I SEE YOU Lise Beumeler Unravelling pathways of recovery after critical illness
I SEE YOU Unravelling pathways of recovery after critical illness Lise Beumeler
Financial support for this thesis was generously provided by 8D Games, GLNP Life Sciences BV, Medical Centre Leeuwarden, and the Rijksuniversiteit Groningen Campus Fryslân. Cover design Lise Beumeler Lay-out Promotie In Zicht | www.promotie-inzicht.nl Printed by Ipskamp Printing © 2023 L.F.E. Beumeler, The Netherlands. All rights reserved No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any from or by any means without permission of the author. Alle rechten voorbehouden. Niets uit deze uitgave mag worden vermenigvuldigd, in enige vorm of op enige wijze, zonder voorafgaande schriftelijke toestemming van de auteur.
PhD thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. C. Wijmenga and in accordance with the decision by the College of Deans. This thesis will be defended in public on Thursday 9 March 2023 at 13.00 hours by Lise Frieda Elisabeth Beumeler born on 10 March 1992 in Nijmegen I see you: unravelling pathways of recovery after critical illness
Supervisors Prof. E.C. Boerma Prof. G.J. Navis Co-supervisors Dr. T. van Zutphen Dr. H. Buter Assessment Committee Prof. E.J. Finnema Prof. D. van Dijk Prof. P.J.M. Weijs Paranimfen Edith Visser Bianca Dijkstra
TABLE OF CONTENTS Chapter 1 General introduction 7 Part 1: Identifying limited recovery 19 Chapter 2 Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-centre study 21 Chapter 3 The prevalence of mental frailty in ICU-survivors and informal caregiver strain: a 1-year retrospective study of the Frisian aftercare cohort 39 Chapter 4 Long-term health-related quality of life, healthcare utilisation and back-to-work activities in intensive care unit-survivors: prospective confirmatory study from the Frisian aftercare cohort 57 Part 2: Malnutrition and frailty in ICU-patients 77 Chapter 5 The predictive value of phase angle on long-term outcome after ICU-admission 79 Chapter 6 Inadequate protein and energy intake in intensive care unit survivors during the first year of recovery: the Frisian Aftercare cohort study 91 Part 3: Improving recovery after critical illness 109 Chapter 7 The effect of protein provision and exercise therapy on patient-reported and clinical outcomes in ICU-survivors: a systematic review 111 Chapter 8 The feasibility of Virtual Reality therapy for upper extremities mobilisation during and after ICU-admission 175 Chapter 9 Discussion and future perspectives 193 Chapter 10 Nederlandse Samenvatting 207 Chapter 11 Appendices 217
CHAPTER 1 General introduction
9 GENERAL INTRODUCTION 1 THE POST-INTENSIVE CARE SYNDROME Being critically ill can have a long-term impact on a patient’s health and wellbeing. The consequences of critical illness and prolonged treatment in an Intensive Care Unit (ICU) are nowadays characterised as the post-intensive care syndrome (-family), or PICS(-F).1,2 A variety of physical and mental health problems result in a reduced health-related quality of life (HRQoL) in some patients, but not all.3–5 Long-lasting immobility in ICU, mechanical ventilation and the use of neuromuscular blockers, among others, often result in ICU- acquired weakness (ICU-AW) and impaired physical functioning.6 Common mental health problems post-ICU are depression, anxiety, trauma, fatigue, and cognitive dysfunction.7–10 Additionally, an ICU-admission can have a large impact on loved-ones and informal caregivers of the patient, often resulting in symptoms of trauma and increased caregiver burden.11 However, it is still unclear which patients are most at risk for long-term health deficits. Impaired recovery in ICU-survivors and their informal caregivers can have widespread consequences. It has been previously described that PICS and long-termhealth problems can result inmore hospital and ICU-readmissions.12 In addition, survivors have three to five times higher healthcare costs than healthy controls in their age-group.13 Furthermore, long-term lack of recovery reflects in an inability to return to work in 30-50% of ICU-survivors.14–16 Nevertheless, the full scope of long-term consequences of critical illness is yet to be explored. To facilitate this, it is essential to perform in-depth research on group and individual recovery trajectories and develop aftercare services or transmural care chains that are tailored towards the individual needs of the patients. However, to provide adequate aftercare properly aligned with both individual needs and the current state of research, a shift in focus in research and clinical practice is essential. Box 1 Meaningful Recovery A newly introduced term for integrated recovery based on the Positive Health framework by Machteld Huber (2011), where the emphasis is not on illness, but on the people themselves; on their resilience and on what it is that makes their lives meaningful.19 In this case; to regain physical, mental and cognitive wellbeing resulting in the capability of ICU-survivors and their informal caregivers to be able to participate in society in a way that is meaningful to them.
