Pathophysiology of surgical stress and the rationale for prehabilitation

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1 Improving Surgical Outcomes with Multimodal Prehabilitation in Colorectal Cancer Patients Pathophysiology of surgical stress and the rationale for prehabilitation Francesco Carli McGill University Montreal, Canada Canadian Nutrition Society, Winnipeg, May 2015

2 Disclosure President of Peri-Operative Program (POP) Charitable Foundation

3 Objectives Review the pathophysiology of stress induced by surgery and cancer Discuss the risk factors leading to postoperative complications Introduce the concept of surgical prehabilitation Review some of the preliminary work available

4 SURGICAL STRESS Il-1a, TNF-a, IL-6

5 What about cancer and metabolism? Cancer cells display metabolic changes to meet high energy demand Increased dependence on sugars for energy production, and other substrates such as proteins with high turnover Higher the reliance of tumors on energy metabolism, higher its aggressiveness

6 High rate of postoperative morbidity after elective abdominal surgery Schilling et al. JACS 2008

7 High rate of postoperative morbidity after elective abdominal surgery 5 years later Lucas DJ, Surgery, 2013, Dec 6,076 resections for esophageal, gastric, pancreatic, hepatobiliary, and colorectal cancers at 316 hospitals from the 2006 to 2011 ACS NSQIP 3% esophagectomy, 5% gastrectomy, 16% pancreatectomy, 4% hepatectomy, 63% colectomy, and 9% proctectomy 21-45% of patients experienced a postoperative complication and % died. The incidence of patients with any complication 24%

8 Risk factors for prolonged recovery preop physical performance, along with serious postop complications and worse depressive status, predict recovery of IADL after major abdominal surgery in elderly Odds ratio 95% CI p value Serious complication Physical performance status* Geriatric Depression Scale Folstein Mini-Mental State Creatinine>133 umol/l Albumin <30 g/l CHF on CXR Male Age,y *score combining Timed Up and Go, Functional Reach, and Hand Grip Strength using Components Analysis Lawrence et al, JACS, 2004

9 Factors that predict complications: - Age >75 y - BMI >25 - COPD - ETOH - Duration of surgery

10 ACS risk calculator: 15 variables predicting higher risk Not Modifiable ASA III/IV Sepsis Indication for surgery Disseminated cancer Extent of surgery Emergent Age >65 Creatinine COPD Wound class PTT >35 Potentially Modifiable Functional health status BMI Dyspnea Albumin 35 Cohen, Bilimoria, Ko, Hall. JACS 2009

11 Preoperative nutritional state elective abdominal surgery, n=1085 Nutritional Risk Screening > * p =0.008 * Preoperative Nutrition * p=0.008 No Preoperative Nutrition No complications Complications Bin J. et al Nutrition 28 (2012)

12 Who are these people at risk? Elderly Frail Poor nutritional status With comorbidities Obese, metabolic syndrome Sedentary Cancer Depressed Anemic limited physiological reserve

13 What do we do now for our surgical patients? Functional reserve Pre-existing Medical Conditions Functional Capacity Psychological Status Pharmacological/ Procedural interventions Nutritional Physical Mental

14 Trajectory of functional ability throughout the surgical process Carli F, Zavorsly G 2005, Level of Functional ability Prehabilitation phase Surgical Procedure Rehabilitation phase Post rehabilitation phase Prehab patient Non-prehab patient

15 What and why prehabilitation? To use the preoperative time: + to optimize the physical, nutritional, emotional, medical and pharmacological conditions With the intent to: + improve postoperative functional capacity + impact on perioperative medical and surgical morbidity

Moderate-poor methodological quality Majority found improved postop: Pain, LOS, physical function Equivocal benefits

17 Systematic Review & Meta-Analysis of Systemic Prehabilitation Inclusion criteria: Total body MSK + aerobic exercise & postop outcomes Results: K=21 (17 RCTs); median sample n=54 13 orthopaedic, 1 abdominal, 3 cardiac Moderate-poor methodological quality Majority found improved postop: Pain, LOS, physical function Equivocal benefits to: Aerobic fitness, complications & QOL Adverse event in 2/669 prehab patients Length of Stay (Santa Mina et al, 2014, Physiotherapy)

