F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.150880.1 Systematic Review Articles Impact on postoperative complications of combined prehabilitation targeting co-existing smoking, malnutrition, obesity, alcohol drinking, and physical inactivity: a systematic review and meta-analysis of randomised trials

[version 1; peer review: 1 approved with reservations]

 Lydom Line N Conceptualization Data Curation Formal Analysis Investigation Methodology Project Administration Resources Visualization Writing – Original Draft Preparation https://orcid.org/0000-0001-9431-9984 1 Jensen Sofie Anne-Marie S Conceptualization Data Curation Formal Analysis Investigation Methodology Project Administration Resources Visualization Writing – Original Draft Preparation 1 Lauridsen Susanne V Conceptualization Data Curation Funding Acquisition Investigation Methodology Resources Supervision Writing – Review & Editing 1 2 Rasmussen Mette Conceptualization Data Curation Formal Analysis Funding Acquisition Investigation Methodology Resources Supervision Visualization Writing – Review & Editing https://orcid.org/0000-0003-2847-1544 1 3 Christensen Robin Conceptualization Data Curation Formal Analysis Investigation Methodology Resources Writing – Review & Editing 1 4 Joensen Ulla N Conceptualization Data Curation Funding Acquisition Investigation Methodology Project Administration Resources Supervision Writing – Review & Editing 5 6 Rosenberg Jacob Conceptualization Data Curation Investigation Methodology Resources Supervision Writing – Review & Editing https://orcid.org/0000-0002-0063-1086 2 6 Tønnesen Hanne Conceptualization Data Curation Formal Analysis Funding Acquisition Investigation Methodology Project Administration Resources Supervision Writing – Original Draft Preparation https://orcid.org/0000-0002-7161-3416 a 1 3 The Parker Institute, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark Centre for Perioperative Optimization, Department of Surgery, Herlev Hospital, Herlev, Denmark Department of Health Sciences, Lunds Universitet, Lund, Skåne County, Sweden Cochrane Denmark & Centre for Evidence-Based Medicine Odense (CEBMO), Department of Clinical Research, University of Southern Denmark, Odense, Denmark Department of Urology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark Hanne.Tonnesen@regionh.dk

Competing interests: Authors Hanne Tønnesen and Susanne V Lauridsen are co-authors of one of the included studies.

 26 6 2024 2024 13 694 13 6 2024 Copyright: © 2024 Lydom LN et al. 2024 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background

This study aimed to compare the effect on postoperative complications of prehabilitation targeting predefined co-existing risky lifestyle factors with usual preoperative routines in surgical patients.

 Methods

This systematic review followed the PRISMA 2020 guideline and the protocol (CRD42022282611). Five databases were searched from inception to November 7, 2022 for randomised controlled trials on prehabilitation targeting ≥2 predefined risky lifestyles compared with usual preoperative routines. Risky lifestyles included Smoking, Nutrition (malnutrition and/or BMI>25), risky Alcohol intake, and Physical inactivity (SNAP). Primary outcome was postoperative complications ≤30 days. Cochrane’s risk-of-bias tool 2 was used and meta-analyses were conducted. GRADE was used to assess certainty of evidence.

 Results

The search resulted in 20,862 records. At full-text screening, only two (120 participants) of 24 identified trials on combined SNAP intervention had ≥2 predefined risk factors and were included. One (n=110) on intensive physical and brief nutritional intervention to frail patients with colorectal cancer resection reported complication rates of 45% in both groups (relative risk (RR) 1.00, 95% CI 0.66 to 1.51). The other study (n=10, subgroup) on intensive alcohol and smoking intervention in patients with bladder cancer undergoing radical cystectomy, reported complications in 3/7 vs 3/3 participants (RR 0.50, 95% CI 0.21 to 1.19). The meta-analysis estimated a RR of 0.79 (95% CI 0.41 to 1.51, I 2 51%).

 Conclusion

Two small of the 24 trials on prehabilitation targeted co-existing and predefined risky SNAP factors and the effect on postoperative complications is very uncertain. Future prehabilitation research involving patient needs is warranted.

 Prehabilitation Postoperative complications Surgery Lifestyle THE OAK FOUNDATION OCAY-18-774-OFIL Kræftens Bekæmpelse R223-A13094 This work was supported in part by The Danish Cancer Society (R223-A13094) as part of the COMPAS Project. The Parker Institute, Bispebjerg and Frederiksberg Hospital is supported by a core grant from the Oak Foundation (OCAY-18-774-OFIL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction

Surgery is a pivotal part of the treatment of numerous medical conditions. The estimated global volume of surgical procedures was 313 million procedures in 2012 and this has since increased. 1 Development of complications is still a major challenge worldwide 2 , 3 despite the improvements in perioperative care in the last decades including improved surgical and anaesthesiologic techniques, preoperative interventions targeting co-morbidities, and enhanced postoperative recovery programmes. 4 – 6 The consequences of complications include prolonged recovery, reduced quality of life and life expectancy, as well as increased health care costs. 7 – 10

Postoperative morbidity is in part related to preoperative modifiable risk factors such as smoking, 11 , 12 nutrition (overweight/obesity, malnutrition), 13 – 15 risky alcohol drinking, 16 and physical inactivity 17 – 19 (SNAP). The SNAP factors compromise several organ functions of importance for successful outcome after surgery. 13 , 20 – 23 While daily smoking, risky alcohol intake, or malnutrition are followed by a general 50% increased complication rate across different types of surgery, 11 , 13 , 16 overweight or obesity are associated with increased complications to a minor degree. 24 , 25 Low physical activity level is associated with increased risk of complications, length of stay and postoperative mortality. 18 , 26 – 29

The SNAP factors are modifiable by prehabilitation, 20 , 22 , 30 , 31 but the impact on postoperative morbidity differs among the SNAP factors. 32 , 33 Only the most intensive programmes targeting smoking, alcohol, and malnutrition reduce complication rates by half. 13 , 32 , 33 Recent systematic reviews have shown an improvement after preoperative physical training programmes of functional capacity both pre- and postoperatively, however, no effect on postoperative complications has been shown. 34 , 35 The effect of overweight or obesity interventions have only poorly been investigated outside bariatric surgery. 36 Until now, the large majority of the evidence from SNAP interventions are based on investigating one risky SNAP factor intervention at a time. 37 , 38 This is despite of up to half of hospital patients have co-existing SNAP factors, 39 – 41 such as smoking and overweight or frailty involving both malnutrition and physical inactivity, which potentiate the risk at surgery. 14 , 42 This calls for risk reduction through targeted combined prehabilitation.

The aim was to compare the effect on postoperative complications of prehabilitation targeting predefined co-existing risky SNAP factors with usual preoperative routines in surgical patients. We hypothesised the combined prehabilitation would reduce the postoperative complications compared to usual preoperative routines.

 Methods

This systematic review and meta-analysis was conducted and reported according to the Cochrane Handbook for Systematic Reviews of Interventions 43 and in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 44 and AMSTAR (Assessing the methodological quality of systematic reviews) 45 Guidelines. The protocol was registered on PROSPERO ( CRD42022282611) before retrieval of data.

Eligibility criteria

We included randomised controlled trials enrolling populations of adult patients (≥18 years) undergoing any surgical intervention and having at least two of the five predefined risky SNAP factors (daily smoking, alcohol intake > 2 drinks daily (= above 24 g ethanol) or 14 drinks weekly, malnutrition (defined as either weight loss of 10-15% within the last 6 months, BMI < 18.5, Subjective Global Assessment (SGA) Grade C, Nutritional Risk Screening (NRS) > 5, or preoperative serum albumin < 30 g/l), BMI > 25 and physical activity < 4 hours/week), or as described by the authors and receiving a combined intervention initiated preoperatively and targeting those lifestyles. Populations in need for combined frailty intervention were accepted if the frailty screening tool involved at least two of the predefined risky lifestyles of interest in this review. Studies were excluded if their population did not have predefined risky lifestyles. Only face-to-face interventions (physical or online) were included. Intensive interventions were defined as having at least four sessions, each lasting longer than ten minutes and including education, motivational and (if relevant) pharmaceutical support. 32 , 46 The intervention was compared with usual preoperative routines.