10 CHAPTER 1 SHIFTING FOCUS Since the number of patients surviving an admission to the ICU has increased over the last decade, a shift in focus is needed to grasp the full sequalae of this major life event.17 Each year, between 60.000 and 80.000 people are admitted to the ICU in the Netherlands.18 Of these patients, around a third are admitted per protocol following a planned surgical intervention. It is commonly known that unplanned ICU-admissions are associated with longer ICU length of stay (LOS) and a higher severity of illness, reflecting in an increased risk for long- term impaired health. However, in this patient group in particular, commonly used markers for recovery, often referred to as lack of mortality or readmission to the hospital, may not suffice in predicting meaningful recovery in the post-acute phase. Although ICU-discharge usually means the patient is no longer in an acute, life-threatening situation, this is only just the starting point for the complex road to recovery. Looking beyond mortality and considering the multifactorial nature of meaningful recovery is essential to acquire in-depth information regarding the long-term impact of critical illness (Box 1 & Figure 1). Figure 1. A selection of important pre, during, and post-ICU factors impacting the ability to reach meaningful recovery. Meaningful recovery Preadmission frailty Comorbidities Nutritional status Socioeconomic context ICU & hospital characteristics ICU treatment Delirium Physiological changes Rehabilitation potential Persistent disease factors Available aftercare Social support
11 GENERAL INTRODUCTION 1 MEASURING PREADMISSION HEALTH STATUS One of the major limitations in outcome research of ICU-survivors is the lack of baseline information regarding the patient’s health status. Due to the acute setting in the emergency ward and the ICU, obtaining a detailed picture of the premorbid status of the patients can be troublesome. Therefore, previously conducted research mainly focussed on baseline HRQoL-measures and physical functioning of elective surgical patients, although this group may be the least at risk for non-recovery.19,20 In addition, at admission a large proportion of patients is malnourished (38-78%) and physically frail (30%).21,22 In contrast to the often adopted strategy to look for single markers to predict recovery, these composite measures can provide important information on the patient’s health status at admission. The composite measure frailty has been identified as an ageing-associated reduced homeostatic reserve rendering the individual more vulnerable to adverse events.23 The frailty state is characterised by chronic undernutrition, sarcopenia, reduced energy expenditure, and a decreased metabolic rate. Several indicators -like the Clinical Frailty Scale (CFS)- can be used to assess frailty at ICU-admission.24,25 Several studies indicate patients with preadmission frailty as those that have a higher risk of hospital (risk ratio (RR), pooled: 1.71 [1.43-2.05]) and long-term mortality (RR, pooled: 1.53 [1.40-1.68]), with lower quality of life scores in the first year after ICU-admission (Figure 2).26 Due to the acute setting before and during ICU-admission, it is not always feasible to directly assess preadmission health status via the patient. Proxy measurements can be a useful tool in this instance. Retrospective assessment of health-related quality of life via proxy has been shown to be feasible and reliable in ICU-patients.28 Combining these measures with indicators of frailty and malnutrition may be a valuable tool in obtaining an integrative picture of the health status of the patient before critical illness, which can lead to improved treatment and support during and after ICU-admission. RECOVERY AFTER CRITICAL ILLNESS To improve the health status of critically ill patients, rehabilitation starts immediately after admission to the ICU-ward. Combining early mobilisation with targeted nutritional therapy has been used in an attempt to attenuate loss of muscle mass and function.29,30 However, evidence on the effectiveness of these interventions is often inconclusive due to differences in mobilisation
12 CHAPTER 1 protocol, retrospective study setting, and high heterogeneity of the patient population.31 Additionally, exercise and nutritional targets are not always met due to various disease and treatment-related barriers.32,33 Regarding nutritional therapy, which primarily focusses on energy and protein intake to facilitate high energy expenditure and muscle preservation, common barriers are appetite and taste changes or alterations in dietary protocols after transfer to the general hospital ward (Figure 3).34,35 In general, patients are transferred either to a general ward or a rehabilitation facility after ICU-discharge.36 Rehabilitation practices after ICU are primarily focussed on regaining functional independence to facilitate the transfer to the Figure 2. Possible trajectories of ICU-patients with and without frailty at admission.27 Adapted with permission of the American Thoracic Society. Copyright © 2022 American Thoracic Society. All rights reserved.
