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Corresponding author. Address for correspondence: Marc Licker, MD, Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital Geneva and Faculty of Medicine, CH-1206 Geneva.
Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, SwitzerlandFaculty of Medicine, University of Geneva, Geneva, Switzerland
Impairment in aerobic fitness is a potential modifiable risk factor for postoperative complications. In this randomized controlled trial, we hypothesized that a high-intensity interval training (HIIT) program enhances cardiorespiratory fitness before lung cancer surgery and therefore reduces the risk of postoperative complications.
Methods
Patients with operable lung cancer were randomly assigned to usual care (UC) (n = 77) or preoperative rehabilitation based on HIIT (Rehab) (n = 74). Maximal cardiopulmonary exercise testing and the 6-minute walk test were performed twice before surgery. The primary outcome measure was a composite of death and in-hospital postoperative complications.
Results
The groups were well balanced in terms of patient characteristics. During the preoperative waiting period (median 25 days), the peak oxygen consumption and the 6-minute walking distance increased (median +15%, interquartile range, 25th to 75 percentile [IQR25%–75%, %] = +9% to +22%, p = 0.003 and +15%, IQR25%–75% = +8% to +28%, p < 0.001, respectively) in the Rehab group, whereas peak oxygen consumption declined in the UC group (median –8%, IQR25%–75% = –16% to 0%], p = 0.005). The primary end point did not differ significantly between the two groups: at least one postoperative complication developed in 27 of the 74 patients (35.5%) in the Rehab group and 39 of 77 patients (50.6%) in the UC group (p = 0.080). Notably, the incidence of pulmonary complications was lower in the Rehab compared with in the UC group (23% versus 44%, p = 0.018), owing to a significant reduction in atelectasis (12.2% versus 36.4%, p < 0.001), and this decrease was accompanied by a shorter length of stay in the postanesthesia care unit (median –7 hours, IQR25%–75% = –4 to –10).
Conclusions
In this randomized controlled trial, preoperative HIIT resulted in significant improvement in aerobic performances but failed to reduce early complications after lung cancer resection.
Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
Advanced age, cancer stage, associated illnesses and impaired cardiorespiratory fitness (CRF) are predictive factors of major postoperative complications and long-term survival.
The European Respiratory Society and European Society of Thoracic Surgeons clinical guidelines for evaluating fitness for radical treatment (surgery and chemoradiotherapy) in patients with lung cancer.
Peak oxygen consumption (peako2) reflects the integrative ability of the pulmonary, circulatory, and autonomic neural systems to maximally deliver oxygen to the working skeletal muscles. Cutoff values for o2 of approximately 16 mL/kg per minute and a 10- to 12-mL/kg per minute anaerobic threshold (AT) have been shown helpful to discriminate between patients at low risk and those at higher risk of major postoperative complications.
Comparison of the prognostic accuracy of scoring systems, cardiopulmonary exercise testing, and plasma biomarkers: a single-centre observational pilot study.
Although implementation of exercise-based rehabilitation programs has been shown effective in improving CRF and quality of life of these patients, rehabilitation is largely underutilized because of scarce scientific evidence and uncertainties regarding the modalities on how to implement physical therapy over the limited preoperative time period.
Recent evidence has highlighted the potential of low-volume, high-intensity interval training (HIIT) for inducing a protective cardiopulmonary phenotype while enhancing oxygen extraction in skeletal muscle by increasing capillary density and mitochondrial oxidative capacity.
In this trial, we aimed to evaluate and compare short-term preoperative HIIT to usual care (UC) in patients undergoing NSCLC resection by assessing CRF parameters and the incidence of postoperative complications. We hypothesized that exercise-induced improvement in CRF would enhance protective defense mechanisms among surgical candidates, making them more resistant to physiological alterations consequent to surgical stress.
Methods
Study Design
The Lung Cancer Rehabilitation Study was a prospective randomized, open, blinded end point controlled trial using assessor blinding and intention-to-treat analysis. It was registered at the National Institutes of Health ClinicalTrials.gov website (NCT01258478) and conducted at the University Hospital of Geneva and the Hospital of Valais.
Patients
After approval by the local ethics committees (protocol no. 06-225), written informed consent was obtained from all eligible adult patients with proven or suspected NSCLC, stage IIIA or less. The criteria of resectability were based on the recommendations of the European Respiratory Society (ERS) and the European Society of Thoracic Surgery.