18 Our McGill experience

19 Pilot data on the impact of intense exercise on VO 2 max n=28 (13 prehab, 15 controls) colorectal surgery, low fitness, 55 yrs old; BMI 26 kg/m 2 Home based, 7x per week, 45-65% HRR, bike 4 weeks Exercise compliance days 71(23)% (range 33-90%) 4 weeks prehabilitation: 15% increase in VO 2max (L/min) 18% increase in VE max (L/min) 9% increase in peak power (W) No changes in controls Kim DJ, 2009;217(2):

20 Timeline: our previous prehab studies RCT Intense exercise vs. walking & breathing 2010 Pilot prehab vs.historical RCT Prehab vs. rehab control RCT Prehab Nutrition Carli, F et al.bjs.2010; Li et al. Surg Endosco. 2012; Gillis C et al. Anesthesiology.2014

21 Functional walking capacity is a reliable outcome measure of recovery Six-Minute Walk Test Objective,Reproducible Essential to everyday activities Integrates balance, speed, endurance Validated measure of surgical recovery Cheap, no equipment needed. Minimal important difference = 20 meters the smallest change in an outcome measure perceived as beneficial by patients undergoing colorectal surgery Predicted 6MWT = 868 (age x 2.9) (female x 74.7)

22 Average change in Meters Impact of Pre-operative Change in Physical Function on Surgical Recovery after Colorectal Surgery Mayo N, Feldman L, Carli F, Surgery, 2011 Improved No Change Deteriorated Baseline Pre-surg 9 weeks Prehabilitation Phase High rate of serious complications 18% vs 2%

23 Message = Intense exercise is not enough Despite exercise, 1/3 of patients deteriorated while waiting for surgery and only 40% of patients recovered to baseline 10 weeks postop Patients in the walk/breathing group did better than the biking group- Why did this happen? Poor Compliance / too intense Anxiety & depression in 20% Lack of social support Lack of continuity to postop period No nutritional intervention Lack of Enhanced Recovery Program

24 Multimodal Prehabilitation to Increase Functional Reserve Up to 1/3 of patients are at nutrition risk Aerobic and resistance exercise Patients may have mood changes like anxiety / depression while waiting for surgery Whey Protein Supplementation Anxiety Reduction

25 Study Design : trimodal intervention Surgery Prehab (n=39) Multimodal Program Multimodal Program Rehab (n=38) Multimodal Program Baseline Preoperative 4 weeks 8 weeks Multimodal Program: 1) Home based aerobic & resistance exercise program 2) Nutritional counseling with whey-protein supplementation 3) Anxiety reduction exercises

26 Multimodal Prehabilitation vs Rehabilitation: Randomized Controlled Trial Gillis C, Anethesiology, 2014 P<0.01 no prehab, no rehab Surg End 2012

27 Proportion of Change Preoperatively Prehabilitation Chart Title Rehabilitation 15% 50% 35% 54% 23% 23% Above Baseline (>20m) At Baseline (within 20m) Below baseline (< - 20m) p < 0.01

28 Proportion of patients recovered by 8 weeks Prehabilitation Rehabilitation 21% 57% 44% 35% 23% 20% Above Baseline (>20m) At Baseline (within 20m) Below baseline (< - 20m) p < 0.01

Functional walking capacity is a reliable outcome measure of recovery Six-Minute Walk Test Objective,Reproducible Essential to everyday activities Integrates balance, speed, endurance Validated

29 Functional walking capacity is a reliable outcome measure of recovery Six-Minute Walk Test Objective,Reproducible Essential to everyday activities Integrates balance, speed, endurance Validated measure of surgical recovery Cheap, no equipment needed. Minimal important difference = 20 meters the smallest change in an outcome measure perceived as beneficial by patients undergoing colorectal surgery Predicted 6MWT = 868 (age x 2.9) (female x 74.7) <60% of predicted = around 400 m)

30 Distance (m) The elderly with high ASA and low 6MWT have the greatest increase in functional capacity <60% predicted >60%predicted 0 Baseline Before surgery Predicted 6MWD<60% Predicted 6MWD>60% Sample Baseline 6MWD (mean+sd) Age (mean+sd) Preoperative 6MWD (mean+sd) Difference (mean+sd) m y m 47+8 m m y m 25+6 m p value