 Information sources & search strategy

We searched Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and CINAHL on March 3, 2021 with an update on November 7, 2022. Our search strategy for MEDLINE was developed in consultation with an information specialist from the Cochrane Anaesthesia Group. It was combined with the Cochrane Highly Sensitive Search Strategy, with use of the sensitivity- and precision-maximising version, for identifying RCTs 47 (see extended data file). Similar strategies were developed for the other databases. The search was performed without restrictions for language or publication year. In addition, we performed a simple keyword search (“ multimodal prehabilitation surgery RCT”) in Google Scholar with a check-up of the first 200 references and a snowball search by manually scanning the reference lists of included trials and of topic relevant systematic reviews.

 Study selection

Screening of articles was conducted using Covidence® with an institutional subscription. Two reviewers screened all titles and abstracts, independently. Likewise, all full text articles were screened by two other reviewers. Any disagreements were discussed and resolved within the author group. with an institutional subscription. Two reviewers screened all titles and abstracts, independently. Likewise, all full text articles were screened by two other reviewers. Any disagreements were discussed and resolved within the author group.

 Data collection and items

Data extraction was performed in collaboration of two reviewers with all discrepancies discussed and resolved within the author group. The following data were extracted from all studies into a pre-defined Excel-sheet: authors, year of publication, country, number of patients, patient characteristics (age, sex, ASA-score, SNAP factors), type of surgery, indication for surgery, intervention characteristics (targeted risky SNAP factors, intensity of intervention, preoperative duration, compliance measured as meeting adherence, additional interventions), definition of control groups, drop-outs, and length of follow-up.

The primary outcome was complications within 30 postoperative days, defined by requiring treatment and categorised according to a standardised methodology e.g., the Clavien-Dindo classification, 48 comprehensive complication index, 49 or as described by the authors.

We only included published randomized controlled trials (RCTs) including cluster and pilot RCTs. Secondary outcomes were extracted if present in the studies: length of stay (LoS), readmissions, adverse events of the lifestyle intervention, successful risk reduction perioperatively and long-term, and effect on patient reported long-term (one year) quality of life (QoL).

Successful risk reduction was defined as quit smoking, quit drinking, no overweight or obesity, no malnutrition, physical activity >4h/week as well as change of at least 1 step on the ASA-score 50 regarding risky lifestyles or any change of at least 1 unhealthy lifestyle. For long-term successful risk reduction same definitions were applied except for alcohol which needed to be below risky limits instead of zero intake exclusively.

When doubts about extraction of data, trial authors were contacted by email for clarification. For studies that included a subset of eligible participants, we obtained data for only the subgroup of interest.

 Risk of bias assessment

Risk of bias in the individual studies was assessed independently by two reviewers using the Cochrane Handbook’s risk-of-bias tool (RoB2) for RCTs. 51 Any discrepancies or doubts were discussed and resolved together with a third reviewer. For each outcome in each study, all signalling questions were answered for the five bias domains: the randomization process, deviation from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. For each domain the responses were collated to a final judgement. In addition, the overall judgement of either low risk of bias, some concerns or high risk of bias was assigned based on the five bias domains.

 Data synthesis and statistical analysis

To reduce the impact of bias due to missing data in the synthesis, we contacted the authors of the studies in case of missing estimates. In addition, in the data extraction we adhered to the best of our abilities to the intention-to-treat principle. 52 Meta-analyses were performed using Review Manager 5.4® (RevMan [Computer program]. Version 5.4. The Cochrane Collaboration, 2020). The effect measure of choice for the binary outcomes (e.g., postoperative complications) was the relative risk (RR) with 95% confidence intervals (95% CI) in order to assess the likelihood of the event happening in the experimental intervention group relative to the control comparator. 53 Secondary outcomes were expressed similarly except LoS and quality of life (continuous outcome measures), which were estimated based on the difference between means. 54 If data were presented as median and IQR, the assumption was that the mean approximately corresponded to the median while SD was estimated as IQR/1.35. 55

A meta-analysis for the relative risks of postoperative complications as well as for the secondary outcomes was conducted based on a random-effects model per default (DerSimonian and Laird) 56 and the results presented in Forest plots. Clinical heterogeneity was considered and evaluated qualitatively, and the statistical heterogeneity was assessed as I 2-values as well as from the poor overlap in the visualized 95% CIs in the Forest plots. 56 In addition, we planned subgroup analyses on different combinations of the five risky lifestyles, intensive interventions, elderly patient groups, and different types of surgery as well as sensitivity analyses.

According to the new guidelines by The Institute for Quality and Efficiency in Health Care (IQWiG) it is recommended to use a fixed-effect model in the case of very few studies, so we also conducted these for the purpose of sensitivity analysis on the primary outcome. 57

According to the original protocol, we also applied a network meta-analysis technique in order to simultaneously compare three or more interventions in order to enable a comparison between multiple interventions since direct comparisons are limited. We estimated the odds ratios by default from the random effects network meta-analysis model with binomial likelihood and logit link. 58 For these (arm based) network meta-analyses, we used generalised linear mixed models combining a series of 2×2 tables, with the odds ratio modelled as a linear combination of study level covariates and random effects, representing variation between studies. 59

On the basis of the comparison of the individual OR values to the overall event rate in the treatment as usual groups as a proxy for baseline risk, we would estimate the number needed to treat (NNT) in order to get an extra patient without complications with 95% CI. We considered two-sided P-values less than 0.05 and 95% CIs for the RR values for binary outcomes that did not include 1 to be statistically significant. Summary assessments of the quality of evidence for each important outcome were performed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach 60 , 61 which includes four levels of quality of evidence (high, moderate, low, and very low) and presented in a summary of findings table.

 Results

As illustrated in the PRISMA flowchart, the literature search revealed a total of 20,863 different records identified from various sources; these were screened for eligibility based on title and abstract, and 188 studies were subsequently assessed in full text. A total of 24 studies apparently met the inclusion criteria except for the criterion of at least two predefined risky SNAP factors. Consequently, we were only able to include two RCTs fulfilling our stringent eligibility criteria 62 , 63 ( Table 1).