13 GENERAL INTRODUCTION 1 home or long-term care situation. However, not all patients are eligible to participate in rehabilitation practices after hospital discharge. Some can participate in dedicated programs, like the cardiac rehabilitation, but others have to arrange aftercare services for themselves.37 Keeping in mind the complexity of recovery, the lack of aftercare options for ICU-survivors is remarkable and undesirable. However, implementation of aftercare services is troublesome and their specific effects are still unclear.38,39 INNOVATION IN ICU-REHABILITATION Although the ICU is rarely the end station in the patient journey, it is essential that researchers, medical professionals and policy makers collaborate on improving aftercare services to reduce long-term health deficits in patients and informal caregivers after critical illness. More research is needed to specifically identify patients at risk of impaired recovery and in need of additional (long-term) care. One of the key factors in this search is finding new and innovative ways to acquire adequate information on the patient’s pre-ICU status. Additionally, investigating areas of improvement during and after ICU-admission to facilitate meaningful recovery, e.g. nutritional intake, can provide valuable targets for future intervention studies to set up interdisciplinary aftercare trajectories. Finally, using smart technology and eHealth can assure Figure 3. Barriers to nutritional adequacy in ICU-survivors (adapted from Ridley et al. 2020). Clinical barriers Communication issues Premature enteral feeding tube removal Insufficient patient handover Reduced staff ratios on ward Knowledge deficits System barriers Food service rigidity Protected mealtimes Patient barriers Poor appetite Hormone disturbances Disrupted sleep Lack of time awareness Swallowing disorders Gastrointestinal distrurbances
14 CHAPTER 1 aftercare initiatives are accessible for all patients and caretakers, independent of mobility challenges, to improve quality of (after)care. AIM AND OUTLINE OF THE THESIS To improve the quality of aftercare of ICU-survivors and their informal caregivers in the northern part of the Netherlands, the Medical Centre Leeuwarden initiated a specialised post-ICU outpatient clinic in 2012. From this moment on, long-term ICU-patients, i.e. patients with a LOS/duration of mechanical ventilation of at least 48 hours, were invited to visit the clinic with their informal caregivers, if desired. To further investigate ways to improve the aftercare trajectory, the transdisciplinary project leading to this thesis was initiated. The general aim of this thesis is to describe the road to recovery after critical illness in long-term ICU-patients. This thesis specifically investigates which patients are at risk of limited recovery throughout the first year after discharge and looks for possible targets for future interventional research. In this thesis, the extensive consequences of critical illness for patients and their informal caregivers are assessed (part 1), the incidence and consequences ofmalnutrition and frailty in ICU-patients are investigated (part 2), and results of interdisciplinary initiatives to improve recovery are reported (part 3). At the end of part 3, a leap into the future of accessible aftercare is taken with a user-centred Virtual Reality game for physical rehabilitation during and after ICU-admission.
