Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Li, 2021

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs / cohort / case-control studies.

Literature search up to October 2020

A: Dong, 2017

B: Muehling, 2008

C: Boujibar, 2018

D: Brunelli, 2017

E: Chen, 2020

F: Gao, 2015

G: Glogowaska, 2017

H: Gonzales, 2018

I: Haro, G 2019

J: Huang, 2018

K: Khandhar, 2018

L: Li, M, 2019

M: Lv, H 2019

N: Madani, 2015

O: Murayama, 2006

P: Numan, 2012

Q: Rice D, 2020

R: Salati, 2020

S:Shiono, 2019

T: Tahiri, 2020

U: van Haren, 2018

Study design:

A: RCT

B: RCT

C: cohort (retrosp.)

D: cohort (retrosp.)

E: cohort (retrosp.)

F: cohort (prosp.)

G: cohort (prosp.)

H: cohort (ambisp.)

I: cohort (prosp.)

J: cohort (retrosp.)

K: cohort (retrosp.)

L: cohort (retrosp.)

M: cohort (prosp.)

N: cohort (retrosp.)

O: cohort (retrosp.)

P: cohort (prosp.)

Q: cohort (retrosp.)

R: cohort (retrosp.)

S: cohort (retrosp.)

T: cohort (retrosp.)

U: cohort (retrosp.)

Setting and Country:

A: China

B: Germany

C: France

D: UK

E: China

F: China

G: Poland

H: Switzerland

I: USA

J: China

K: USA

L: China

M: China

N: Canada

O: Japan

P: Netherlands

Q: USA

R: Italy

S: Japan

T: Canada

U: USA

Source of funding and conflicts of interest:

This work was supported by the National Natural Science Foundation of China (no. 8162292, 81802397), the

Jinan Science and Technology Bureau (no. 2019GXRC051),

the Natural Science Foundation of Shandong Province

(no. ZR2017BH035), and the Taishan Scholar Program of

Shandong Province (no. ts201712087).

The authors have no conflicts of

interest to declare.

Inclusion criteria SR:

(I) involved adult

patients undergoing elective pulmonary resection (wedge

resection, lobectomy, pneumonectomy, etc.), (II) involved

patients who received an ERAS program (we recognized

a total of 25 elements in studies encompassing all phases

of perioperative care [pre-, intra-, and postoperative]

(III) involved an ERAS program with at least 4 elements that covered at least 2 phases of perioperative care, (IV) involved a traditional care

control group that had adopted at least 3 elements fewer than the ERAS group, (V) reported at least 1 of the outcome

measures of interests (see below), and (VI) written in English.

Exclusion criteria SR:

(I) ineligible

article types, such as case report, reviews, and conference

abstracts; (II) no outcomes of interest present; (III) inclusion of nonhuman participants or written in languages other than English.

21 studies included

Important patient characteristics at baseline:

N (ERAS versus control)

A: 17, 18

B: 30, 28

C: 19, 15

D: 235, 365

E: 169, 168

F: 71, 71

G: 215, 187

H: 50, 50

I: 126, 169

J: 38, 45

K: 304, 100

L: 72, 72

M: 55, 55

N: 107, 127

O: 113, 105

P: 75, 94

Q: 123, 123

R: 232, 232

S:126, 126

T: 98, 98

U: 342, 1615

Mean age (ERAS versus control)

A: 55.1, 56.5

B: 67, 64

C: 65, 69

D: 69.7, 68.8

E: 57.6, 57.2

F: 66.3, 59.7

G: 59, 55

H: 64, 68

I: 67, 67

J: 60.7, 59.6

K: 66.2, 66.2

L: 63.1, 63.5

M: 57.1, 56.8

N: 67, 64

O: 63, 64

P: 60, 58

Q: 62, 61

R: 68.2, 67.7

S: 70, 70

T: 65.2, 66.2

U: 66, 65

Sex (% male ERAS versus control)

