https://orcid.org/0000-0002-2434-4997
Figures
Abstract
Background
The rising prevalence of modifiable lifestyle-related risk factors (e.g. overweight and physical inactivity) suggests the need for effective and safe preoperative interventions to improve outcomes after cardiac surgery. This retrospective study explored potential short-term postoperative benefits and unintended consequences of a multidisciplinary prehabilitation program regarding in-hospital complications.
Methods
Data on patients who underwent elective cardiac surgery between January 2014 and April 2017 were analyzed retrospectively. Pearson’s chi-squared tests were used to compare patients who followed prehabilitation (three times per week, at a minimum of three weeks) during the waiting period with patients who received no prehabilitation. Sensitivity analyses were performed using propensity-score matching, in which the propensity score was based on the baseline variables that affected the outcomes.
Results
Of 1201 patients referred for elective cardiac surgery, 880 patients met the inclusion criteria, of whom 91 followed prehabilitation (53.8% ≥ 65 years, 78.0% male, median Euroscore II 1.3, IQR, 0.9–2.7) and 789 received no prehabilitation (60.7% ≥ 65 years, 69.6% male, median Euroscore II 1.6, IQR, 1.0–2.8). The incidence of atrial fibrillation (AF) was significantly lower in the prehabilitation group compared to the unmatched and matched standard care group (resp. 14.3% vs. 23.8%, P = 0.040 and 14.3% vs. 25.3%, P = 0.030). For the other complications, no between-group differences were found.
Citation: Hartog J, Mousavi I, Dijkstra S, Fleer J, van der Woude LHV, van der Harst P, et al. (2021) Prehabilitation to prevent complications after cardiac surgery - A retrospective study with propensity score analysis. PLoS ONE 16(7): e0253459. https://doi.org/10.1371/journal.pone.0253459
Editor: Robert Jeenchen Chen, Ohio State University Wexner Medical Center Department of Surgery, UNITED STATES
Received: January 18, 2021; Accepted: June 4, 2021; Published: July 16, 2021
Copyright: © 2021 Hartog et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This study was financially supported by Edwards Lifesciences SA, Abbott (former St. Jude Medical Nederland B.V.) and ‘Stichting Beatrixoord Noord-Nederland’, who were not involved in the study design or execution. This work was supported by Edwards Lifesciences SA [grant number EV 102016 to JH], Abbott (formerly St. Jude Medical Nederland B.V.) [to JH], and “Stichting Beatrixoord Noord-Nederland” [grant number 210.178 to SD]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: JH, SD, and MAM report grants from Edwards Lifesciences, SA, Abbott (former St. Jude Medical Nederland B.V.), and ‘Stichting Beatrixoord Noord-Nederland’. MAM reports grants from AtriCure, Getinge and consultancy from LivaNova. The remaining authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products provided by Edwards Lifesciences, which are associated with this research.
Introduction
More than 15,000 patients with ischemic heart disease, which is the leading cause of death in Western countries, undergo a coronary artery bypass graft (CABG), valve, and/or aortic surgery in the Netherlands [1, 2]. Although mortality has decreased due to improvements in operative care, the risks of postoperative complications are still high. Approximately 30% of the procedures are complicated by arrhythmias [3], 33% by lung complications [4], and 26% by delirium [5]. The occurrence of postoperative complications hampers the recovery after surgery and can lead to a higher rate of mortality or loss of independence [6]. A decline in postoperative complications would thus reduce the patient burden and healthcare costs. Therefore, it is important to explore whether the risks of complications can be reduced before surgery.
It is well known that the risk of complications has been associated with the preoperative state of the patient. Several risk factors, such as age or type of surgery, are unchangeable. However, some lifestyle-related risk factors are modifiable. For example, physical inactivity (present in ~45% of the cardiac surgery patients) has been associated with an increase in atrial fibrillation (AF) and delirium after cardiac surgery [7, 8]. Furthermore, Hulzebos et al. (2003) [4] showed that recent smoking behavior and poor lung function were risk factors for postoperative pulmonary complications. Smoking was also associated with postoperative AF [6]. Poor preoperative nutrition status (present in ~80%) has also been associated with adverse surgery outcomes [9, 10]. These findings suggest that postoperative complications could be prevented by enhancing preoperative physical and mental status.