15 GENERAL INTRODUCTION 1 Part 1: Identifying limited recovery Chapter 2 describes a retrospective study on recovery of physical functioning in the first year after ICU-admission. In this chapter, impaired physical functioning at the outpatient clinic visit is proposed as a marker for long-term non-recovery. Chapter 3 introduces a new concept of mental frailty after ICU-discharge. In this chapter, the prevalence of mental frailty and the consequences for ICU-survivors and their informal caretakers during recovery are determined. Chapter 4 discusses recovery in health-related quality of life, healthcare utilisation, and back to work practices of an intensive 1-year prospective cohort study. Part 2: Malnutrition and frailty in ICU-patients Chapter 5 presents the use of the bioimpedance (BIA)-derived phase angle -a proxy for malnutrition and physical frailty- as a marker for 1-year mortality. Chapter 6 discusses long-term dietary intake and nutritional practices during ICU-stay and the first year of ICU-recovery. Part 3: Improving recovery after critical illness Chapter 7 reports the findings of an extensive systematic review on the effect of dietary and exercise interventions on nutrition-related outcomes. Chapter 8 presents a user-centred Virtual Reality-exergame to improve physical recovery during and after ICU-stay. Chapter 9 elaborates on the main findings of this thesis. Furthermore, clinical implications, recommendations for research and future perspectives from the Frisian cohort initiative are shared.
16 CHAPTER 1 REFERENCES 1. Inoue S, Hatakeyama J, Kondo Y, Hifumi T, Sakuramoto H, Kawasaki T, et al. Post-intensive care syndrome: its pathophysiology, prevention, and future directions. Acute Med Surg. 2019 Apr 25;6(3):233‑46. 2. Davidson JE, Jones C, Bienvenu OJ. Family response to critical illness: postintensive care syndrome-family. Crit Care Med. 2012 Feb;40(2):618‑24. 3. Taboada M, Moreno E, Cariñena A, Rey T, Pita-Romero R, Leal S, et al. Quality of life, functional status, and persistent symptoms after intensive care of COVID-19 patients. Br J Anaesth. 2021 Mar;126(3):e110‑e113. 4. da Costa JB, Taba S, Scherer JR, Oliveira LLF, Luzzi KCB, Gund DP, et al. Psychological disorders in post-icu survivors and impairment in quality of life. Psychol Neurosci. 2019;12(3):391‑406. 5. Hofhuis JGM, Schrijvers AJP, Schermer T, Spronk PE. Health-related quality of life in ICU survivors-10 years later. Sci Rep. 2021 Jul;11(1):15189. 6. Lee M, Kang J, Jeong YJ. Risk factors for post-intensive care syndrome: A systematic review and meta-analysis. Aust Crit Care; 2020 May;33(3):287‑294. 7. Askari Hosseini SM, Arab M, Karzari Z, Razban F. Post-traumatic stress disorder in critical illness survivors and its relation to memories of ICU. Nurs Crit Care. 2021 Mar;26(2):102‑8. 8. Jackson JC, Pandharipande PP, Girard TD, Brummel NE, Thompson JL, Hughes CG, et al. Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study. Lancet Respir Med. 2014 May;2(5):369‑379. 9. Nikayin S, Rabiee A, Hashem MD, Huang M, Bienvenu OJ, Turnbull AE, et al. Anxiety symptoms in survivors of critical illness: a systematic review and meta-analysis. Gen Hosp Psychiatry. 2016 Nov-Dec;43:23‑29. 10. Estrup S, Kjer CKW, Vilhelmsen F, Poulsen LM, Gøgenur I, Mathiesen O. Cognitive Function 3 and 12 Months After ICU Discharge-A Prospective Cohort Study. Crit Care Med. 2018 Dec;6(12):e1121‑e1127. 11. van den Born-van Zanten SA, Dongelmans DA, Dettling-Ihnenfeldt D, Vink R, van der Schaaf M. Caregiver strain and posttraumatic stress symptoms of informal caregivers of intensive care unit survivors. Rehabil Psychol. 