Full-text studies with multimodal interventions.
Author Year Country Type of surgery (N o randomized) SNAP inclusion criteria SNAP int. (intensity) Additional int. Type of control Postoperative complication definition Complications IG vs. CG N E/N o included in analysis (%)
Included: Two preidentified risk-factors
Carli 62 2020 Canada Colorectal cancer resection (120) N+P: Frailty (Fried) P (I) N (B) S (B) A (B) Psych. Int. Rehab –programme identical to prehab. Complications 30 days See Figure 2
Lauridsen 63 2022 Denmark Radical cystectomy for bladder cancer (13) S (daily) + A (≥3u/day) S (I) A (I) - Standard care Complications 30 days See Figure 2
Excluded: One preidentified risk-factors
Barberan-Garcia 84 2018 Spain Major abdominal surgery Benign or malignant (144) P: Duke Activity Status Index P (I) N m (B) S (B) A (B) - P (B) N m (B) S (B) A (B) Complications 30 days 19/62 (31) vs. 39/63 (62)
Goodman 81 2007 UK Coronary artery bypass surgery (188) N o: BMI>28 P (I) N (I) Medication optimization Standard care Postoperative complications Data not shown
Kalarchian 2013 82 , 94 USA Bariatric surgery (240) N o: BMI>40 or BMI 35-40 P (I) N o (I) - Standard care: P (B) N (B) Adverse events 30 days 1/71 vs. 0/72
Liang 83 , 95 2018 USA Ventral hernia repair (118) N o: BMI 30-40 kg/m2 P (I) N o (I) - Standard counseling 30 days surgical site occurrences 3/44 (7) vs 6/34 (18)
McIsaac 85 2022 Canada Intra-abdominal or thoracic cancer resection (204) Frailty (Clinical Frailty scale) P (B) N (B) - Standard care In-hospital complications 42/94 (45) vs. 52/88 (59)
Sawatzky 86 2014 Canada Coronary artery bypass graft (17) P: Sedentary P (I) N (I) Education on risk factor management Standard care Operative + postoperative complications 30 days 4/8(50) vs. 4/7(57)
Excluded: No preidentified risk-factors
Allen 65 2022 UK Esophago-gastric cancer resection (54) None P (I) N (?) Psych. and medical coaching Standard care Clavien–Dindo class > IIIa 7/22 (32) vs. 12/23 (52)
Ausania 66 2019 Spain Pancreatico-duodenectomy Malignant (48) None P (I) N m (B) - Standard care Complications 30 days 6/18 (33) vs. 12/22 (54)
Bousquet-Dion 67 2018 Canada Non-metastatic colon or rectal cancer resection (80) None P (I) N m (B) Anxiety-reduction P (B) as rehab. N m (B) Complications 30 days 14/37 (38) vs. 8/26 (31)
Ferreira 68 2021 Canada Lung cancer resection (124) None P (B) N (B) (prehab.+ rehab.) Anxiety-reduction P (B) N (B) (8 weeks rehab.) Complications (Clavien-Dindo 1-5) 27/52 (52) vs. 26/43 (61)
Fulop 69 2021 Hungary Colorectal resection Benign or Malignant (184) None P (I) N (B) A (B) S (B) Anxiety-reduction Standard care Complications 30 days 17/77 (22) vs. 16/72 (22)
Gillis 70 2014 Canada Colorectal cancer resection (89) None P (B) N m+o (B) (prehab.+ rehab.) Anxiety-reduction P (B) N (B) (8 weeks rehab) Complications 30 days 12/38 (32) vs. 17/39 (44)
Kaibori 71 2013 Japan Liver resection Malignant (51) None P (?) N (B) - N (B) Morbidity: Yes 2/25 (8) vs. 3/26 (12)
Lawson 72 , 96 2021 Canada Thoracotomy for lung cancer (34) None P (I) N (B) S (B) Anxiety-reduction S (B) Clavien–Dindo 1-3 + 30 days 11/20(55) vs. 4/8 (50)
Liu 73 2020 China Thoracoscopic lobectomy Malignant (85) None P (B) N (B) Mental relaxation skills Standard care Clavien–Dindo > 2-3 + 30 days 4/37 (11) vs. 5/36 (14)
López-Rodríguez-Arias 74 2021 Spain Colorectal cancer resection (20) None P (B) N (B) Anxiety-reduction Standard care Complications 30 days 2/10 (20) vs. 5/10 (50)
Minnella 75 2018 Canada Esophago-gastric cancer resection (68) None P (B) N (B) - Standard care Clavien-Dindo 1-5 complications 30 days 14/24 (58) vs. 18/25 (72)
Minnella 76 2021 Canada Radical cystectomy Malignant (70) None P (B) N (B) Anxiety-reduction Standard care Clavien-Dindo 1-5 complications 30 days 16/30 (53) vs. 16/28 (57)
Molenaar 77 2023 Netherlands Colorectal cancer resection (269) None P (I) N (?) S(?) Anxiety-reduction Standard care Complications 30 days 39/123 (32) vs. 54/128 (42)
Nielsen 78 , 97 2008 Denmark Lumbar fusion (73) None P (B) S (I) A (I) - Standard care Major complications 30 days 8/28 (29) vs. 8/32 (25)
Nguyen 79 2022 France Total knee replacement (262) None P (I) N (B) Anxiety-reduction Standard care Adverse events ?
Stein 80 1970 USA Thorax, abdominal or other surgery (48) None P (I) - Chest physio. S (?) Medication per indication Standard care Pulmonary complications grade 1-4 5/23 (44) vs. 15/25 (60)

A: Alcohol, B: Brief intervention, BMI: Body mass index, CCI: Comprehensive Complication Index, CG: Control group, ERAS: Enhanced recovery after surgery, I: Intensive intervention, IG: Intervention group, Int: Intervention , N: Nutrition, N E : Number of patients with event, N o : Number of participants included in the study, N o : Obesity, N m : Malnutrition, P: Physical activity, Physio: Physiotherapy, Prehab: Prehabilitation (preoperative), Psych: Psychologic, Rehab: Rehabilitation (postoperative), QoL: Quality of life, S: Smoking, u: units ?: No information available.

One of the two included studies was a multicentre RCT with stratification for smoking, alcohol and both had a small subgroup (n=10) investigating the effect of combined intensive smoking and alcohol cessation intervention for patients with these predefined risk factors undergoing radical cystectomy for bladder cancer. 63 In total, the sub-group consisted of 13 (eight in intervention group + five in control group) patients, but three did not undergo surgery leaving ten patients (seven in intervention group + three in control group) ( Table 2). The other included study (n=110) investigated the effect of a brief nutrition and intensive physical activity intervention on patients undergoing colorectal cancer surgery. 62 They included their patients based on being frail preoperatively according to the Fried Frailty Index, 64 which includes both elements of physical capability and malnutrition. Patients who were current smokers or had a risky alcohol intake were counselled regarding cessation, but no information regarding counselling content or lifestyle improvement were described ( Table 2). None of the two included studies received funding from foundations involved in any part of the trials (designing of study, study conduction, dissemination of results etc) except the funding.

Study and baseline characteristics of the included studies.
Study Carli 2020 62 Lauridsen 2022 63
Follow-up time Before surgery + 4weeks after surgery 6weeks + 3, 6, 12months after inclusion
Duration of intervention (protocol) 4 weeks 6 weeks
Group allocation IG CG IG CG
Baseline to surgery days, median (IQR) 40 (28-50) 35 (22-55) 8 (7-22) 13 (12.5-23)
Adherence to intervention mean (SD) 80% (27%) a - 100% b -
Number of patients undergoing surgery 55 55 7 3
Men, N (%) 29 (52.7) 23 (41.8) 7 (100%) 3 (100%)
Age, median (IQR) 78 (72-82) 82 (75-84) 63 (58-69) 71 (68-72)
ASA score, N (%)
II 19 (34.5) 9 (16.4) 2 (28.5) 3 (100)
III 33 (60.0) 43 (78.2) 3 (43) 0
IV 3 (5.5) 3 (5.5) 0 0
No information 2 (28.5)
Current smokers, N (%) 6 (10.9) 5 (9.1) 7 (100) 3 (100)
Malnutrition, N (%) B: 27 (50.0) c B: 12 (26.7) c 0 d 0 d
C: 11 (20.4) c C: 13 (28.9) c
BMI ≥ 30, N (%) 14 (25.5) 16 (29.6) 1 (14.3) 0
Risky alcohol use, N (%) 5 (9.1) e 3 (5.5) e 7 (100) f 3 (100) f
Physical active ≤ 30 min/day, N (%) - - 2 (29) 1 (33)

A: Alcohol, ASA: American Society of Anesthesiologists, au: alcohol units, BMI: Body mass index, CG: Control group, IG: Intervention group, IQR: Inter quartile range, min: minutes, N: Number of, SD: Standard deviation.

Overall adherence to the programme (supervised and homebased; exercise and nutritional components).

Attendance rate at the 5 planned meetings

Subjective global assessment. B indicates nutrition risk and C malnutrition.

Weight loss > 5% in the last month or food intake 0-25% of normal requirement in preceding week or BMI <18.5 + impaired general condition

For men: (>15 standard drinks per week) and women: (>10 standard drinks per week).