Cardiac rehabilitation (CR) has been suggested to improve the preoperative status of the patient and therefore be potentially effective in preventing postoperative complications. The aim of CR is “to influence favourably the underlying cause of cardiovascular disease, as well as to provide the best possible physical, mental and social conditions” [11]. However, the evidence for the benefits and risks of preoperative CR (prehabilitation) is scarce. Evidence is usually derived from small trials investigating the effect of a single-component prehabilitation program, which often consist of inspiratory muscle training (IMT), on pulmonary complications, length of stay, and mortality [12, 13]. A multidisciplinary prehabilitation program consisting of different components (e.g. whole body exercise, dietary, and psychological guidance) can be effective on multiple aspects and might therefore be more effective than a single-component program. Since very little is known about the unintended consequences and effects of such multidisciplinary program, it is relevant to explore the effects of a multidisciplinary prehabilitation program on pulmonary complications as well as on other postoperative complications, such as arrhythmias or delirium.
This explorative study was designed to analyze retrospectively the potential short-term postoperative benefits regarding in-hospital complications and unintended consequences of a standardized multidisciplinary prehabilitation program (including aerobic exercise) compared to standard care. Although this is an exploratory study, based on the shown effects of preoperative IMT [12, 13], we expect a lower rate of in-hospital complications and no unintended consequences in patients who followed multidisciplinary prehabilitation.
Materials and methods
Study design, setting, and sample size
In this retrospective study, data were collected from 880 patients who underwent elective cardiac surgery at the University Medical Center Groningen (UMCG, the Netherlands) between January 2014 and April 2017. The Heart Center of the UMCG is one of the 17 Heart Centers in the Netherlands specialized in cardiac surgery. In addition to patients referred from the UMCG, patients from closely collaborating hospitals (located 5 to 60 kilometers from the UMCG) also underwent cardiac surgery in the UMCG. All admitted patients (regardless of whether they were referred externally or internally) received one preoperative consultation in the UMCG during the waiting period and followed the standard hospital protocol of the UMCG. However, in February 2015 a multidisciplinary preoperative and postoperative rehabilitation program (the Heart-ROCQ pilot program) was implemented in the UMCG for internally referred patients. This resulted in a subgroup (n = 91) that followed prehabilitation and a subgroup (n = 789) that did not receive any prehabilitation during the waiting time.
Participants
Adults admitted for elective (i.e. no main stem stenosis, unstable angina pectoris, or progressive symptoms) coronary artery bypass graft (CABG), valve surgery, aortic surgery, or combined procedures were included. Patients were excluded when accepted for transcatheter aortic valve implantation, aortic dissection, aortic descending repair, Morrow procedure, or congenital procedure. Furthermore, patients that were registered as objecting to the use of their medical data were excluded. Patients who were not able or not motivated to follow prehabilitation or followed a divergent rehabilitation program (i.e. an adapted prehabilitation program without aerobic cycling or an early-initiated postoperative inpatient CR program) were also excluded.
Intervention
Patients who followed the Heart-ROCQ pilot program in addition to the standard surgical care were referred to as the PRE-group. Fig 1 gives an overview of the Heart-ROCQ pilot program, which was conducted at the UMCG, Center for Rehabilitation (located 6 km from the UMCG hospital).
The prehabilitation program was part of a pilot of the Heart-ROCQ program28, which continued with a clinical inpatient rehabilitation phase following discharge from the hospital. Including two group education sessions about basic training principles and forced expiration technique and huff and cough techniques and 30 minutes sessions of body awareness were given every 2 weeks. bIncluding intake, individual sessions on indication, and group education on cardiovascular risk factors; cOnly for patients who smoke; H: Hospitalization; ICU: Intensive care unit; IMT: Inspiratory muscle training; Max-IP: Peak inspiratory pressure; PRE-group: patients who followed the prehabilitation program; RPE: rate perceived exertion; SC-group: Standard Care group, who did not have the option to follow prehabilitation; 1RM: One Repetition Maximum, estimated based on 6-10RM.
