed of a retrospective nature and therefore waived the need for informed consent. Both the researchers and the members of the ethical committee agreed it would be not possible and undesirable to obtain informed consent in retrospect. To further accommodate reviewer 3’s response, the English correspondence letter of our local ethical committee and the research protocol that was send for review are added in this resubmission.

We hope that our modifications render our manuscript in its current form suitable for publication in PLOS ONE.

Yours sincerely,

On behalf of the authors,

Lise Beumeler

2 Dec 2020

Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-center study

PONE-D-20-21277R1

Dear Dr. Beumeler,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Academic Editor

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Additional Editor Comments (optional):

The editor believes the ethical concerns raised by the reviewers have been clarified and other major critiques regarding analyses and interpretation addressed.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Beumeler et al have improved the quality of their submitted manuscript.

All comments mentioned have been adequately addressed.

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Reviewer #2: Yes: Eleftherios Karatzanos, PhD

4 Dec 2020

PONE-D-20-21277R1

Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-centre study

Dear Dr. Beumeler:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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