A: 76, 78

B: 66.7, 82.1

C: 78.9, 66.6

D: 42, 40

E: 65.1, 64.9

F: 56.3, 62.0

G: 52.6, 54.5

H: 48, 36

I: 31.0, 43.8

J: 42.1, 55.6

K: 58.6, 53.0

L: 58.3, 55.6

M: 56.4, 63.6

N: 61, 45

O: 58.4, 50.5

P: 57.3, 58.5

Q: 53, 54

R: NR, NR

S: 66.7, 68.3

T: 36.7, 29.6

U: 47.4, 50

ERAS elements (ERAS versus control)

A: 14, 8

B: 7, 4

C: 5, 2

D: 15, 8

E: 7, 4

F: 6, 3

G: 5, 1

H: 16, 10

I: 17, 5

J: 22, 5

K: 11, 2

L: 6, 3

M: 10, 2

N: 10, 3

O: 9, 3

P: 8, 0

Q: 11, 5

R: 5, 0

S: 11, 5

T: 6, 1

U: 10, 5

Describe intervention:

ERAS protocol (at least 4 elements that covered at least 2 phases of perioperative care.

Describe  control:

Pre-ERAS (at least 3 elements fewer than the ERAS group).

End-point of follow-up:

Not reported.

For how many participants were no complete outcome data available?

Not reported.

Outcome measure-1

In-hospital mortality

Pooled effect (random effects model): The pooled RD of all

13 studies was -0.00 (95% CI: -0.01 to 0.00). I² 0%.

Outcome measure-2

Postoperative complications

Pooled effect (random effects model): The pooled RR of all

18 studies was 0.64 (95% CI: 0.52 to 0.78). I² 63%.

Outcome measure-3

Postoperative length of stay

Pooled effect (random effects model): The pooled SMD of all

7 studies was -1.58 (95% CI: -2.38 to -0.79;. I² 98%.

Outcome measure-4

Readmission rate

Pooled effect (random effects model): The pooled RR of all

11 studies was 1.00 (95% CI: 0.76 to 1.32). I² 0%.

Outcome measure-5

Quality of life

Not reported.

Outcome measure-6

Functional recovery

Not reported.

Facultative:

Through this meta-analysis, we found that patients treated

with the ERAS program had a lower risk of developing

postoperative complications and a decreased postoperative

LOS.

No publication bias was found using both Begg’s test and Egger’s test.

To explore the source of high heterogeneity (postoperative complications), we omitted

the individual studies sequentially (27). Fortunately, we found a significantly reduced heterogeneity after excluding the studies performed by Gao et al. in 2015 I2= 35%; P=0.08), as shown in Figure 4.

This review had some limitations. First, the majority of the included studies were cohort studies, and only 2 RCTs were included. Moreover, the majority of eligible cohort studies were separate-sample pre-post-test designs. These types of studies have some limitations, such as nonparallel controls and cohort selection, which might have introduced biases and reduced the reliability of the results. Second, the ERAS protocols of the included studies were significantly

different, and the implementation standards of the ERAS program varied between each country and region, possibly producing bias and reducing the credibility of the results. In addition, there were differences in patient compliance with the ERAS program (64,65), which might have led to obvious heterogeneity in the results. Third, we did not analyze patient-reported outcomes such as pain score and

QoL because published research did not provide these types of data.

Li, 2021

Yes

 Yes

No

The studies that are excluded after reading the full tekst are not referenced with reasons.

Yes

Unclear

Not reported.

Yes

No

The amount of ERAS items differ substantially between the studies and the implementation standards of the ERAS program varied between each country and region.

Yes

No publication bias.

Yes

No conflicts of interest reported.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Wang, 2021

Type of study:

cohort

Setting and country: retrospective, China

Funding and conflicts of interest: The authors declare that they have no competing interests. Funding was not applicable.

Inclusion criteria:

(1) diagnosis with primary non-small-cell lung cancer (NSCLC); (2) anatomical lung resection, including

lobectomy and segmentectomy; and (3) ≥18 years old.