31 Percentage 80 the gains in 6MWD during prehabilitation continue in the postoperative period (> 20m) * p= n = 40 n = 66 0 Baseline 6MWD < 60% predicted Baseline 6MWD > 60% predicted

32 Percentage 90 Percentage of patients returning to baseline 6MWD at 4 weeks after surgery (within 20m) * p= n = 35 n = 62 Baseline 6MWD < 60% predicted Baseline 6MWD > 60% predicted

6 Minute Walk Test : Patient-Centered Outcome A simple test that measures: force, endurance, balance, activities of daily living, including self care and community mobility A 6MWD of 322 meters is

33 6 Minute Walk Test : Patient-Centered Outcome A simple test that measures: force, endurance, balance, activities of daily living, including self care and community mobility A 6MWD of 322 meters is needed to be able to cross 2 lanes of traffic while green light is flashing (0.8 m/s) A 6MWD of 370 meters is needed to be able to cross 3 lanes of traffic while green light is flashing (1.0 m/s) A 6MWD of > 400 meters is needed to be able to cross 4 lanes of traffic. Criterion for independency and mobility

34 Prehab enhances functional capacity in patients with low reserve 3 Lanes of Traffic 368m; 1.0m/s 2 Lanes of Traffic 322m; 0.8m/s

35 Preliminary findings from our studies 3-4 weeks of preoperative multimodal interventions impact on postoperative functional walking capacity. (PROOF OF CONCEPT) Moderate and vigorous physical activities increase, and lean body mass increases Those with low baseline reserve have the greatest increase in functional capacity Supervised exercise in hospital is feasible and helps patients to recover to baseline at 4 weeks.

Charlebois P, Stein B, Feldman L, Zavorsky G, Kim DJ, Scott S, Mayo NE.

36 %Recovered to baseline functional walking capacity (6MWT ± 20m) at 8-9 weeks Moriello C, Mayo NE, Feldman L, Carli F Arch Phys Med Rehab, 2008 Carli F, Charlebois P, Stein B, Feldman L, Zavorsky G, Kim DJ, Scott S, Mayo NE. BJS, 2010 Li C, Carli F, Liberman S, Charlebois P, Stein B, Kaneva P, Feldman LS, Surg End, 2013

analgesics/ NSAID s ERAS Prevention of ileus/ prokinetics CHO - loading/ no fasting Minimal invasive surgery

37 Peri-op fluid management Epidural Anaesthesia Fast acting anesthtetics Prehabilitation DVT prophylaxis No - premed Pre-op councelling No bowel prep Early mobilisation Perioperative Nutrition Temperature control Oral analgesics/ NSAID s ERAS Prevention of ileus/ prokinetics CHO - loading/ no fasting Minimal invasive surgery No NG tubes Early removal of catheters/drains Fearon et a al 2005, Lassen et al Arch Surg 2009, ERAS Guidelines 2012

38 Thanks to our prehabilitation team: surgeons, internists, oncologists, anesthesiologists, nutritionists, kinesiologists, psychologists, scientists

39 Examine the impact of nutritional status and nutritional interventions on the pre-surgical colorectal population Chelsia Gillis PDt, MSc

40 Nutritional Care for Colorectal Surgery Avoid undernutrition as a consequence of: inadequate food intake metabolic alterations inflammatory response Preoperative Perioperative Postoperative Support anabolism Braga, M et al. Clin Nutr. 2009

41 Nutrition & Colorectal Cancer Inflammatory response: tumour itself or systemic response to the tumour Metabolic alterations: perturbations in glucose metabolism acceleration of skeletal muscle catabolism alterations in amino acid requirements Van Custem E et al. Eur J Oncol Nurs

42 Nutritional Adequacy Before Surgery Karlsson Burden Lohsiriwat Gillis Design Retrospective Prospective Prospective Prospective n Population Assessment tool Colorectal cancer outpatients Colorectal cancer surgery Colorectal cancer surgery Colorectal surgery PG-SGA SGA SGA PG-SGA Well-nourished 58.8 % 64.4% 63% Nutrition Risk 24.7 % 32.2% 29% Severe 16.6 % 3.4% 8% Summary ~1/4 experienced symptoms that prevented adequate food intake 41.3 % at nutritional risk or severely undernourished 35.6 % at nutritional risk or severely undernourished 37 % at nutritional risk or severely undernourished arlsson S et al. Gastroenterology Nursing. 2009; Burden ST et al. J Hum Nutr Diet.2010; Lohsiriwat V. Tech Coloproctol.2014; Gillis C et al. NCP. 2015