The European Respiratory Society and European Society of Thoracic Surgeons clinical guidelines for evaluating fitness for radical treatment (surgery and chemoradiotherapy) in patients with lung cancer.
Exclusion criteria were any contraindication to performing CPET (e.g., uncontrolled cardiac disease, severe pulmonary hypertension), limitations impeding cycling, or the inability to adhere to a rehabilitation program.
Randomization
Consenting patients were randomized on a 1:1 basis into a rehabilitation (Rehab) arm and UC arm by using a permuted block of four patients. The randomization sequence was developed before initiation of the trial and concealed until after enrollment.
the HIIT program was designed in cooperation with experienced physical therapists specialized in rehabilitation. Participants in the Rehab group exercised on a cycling ergometer in the outpatient clinic two to three times a week under the supervision of physiotherapists. After a 5-minute warm-up period at 50% at peak work rate (peakWR) the patients completed two 10-minute series of 15-second sprint intervals (at 80%–100% peakWR) interspersed by 15-second pauses and a 4-minute rest between the two series. The patients then cooled down with a 5-minute active recovery period at 30% peakWR. The work rate was adjusted by the physiotherapist during each session to target near-maximal heart rates toward the end of each series of sprints on the basis of the individual’s exercise response. Additional exercises, such as leg press, leg extension, back extension, seat row, biceps curls, or chest and shoulder press, were proposed on an individual basis.
Patients in the two groups were given advice regarding active mobilization (at least four 30-minute walks per week) and risk factor management (e.g., healthy nutrition and smoking and alcohol cessation).
Lung resections were performed by open thoracotomy or video-assisted thoracic surgery and, standardized perioperative interventions included antibiotic prophylaxis, restrictive fluid management, thoracic epidural analgesia, and protective lung ventilation.
After surgery, patients were managed in a postanesthesia care unit (PACU) and were transferred to the surgical ward when the discharge criteria were met.
An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease.
Symptom-limited CPET was performed on an upright electronically braked cycle ergometer with breath-by-breath expired gas analysis (2200 SP [SensorMedics, Yorba Linda, CA]); peak heart rate (peakHR) and peako2 were determined as the highest average values over 30 seconds, and peakWR was identified at the highest exercise level or interpolated if the last stage was not maintained for 2 minutes.
Peak oxygen pulse was calculated by dividing peako2 by the peakHR. The AT was determined using the V-slope method as the primary criterion and the first rise in the ventilatory equivalent for oxygen (expired volume per unit time/peako2) as a secondary criterion.
All respiratory function tests and physiologic measurements were performed according to the ERS/American Thoracic Society and ERS standards and expressed as absolute and predicted values (percentages) based on age, sex, and weight of the patients.
On the day of enrollment, collected data included demographic and clinical information as well as the results of lung function and blood laboratory tests. The revised cardiac risk index was computed for each patient.
Two to 4 days before surgery (after the rehabilitation or control period), the CPET and the 6MWT were repeated and a multiaxis accelerometer (ActiSmile SA, Baar, Switzerland) was used to estimate daily physical activity (average value of the last 3 days before surgery).
Surgical and anesthetic data were extracted from the electronic patient data management system. Postoperatively, patients were followed until hospital discharge to report any adverse events according to a modified version of the thoracic mortality and morbidity (TMM) classification system (see Supplementary Material).
The primary outcome was a composite end point of postoperative morbidity (30-day mortality or any complications with TMM grades of ≥2). Secondary outcomes were the preoperative changes in CPET parameters (peako2, AT, and peakHR) and in 6MWT distance (in meters), the incidence of postoperative complications with TMM grades of ≥2, length of stay in the PACU, and the rate of admission to the intensive care unit. A positive response to rehabilitation was defined by meaningful changes in peako2 (≥10%) or the 6MWT (≥30 m) occurring between the first and the second preoperative measurements.
An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease.
Adherence to the HIIT program was defined as the ratio of the number of attended sessions to the number prescribed. All serious adverse events (SAEs) during the HIIT were reported to the study coordinator and to the data monitoring and safety committee.
Sample Size
On the basis of a previous cohort study, we assumed a 22% incidence of complications and expected a 50% reduction of postoperative morbidity after implementation of preoperative rehabilitation.