Exclusion criteria:

(1) benign lesions or other pathological types except NSCLC; (2) other surgical approaches except anatomical lung resection;

N total at baseline:

Intervention: 691

Control: 1058

Important prognostic factors²:

For example

age (IQR)

I: 61.0 (56.0, 67.0)

C: 61.0 (53.0, 68.0)

Sex (M/F):

I: 351 / 340

C: 527 / 531

Groups comparable at baseline?

Compared with the routine pathway group, the ERAS group was found to have a higher proportion of

VATS.

Describe intervention (treatment/procedure/test):

ERAS protocol:

- General patient admission education, instruction about ERAS principles and ERAS member responses to the patients. The specialized nurse was mainly responsible for the session. Smoking and alcohol cessation for 2 weeks and 4 weeks respectively.

- Perioperative respiratory training and mobilization.

- VTE prophylaxis education preopeartive VTE risk rating, early mobilization after surgery.

- small-bore chest tubes, drain removed < 400 ml and no air flow.

- no urinary catheter

- standardized postoperative pain management

- early oral intake, median chain triglyceride diet suppoted by the nutriology department.

Describe  control (treatment/procedure/test):

Pre-ERAS protocol (routine pathway):

- General patient admission education introduced by video

- No perioperative respiratory training and mobilization

- No standardized VTE management

- chest tube management: 2 28-F chest tube; removal after drainage volume < 200

- routine urinary catheter was used

- non-standardized postoperative pain management.

- non-standardized postoperative nutrition management.

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported.

Incomplete outcome data:

Not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I: 4/691 (0.6%)

C:  6/1058 (0.6%)

Overall postoperative complications

Not reported.

length of stay (postoperative)

I: 4.0 (IQR 2, 6)

C: 6.0 (IQR 4, 9)

readmissions

not reported

quality of life

not reported

functional recovery

not reported

Conclusion: Implementation of an ERAS pathway shows improved postoperative outcomes, including shortened

LOS, lower in-hospital costs, and reduced occurrence of PPCs, providing benefits to the postoperative recovery of

patients with lung cancer undergoing surgical treatment.

Peng, 2021

Type of study: cohort

Setting and country: retrospective, USA

Funding and conflicts of interest:  Funding

Was provided

By grants

UL1TR001855

and

UL1TR000130 from the National Center for Advancing Translational

Science (NCATS) of the US National Institutes of Health for Dr.

Ding.

The authors have no conflicts of interest to

disclose.

Inclusion criteria:

All patients undergoing anatomic lung resection between April 2017 and April 2019.

Exclusion criteria:

Incomplete datasets, extended resections (pneumonectomy), or non-resectional operations.

N total at baseline:

Intervention: 67

Control: 64

Important prognostic factors²:

For example

age (range):

I: 64.0 (21-86)

C: 64.5 (26-89)

Sex:

I: 61.2% M

C: 50 % M

Open Surgery:

I: 40.3 %

C: 28.1%

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

ERAS protocol:

- early mobilization

- limited invasive monitoring

- euvolemia

- non-narcotic analgesia

- intraoperative regional blocks instead of thoracic epidurals.

Describe  control (treatment/procedure/test):

Pre-ERAS

Not described.

Length of follow-up:

30 days

Loss-to-follow-up:

NA – incomplete datasets were excluded on beforehand.

Incomplete outcome data:

NA – incomplete datasets were excluded on beforehand.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

None of the patients died within 30 days after surgery in both the intervention and control group.

Overall complications

Not reported.

length of stay (hospital)

not reported, only hospital length of stay.

Readmissions (within 30 days)

I: 6 (9%)

C: 3  (4.7%)

quality of life

Not reported.

functional recovery

Not reported.

Conclusion: Implementation of an ERAS protocol for pulmonary resection, which dictated reduced ICU admissions, did not increase major postoperative morbidity. Additionally, ERAS-enrolled patients reported improved postoperative

pain control despite decreased opioid utilization.

There was no transitional period after introduction of the institutional ERAS protocol, and all surgeons immediately and unanimously participated in its use.

Supplemental material laat zien dat het voldoet aan de criteria van het SR van Li 2021 wat betreft de ERAS elementen.