CYTOKINES glycerol acute phase proteins GLYCOLYSIS LIPOLYSIS

43 SURGICAL STRESS GLYCOGENOLYSIS GLUCONEOGENESIS lactate pyruvate amino acids [GLUCOSE] COUNTERREGULATORY HORMONES CYTOKINES glycerol acute phase proteins GLYCOLYSIS LIPOLYSIS PROTEOLYSIS Physiologic Reserve Adapted from Slide by Ralph Lattermann

44 Nutritional Adequacy After Surgery Do Colorectal Cancer Patients Eat for Recovery? Our Experience Values (n=40) are presented as means+ standard deviation Gillis C et al. NCP. 2015

45 Nutritional Adequacy After Surgery Do Colorectal Cancer Patients Eat for Recovery? Our Experience Factors Yes (%) No (%) NA(%) I understand how to order the menu Choosing the right food is difficult, there isn t enough information When the food arrives I always want what I ve ordered Values (n=40) are presented as a percentage. Patients completed the food access questionnaire on postoperative day 2 Gillis C et al. NCP. 2015

46 umol/kg/hr Nutrition For Recovery: Amino Acids Colon resection patients (n=16) received infused dextrose only at 50% REE OR dextrose at 50% REE with AA at 20% REE at surgical incision until postop day 2 Postoperative Day 2 vs dextrose (p<0.05) Proteolysis Synthesis Leu Balance Dextrose Dex & AA Schricker T et al. Br J of Surg. 2005

47 Practice Guidelines ESPEN Severely malnourished patients = 7-14 days of preoperative nutrition support ERAS Severely malnourished patients = 7-10 days of preoperative supplementation with oral nutrition supplements Surgical summit consensus The purpose of preoperative nutrition is to prepare (or optimize) the patient for surgery, not necessarily to replace nutrition deficits. Prehabilitation? Braga, M et al. Clin Nutr. 2009; Gustafsson UO et al. Clin Nutr. 2012; McClave S et al. JPEN. 2013

48 INTERVENTION Colorectal cancer Recruitment at colorectal clinic Baseline assessment 4 weeks before surgery Exercise program Aerobic exercise at home 50% of maximal HRR 20min aerobic & resistance exercise 3x/w Nutrition counselling Suppl with whey protein Preoperative assessment SURGERY Stress reduction intervention Reinforce program Anxiety reducing, coping strategies CD for relaxation PREHABILITATION 4 weeks post assessment 8 weeks post assessment

49 Prehabilitation: Nutritional Component At time of consent, patients are instructed to complete a three-day estimated food record of two week days and one weekend day Dietary protein and energy intake are estimated from the food records Food choices evaluated

Prehabilitation: Nutritional Component Nutrition care plans based on: Nutritional requirements Indirect calorimetry Protein at 20% of total

50 Prehabilitation: Nutritional Component Nutrition care plans based on: Nutritional requirements Indirect calorimetry Protein at 20% of total energy expenditure or g protein/kg of ideal body weight Food choices Biological indices Anthropometry Medical history & clinical status

51 Prehabilitation: Nutritional Component Focus on meeting energy and protein requirements Management of cancerrelated symptoms Blood glucose control Optimize body composition Weight loss/gain if necessary Optimize nutrient intake

52 Prehabilitation Supplementation: Whey Protein Rapidly digested Rich in essential AA including leucine Immunomodulating properties Readily available Castellanos, D. et al., Nutr. Clin. 2006; Protein Quality Evaluation, Report of the Joint FAO/WHO Consultation 1991

53 Prehabilitation Supplementation: Whey Protein Supports muscle protein synthesis after exercise

54 Nutrition Prehabilitation Pilot: Study Design Surgery (n=22) Nutritional Counselling + Whey Protein Nutritional Counselling + Whey Protein (n=21) Nutritional Counselling + Placebo Nutritional Counselling + Placebo Baseline Preoperative 4 weeks 8 weeks Median duration: 24.5 [ ] Primary Outcome: Six minute walk test (6MWT)