A sample of 178 patients per group was required (80% power, two-sided test, type I error of 0.05) and to allow for dropouts, and we intended to randomize 400 patients (200 per group). Given concerns regarding the occurrence of SAE and a possible changing pattern of clinical outcome, two interim analyses were planned after the inclusion of 120 and 240 patients as recommended by the data monitoring and safety committee. The rules for stopping or continuing were based on the following: SAEs related to the HIIT, changes in the rate of postoperative complications, and between-group difference in the primary end point or at least two secondary end points. The first interim analysis showed an overall incidence of complications of 46%; therefore, 44 additional patients were deemed necessary to complete the study.
Statistical Analysis
All data were analyzed using statistical software SPSS version 11.5 (SPSS, Inc., Chicago, IL) and tested with the Kolmogorov-Smirnov test for normality. Summary descriptive statistics were expressed as frequencies (and percentages), medians (and interquartile range, 25th to 75 percentile [IQR25%–75%]), or means (and SD). Intergroup differences were analyzed by a two-sided unpaired t test, Mann-Whitney U test, or χ2 test with Yates corrections where appropriate. Physiologically important changes were estimated as effect sizes (ESs) using Cohen’s guidelines,
whereby a value of 0.2 denotes a small ES 0.5 denotes a medium ES, and 0.8 denotes a large ES. The ES induced by the intervention was calculated by subtracting the mean changes in the UC group from the mean change in the Rehab group divided by the pooled standard deviation. Prespecified analyses using a generalized linear model were conducted to explore modification of response to HIIT by patients' characteristics and cancer stages as well as the impact of these variables on the occurrence of postoperative complications. All statistical tests were two sided and conducted at the 5% significance level.
Results
Study Population
Between October 2011 and October 2014, 189 patients were screened, 164 provided consent, and 13 were excluded (Fig. 1). Therefore, 151 patients were analyzed, 77 in the UC group and 74 in the Rehab group. The time delay from the date of enrollment to surgery was similar in the two groups (a median of 26 days in the Rehab group [IQR25%–75% = 21–33] and a median of 25 days in the UC group [IQR25%–75% = 20–40]).
The two groups did not differ regarding preoperative demographic, clinical, and functional data (Tables 1 and 2). Surgical characteristics and anesthetic management were also similar in the two groups: more than 80% of patients underwent major lung resection through open thoracotomy and received thoracic epidural analgesia (Table 3). In the Rehab group, the rate of adherence to the prescribed training sessions was 87 ± 18% (a median of eight sessions [IQR25%–75% = 7–10]), and no SAE was reported during the HIIT sessions. The daily step count tended to be higher in the Rehab group (7243 ± 3934 steps versus 6315 ± 3690 steps in the UC group, p = 0.082).
Table 1Demographic and Clinical Characteristics of the Study Population
Variables
Usual Care (n = 77)
Rehabilitation (n = 74)
p Value
Age, y
64 (10)
64 (13)
0.737
Body mass index, kg/m2
24.4 (4.1)
25.0 (4.5)
0.365
Male sex
50 (65)
41 (55)
0.637
ASA classes 3 and 4
28 (36)
22 (30)
0.394
Chronic obstructive pulmonary disease
27 (35)
30 (41)
0.506
Hypertension
32 (42)
33 (45)
0.744
Diabetes mellitus
11 (14.3)
10 (13.5)
0.890
Coronary artery disease
8 (10.4)
10 (13.5)
0.621
Heart failure
8 (10.4)
8 (10.8)
0.989
Cardiac arrhythmias
5 (6.5)
3 (4.1)
0.719
History of stroke
1 (1.3)
6 (8.1)
0.060
Renal dysfunction (eGFR <60 mL/min)
6 (7.8)
4 (5.4)
0.746
Peripheral arterial disease
13 (16.9)
16 (21.6)
0.537
Revised cardiac risk index
1 (1-2)
1 (1-2)
0.342
Alcohol
25 (32.5)
15 (20.3)
0.820
Smoking
0.451
Current
39 (51)
28 (39)
Past
31 (40)
43 (58)
No
7 (9.1)
4 (5.4)
Chronic drug treatment
β-Blockers
13 (16.9)
11 (14.9)
0.825
ACE inhibitors or AII blockers
11 (14.3)
18 (24.3)
0.149
Statins
8 (10.4)
13 (17.6)
0.243
Steroids
7 (9.1)
10 (13.5)
0.447
Antiplatelets
13 (16.9)
19 (25.7)
0.233
Neoadjuvant chemotherapy
9 (11.7)
6 (8.1)
0.589
Note: Data are presented as numbers (%), means (SD), or medians (interquartile range, 25th to 75th percentile). Data are analyzed by unpaired Student's t test, Mann-Whitney U test, or chi-square test.