Comparison
Before February 2015, no prehabilitation was offered at the UMCG or at the referring hospitals. Only after discharge from the UMCG, an outpatient CR was offered as standard care in the referral hospital [14]. Patients who did not have the option to follow prehabilitation (i.e. patients who underwent surgery before February 2015 or were referred from a peripheral hospital) and thus followed only the standard surgical care, were referred to as the Standard-Care (SC) group.
Ethics and endpoint
The postoperative in-hospital complications investigated in this study are shown in Table 1. At the UMCG, delirium is diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [15], and lung infections are diagnosed using the clinical definition of hospital-acquired pneumonia [16]. All patients received Beta-blockers postoperatively, unless they had conduction disturbances.
Major adverse clinical events (i.e. death, myocardial infarction, stroke, hospital readmission, change in surgery urgency, or sudden cardiac death) were evaluated during prehabilitation to investigate unintended consequences.
All collected data were de-identified according to the rules of the Dutch Privacy Law. A waiver for this study was granted by the Medical Ethics Review Board of the UMCG (METc UMC Groningen). Data were collected between March 2016 and February 2018 from existing databases (the Dutch registration database and the database of the intensive care unit) and medical records.
Statistical analyses
Descriptive statistics included means (±SD) or median (interquartile range) for continuous variables and counts (percentages) for binary or categorical outcomes. Differences between the PRE-group and the SC-group were tested using the Pearson’s chi-squared test. To reduce bias and improve balance between the groups, sensitivity analyses were performed using propensity-score matching [17, 18]. Before performing propensity-score matching, univariate analyses were conducted (IBM SPSS Statistics, version 23) on the baseline variables to identify which variables affected the outcomes. The variables that were significantly associated with the outcomes (Tables 2 and 3) were used in a logistic regression model to estimate the propensity score (i.e. the probability of treatment assignment) [19, 20]. The R package ‘MatchIt’ was used to perform Nearest-Neighbour-Matching. The matching procedure was performed without replacement and the “greedy” approach was used (i.e. it matched the closest control patient to the treated patient that had not yet been matched. The random order of selecting the treated patient affects the match process) [18–20]. In addition, different ratio’s and caliper distances were used to find the optimal match. To find the optimal match, the balance of the baseline variables between the PRE-group and matched SC-group was checked by comparing the standardized mean differences and using Q-Q plots of the two empirical quantile functions (PRE- and SC-group) of each baseline variable [19]. The matched sample was most optimal (i.e. maximum balance, reduced heterogeneity and a large number of observations remaining) when no caliper distance and a ratio of 1:3 was used. The standardized difference of each baseline variable was less than 0.1 indicating a negligible difference between the PRE-group and matched SC-group [21] (S2 Appendix). The Pearson’s chi-squared tests were performed using Stata (Version SE15.0). Level of significance was set at P<0.05 and statistical tests were all two-sided.
Results
Between January 2014 and April 2017 1201 patients underwent elective cardiac surgery at the UMCG. In total 192 patients were excluded based on having had preoperative endocarditis, type of surgery, or being registered as objecting to the use of their medical data for scientific purposes (Fig 2). Of the patients, 97 were approached to follow prehabilitation, but were not motivated or able to follow it. Six patients followed an adapted program due to comorbidities and 26 patients followed an early-initiated postoperative inpatient CR program. Finally, 91 patients were in the PRE-group and 789 in the SC-group.
aPatients who were not able to cycle on an ergometer and followed other exercise modalities.
Characteristics
The average duration of the prehabilitation program was 33.9±12.4 days. Tables 2 and 3 show preoperative and postoperative characteristics of the PRE-group and SC-group. Overall, the majority was male (70.5%), older than 65 years (60%) and overweight (72%, BMI>25.0kg/m2). Furthermore, 28% was obese (BMI>30.0kg/m2) and 20% suffered from diabetes. The prevalence of chronic lung disease and NYHA-class before surgery was significantly higher in the unmatched SC-group. In addition, there was a significant difference in complexity of surgery and on-pump and off-pump surgery between these groups. The PRE-group showed more isolated CABG interventions compared with more single valve interventions in the unmatched SC-group. Consequently, in the unmatched SC-group significantly more cardiopulmonary bypass surgeries were performed. Following the propensity analysis the balance of the baseline characteristics was improved between the PRE- and matched SC-group (Tables 2, 3, and S2 Appendix).