≥ 3 units of alcohol (36 g) daily.

 Risk of bias

Risk of bias assessment for the two included studies are presented in Figure 1. Being behavioural intervention studies blinding of patients and study personnel was not possible. Otherwise, both studies were judged to have a low risk of bias in almost all domains for both primary and secondary outcomes. Exceptions were the secondary outcomes of successful risk reduction at the end of intervention in Carli et al. 62 and at 12 months in Lauridsen et al. 63 In Carli et al. less than 80% of the control group attended follow-ups. Furthermore, most of the non-attendances at follow-up were not justified. One could wonder whether the non-attendances at follow-up were the patients in the worst physical shape/with the least improvement, thereby inducing bias due to missing results. Therefore, the domain of missing outcome data was assessed as having a high risk of bias. The problems with follow-up data in Lauridsen et al. was explained by death of patients. One patient in each group died within 90 days due to complications, the rest due to recurrence of their bladder cancers, therefore the domain received some concerns instead of high risk of bias. To identify publication bias we planned to produce funnel plots but too few studies were identified for this.

Risk of bias for included randomized controlled trials according to Cochrane’s risk of bias 2 tool. <sup> <xref ref-type="bibr" rid="ref51">51</xref> </sup>

+: low risk of bias, !: some concerns, -: high risk of bias, D1: randomization process, D2: deviations from the intended interventions, D3: missing outcome data, D4: measurement of the outcome, D5: selection of the reported result.

 Postoperative complications

None of the two included studies reported a statistically significant difference in postoperative complications within 30 days between intervention and control groups. Carli et al. 62 reported complications in 25 of 55 (45.5%) participants in both intervention and control group entailing a relative risk of 1.00. Lauridsen et al. 63 reported complications in three of seven participants and three of three participants, respectively. The relative risk was 0.5. The meta-analysis based on a random-effects model estimated a weighted relative risk of 0.79 ( Figure 2). The meta-analysis based on a fixed-effect model estimated a weighed relative risk of 0.92, 95% CI [0.63, 1.34]; I 2: 51%.

Forest plot with postoperative complications within 30 days.

CI: confidence interval, P: p-value, SD: standard deviation, Z: z-value.

According to the protocol, we performed a network meta-analysis comparing all intervention groups as if it had been compared in one large trial. When comparing an intensive (I) physical activity and brief (B) nutrition, smoking and alcohol cessation intervention (P INSA B) with an intensive smoking and alcohol cessation intervention (SA I) the risk of complications could potentially be unfavorable for P INSA B (OR = 1.19 [0.26 to 5.45]). SA I on the other hand might reduce the risk of complications when compared to treatment as usual (TAU) (OR = 0.79 [0.17 to 3.60]), but when TAU was compared to P INSA B there was no reason to suspect any difference in risk of complications (OR = 0.94 [0.46 to 1.92]).

 Secondary outcomes

Carli et al. reported an identical length of stay in both groups of 4 days (mean difference 0.00, CI 95% [-1.38, 1.38]) while Lauridsen et al. reported length of stay of 7.3 days in the intervention group versus 11.7 days in the control group. The mean difference was -4.40 with CI 95% [-9.10, 0.30] pointing towards a shorter length of stay in the intervention group but still not statistically significant. Meta-analysis estimated a weighted mean difference of -1.60 days ( Figure 3).

Forest plot with length of stay.

CI: confidence interval, P: p-value, SD: standard deviation, Z: z-value.

It was not possible to conduct meta-analyses for the remaining secondary outcomes due to less than two studies reporting the outcomes. Carli et al. reported readmissions within 30 days in two of 55 (3.6%) participants versus five in 55 (9.1%) participants in the intervention and control groups, respectively (RR 0.40 [0.08, 1.97]). Lauridsen et al. reported readmissions within 90 days in five of seven participants versus two in two participants, respectively (RR 0.71 [0.45, 1.14]). Carli et al. did not report on long-term quality of life. Lauridsen et al reported one-year QoL and VAS QoL measured by the EQ-5D instrument. Mean difference for one-year QoL and VAS QoL was 0.06, 95% CI [-0.19, 0.32] and 2.4, 95% CI [-33.8, 38.6], respectively.

Regarding successful risk reduction, data were sparse and reported on few SNAP factors. All available results are reported as intention to treat in Table 3. Both studies reported no adverse events due to the interventions. The data available did not allow for any subgroup analyses to be made.

Successful risk reduction of reported SNAP factors as intention to treat numbers.
Risk factor Number of patients with successful risk reduction RR [95% CI] Study
Intervention Control
End of intervention
Smoking 3/7 1/3 1.29 [0.21, 7.89] 63
Alcohol 3/7 0/3 3.50 [0.23, 52.56] 63
Smoking and alcohol 3/7 0/3 3.50 [0.23, 52.56] 63
Physical activity (6MWT) 26/55 10/55 2.60 [1.39, 4.86] 62
Long-term (1 year)
Smoking 1/7 0/3 1.50 [0.08, 29.15] 63
Alcohol 2/7 2/3 0.43 [0.10, 1.77] 63
Smoking and alcohol 1/7 0/3 1.50 [0.08, 29.15] 63

CI: confidence interval, ITT: intention to treat, RR: relative risk, 6MWT: six-minute walk test.

 Certainty of evidence

The GRADE assessments of the quality of evidence for the meta-analysis outcomes for postoperative complications and length of stay are summarized in Table 4, including descriptions for downgrading the quality of the evidence.

Summary of findings.
SNAP prehabilitation compared to treatment as usual in adult patients undergoing surgery
Patient or population: Adult surgical patients Setting: Face-to-face interventions Intervention: SNAP prehabilitation Comparison: Treatment as usual
Outcomes Anticipated absolute effects * (95% CI) Relative effect (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Comments
Risk with treatment as usual Risk with SNAP prehabilitation
Postoperative complications 483 per 1.000 381 per 1.000 (198 to 729) RR 0.79 (0.41 to 1.51) 120 (2 RCTs) ⨁⨁◯◯ Low a , b , c
Length of Stay (LoS) follow-up: mean 30 days MD 1.6 days lower (5.75 lower to 2.55 higher) - 120 (2 RCTs) ⨁◯◯◯ Very low c , d
Readmission 30 days 91 per 1.000 36 per 1.000 (7 to 179) RR 0.40 (0.08 to 1.97) 110 (1 RCT) -
Readmissions 90 days 1.000 per 1.000 710 per 1.000 (450 to 1.000) RR 0.71 (0.45 to 1.14) 9 (1 RCT) -

The individual successful SNAP-factor risk reductions were only reported in one study each.

The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MD: mean difference; RR: relative risk; SNAP: smoking, nutrition (overweight/obesity and malnutrition), alcohol, physical inactivity.

GRADE Working Group grades of evidence.

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Explanations.

Moderate statistical heterogeneity assessed as no serious inconsistency.

Downgraded for indirectness. Different SNAP-interventions being compared.

Downgraded for imprecision. Few patients and the confidence interval encompass both benefit and harm.

Downgraded for inconsistency. Substantial statistical heterogeneity.

 Discussion

Surprisingly, this systematic review identified only two randomized trials of prehabilitation before surgery targeting two or more co-existing and predefined risky SNAP factors (like physical activity below four hours per week and daily smoking) compared to treatment as usual or no treatment. More than 20 randomized trials on multimodal SNAP factor prehabilitation has been published and all but two had only one or no predefined risky SNAP factor as inclusion criteria. The lack of preidentified risk factors may result in populations with mixed needs for prehabilitation, thus, offering prehabilitation to both patients with and without risky SNAP factors thereby with or without a need for prehabilitation. We found no significant effect on postoperative complications in the two included studies.