ASA, American Society Association physical status classification; eGFR, estimated glomerular filtration rate; ACE, angiotensin-converting enzyme; AII, angiotensin II.
Table 2Laboratory and Functional Characteristics of the Study Population
Variables
n
Usual Care (n = 77)
Rehabilitation (n = 74)
p Value
Laboratory values
Hemoglobin, g/liter
151
135 (34)
131 (31)
0.567
Creatinine, μm/liter
151
80 (27)
76 (22)
0.550
NT-pro BNP, ng/liter
121
35 (19–68)
31 (17–80)
0.703
hsCRP, mg/liter
121
4.1 (1.7–14.9)
4.8 (2.3–11.5)
0.466
Pulmonary function
FVC, % predicted
151
104 (21)
102 (18)
0.441
FEV1, % predicted
151
88 (19)
86 (22)
0.588
ppoFEV1, % predicted
151
65 (14)
63 (17)
0.658
Dlco, % predicted
151
76 (19)
75 (21)
0.900
ppoDlco, % predicted
151
64 (17)
62 (19)
0.832
Cardiopulmonary exercise test
peako2, mL/kg/min
151
20.4 (5.7)
19.9 (5.7)
0.557
peako2, % predicted
151
82 (19)
83 (22)
0.833
Anaerobic threshold, %
136
48 (12)
50 (16)
0.314
e/o2, liters/mL
136
36.6 (5.8)
35.6 (5.2)
0.245
e/co2, liters/min
136
36.4 (5.2)
36.6 (4.7)
0.731
peakWR, W
150
101 (39)
96 (39)
0.421
HR at rest, beats/min
149
73 (14)
72 (12)
0.757
peakHR, beats/min
149
138 (21)
136 (20)
0.537
peakO2 pulse, mL/beat
146
10.3 (2.7)
10.3 (3.0)
0.903
peakPao2, kPa
126
11.3 (3.7)
10.3 (4.1)
0.343
Distance in 6MWT, m
151
368 (143)
398 (167)
0.072
peakHR, beats per min
121
112 (42)
111 (41)
0.604
Note: Data are presented as means (SD) or median (interquartile range, 25th to 75th percentile) and analyzed by unpaired Student's t test or Mann-Whitney U test.
NT-proBNP, N-terminal pro B-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; Dlco, diffusion capacity for monoxide; ppo, predicted postoperative; e/co2, ventilatory equivalents of expired carbon dioxide; e/o2, ventilatory equivalents of consumed oxygen; peako2 peak, maximum oxygen uptake; peakWR, peak work rate; HR, heart rate; peakHR, peak heart rate; peakPao2, peak partial pressure of oxygen, alveolar.
In-hospital clinical outcome data were available in all participants. As shown in Table 4, a total of 66 patients reached the composite postoperative mortality-morbidity end point, including 27 of the 74 patients (35.5%) in the Rehab group and 39 of 77 patients (50.6%) in the UC group (relative risk = 0.70, 95% confidence interval [CI]: 0.48–1.02).
Table 4Primary and Secondary Outcomes after Lung Resection
Compared with baseline measurements, significant changes in CPET and 6MWT parameters occurred at the end of the preoperative waiting period (Table 5). In the UC group, the peako2 declined during the preoperative waiting period (median –8% [IQ25%–75% = –16% to 0%], p = 0.005). In contrast, in the Rehab group, there were significant increases in peako2 (median +15% [IQR25%–75% = +9% to +22%], p = 0.004), in peakWR (median +6% [IQR25%–75% = 0% to +17%]; p = 0.003), and in walking distance at the 6MWT (median +15% [IQR25%–75% = +8% to +28%], p < 0.001) with a nonsignificant increase in AT (median +8% [IQR25%–75% = –7% to + 20%], p = 0.083). The ES of the Rehab intervention was significant regarding peako2 (0.46, 95% CI: 0.26–0.66) and walking distance (0.49, 95% CI: 0.24–0.74), and nonsignificant regarding the AT (0.20, 95% CI: –0.95 to 0.45), peak O2 pulse (0.29, 95% CI: –0.99 to 0.59), peakHR (0.15, 95% CI: –0.94 to 0.36) and peakWR (0.28, 95% CI: –0.98 to 0.58). The target physiological end points were achieved in 75.7% of rehabilitated patients and this functional improvement was consistent regardless of patient characteristics and cancer stages (Fig. 2). Attendance of the prescribed training sessions did not differ between responders and nonresponders (89% versus 81%).