Forster, 2021

Type of study: cohort

Setting and country: retrospective,

Funding and conflicts of interest: No funding. The authors have no conflicts of

interest to declare.

Inclusion criteria:

adult patients (age ≥18 years) with NSCLC of any stage who underwent a VATS lobectomy between January 2014 and October 2019 in our

institution.

Exclusion criteria:

Patients with intra-operative conversion to thoracotomy, patients presenting metastatic lesions, and patients with emergency procedures were excluded.

N total at baseline:

Intervention: 140

Control: 167

Important prognostic factors²:

For example

age median (IQR):

I: 67 (59 – 72)

C:67 (60 – 74)

Sex:

I: 47.1% M

C: 58.7% M

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

ERAS protocol

- information by clinical nurse, information booklet.

- two packs of carbohydrate drink the day before the operation, one pack 2 hours before surgery and 3 pack per day during post-operatieve hospitalization.

- no preoperative sedation.

- LMWH VTE prophylaxis

- induction of antbiotic prophylaxis

- intercostal nerve block with bupivacaine and IV perfusion of NSAID and paracetamol; propofol or halogenated anaesthetics gases

- intraoperative warming

- avoidance of fluid overload

- no urinary catheter

- single chest tube, electronic drainage system, suction -20 H2)

- early removal of the chest tube if no air leak over 6 hours and < 400 ml/24h.

- paracetamol, NSAIDs, morphine, tramadol (after chest tube removal)

- prophylaxis with ondansetron, decamethasone 21-phosphate disodium

- early feeding

- mobilization within 24 hours

- postoperatieve transfer to continous care reserved for cardio-pulmonary comorbidities, or difficulty to mobilize.

Describe  control (treatment/procedure/test):

Pre-ERAS

- no education

- no carbohydrate drink

- preoperative sedation

- LMWH VTE prophylaxis

- induction of antbiotic prophylaxis

- epidural catheter or intercostal nerve block with bupivacaine, opioids, paracetamol; halogenated anaesthethics gases or propofol

- intraoperative warming

- no standardized avoidance of fluid overload

- urinary catheter only if epidural catheter

- one or two chest tubes, digital chest drainage or water seal, suction -20 cmH2), drain removed if no air leak over 6 hours and < 250 ml/24h

- post-operative analgesia: paracetamol, fixed doses morphine s.c. tramadol (after chest tube removal).

- PONV not standardized

- early feeding

- no standardized mobilization within 24 hours.

- routinely post-operative transfer to the continuous care.

Length of follow-up:

30 days after surgery.

Loss-to-follow-up:

Not reported.

Incomplete outcome data:

Not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

Not reported.

Overall complications

I: 41/140

C: 61/167

Propensity score-matched average treatment effect: -0.13 (-0.25, -000.3).

Postoperative length of stay

Not reported.

Readmissions (30-day)

I: 5 (3.6%)

C: 9 (5.4%)

quality of life

not reported.

Functional recovery

Not reported.

All patients received VATS

Ni, 2021

Type of study: cohort

Setting and country: retrospective, China

Funding and conflicts of interest: no funding. The authors have no conflicts of interest to declare.

Inclusion criteria:

All patients that underwent thoracoscopic lobectomy were eligible for inclusion

Exclusion criteria:

Patients were excluded if they received secondary surgery due to complications, lack of perioperative related clinical data, formulated perioperative rehabilitation management regulations were not strictly followed during the perioperative period, patients who had refused early discharge.