The large majority of RCTs evaluating combined interventions mainly involved physical training and nutritional support, but they did not deliver the prehabilitation based on specified risky SNAP factors presented in the inclusion criteria ( Table 2). This contrasts with other prehabilitation programmes, e.g., to quit smoking and alcohol prior to surgery, which would not be offered to persons without risky alcohol or tobacco use.

Most of the excluded studies recruited participants on the basis of diagnosis or type of surgery rather than identified individual needs for prehabilitation. 65 – 80 Another six studies on combined interventions included participants based on only one predefined risky SNAP factor; overweight 81 – 83 or limited physical activity, function, or sedentary lifestyle. 84 – 86 In the 22 excluded studies, there seems to be a discrepancy between the patients’ needs for prehabilitation and the programmes delivered. This may explain the inconsistency in impact on postoperative complications.

Frailty is a medical syndrome characterized by “diminished strength, endurance, and reduced physiologic function”, 87 which leaves the individual with decreased tolerance of stressors and vulnerable to adverse outcomes. 88 Numerous screening tools exist, however, we have only included randomized trials using tools that include two or more of the predefined risk factors of relevance for this systematic review e.g. the Fried Frailty Index, 64 which involves weight loss and reduced physical activity in addition to muscular weakness, slow walking, and exhaustion. 42 The Fried Frailty Index is used in the included study by Carli et al. 62 and this frailty diagnosis is closely related to the development of postoperative complications. 42 However, the evidence from RCTs of frailty intervention is sparse, 89 , 90 but studies are ongoing. 91 , 92

The included randomized trial on intervention for co-existing risky alcohol and tobacco use prior to major surgery is based on the major risk reducing effect on the separate preoperative intensive smoking or alcohol intervention. 12 , 32 , 33 It is only a minor subgroup from a larger study, but we have not been able to identify other studies of combined intervention for these risk factors. However, studies on non-surgical patients have shown successful quitting with the combined intervention, thereby indicating that this could be successful in relation to surgery. 93

A strength in this review is the substantial search of electronic databases using a highly sensitive search strategy developed in consultation with an information specialist. Another strength is that we only included studies where participants were selected and offered interventions based on five predefined risk factors associated with increased risk of postoperative complications, specifically according to the individual patient’s risk profile. One may consider the inclusion of any type of surgery as a weakness, however, several of the risky SNAP factors have been shown to increase complication rates with around 50% across different kinds of surgery. 11 , 13 , 16

The limited number and the small size of the included studies are weaknesses. Especially, the combined alcohol and smoking cessation intervention constitutes a very small sub-group with unequal allocation to intervention- and control group despite of stratification, probably due to recruitment from five centres. 63 The other included study evaluated frailty intervention based on Fried Frailty Index with five parameters in total. However, it is not clear to which degree the two SNAP factors weight loss and low physical activity were present in the included participants. 62 None of the two included studies intervened or reported outcomes on all the risky SNAP factors identified in baseline data. The biases above further impact the limitation of this review. In addition, both studies were conducted on patient groups with specific cancers in Western high-income countries (Canada and Denmark). Therefore, the results must be interpreted with caution, and the generalisation should be carefully considered.

Prehabilitation aiming at combined risky SNAP factors seems to have potential to abate postoperative complications, and probably long-term health. This untapped potential has not been defined yet, which may have impact for the individual patients and their families as they will continue suffering from potentially avoidable complications after surgery.

Complications are also resource consuming, adding to the workload of the health professionals, the economic burden on the healthcare system and the society at large. Furthermore, offering effective interventions only to those in need of risk reduction will lessen the socio-economic expenses of prehabilitation.

Conduction of high-quality large-scale studies on combined interventions targeting individual co-existing and predefined risky SNAP factors are strongly requested. The combined intervention programmes should build upon the individual patient needs from preoperatively identified SNAP factors and establish new evidence regarding impact on surgical outcome at short term and health on longer term.

 Conclusion

This review only identified two small trials that did not demonstrate statistically significant effects on postoperative complications after prehabilitation targeting co-existing and predefined risky SNAP factors. There is a lack of randomised trials evaluating the effect of individualised, combined prehabilitation programmes delivered in accordance with individual patients’ preoperative risky SNAP factors. While the meta-analysis did not demonstrate statistically significant effects on postoperative complications in this context, the study underscores the importance of involving patient needs in future research and evidence-based strategies to optimize surgical outcomes.

 Author contributions

The corresponding author attests that all listed authors meet the ICMJE authorship criteria and that no others meeting the criteria have been omitted.

Reporting Guidelines

We have used the repository Open Science Framework for the PRISMA checklist and flowchart. The name of the project is ‘Impact on postoperative complications of combined prehabilitation targeting co-existing smoking, malnutrition, obesity, alcohol drinking, and physical activity: a systematic review and meta-analysis of randomised trials’. https://doi.org/10.17605/OSF.IO/RKAVF

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).

 Ethics and consent statement

Ethics and consent not required.

 Software availability statement

We used Review Manager 5.4® (RevMan [Computer program]. Version 5.4. The Cochrane Collaboration, 2020). for the meta-analysis. Review Manager 5.4® is no longer available for download, but a web version can be used with a paid licence. However, an open access alternative is OpenMeta[Analyst].

We used Covidence for the screening of references with a paid institutional license. However, a limited open access alternative is the web tool Rayyan.

 Data availability

We have used the repository Open Science Framework for extended data ( complete search strings) and reporting guidelines (PRISMA checklist and PRISMA flowchart). 98 The name of the project is: Impact on postoperative complications of combined prehabilitation targeting co-existing smoking, malnutrition, obesity, alcohol drinking, and physical inactivity: a systematic review and meta-analysis of randomised trials. https://doi.org/10.17605/OSF.IO/RKAVF https://doi.org/10.17605/OSF.IO/RKAVF.

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).

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BMC Health Serv. Res. 2008;8:209. 18842157 10.1186/1472-6963-8-209 PMC2586633 Gram-Hanssen A : Impact on postoperative complications of combined prehabilitation targeting co-existing smoking, malnutrition, obesity, alcohol drinking, and physical activity: a systematic review and meta-analysis of randomised trials. Open Science Framework. (last accessed 31.05.2024). 10.17605/OSF.IO/RKAVF 10.5256/f1000research.165488.r314669 Reviewer response for version 1 Neumann Tim 1 Referee https://orcid.org/0000-0003-2344-2162 Department of Anaesthesiology and Intensive Care Medicine; Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany

Competing interests: No competing interests were disclosed.

 24 9 2024 Copyright: © 2024 Neumann T 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

Lydom et al. conducted a systematic review and meta-analysis to examine the effect of combined prehabilitation in surgical patients targeting co-existing smoking, malnutrition, obesity, alcohol drinking, and physical inactivity (SNAP) on postoperative complications ≤30 days. Complications after surgery are highly relevant for patients as well as for the health system. Any reduction of complications is important. Studies addressing single SNAP risks with risk reducing interventions to patients undergoing operations have shown some benefit.

It is unclear how two (!) or more interventions combined work for patients having two or more risk factor in comparison to treatment as usual or no treatment. This is a clinically relevant question for patients with two or more SNAP risk factors. It was of interest to learn from this study, that with this search strategy only two small randomized trials of prehabilitation before surgery targeting two or more co-existing and predefined risky SNAP factors were identified. This research question has not been addressed so far. 

Patients before surgery were frail in one study, and were small subgroup with risky substance use (alcohol and smoking) in the other study. The effect of combined SNAP interventions on postoperative complications was found to be very uncertain.

The following comments may be used to enhance the clarity and usefulness of this publication for the readers of this journal.

Abstract Background, Introduction, Methods: Aim

There is a difference between the aim as stated in Abstract’s Background, the aim as stated at the end of Introduction, and the aim as outlined by the search strategy.