Postoperative complications
Table 4 shows the incidence of the complications per group. AF was the most common complication, which was significantly lower in the PRE-group compared to the SC-group (P = 0.040 and P = 0.030 for resp. the unmatched and matched groups). The other complications were not significantly different between the groups.
Safety
The surgery urgency changed from elective to urgent or emergent in three patients of the PRE-group (3.3%). This was comparable to the SC-group in which the surgery of 27 patients (3.4%) was moved forward. One patient was hospitalized during prehabilitation due to an infected wound seroma. The adverse events of the PRE-group did not occur during or directly after a prehabilitation session.
Discussion
The aim of this study was to explore the potential short-term postoperative benefits and unintended consequences of prehabilitation with respect to in-hospital complications. Our analyses showed a significant decrease of AF in patients who followed prehabilitation compared to (matched) patients who did not follow prehabilitation. No unintended consequences or benefits of prehabilitation were shown regarding the other in-hospital complications and adverse events during prehabilitation.
To the best of our knowledge, this is the first study that has investigated the effects of a multidisciplinary prehabilitation program on postoperative complications such as AF and delirium. Preventing these complications would help to reduce mortality, morbidity and healthcare costs [6, 22–24]. The incidence of AF was almost 2-fold lower in the PRE-group compared with the SC-group. The development of postoperative AF has, regardless the use of a cardiopulmonary bypass, been associated with an increase of preoperative and postoperative inflammatory markers [3, 25]. Inflammation is therefore suggested as an important factor in the multifactorial pathophysiological mechanisms that cause postoperative AF [26]. On the other hand, the anti-inflammatory effects of exercise, healthy food, and psychological stress reduction (offered to the PRE-group) are well stated [27–29]. Therefore, it would be interesting to research whether there might be a causal relation between the possible anti-inflammatory effects of the Heart-ROCQ-pilot program on the pre- and postoperative inflammatory state and the risks of AF.
Regarding the other postoperative complications, there were no significant differences, which lead to the assumption that the prehabilitation program (including aerobic exercise) was safe. However, the definition of postoperative complications was based on clinical findings and routine testing instead of systematic monitoring. Therefore, the incidence of postoperative complications might have been underestimated, which resulted, together with a limited sample size of the PRE-group, in a lower power of the study. Similar results were found regarding PMV and all-cause mortality [12]. In contrast to other studies including high-risk patients, our study, which included an all-comers sample, found no reduction in lung infection. Lung infection was also not reduced after prehabilitation in surgical lung cancer patients, although other pulmonary complications were decreased [30]. The content and duration of prehabilitation were different in these studies. Cardiac patients in other studies received inspiratory muscle training (IMT) on a daily basis, whereas patients in our study received a multidisciplinary prehabilitation program (including IMT) for three times per week over a longer period. In general short (1–2 weeks) and intensive (3–10 times per week) programs were offered to surgical lung cancer patients resulting in preoperative physical improvement and a shorter hospital stay[30]. However, it is still unclear which complications can be prevented by this physical improvement. Also, the feasibility and trainability of these programs with higher exercise intensity is unknown in cardiac patients. Results on the feasibility and trainability of our prehabilitation program are submitted.
A strength of this retrospective study design is that it includes an all-comers population, which are observed in a real-life setting. However, a limitation was that patients were not randomized. Patients with a higher NYHA-class and chronic lung disease were less often referred to prehabilitation. Possibly, these patients were operated with higher priority. Furthermore, patients from the PRE-group were mainly referred from the UMCG, while patients from the SC-group were mainly referred from peripheral hospitals. However, the referring hospital was not associated with postoperative outcomes (S1 Appendix). Propensity-score matching was used to minimize bias and to improve the balance between the groups [18]. Patients from 2014 were also included resulting in a larger control group. This gave the advantage that each treated patient could be matched to three control patients, resulting in an increased precision of the match and a reduction in the bias [19]. In a re-analysis of patients included from 2015 and onwards, the same trends were found (S3 Appendix). Although we created well-balanced groups, we cannot rule out the possibility of a certain degree of selection bias or unmeasured confounding factors that contributed to our findings. We hope the future results of our on-going study will serve as a sufficiently and carefully organized study that rules out the elements of bias and confounding factors [31].