N total at baseline:

Intervention: 508

Control: 629

Important prognostic factors²:

For example

age ± SD:

I: 60.5 (18.8)

C: 62.9 (16.3)

Sex:

I: 57.1% M

C: 59.5% M

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

ERAS protocol:

Pre-operative:

(I) Detailed preoperative education to make patients aware of the rapid

recovery process and cooperation matters; (II) NSAIDs COX-2 inhibitor was

taken orally 2 days before surgery; (III) correct anemia, lung function training,

nutrition support; (IV) 400 mL of carbohydrate was added to clear fluid 2 h

before surgery; (V) avoid sedative-hypnotic drugs before surgery; (VI) adjust

the preoperative anticoagulation program; (VII) risk assessment of venous

thromboembolism; (VIII) nutritional status assessment

Intraoperative:

I) Preoperative prophylactic use of antibiotics; (II) protective lung ventilation

strategy and body temperature protection measures; (III) the catheter was removed without indwelling or after surgery; (IV) endoscopic vision of the

lower intercostal nerve block; (V) carefully expand the lung to suture air

28# leakage and hemostasis before closing the chest cavity; (VI) all chest

tubes were placed at the top of the chest for drainage; (VII) intraoperative

intravenous fluid supply was limited to about 500 mL, and postoperative daily

fluid supply was less than 1,000 mL

Postoperative:

(I) Intravenous NSAIDs COX-2 inhibitors were used every 12 h for the first

3 days after surgery, and oral administration continued for 4 days on the

fourth day; (II) start to get out of bed 6 h after the operation, and set the

postoperative walking amount; (III) control intravenous fluids; (IV) prevent nausea and vomiting; (V) early removal of chest tube (<500 mL/d); (VI) prevention of deep vein thrombosis; (VII) get out of bed on the day after the

operation. On the first day after the operation, get out of bed with chest tube

twice a day, 6 min/200 m or more each time; (VIII) use a breathing trainer.

Describe  control (treatment/procedure/test):

No ERAS protocol:

Pre-operative:

I) Preoperative fasting and drinking were forbidden for more than 6 h; (II)

anxious patients could be administered preoperative sedative sleep and other

drugs.

Intraoperative:

(I) Preoperative prophylactic

administration of antibiotics; (II) preoperative indwelling catheter and return to ward; (III) minimally invasive

surgery; (IV) superior lobectomy was performed with two roots, and middle

and lower lobectomy was performed 28# with a single

thoracic duct drainage; (V) intraoperative fluid supply

was 1,000 mL, and postoperative fluid

supply was 1,500 mL/d

Postoperative:

(I) On demand opioid intramuscular analgesia; (II) prevention of excessive

vomiting; (III) the chest tube was removed after <200 mL/d; (IV) do not restrict intravenous fluid, according

to the patient’s will to get out of bed, strengthen cough to promote cough; (V)

prevention of deep vein thrombosis; (VI)

stepped-up routine back patting for expectoration.

Length of follow-up:

Not reported.

Loss-to-follow-up:

NA – only complete datasets were included.

Incomplete outcome data:

NA – only complete datasets were included.

Outcome measures and effect size (include 95%CI and p-value if available):

mortality

not reported.

complications

I: 69/508

C: 116/629

Length of stay (d)

I: 2.74 (0.80)

C: 5.70 (1.10)

Readmissions

I: 2 (group A+B+C)

C:1  (group B+C)

quality of life

not reported.

functional recovery

not reported.

Khoury, 2021

Type of study: cohort

Setting and country: retrospective, USA

Funding and conflicts of interest: not reported.

Inclusion criteria:

adult patients undergoing pulmonary resections (wedge resection, segmentectomy, lobectomy and bilobectomy).

Exclusion criteria:

Only a patient’s first thoracic operation was eligible, redo surgeries and unexpected returns to the operation room were excluded, as well as trauma patients. Patients were also excluded when they simultaneously underwent esophagectomy, pneumonectomy, or coronary artery bypass grafting.

N total at baseline:

Intervention: 131

Control: 133

Important prognostic factors²:

For example

age (IQR):

I: 61 (54-68)

C: 64 (55-70)

Sex:

I: 38 % M

C: 50% % M

Groups comparable at baseline? Post-ERAS patients were less likely to be male and more likely to  have preoperative or longstanding steroid use.

Describe intervention (treatment/procedure/test):

ERAS protocol:

Preoperative

- Tobacco cessation Incentive spirometry

education

- Preoperative nutritional screening and

oral carbohydrate loading

Day of surgery:

- Preoperative medications: Tylenol 1000 mg PO, Celebrex 200 mg

PO, Pregabalin 100 mg PO

- Consumption of clear fluids up until 2 h before surgery.