The “combined prehabilitation” is mentioned in the aim in the introduction chapter, not in the Abstract Background, (here: “…prehabilitation targeting predefined co-existing risky lifestyle factors with usual preoperative routines in surgical patients”), whereas in the eligibility criteria it is phrased “at least two of the five predefined risky SNAP factors” and “combined intervention initiated preoperatively”. It would be helpful, if the aim is stated identical at all places.

Introduction: Devising the research question

The rationale for comparing clinical pathways with interventions for patients with two or more factor and excluding those with only one SNAP risk factor might be better explained. Every patient with a defined risk should receive the appropriate intervention. Prehabilitation measures should be offered from a clinician’s point of view according to the patient needs and regardless of the number SNAP risks, and if provided, as intensive as needed. This systematic review addresses the clinical situation in which one needs the evidence that an offer of a combined intervention (regardless of SNAP risk combination) for those surgical patients only with 2 or more risk factors works better than treatment as usual (TAU). In this systematic review, studies reporting complications of one single SNAP factor only with one tailored intervention only were not considered and excluded from analysis. It is unclear why and whether two different interventions should work differently, when offered simultaneously. This might be discussed.

Method:

Data synthesis and statistical analysis data extraction and meta-analytical procedures were done extensively and excellent along the Cochrane Collaboration guidelines, although the number of studies (n = 2) and included patients N = 103) was small.

Method/Results:

The method of Risk Ratio Mantel-Haenszel random-effects method Figure 2 should be explained in the method section:  The RR calculation in in the Table 2 Forest plot with postoperative complications within 30 days in the Lauridsen et al (2022) study should be explained, as (3/7)/(3/3)=0.42.

In the figure legends of the tables all abbreviations should be explained.

Results, Table 1:

On missing word “end” in Table 1: “Lauridsen 2022 Successful risk reduction at the end of intervention”

Discussion: Future research strategies

It was called for conducting high-quality large-scale studies, especially RCTs on combined interventions targeting individual co-existing and predefined risky SNAP factors. Will the findings of this SR be helpful devising future research? How would one take such results into account when devising the research question? It was also stated that “the combined intervention programs should build upon the individual patient needs from preoperatively identified SNAP factors and establish new evidence regarding impact on surgical outcome at short term and health on longer term”.

Before an ethical RCT a prior probability about roughly 50:50 is assumed that the intervention works better. How TAU should be defined? It would be of interest, how the authors would suggest a study design, especially the TAU control condition after this systematic review and in the light of the evidence about single interventions. In the times of ERAS pathways, the TAU is not the same anymore as it was when SNAP risks were followed by a general 50% increased complication rate. How would one integrate existing and developing ERAS concepts into high-quality large-scale studies? How would one deal with the narrowing effect of intervention gap (Lauridsen et al. 2022) when designing this study?  Considering the variety of ERAS recommendations with outcome relevance, including the recommendation to address the SNAP risks, one must consider the intensity of each intervention, the reach into target population, the possible efficacy, effectiveness and efficiency, the staff’s adoption, settings, systems and communities variables, implementation consistency, costs and adaptions made during delivery, and maintenance/sustainment of intervention effects in individuals and settings over time. Very complex.

When calculating sample size for future studies, would it be helpful to consider the findings of this review?

Discussion: Socio-economic expenses of prehabilitation: only to those in need?

It was stated in the conclusion that this study underscored the importance of involving patient needs in future research and evidence-based strategies to optimize surgical outcomes. It was also stated in the discussion, that “offering effective interventions only to those in need of risk reduction will lessen the socio-economic expenses of prehabilitation”. Is this a conclusion from the findings of the study? Is this meant as a general statement, and /or is it based on previous findings, such as the studies in the reference list “65–80” as mentioned on page 13: “Most of the excluded studies recruited participants on the basis of diagnosis or type of surgery rather than identified individual needs for prehabilitations 65–80”? However, one has to keep in mind that in these studies the concept was to increase the functional capacity together with an evidence-based design to reduce perioperative stress and maintain physiological function and accelerate recovery after surgery and reduce complications. Activating patients in special holistic programs may also have other potential benefits.

This should be to the benefit of all patients, regardless of whether individual risks exist.  Clarification is recommended.

Conclusion, last sentence:

The importance of involving patient needs in future research and evidence-based strategies to optimize surgical outcomes is generally recognized. It does not become entirely clear how this study specifically underscores this.

Discussion:

The limited number and the small size of the included studies is not a weakness, but an important finding: Research has not addressed this research question yet.

Minor-

Introduction:

The authors called for risk reduction through targeted combined prehabilitation. This sentence might exclude those with a single SNAP risk in the context of this paper, which is most likely not intended by the authors. Rewording should be considered.

Method:

Concerning the outcome variable “overweight” or “obesity”: To become non-overweight, non-obese can take very long, even when weight loss was achieved,  the patient would be still scored to be at risk. Not being at risk due to is difficult to achieve in severely obese patients, even when an intervention is effective, as weight reduction might take more time.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly

Is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.

If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Yes

Are sufficient details of the methods and analysis provided to allow replication by others?

Yes

Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Reviewer Expertise:

perioperative medicine, health promotion, substance use and addiction medicine

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Lydom Line The Parker institute, Not Applicable, Frederiksberg, Denmark

Competing interests: No competing interests were disclosed.

 2 4 2025

Dear Reviewer

Thank you very much for the peer-review and the valuable comments. We have addressed them one by one below. Changes in and additions to the article manuscript have been written in italics and marked changes to the text are underscored in the response sections below.

We have uploaded an up-to-date version of the article including the changes below and including track changes:

1.

Abstract Background, Introduction, Methods: Aim

There is a difference between the aim as stated in Abstract’s Background, the aim as stated at the end of Introduction, and the aim as outlined by the search strategy.

The “combined prehabilitation” is mentioned in the aim in the introduction chapter, not in the Abstract Background, (here: “…prehabilitation targeting predefined co-existing risky lifestyle factors with usual preoperative routines in surgical patients”), whereas in the eligibility criteria it is phrased “at least two of the five predefined risky SNAP factors” and “combined intervention initiated preoperatively”. It would be helpful, if the aim is stated identical at all places.

Response:

 Thank you for noticing the differences. We appreciate your attentiveness as it of course is much clearer if the aim is stated identically at all places. Therefore, we have changed the aim in the abstract and at the end of the introduction section so that they are identical and include the terms “combined prehabilitation”, “predefined co-existing risky SNAP factors”, and “usual preoperative routines”.

The aim is now stated both places as:

This study aimed to compare the effect on postoperative complications of combined prehabilitation targeting predefined co-existing risky SNAP factors with usual preoperative routines in surgical patients.

The hypothesis at the end of the introduction section has also been revised so it uses the same terms:

We hypothesised the combined prehabilitation based on predefined co-existing risky SNAP factors would reduce the postoperative complications compared to usual preoperative routines.

We have also revised the eligibility criteria in the methods section, as recommended, so they contain the exact same terms for clarity:

We included randomised controlled trials enrolling populations of adult patients (≥18 years) undergoing any surgical intervention and having predefined co-existing risky SNAP factors, defined as at least two of the five risky SNAP factors (daily smoking, alcohol intake > 2 drinks daily (= above 24 g ethanol) or 14 drinks weekly, malnutrition (defined as either weight loss of 10-15% within the last 6 months, BMI < 18.5, Subjective Global Assessment (SGA) Grade C, Nutritional Risk Screening (NRS) > 5, or preoperative serum albumin < 30 g/l), BMI > 25 and physical activity < 4 hours/week), or as described by the authors and receiving a combined prehabilitation initiated preoperatively and targeting those lifestyles.

2.