Table 5Changes in Cardiopulmonary Exercise Test and 6-Minute Walk Parameters before and after Usual Care or Rehabilitation
Variables
n
Usual Care (n = 77)
Rehabilitation (n = 74)
p Value
Δpeako2 at CPET, mL/kg per min
151
–1.5 (–3.2 to 0.5)
+2.9 (1.1 to +4.2)
0.004
ΔAT at CPET, %
136
–2.5 (–6.9 to 3.1)
+3 (–2.1 to +8.3)
0.183
Δe/o2 at CPET, liters/mL
136
–1.8 (–7.2 to +4.1)
–1.1 (–6.8 to +3.7)
0.845
Δe/co2 at CPET, liters/min
136
–0.6 (–4.8 to +4.2)
–0.7 (–5.9 to +5.2)
0.731
ΔpeakWR at CPET, W
150
–4 (–9 to + 1)
+8 (+1 to +15)
0.021
ΔpeakHR at CPET, beats/min
149
–9 (–16 to 0)
–5 (–11 to +1)
0.237
Δpeak O2 pulse at CPET, mL/beat
146
+0.1 (–1.9 to +2.3)
+0.9 (–0.9 to +2.5)
0.303
ΔDistance 6MWT, m
148
–2 (–9 to +5)
+66 (+8 to + 125)
0.001
ΔpeakHR 6MWT, beats/min
120
–1 (–10 to + 8)
0 (–12 to +9)
0.804
Note: Data are presented as medians (interquartile range, 25th to 75th the percentile) and analyzed by the Mann-Whitney U test.
peako2, peak oxygen consumption; CPET, cardiopulmonary exercise testing; peakWR, peak work rate; peakHR, peak heart rate; 6MWT, 6-minute walk test; e/co2, ventilatory equivalents of expired carbon dioxide; e/o2, ventilatory equivalents of consumed oxygen.
Figure 2Distribution of patients according to physiological changes observed in the preoperative period. Responders (dark bar) experienced at least a 10% increase in peak oxygen uptake (peako2) or an increase of at least 30 m at the 6-minute walk test. Nonresponders (gray bars) experienced lesser changes or decreases in peako2 or 6-minute walking distance. BMI, body mass index; COPD, chronic obstructive pulmonary disease.
The incidence of cardiovascular and surgical complications, as well as the rate of admission in the intensive care unit and the hospital length of stay, did not differ between the two groups. In contrast, the incidence of postoperative pulmonary complications was lower in the Rehab group (23% versus 44% in the UC group p = 0.018) owing to a reduced rate of atelectasis (12.2% versus 36.4%, p < 0.001), and this was accompanied by a shorter stay in the PACU (median –7 hours, IQR25%–75% = –4 to –10) compared with in the UC group. Subgroup analysis revealed that the beneficial effect of rehabilitation on postoperative pulmonary complications was larger among responders than among nonresponders (relative risk = 0.25, 95% CI: 0.12–0.53) and consistent among men, elderly patients, overweight patients, those with cardiac risks factors, those with preserved aerobic capacity, and those with and without chronic obstructive pulmonary disease (COPD) (Fig. 3).
Figure 3Effect of rehabilitation intervention on postoperative pulmonary complications in prespecified subgroups. CI, confidence interval; BMI, body mass index; peako2, peak oxygen uptake; COPD, chronic obstructive pulmonary disease.
Regression analysis showed that independent predictors of postoperative pulmonary complications were preoperative peako2, rehabilitation intervention, and COPD (Wald coefficient = 10.0, 7.5, and 4.1 and p = 0.002, 0.006, and, 0.043, respectively).
Discussion
This study demonstrates that preparing patients before lung cancer resection with an HIIT program enhances their physical fitness but fails to improve postoperative clinical outcome.
At patient enrollment, the mean peako2 (20 mL/kg per minute) and mean 6MWT distance (383 m) were respectively an average of 18% and 42% below the values expected for age- and sex-matched sedentary individuals. In a multicenter trial including 346 patients with NSLC, Loewen et al. reported even greater preoperative impairment in aerobic capacity (mean peako2 of 15.8 mL/kg per minute) and a larger proportion of patients with low preoperative peako2, which has been shown to be predictive of major cardiopulmonary complications.