2016 May;61(2):173‑178. 12. Hill AD, Fowler RA, Pinto R, Herridge MS, Cuthbertson BH, Scales DC. Long-term outcomes and healthcare utilization following critical illness--a population-based study. Crit Care. 2016 Mar;20:76. 13. van Beusekom I, Bakhshi-Raiez F, de Keizer NF, van der Schaaf M, Busschers WB, Dongelmans DA. Healthcare costs of ICU survivors are higher before and after ICU admission compared to a population based control group: A descriptive study combining healthcare insurance data and data from a Dutch national quality registry. J Crit Care. 2018 Apr;44:345‑351. 14. Kamdar BB, Suri R, Suchyta MR, Digrande KF, Sherwood KD, Colantuoni E, et al. Return to work after critical illness: a systematic review and meta-analysis. Thorax. 2020 Jan;75(1):17‑27. 15. van der Schaaf M, Beelen A, Dongelmans DA, Vroom MB, Nollet F. Poor functional recovery after a critical illness: a longitudinal study. J Rehabil Med. 2009 Nov;41(13):1041‑1048. 16. Hodgson CL, Haines KJ, Bailey M, Barrett J, Bellomo R, Bucknall T, et al. Predictors of return to work in survivors of critical illness. J Crit Care. 2018 Dec;48:21‑25. 17. Máca J, Jor O, Holub M, Sklienka P, Burša F, Burda M, et al. Past and Present ARDS Mortality Rates: A Systematic Review. Respir Care. 2017 Jan;62(1):113‑122. 18. Stichting NICE. Nationale Intensive Care Evaluatie. [Internet]. Available from: https://www. stichting-nice.nl/. [Accessed 17th June 2022]. 19. Rijnhart-deJongH, HaenenJ, Bol RaapG, Jekel L, VossenbergT, BondarenkoO, et al. Determinants of non-recovery in physical health-related quality of life one year after cardiac surgery: a prospective single Centre observational study. J Cardiothorac Surg. 2020 Sep;15(1):234. 20. Abelha FJ, Luís C, Veiga D, Parente D, Fernandes V, Santos P, et al. Outcome and quality of life in patients with postoperative delirium during an ICU stay following major surgery. Crit Care. 2013 Oct 29;17(5):R257.
17 GENERAL INTRODUCTION 1 21. Muscedere J, Waters B, Varambally A, Bagshaw SM, Boyd JG, Maslove D, et al. The impact of frailty on intensive care unit outcomes: a systematic review andmeta-analysis. Intensive CareMed. 2017 Aug;43(8):1105‑1122. 22. LewCCH, Yandell R, Fraser RJL, Chua AP, ChongMFF, Miller M. Association BetweenMalnutrition and Clinical Outcomes in the Intensive Care Unit: A Systematic Review [Formula: see text]. JPEN J Parenter Enteral Nutr. 2017 Jul;41(5):744‑758. 23. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-156. 24. Guidet B, de Lange DW, Boumendil A, Leaver S, Watson X, Boulanger C, et al. The contribution of frailty, cognition, activity of daily life and comorbidities on outcome in acutely admitted patients over 80 years in European ICUs: the VIP2 study. Intensive Care Med. 2020 Jan;46(1):57‑69. 25. Church S, Rogers E, Rockwood K, Theou O. A scoping review of the Clinical Frailty Scale. BMC Geriatr. 2020 Oct 7;20(1):393. 26. Montgomery CL, Rolfson DB, Bagshaw SM. Frailty and the Association Between Long-Term Recovery After Intensive Care Unit Admission. Crit Care Clin. 2018 Oct;34(4):527‑547. 27. Singer JP, Lederer DJ, Baldwin MR. Frailty in Pulmonary and Critical Care Medicine. Ann Am Thorac Soc. 2016 Aug;13(8):1394‑1404. 28. Hofhuis J, Hautvast JLA, Schrijvers AJP, Bakker J. Quality of life on admission to the intensive care: can we query the relatives? Intensive Care Med. 2003 Jun;29(6):974‑979. 29. Fetterplace K, Deane AM, Tierney A, Beach LJ, Knight LD, Presneill J, et al. Targeted Full Energy and Protein Delivery in Critically Ill Patients: A Pilot Randomized Controlled Trial (FEED Trial). JPEN J Parenter Enteral Nutr. 2018 Nov;42(8):1252‑1262. 