Introduction: Devising the research question

The rationale for comparing clinical pathways with interventions for patients with two or more factor and excluding those with only one SNAP risk factor might be better explained. Every patient with a defined risk should receive the appropriate intervention. Prehabilitation measures should be offered from a clinician’s point of view according to the patient needs and regardless of the number SNAP risks, and if provided, as intensive as needed. This systematic review addresses the clinical situation in which one needs the evidence that an offer of a combined intervention (regardless of SNAP risk combination) for those surgical patients only with 2 or more risk factors works better than treatment as usual (TAU). In this systematic review, studies reporting complications of one single SNAP factor only with one tailored intervention only were not considered and excluded from analysis. It is unclear why and whether two different interventions should work differently, when offered simultaneously. This might be discussed.

Response:

Thank you for the comments and reflections. We agree that patients with an identified need should receive prehabilitation regardless of the number of SNAP factors they have and that it should be offered as intensive as needed. The effect of several of the single snap factor interventions have been investigated previously in systematic reviews or addressed in guidelines referencing existing studies (reference 13, 32, 33 in the review). Furthermore, many patients are now living with more than one SNAP factor which seems to potentiate the risk of complications after surgery. For example, a study by Park et al. found that the combination of being obese and smoking at the same time potentiated the risk of complications after surgery. Therefore, we have chosen that the focus of this review would be to investigate the effect of combined prehabilitation targeting preidentified co-existing risky SNAP factors. Also, we expected many studies investigating combined prehabilitation interventions to have an eligibility criterion of the SNAP factors being intervened on to be preidentified in their population. Therefore, we were very surprised to find only two studies. In retrospect, it would have been interesting to include studies on single SNAP interventions to see if these studies targeted predefined SNAP factors and the effect of the interventions or if they were conducted on mixed populations SNAP-wise. Unfortunately, this is not within the scope of this review and not possible to add due to the search string but it would be very interesting to investigate in a future systematic or scoping review.

To make the rationale and our chosen scope of this review clearer we have added the following elaboration of the potentiated effect of two risky SNAP factors in the introduction just before the aim section:

This is despite of up to half of hospital patients have co-existing SNAP factors, 39 – 41 such as smoking and overweight or frailty involving both malnutrition and physical inactivity which significantly potentiate the risk at surgery. 14 , 42 For example Park et al. found that the combination of being obese and smoking at the same time potentiated the risk of complications after surgery. 14 As the risk of the two risk factors in combination seems to potentiate each other, it points even more towards the relevance of investigating the effect of combined prehabilitation.

3.

Method:

Data synthesis and statistical analysis data extraction and meta-analytical procedures were done extensively and excellent along the Cochrane Collaboration guidelines, although the number of studies (n = 2) and included patients N = 103) was small.

Method/Results:

The method of Risk Ratio Mantel-Haenszel random-effects method Figure 2 should be explained in the method section:  The RR calculation in in the Table 2 Forest plot with postoperative com-plications within 30 days in the Lauridsen et al (2022) study should be explained, as (3/7)/(3/3)=0.42.

Response:

The reviewer raises a valid point regarding the need for a clearer explanation of the risk ratio (RR) calculation in the Mantel-Haenszel random-effects method and its application in Figure 2.

We understand that the manually calculated RR for the smaller study is approximately 0.43, based on the crude event rates (3/7 vs. 3/3). However, the RR reported in our meta-analysis (0.5) was derived using the Mantel-Haenszel method with random effects, as implemented in RevMan. This incorporates a correction that results in slight differences between manually calculated crude RRs and those derived via meta-analytic methods, particularly in small or sparse datasets, where the RR is reduced. Overall, the larger dataset, the closer to the crude rate (and the smaller confidence interval). E.g., the Lauridsen Study: RR = 0.50 [0.21, 1.19], a hypothetic 10 times larger study with similar results: 0.44 [0.33, 0.57] or 100 times larger: 0.44 [0.33, 0.57]. Therefore, the discrepancy between the manual RR (0.43) and the RevMan-reported RR (0.5) arises due to differences in calculation approach.

We have now updated the data synthesis and statistical analysis subsection in the methods section so it includes the description of the reason for and the use of the modified Mantel-Haenszel random-effects method for meta-analysis:

A meta-analysis for the relative risks of postoperative complications as well as for the secondary outcomes was conducted based on a random-effects model (modified Mantel-Haenszel) 56 and the results presented in Forest plots. The random-effects model was chosen beforehand, as we planned to include different types of surgical procedures and different types of interventions targeting two or more predefined risky SNAP factors; thus, this systematic review would not fulfil the criteria for using the fixed model for the meta-analysis.

Furthermore, we have rearranged the order of the text sections in this subsection.

4.

In the figure legends of the tables all abbreviations should be explained.

Response:

Thank you for the comment. We can see that in the online version the table legends have disappeared. They are present when the article is downloaded as a pdf format. When we downloaded the article as a DOC-file, the table legends with explanations of the abbreviations disappeared again. We can see how it is confusing.

We have reviewed all legends for the figures and tables and made sure all abbreviations are explained in the legends. In the new updated article we have added all explanations of the abbreviations again.

5.

Results, Table 1:

On missing word “end” in Table 1: “Lauridsen 2022 Successful risk reduction at the end of intervention”

Response:

Thank you very much for noticing the missing word. We believe it is in Figure 1 were we can see that you are right that it is missing. We have added “end” to “Lauridsen 2022 Successful risk reduction at the end of intervention” in Figure 1.

6.

Discussion: Future research strategies

It was called for conducting high-quality large-scale studies, especially RCTs on combined interventions targeting individual co-existing and predefined risky SNAP factors. Will the findings of this SR be helpful devising future research? How would one take such results into account when devising the research question? It was also stated that “the combined intervention programs should build upon the individual patient needs from preoperatively identified SNAP factors and establish new evidence regarding impact on surgical outcome at short term and health on longer term”.

Response:

Thank you for the valuable reflections and these questions. We believe that the findings of this review highlight the need for considering including predefined risk factors in the research question and the inclusion criteria in future research and we have added this reflection at the end of the discussion section (including small revisions of the text already there):

The findings of this review show a lack of studies providing combined prehabilitation based on patient needs present in the study population. Therefore , conduction of high-quality large-scale studies on combined prehabilitation targeting co-existing and predefined risky SNAP factors are strongly requested. The combined prehabilitation should build upon the individual patient’s needs from preoperatively identified SNAP factors to establish new evidence regarding impact on surgical outcome at short term and health on longer term. Future research should consider explicitly including a demand of predefined risk factors in the research question and in the inclusion criteria, ensuring that interventions are targeted to co-existing risky SNAP factors.

7.

Before an ethical RCT a prior probability about roughly 50:50 is assumed that the intervention works better. How TAU should be defined? It would be of interest, how the authors would suggest a study design, especially the TAU control condition after this systematic review and in the light of the evidence about single interventions. In the times of ERAS pathways, the TAU is not the same anymore as it was when SNAP risks were followed by a general 50% increased complication rate. How would one integrate existing and developing ERAS concepts into high-quality large-scale studies?

Response:

We agree that the ethical perspective is important. While there is some evidence for the superiority of prehabilitation targeting some of the single risky SNAP factors, uncertainty still exist whether combined prehabilitation targeting co-existing SNAP factors will provide superior benefits. A study using standard care as it is structured at the specific institution ensures that no harm is done to the TAU group by withholding care compared to not participating in the study. The TAU group should, therefore, be allowed to receive potential SNAP interventions if it is part of the standard care at the institution so that they do not receive worse care than if not participating in the study.

We have added the following reflections on how the TAU group should be defined at the end of the discussion section:

When designing the studies, researchers need to take into account the varying levels of implementation of ERAS that may add to narrowing the gap of the effect of the interventions. The standard care and ERAS components implemented vary across institutions, surgical specialties, and procedures. 4 This makes it complex to estimate the actual intervention effect and compare effects properly across studies. TAU should align with the standard care provided at the specific institution and for the relevant procedure to ensure that the TAU group does not receive inferior care compared to patients not participating in the studies. As a result, the definitions of TAU groups will vary between studies, highlighting the need for a detailed description of TAU content including specifying adherence to ERAS guidelines and the intensity of potential SNAP interventions. Additionally, the content of the intervention group including the intensity of the interventions should be described with equal detail. The thorough description and transparency is essential for enabling meaningful future meta-analyses.