In conclusion, prehabilitation (including aerobic exercise) is a promising therapy, it is inexpensive and easy to implement, since postoperative rehabilitation is already implemented as standard care. It might be beneficial to prevent postoperative AF and patients were not at higher risk for postoperative complications, suggesting the program is safe. Well-powered randomized controlled trials are needed to confirm these findings and further explore the preoperative and (short- and long-term) postoperative effects of prehabilitation and of who will benefit from prehabilitation.
Supporting information
S2 Appendix. Balance between matched and unmatched data.
https://doi.org/10.1371/journal.pone.0253459.s002
(DOCX)
S3 Appendix. Re-analysis of data from 2015 and onwards.
https://doi.org/10.1371/journal.pone.0253459.s003
(DOCX)
Acknowledgments
We thank Willem Dieperink and Tjalling Waterbolk for their help with the data collection. Mike DeJongste is thanked for his support in the study.
References
- 1. GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1908–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1151–210. pmid:28919116
- 2. Maessen JG, Nederlands Hart Registratie (NHR) Rapportage 2020 [Report]. 2020. Available from: https://nederlandsehartregistratie.nl/publicaties/
- 3. Weymann A, Popov AF, Sabashnikov A, Ali-Hasan-Al-Saegh S, Ryazanov M, Tse G, et al. Baseline and postoperative levels of C-reactive protein and interleukins as inflammatory predictors of atrial fibrillation following cardiac surgery: a systematic review and meta-analysis. Kardiol Pol. 2018 Feb 16;76(2):440–51. pmid:29354906
- 4. Hulzebos EHJ, Van Meeteren NLU, De Bie RA, Dagnelie PC, Helders PJM. Prediction of postoperative pulmonary complications on the basis of preoperative risk factors in patients who had undergone coronary artery bypass graft surgery. Phys Ther. 2003;83(1):8–16. pmid:12495408
- 5. Kassie GM, Nguyen TA, Kalisch Ellett LM, Pratt NL, Roughead EE. Preoperative medication use and postoperative delirium: a systematic review. BMC Geriatr. 2017 Dec 29;17(1):298. pmid:29284416
- 6. Hashemzadeh K, Dehdilani M, Dehdilani M. Postoperative Atrial Fibrillation following Open Cardiac Surgery: Predisposing Factors and Complications. J Cardiovasc Thorac Res. 2013;5(3):101–7. pmid:24252985
- 7. Ogawa M, Izawa KP, Kitamura A, Ono R, Satomi-Kobayashi S, Sakai Y, et al. Preoperative physical activity in relation to postoperative delirium in elective cardiac surgery patients. Int J Cardiol. 2015;201:154–6. pmid:26298363
- 8. Giaccardi M, MacChi C, Colella A, Polcaro P, Zipoli R, Cecchi F, et al. Postacute rehabilitation after coronary surgery: The effect of preoperative physical activity on the incidence of paroxysmal atrial fibrillation. Am J Phys Med Rehabil. 2011;90(4):308–15. pmid:21765246
- 9. Ruiz-Núñez B, Van den Hurk GHAM, De Vries JHM, Mariani MA, DeJongste MJL, Dijck-Brouwer DAJ, et al. Patients undergoing elective coronary artery bypass grafting exhibit poor pre-operative intakes of fruit, vegetables, dietary fibre, fish and vitamin D. Br J Nutr. 2015;113(9):1466–76. pmid:25827177
- 10. Zittermann A, Kuhn J, Dreier J, Knabbe C, Gummert JF, Börgermann J. Vitamin D status and the risk of major adverse cardiac and cerebrovascular events in cardiac surgery. Eur Heart J. 2013;34(18):1358–64. pmid:23315905
- 11.
BACPR. The British Association for Cardiovascular Prevention and Rehabilitation (BACPR) standards and core components for cardiovascular disease prevention and rehabilitation, 2nd edition, 2012.