30. Ferrie S, Allman-Farinelli M, Daley M, Smith K. Protein Requirements in the Critically Ill: A Randomized Controlled Trial Using Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2016 Aug;40(6):795‑805. 31. Menges D, Seiler B, Tomonaga Y, Schwenkglenks M, Puhan MA, Yebyo HG. Systematic early versus late mobilization or standard early mobilization in mechanically ventilated adult ICU patients: systematic review and meta-analysis. Crit Care. 2021 Jan;25(1):16. 32. Moisey LL, Pikul J, Keller H, Yeung CYE, Rahman A, Heyland DK, et al. Adequacy of Protein and Energy Intake in Critically Ill Adults Following Liberation From Mechanical Ventilation Is Dependent on Route of Nutrition Delivery. Nutr Clin Pract. 2021 Feb;36(1):201‑212. 33. de Koning M-SLY, Koekkoek WACK, Kars JCNH, van Zanten ARH. Association of PROtein and CAloric Intake and Clinical Outcomes in Adult SEPTic and Non-Septic ICU Patients on Prolonged Mechanical Ventilation: The PROCASEPT Retrospective Study. JPEN J Parenter Enteral Nutr. 2020 Mar;44(3):434‑443. 34. Chapple L-AS, Weinel LM, Abdelhamid YA, Summers MJ, Nguyen T, Kar P, et al. Observed appetite and nutrient intake three months after ICU discharge. Clin Nutr. 2019 Jun;38(3):1215‑1220. 35. Ridley EJ, Chapple L-AS, Chapman MJ. Nutrition intake in the post-ICU hospitalization period. Curr Opin Clin Nutr Metab Care. 2020 Mar;23(2):111‑115. 36. Vossenberg-Postma SR, Sikkema YT, Drogt-Bilaseschi I, Bruins-Lange NA, de Jager CM, van Maaren T, et al. Direct transfer of long-stay ICU patients to a nursing-home rehabilitation unit: focus on functional dependency. Intensive Care Med. 2015 Nov;41(11):2031‑2032. 37. Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, Josephson RA, Forman DE, et al. Cardiac Rehabilitation for Patients With Heart Failure: JACC Expert Panel. J Am Coll Cardiol. 2021 Mar 23;77(11):1454‑1469. 38. Prevedello D, Steckelmacher C, Devroey M, Njimi H, Creteur J, Preiser J-C. The burden of implementation: A mixed methods study on barriers to an ICU follow-up program. J Crit Care. 2021 Oct;65:170‑176. 39. Svenningsen H, Langhorn L, Ågård AS, Dreyer P. Post-ICU symptoms, consequences, and follow-up: an integrative review. Nurs Crit Care. 2017 Jul;22(4):212‑220. 40. Huber M, Knottnerus JA, Green L, van der Horst H, Jadad AR, Kromhout D, et al. How should we define health? BMJ (Clinical research ed.). 2011;343: d4163.
PART 1 Identifying limited recovery
CHAPTER 2 Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: a retrospective single-centre study L.F.E. Beumeler, A. van Wieren, H. Buter, T. van Zutphen, N. A. Bruins, C. M. de Jager, M. Koopmans, G.J. Navis and E.C. Boerma Published in PLoS ONE, 2020
22 CHAPTER 2 ABSTRACT Background: 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. Methods: In this single-centre study, retrospective data of adults with an ICU-stay >48 hours who visited the specialised 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. Results: Of 250 patients, 110 (44%) fulfilled the criteria for the NR-group. Neither the severity of illness, type of admission, nor presence of sepsis differed 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. Conclusions: 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.
23 PHYSICAL FUNCTIONING AFTER ICU-ADMISSION 2 2.1 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-termprognosis. 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 specialised 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 generalisation of previously obtained findings troublesome.