8.

How would one deal with the narrowing effect of intervention gap (Lauridsen et al. 2022) when designing this study?  Considering the variety of ERAS recommendations with outcome relevance, including the recommendation to address the SNAP risks, one must consider the intensity of each intervention, the reach into target population, the possible efficacy, effectiveness and efficiency, the staff’s adoption, settings, systems and communities variables, implementation consistency, costs and adaptions made during delivery, and maintenance/sustainment of intervention effects in individuals and settings over time. Very complex.

Response:

We agree that it is very complex, and that the intervention gap is narrowing. There are increasing things to consider and include when designing a future study including all the mentioned above. This is why it is imperative to report the abovementioned aspects in detail in study reports for transparency and so other researchers can evaluate the use of the results properly. We have tried to address this in the additions mentioned in the response to comment number 7. Furthermore, we have added the following in continuation of the additions described in response 7:

Furthermore, due to the complexity alternative statistical methods such as Bayesian metrics could be relevant to consider as they can provide a more nuanced understanding of intervention effectiveness beyond traditional p-values (new reference: Seretny 2022).

9.

When calculating sample size for future studies, would it be helpful to consider the findings of this review?

Response:

Thank you for the relevant comments asking how to use the findings of this systematic review. Since we only found two small RCTs to include and the effect of the meta-analysis  was deemed very uncertain, this review does not offer an adequate foundation for calculating sample size for future multimodal prehabilitation studies. Until further evidence becomes available, sample size calculations should still be guided by estimated effects derived from single-modality studies investigating prehabilitation targeting preidentified risk factors and be approached with caution and conservatism.

10.

Discussion: Socio-economic expenses of prehabilitation: only to those in need?

It was stated in the conclusion that this study underscored the importance of involving patient needs in future research and evidence-based strategies to optimize surgical outcomes. It was also stated in the discussion, that “offering effective interventions only to those in need of risk reduction will lessen the socio-economic expenses of prehabilitation”. Is this a conclusion from the findings of the study? Is this meant as a general statement, and /or is it based on previous findings, such as the studies in the reference list “65–80” as mentioned on page 13: “Most of the excluded studies recruited participants on the basis of diagnosis or type of surgery rather than identified individual needs for prehabilitations65–80”? However, one has to keep in mind that in these studies the concept was to increase the functional capacity together with an evidence-based design to reduce perioperative stress and maintain physiological function and accelerate recovery after surgery and reduce complications. Activating patients in special holistic programs may also have other potential benefits.

This should be to the benefit of all patients, regardless of whether individual risks exist.  Clarification is recommended.

Response:

We agree that holistic programs may offer other potential benefits beyond reducing complications. Patients without risky SNAP factors may still benefit from training or nutritional interventions to, probably, a lesser degree or in areas other than reducing the risk of complications. However, economic resources are often limited, making it important to identify which patients would benefit the most from prehabilitation and to understand the effects of SNAP interventions specifically in these patients, rather than in a mixed population of patients with and without high-risk SNAP factors. The phrase “offering effective interventions only to those in need of risk reduction will lessen the socio-economic expenses of prehabilitation” is intended as a general statement about the possibility of prioritizing resources for those who would derive the greatest benefit from the intervention. It is not directly a finding from our study. We have tried to clarify this by making the following revisions in the discussion section:

Complications are also resource consuming, 7 adding to the workload of the health professionals, the economic burden on the healthcare system, and the society at large. Economic resources often are limited. As those with risky SNAP have an increased risk of complications compared to those without risky SNAP factors, 11 – 19 it seems plausible that prioritizing SNAP prehabilitation to those with risky SNAP factors would likely derive the greatest benefit in terms of reduced postoperative complications. However, as this review shows, the effect of combined prehabilitation in patients with risky SNAP factors is still very uncertain. In the future, when more evidence is available, prioritizing those with the greatest benefit could potentially be relevant to minimize the socioeconomic costs of prehabilitation.

11.

Conclusion, last sentence:

The importance of involving patient needs in future research and evidence-based strategies to optimize surgical outcomes is generally recognized. It does not become entirely clear how this study specifically underscores this.

Response:

Thank you for pointing this out. We agree that maybe the phrasing is a bit wrong. The study does not directly underscore the importance but rather show a lack of studies where prehabilitation is offered based on present risk factors in the population. This is needed to assess the effect of the interventions on patients who have the given risky SNAP factors. To make this clearer, we have revised the end of the conclusion:

The meta-analysis did not demonstrate statistically significant effects on postoperative complications in this context. However, the study underscores the need for more prehabilitation studies with interventions targeting preidentified risky SNAP factors in order to assess the true effect on postoperative complications.

12.

Discussion:

The limited number and the small size of the included studies is not a weakness, but an important finding: Research has not addressed this research question yet.

Response:

Thank you for the comment. We agree that the limited number and small population size is not a weakness of the study in general, but more a weakness related to being able to estimate the effect of combined prehabilitation in this review.

We have changed the phrasing to the following:

The limited number and the small size of the included studies provided a weak foundation for estimating the effect of combined prehabilitation. 

Furthermore, we have made an addition to the conclusion to highlight the surprising finding of a lack of studies evaluating combined prehabilitation targeting predefined risky lifestyles:

This review only identified two small trials that did not demonstrate statistically significant effects on postoperative complications after prehabilitation targeting co-existing and predefined risky SNAP factors. Although surprising, this important finding highlights the lack of randomised trials evaluating the effect of individualised, combined prehabilitation programmes delivered in accordance with individual patients’ preoperative risky SNAP factors. The meta-analysis did not demonstrate statistically significant effects on postoperative complications in this context. However, the study underscores the need for more prehabilitation studies with interventions targeting preidentified risky SNAP factors in order to assess the true effect on postoperative complications.

13.

Minor-

Introduction:

The authors called for risk reduction through targeted combined prehabilitation. This sentence might exclude those with a single SNAP risk in the context of this paper, which is most likely not intended by the authors. Rewording should be considered.

Response:

Thank you for this remark. In a clinical context, we agree that prehabilitation should include those patients living with a single risky SNAP factor. We believe that prehabilitation should target all risky SNAP factors the patient has, not just one if they have more. Therefore, we believed the effect of combined prehabilitation to be worth investigating in this paper and chose to exclude studies only intervening on 1 SNAP factor. We have rephrased the sentence as part of the changes made in regard to comment 2.

14.

Method:

Concerning the outcome variable “overweight” or “obesity”: To become non-overweight, non-obese can take very long, even when weight loss was achieved, the patient would be still scored to be at risk. Not being at risk due to is difficult to achieve in severely obese patients, even when an intervention is effective, as weight reduction might take more time.

Response:

We agree and fully acknowledge that achieving a non-overweight or non-obese status can take considerable time and may not be feasible for all patients with severe obesity during the prehabilitation period. Consequently, this outcome is likely to reflect the effects of the interventions primarily on individuals not too far from the thresholds of being overweight or obese depending on the length of prehabilitation. As a result, the observed effects may substantially underestimate the true impact of the weight-loss interventions. To better capture the benefits of these interventions for individuals who are unlikely to completely abandon their unhealthy lifestyles, we also included a secondary outcome focused on any positive change in lifestyle. However, for future studies, it would probably be beneficial to revise and refine this outcome to assess improvements more effectively in risky lifestyle behaviors.

If some of the included studies had included a weight-loss intervention, the design of the outcome could have been identified as a limitation in the discussion section. However, since neither of the two included studies examined weight-loss interventions, we do not believe this point would add significant value to the paper. Therefore, we have not addressed it in the manuscript.