55 Nutrition Prehabilitation: Patient Characteristics Placebo (n=21) Whey Protein (n=22) Age, years 69.1 (9.4) 67.6 (11.5) Male gender 15 (71%) 13 (59%) BMI at first assessment, kg/m (4.5) 26.6 (5.0) Laparoscopic procedure 15 (75%) 18 (90%) Type of resection Colon 9 (45%) 9 (50%) Rectum 11 (55%) 9(90%) New stoma 4 (21%) 7 (39%) 6-minute walk test, m 440 (89.5) 424 (133) 6-minute walk test, %predicted 67 (14) 63 (18) Data presented as mean (SD), median[iqr] or n(%). No differences observed between groups. Includes right- and left-hemicolectomy and sigmoid resection. Includes anterior resection, low anterior resection, and abdomino-perineal resection.

56 Nutrition Prehabilitation Pilot: Results The change in six minute walk test from baseline to surgery Nutrition Counselling + Placebo Nutrition Counselling + Whey Protein MWT (meters) Antonescu et al. Surgery.2014

Prehabilitation Control Nutrition Prehab 425 393 356 Baseline Preoperative 4

57 6 MWT distance (m) Summary of Evidence: Functional Recovery Change in Functional Trajectory Prehabilitation Control Nutrition Prehab Baseline Preoperative 4 weeks Postop Time of Assessment Li, C et al. Surg Endosco.2012; Gillis C et al. Anesthesiology.2014

58 Summary Nutritional care begins at cancer diagnosis, before surgery, and continues postoperatively. Preliminary evidence suggest that nutrition alone plays an integral role in preparing patients for surgery, and as a component of trimodal prehabilitation. Bottom line: Improvement of modifiable patient risk factors, including nutritional status, can improve functional walking capacity before surgery and may accelerate functional recovery after surgery.

bed! Celena Scheede-Bergdahl, PhD Department of Kinesiology and Physical

59 Improving Surgical Outcomes with Multimodal Prehabilitation in Colorectal Cancer Patients The role of exercise in cancer prehabilitation: bike not bed! Celena Scheede-Bergdahl, PhD Department of Kinesiology and Physical Education Department of Anesthesiology, McGill University

60 Traditional advice You should take it easy You need to rest Sleep is what you need Put your feet up. ACSM Guide to Exercise and Cancer Survivorship, 2011; 50

61 What is wrong with this advice? Although rest is important, sedentary behaviour can become a vicious circle for the cancer patient. The effects of physical inactivity can further impact the patient at a critical time point in their disease trajectory.

62 What we have learned from bed rest studies: Inactivity very quickly results in physical deconditioning and a negative health status.

63 Studies have shown that: 10 days of bed rest results in a diminished muscle mass, muscle strength and physical function in healthy older adults (Cooker RH et al., 2015) 10 days of bed rest results in substantial loss of lower extremity strength, power, and aerobic capacity in healthy older adults (Kortebein P et al., 2008) 9 days of bed rest in young men results in insulin resistance and changes gene expression that negatively affect mitochondrial function, which were only partly normalized after 4 weeks of retraining (Alibegovic AC et al., 2010) 5 days of bed rest results in endothelial dysfunction and elevations in diastolic blood pressure in healthy adults (Vosnova EV et al., 2014) 5 days of bed rest results in 67% decrease in the insulin response to glucose loading in healthy adult subjects (Hamburg NM et al., 2007)

Individuals at risk for developing type 2 diabetes are subject to a disproportionate aggravation of existing systemic low-grade inflammation during periods of physical

64 Individuals at risk for developing type 2 diabetes are subject to a disproportionate aggravation of existing systemic low-grade inflammation during periods of physical inactivity (Højbjerre L et al., 2011). Effects of physical inactivity are critical for surgical process, where inflammation and loss of physical function is already of concern

65 What is the take home message from these studies? As long as the patient is medically cleared and has no contraindication to exercise, we should be encouraging physical activity and not bed rest.