24 CHAPTER 2 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. 2.2 MATERIALS AND METHODS 2.2.1 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 specialised 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 Figure 1. Flowchart of retrieved study data. Received invitation specialized post-ICU clinic (n=591) • Unable/unwilling to visit clinic (n=315) • Deceased before follow-up (n=23) • Incomplete questionnaire at 12 months (n=3) Analysed (n=250) Data retrieval Analysis
25 PHYSICAL FUNCTIONING AFTER ICU-ADMISSION 2 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 (Figure 1). 2.2.2 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 analysed anonymously. 2.2.3 Data collection In the specialised 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,
26 CHAPTER 2 was assessed using the Barthel Index Score (BIS); a 10-item survey with a score range of 0–20 points.15 Handgrip 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 specialised 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. 2.2.4 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- 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, Handgrip 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
27 PHYSICAL FUNCTIONING AFTER ICU-ADMISSION 2 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. 2.3 RESULTS 2.3.1 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 an 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) (Figure 2). 2.3.2 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
28 CHAPTER 2 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, for 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). 2.3.3 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). Figure 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. Physical functioning (RAND-36) (0-100%) Recovery (3m) Non-recovery (3m) Recovery (12m) Non-recovery (12m) 0 50 100 *** *** ***
29 PHYSICAL FUNCTIONING AFTER ICU-ADMISSION 2 Table 2. A. Baseline & ICU-characteristics, B. 3-months post-ICU-admission measurements Characteristics All, n = 250 NR, n = 110 (44 %) R, n = 140 (56%) 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 Mech ventilation (days) 6 [3-12] 7 [4-19] 5 [3-9] .035 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 HGS right hand (%) 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, 3m post-ICU 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 HGS right hand (%) 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; HGS, Hand grip strength; BIS, Barthel index score; MMI, Morton Mobility Index; 6-MWT, 6-minute walk test; BBS, Berg balance scale. Significant differences in bold
30 CHAPTER 2 2.3.4 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 3-month post-ICU, i.e. reaching the age-adjusted reference value of the PF-domain score at 12-months after ICU-admission (Figure 3). The incidence of medical comorbidities at ICU-admission was weakly negatively correlated with recovery (ρ = -0.27, p < 0.001). Of the measures taken at ICU-discharge, LOS ICU, physical performance (i.e. BIS), and hand grip strength were weakly positively correlated with recovery (ρ = 0.06, p < 0.05, ρ = 0.25, p < 0.001, ρ = 0.29, p < 0.01, respectively). Physical performance and handgrip strength at 3-months after discharge were also weakly positively correlated with recovery (ρ = 0.33, ρ = 0.27, p < 0.001). 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 (ρ = 0.40, ρ = 0.37, ρ = 0.43, ρ = 0.60, p < 0.001, respectively). It is of note that there was no significant correlation of either baseline APACHE III or mobility scores at ICU-discharge with recovery. 2.3.5 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 Figure 3. Pairwise correlations with recovery at 12-months after ICU-admission. Significant correlations visualised in black. Pairwise Correlations Spearman's Rho -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 Recovery * Medical comorbidities Recovery * APACHE III Recovery * LOS ICU Recovery * MMI (ICU-discharge) Recovery * BIS (ICU-discharge) Recovery * Handgrip (ICU-discharge) Recovery * Handgrip (3m) Recovery * BIS (3m) Recovery * MMI (3m) Recovery * 6MWT (3m) Recovery * BBS (3m) Recovery * Physical Functioning (3m)
31 PHYSICAL FUNCTIONING AFTER ICU-ADMISSION 2 at baseline, as well as walking distance, mobility, balance, handgrip 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 0.620, CI 0.279–1.377; p = 0.241, corrected for missing values: OR 0.380 CI 0.197-0.734; p = 0.004). 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- 0.192; p = 0.009, corrected for missing values: OR 1.066 CI 1.005–1.132; p = 0.034). 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 < 0.001, corrected for missing values: OR 1.052 CI 1.036–1.069; p < 0.001). The logistic regression model was statistically significant (original data: χ2(3) = 79.1, p < 0.001). The model explained 50.0% (Nagelkerke R2 original data) of the variance in recovery of physical functioning and correctly classified 78.2% of cases. 2.4 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 Norwegianmixed-ICUpopulation,
32 CHAPTER 2 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
33 PHYSICAL FUNCTIONING AFTER ICU-ADMISSION 2 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. 2.4.1 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 patient 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.
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