In contrast to chronic conditions such as COPD and cardiovascular disease, poor aerobic fitness, as well as heavy smoking and alcohol absorption, are amenable to targeted risk-reducing strategies.
Therefore, our short-term HIIT program was intended to augment preoperative physiological reserves and to facilitate postoperative functional recovery. The delay from decision to treat to surgery was within the maximal waiting time of 28 days recommended by the British Thoracic Society.
The Lung Cancer Working Party of the British Thoracic Society Standards of Care Committee BTS recommendations to respiratory physicians for organising the care of patients with lung cancer.
During the 3- to 4-week waiting period, patients receiving UC exhibited a mild decline in CPET parameters and walking capacity that could be attributed to the inflammatory component associated with lung cancer, COPD, and other chronic illnesses.
This impairment in aerobic functional capacity was successfully offset in 76% of patients who were enrolled in a HIIT program. After patients attended 7 to 13 supervised training sessions, their peako2 and walking capacity both improved by a median value of 15%, regardless of their preoperative characteristics. Baseline physiological values, as well as the intensity, the type, and the duration of exercise training, are key factors determining changes in CRF. Endurance training classically entails moderately intense efforts during daily sessions lasting 60 to 120 minutes and scheduled over a prolonged period of 6 to 12 weeks. Such high-volume training has been shown to improve aerobic performances as a result of blood volume expansion, higher cardiac output, and enhanced muscle oxygen extraction.
In contrast, low-volume HIIT (40 minutes two to three times a week for 3 to 4 weeks) has been shown to produce similar or larger gains in peako2 owing to enhanced skeletal muscle oxidative capacity that is independent of any changes in cardiac performance and in the blood's capacity to carry oxygen.
Effectiveness of high-intensity interval training (HIT) and continuous endurance training for VO2max improvements: a systematic review and meta-analysis of controlled trials.
Even a few sessions of HIIT appear sufficient to stimulate transcriptional mitochondrial biogenesis, inducing aerobic phenotypic changes characterized by increased mitochondrial expression/activity of proteins involved in fat oxidation, the tricarboxylic acid cycle, and the electron transport chain.
Improvements in exercise performance with high-intensity interval training coincide with an increase in skeletal muscle mitochondrial content and function.
In the current trial, we reported all TMM complications graded 2 to 4. Hence, the incidence of postoperative complications (overall 37%) was higher than expected from our previous work and higher than reported by others.
Major morbidity after video-assisted thoracic surgery lung resections: a comparison between the European Society of Thoracic surgeons and the Thoracic Morbidity and Mortality system.
The TMM classification has been derived from the Dindo-Clavien scoring system to standardize the reporting of adverse outcome and to overcome the limitations of considering each complication separately.
This composite measure is well validated and widely applied in perioperative medicine to grade the severity of postoperative complications, considering the intensity of therapeutics and resources. In a study involving mostly video-assisted thoracoscopic lung resections, Beck-Schimmer et al. recently reported a 15% incidence of postoperative complications graded 3 to 4.
Besides the different threshold to capture postoperative morbidity, our study population was also at greater risk of postoperative complications given the more invasive surgical approach (an 81% rate of thoracotomies) and a higher proportion of extended resection (e.g., a 20% rate of pneumonectomy or bilobectomy).
Although peako2, peakWR, and walking distance were all increased after five to 10 HIIT sessions, this enhanced aerobic condition did not translate into better clinical outcome, except for a lower rate of atelectasis coupled with a shorter length of stay in the PACU.
Several arguments can be given to explain these findings and, at the same time, to highlight the limitations of this trial. One may argue that the relative risk reduction in primary outcome (approximately –30%) would have been statistically significant if the study had been continued to enroll a total of 362 patients. Downsizing the study sample was justified by the interim analysis showing a higher than expected incidence of postoperative complications (46% instead of the 22% initially estimated). Notably, most patients enrolled after the interim analysis underwent lung resection by video-assisted thoracic surgery instead of open thoracotomy. This less invasive surgical approach contributed to reducing the rate of postoperative complications over the last 6 months of the study regardless of group allocation.