66 So. What can we do?

67 Exercise and the cancer patient People with cancer can safely train and benefit from regular exercise, similarly to those who do not have cancer: Cardiorespiratory fitness Muscular strength and endurance Flexibility Bone health Body composition Well being (reduction in anxiety, improved sleep, increases in energy levels) Improved ability to perform activities of daily living ACSM Guide to Exercise and Cancer Survivorship, 2011

Different strategies for exercise Exercise strategies include: Prevention (chronic) Prehabilitation (acute) Rehabilitation (acute) During treatment

68 Different strategies for exercise Exercise strategies include: Prevention (chronic) Prehabilitation (acute) Rehabilitation (acute) During treatment (acute) Long term life style changes (chronic) Ideally, all of these should be a part of the optimization of health across a life-span in all populations

69 ACSM roundtable on exercise guidelines for cancer survivors, 2010

70 When to intervene? Ideally, as early as possible and BEFORE chronic health conditions become an issue. In reality, intervention is considered when the patient is diagnosed. The majority of research to date focuses on rehabilitation component, which may not be the most effective or opportune time frame. When? Carli and Scheede-Bergdahl, 2015

71 Prehabilitation Intervention PRIOR to major physiological stressors, such as surgery Approximately 4 weeks in length and takes place between time of diagnosis and surgery Period of time where the patient may be the most receptive to intervention.

72 How can exercise play a role in prehabilitation? Exercise is a physiological stress, which requires the body to adapt. The process of the body learning how to adapt to the applied stress = training. Exercise improves functional capacity and physiological reserve Carli and Scheede-Bergdahl, 2015

73 Carli, F. and Zavorsky, G.S. 2005

74 Getting from here.

75 to here

76 Our experience at McGill: 4 weeks of multimodal prehabilitation (time of diagnosis to time of surgery) Goal: to improve functional status prior to surgery

77 Not just exercise!

78 It is very important to maintain an overload stimulus so that improvements continue and do not plateau The Borg scale allows for progression and for days when the patient does not feel well/fatigued/during chemotherapy

79 4 weeks: is it enough? Most training programs in the literature are at least 8 weeks in length. Does 4 weeks offer enough of a stimulus to provoke a change in our patient population?

80 * While awaiting surgery, functional walking capacity increased ( 20 m) in a higher proportion of the prehabilitation group compared with the rehabilitation group (53 vs. 15%, adjusted P = 0.006) A higher proportion of the prehabilitation group were also recovered to or above baseline exercise capacity at 8 weeks compared with the rehabilitation group (84 vs. 62%, adjusted P = 0.049). Seventy-seven patients were randomized to receive either prehabilitation (n = 38) or rehabilitation (n = 39) Gillis C et al., 2014

81 * 67% 40% 34% 42% ASCM guidelines: 150 minutes of moderate to vigorous intensity per week Chen B et al, manuscript in preparation

82 What our preliminary results say: 4 weeks of prehabilitation is sufficient to improve functional capacity as represented by 6MWT 4 weeks is also sufficient to initiate changes in exercise behaviours in the pre-surgical period.

83 Six-Minute Walk Distance (m) Can we do better? Supervised exercise? Prehabilitation With and Without Supervision p= p= Baseline Before surgery 4 weeks, postoperative p= Supervised (N = 25) Awasthi R et al, manuscript in preparation 83

84 Number of Patients Preliminary Results Proportion of Patients Recovered 4 Weeks Postoperatively 36% 40% 32% 12% 48% 32% Supervised Homebased Below Baseline (<20m) At Baseline (-20m to 20m) Above Baseline (>20m) 84

85 What our preliminary results say: Minimally supervised exercise sessions, limited to one session a week before surgery and during the post-surgical follow up has a positive impact on achieving a faster return to baseline functional capacity. A greater proportion (68% vs 52%) were at or above baseline by 4 weeks as opposed to 8 weeks. A faster recovery will allow for the faster initiation of adjunct therapy (chemo)

86 Next steps What works best for each patient? Questionnaire to better determine the needs of each individual and how to personalize the prehabilitation program DOSE! Mechanisms? How do exercise and nutrition interact? Insulin sensitivity? Favouring protein uptake? Feasibility of prehabilitation on more frail populations? Exercise as a means of diminishing risk of future cancer

87 Thank you!

Preoperative functional optimization for better surgical outcome. Francesco Carli McGill University Montreal, Canada

Preoperative functional optimization for better surgical outcome Francesco Carli McGill University Montreal, Canada franco.carli@mcgill.ca F Carli is recipient of a grant of the Rossy Cancer Network (Canada)