- 12. Hulzebos EHJ, Smit Y, Helders PPJM, van Meeteren NLU. Preoperative physical therapy for elective cardiac surgery patients. Cochrane database Syst Rev. 2012 Jan;11:CD010118. pmid:23152283
- 13. Katsura M, Kuriyama A, Takeshima T, Fukuhara S, Ta F. Preoperative inspiratory muscle training for postoperative pulmonary complications in adults undergoing cardiac and major abdominal surgery (Review). Cochrane Database Syst Rev. 2015;(10):CD010356. pmid:26436600
- 14. De Vries H, Kemps HMC, Van Engen-Verheul MM, Kraaijenhagen RA, Peek N. Cardiac rehabilitation and survival in a large representative community cohort of Dutch patients. Eur Heart J. 2015;36:1519–28. pmid:25888007
- 15.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. DC, editor. DC. Washington; 1994.
- 16. Niederman MS. Hospital–Acquired Pneumonia, Health Care–Associated Pneumonia, Ventilator–Associated Pneumonia, and Ventilator–Associated Tracheobronchitis: Definitions and Challenges in Trial Design. Clin Infect Dis. 2010;51(S1):S12–7.
- 17. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70(1):41–55.
- 18. Deb S, Austin PC, Tu J V., Ko DT, Mazer CD, Kiss A, et al. A Review of Propensity-Score Methods and Their Use in Cardiovascular Research. Can J Cardiol. 2016;32(2):259–65. Available from: pmid:26315351
- 19. Ho DE, Imai K, King G, Stuart EA. MatchIt: Nonparametric Preprocessing for Parametric Causal Inference. J Stat Softw. 2007;
- 20. Ho DE, Imai K, King G, Stuart EA. Matching as Nonparametric Preprocessing for Reducing Model Dependence in Parametric Causal Inference. Polit Anal. 2009;15(3):199–236.
- 21. Austin PC, Grootendorst P, Anderson GM. A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: A Monte Carlo study. Stat Med. 2007;26(4):734–53. pmid:16708349
- 22. Koster S, Hensens AG, Schuurmans MJ, van der Palen J. Consequences of delirium after cardiac operations. Ann Thorac Surg. 2012 Mar;93(3):705–11. pmid:21992939
- 23. Iribarne A, Chang H, Alexander JH, Gillinov AM, Moquete E, Puskas JD, et al. Readmissions after cardiac surgery: experience of the National Institutes of Health/Canadian Institutes of Health research cardiothoracic surgical trials network. Ann Thorac Surg. 2014 Oct;98(4):1274–80. pmid:25173721
- 24. Kosuma P, Wachirasrisirikul S, Jedsadayanmata A. Attributable Costs of Postoperative Atrial Fibrillation among Patients Undergoing Cardiac Surgery. Cardiol Res Pract. 2018;2018:1–5. pmid:30050692
- 25. Lo B, Fijnheer R, Nierich AP, et al. C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization. Ann Thorac Surg 2005;79:1530–1535. pmid:15854929
- 26. Boons J, Van Biesen S, Fivez T, et al. Mechanisms, Prevention, and Treatment of Atrial Fibrillation After Cardiac Surgery: A Narrative Review. J Cardiothorac Vasc Anesth 2020;000.
- 27. Giugliano D, Ceriello A, Esposito K. The Effects of Diet on Inflammation. Emphasis on the Metabolic Syndrome. J Am Coll Cardiol. 2006;48(4):677–85. pmid:16904534
- 28. Zanchi NE, Almeida FN, Lira FS, Rosa Neto JC, Nicastro H, da Luz CR, et al. Renewed avenues through exercise muscle contractility and inflammatory status. ScientificWorldJournal. 2012;1–7. pmid:22629149
- 29. Wirtz PH, von Känel R. Psychological Stress, Inflammation, and Coronary Heart Disease. Curr Cardiol Rep. 2017;19(11):1–10.
- 30. Steffens D, Beckenkamp PR, Hancock M, Solomon M, Young J. Preoperative exercise halves the postoperative complication rate in patients with lung cancer: A systematic review of the effect of exercise on complications, length of stay and quality of life in patients with cancer. Br J Sports Med. 2018;52(5). pmid:29437041
- 31. Hartog J, Blokzijl F, Dijkstra S, Dejongste MJL, Reneman MF, Dieperink W, et al. Heart Rehabilitation in patients awaiting Open heart surgery targeting to prevent Complications and to improve Quality of life (Heart-ROCQ): study protocol for a prospective, randomised, open, blinded endpoint (PROBE) trial. 2019;9(9):e031738. pmid:31537574