Cardiovascular complications did not differ between the two groups. The standard risk-reducing strategies that were applied (e.g., preoperative patient assessment, thoracic epidural analgesia, and fluid restriction) resulted in a low rate of myocardial infarct and heart failure (< 5%). Not surprisingly, tachyarrhythmias, the most frequent cardiac adverse event, were not responsive to the effects of rehabilitation as they are mainly related to surgical inflammation, autonomic nerve injuries, and cardiac overload.
Moreover, concerns have been raised about the proarrhythmic effects of HIIT, although the effectiveness of long-term endurance training has been clearly established in improving endothelial dysfunction, myocardial remodeling, cardiac autonomic control, and β-adrenoceptor balance.
The impact of high-intensity interval training versus moderate-intensity continuous training on vascular function: a systematic review and meta-analysis.
Interestingly, pulmonary complications were reduced by 45% in the Rehab group, the greatest impact being on atelectasis and particularly among patients who exhibited a positive response to HIIT. Even if atelectasis graded 2 is often considered benign, the initiation of corrective therapy with continuous positive airway pressure or noninvasive ventilation in the PACU is justified to correct oxygenation disturbances and to prevent further extension and the development of infection. In the Rehab group, the lower incidence of atelectasis was associated with a slight reduction in PACU length of stay (median –7 hours) compared with in the UC group.
Reversal of respiratory muscle dysfunction is an attractive mechanism underlying the protective effects of HIIT in thoracic surgical patients. Indeed, weakness of the respiratory muscles has been consistently reported in patients with low preoperative peako2 and COPD,
which are two features identified as independent predictors of pulmonary complications in the current trial. Using similar short-term total-body aerobic reconditioning programs, Dunham et al. reported up to a 40% increase in maximal inspiratory pressure, with the HIIT modality providing a time-efficient alternative to endurance training in increasing both CRF and respiratory muscle function.
Recent systematic reviews suggest that preoperative, but not postoperative, interventions, including moderately intense aerobic exercise, may contribute to improving functional capacity and to reducing postoperative pulmonary morbidity.
However, no firm conclusions could be drawn given the heterogeneity of patient populations, the variety of interventional approaches, the lack of standardized criteria defining morbidity outcomes, and the small numbers of enrolled patients. To date, only five randomized controlled trials including a total of 196 patients have been published, and none was powered to detect meaningful clinical differences.
The current study including 151 patients is the largest trial conducted so far.
Even though this trial presents negative results regarding the primary outcome, the positive impact on the development of atelectasis should be neither ignored nor overemphasized. Our results are consistent with the hypothesis that HIIT-induced improvement in CRF enables patients to better withstand respiratory derangements, namely, muscular weakness resulting from surgical stress and the residual effects of anesthetic agents, while facilitating lung reexpansion postoperatively. The study was underpowered to detect meaningful difference in major pulmonary complications such as pneumonia or acute respiratory distress syndrome. Moreover, 25% of rehabilitated patients failed to experience any benefit in terms of aerobic fitness or walking capacity despite attending the prescribed training sessions. Nonresponse to specialized rehabilitative interventions has been attributed to genetic factors, physical disabilities, adjunctive chemotherapy, and low volume or low intensity of exercise.
In conclusion, we demonstrated the safety and effectiveness of a short-term exercise training program in improving aerobic performances in patients awaiting lung cancer surgery. However, this HIIT rehabilitation modality failed to produce significant difference in composite morbidity-mortality index compared with UC. Adequately powered randomized studies including high-risk patients and focusing on clinical outcome end points should question the benefits of preoperative rehabilitation interventions.
Acknowledgments
This study was supported by the Clinical Research Center of the University Hospital of Geneva and the Geneva Association Against Cancer. In this trial, pulmonogists (Drs. Paola Gasche-Soccal, Jean-Paul Janssens, Frédéric Lador, Thierry Rochat, and Jean-Marie Tschopp), an oncologist (Dr. Arnaud Roth), thoracic surgeons (Drs. John Robert and Michel Christodoulou), anesthesiologists (Dr. Patrick Ravussin and Dr. Daniel Rudaz), physiotherapists (Mrs. Chetna Bhatia, Mrs. Sarah Fournier, and Mr. Pierre-Yves Roberfroid), and a technician of the pulmonary function lab (Mrs. Nathalie Geraudel) at the University Hospital of Geneva and the Hospital of Valais all participated in patient screening, preoperative preparation, intraoperative management, and postoperative follow-up.
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