Intraoperative

Analgesia (VATS/RATS):

1. Intercostal blocks (T2-T10 levels) with 1:1 mix of 0.25% plain bupivacaine

liposomal bupivacaine.

2. Ketamine infusion: 0.25 mg

Analgesia (thoracotomy):

Thoracic epidural: 0.25% plain bupivacaine infusion, 3-6 mL/h

Fluids:

Establish and maintain euvolemia; frequent arterial blood gas interpretation.

Blood pressure:

Maintain systolic blood pressure >20% baseline.

Vasopressin 0.02-0.04 units

norepinepherine 0.02-0.04

mg

Mechanical ventilation:

Pressure control ventilation

Recruitment breaths q30min

2 lung: tidal volume 5-8 mL/kg (3-5 for ESLD) IBW, FiO2 <0.5 if possible, PEEP 5

1 lung: tidal volume 4-7 mL/kg IBW, FiO2 1.0 and wean by 0.1 q5min,

PEEP 5-8 (3-5 for ESLD)

Respiratory rate: Keep PaCO2 within 10 mm Hg of baseline Antibiotic prophylaxis Prevention of Postoperative Nausea with

Dexamethasone Venous thromboembolism prophylaxis Prevention of intraoperative hypothermia

Minimally invasive surgical technique (VATS, RATS) or muscle-sparing and

nerve-sparing techniques for thoracotomy

postoperative

Analgesia (VATS/RATS):

- NSAIDs-scheduled

- Ketorolac 15 mg IV q8h or ibuprofen 800 mg PO q8h

24 h on POD 0.

- Transition to Ibuprofen 600 mg PO q6hr PRN on POD 1 and until discharge.

- Gabapentin 300 mg PO TID until discharge.

- Tylenol 650 mg PO QID

Until discharge.

Early mobilization

Early chest tube removal (24-h output <250 mL and no air leak)

Early urinary catheter removal.

Describe  control (treatment/procedure/test):

Pre-ERAS

Not described.

Length of follow-up:

30 days

Loss-to-follow-up:

Not reported.

Incomplete outcome data:

Strength of the study is minimal missing data. No details reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I: 2 (2%)

C: 0 (0%)

Complications (any)

I: 44 (34%)

C: 36 (27%)

Postoperative length of stay

Not reported.

readmissions

I: 13 (10%)

C: 11 (8%)

quality of life

not reported

functional recovery

not reported.

Conclusion: In the first year of implementation, median LOS, complications, and 30-day outcomes did not differ significantly between the pre-ERAS and post- ERAS groups.

Tiberi, 2022

Type of study: cohort

Setting and country: retrospective, Italy

Funding and conflicts of interest:

Inclusion criteria:

Patients were considered eligible for inclusion in E.P.C. program

if: = 18 years of age, American Society of Anesthesiologists

score = 3, and scheduled for elective surgery.

Exclusion criteria:

patients undergoing pneumonectomy,

conversion to open surgery, planned postoperative

intensive-care monitoring, lack of care-giver, inability

to collaborate (language barriers, psychiatric pathology).

N total at baseline:

Intervention: 182

Control: 182

Important prognostic factors²:

For example

age ± SD:

I: 66.2 (10.1)

C: 66.7 (9.8)

Sex:

I: 56% M

C: 53.3% M

Groups comparable at baseline? Yes (matched)

Describe intervention (treatment/procedure/test):

ERAS protocol

- preoperative: patients meets the multidisciplinairy team and were informed about all aspects. In particular, preoperative behavioral changes were persecuted requiring smoking cessation and implmeneting physical activity and nutriotnal programs. Patietns were screened for nutritional status and oral nutrition supplements were given if malnourished. Patients received specific chest physiotherapy instruction and a home training protocol was delivered. Patients received a booklet describing all aspects and the procedures included in the program.

- perioperative: antibiotic and venous thromboembolism were optimized and standardized. Procedrures aimed at preventing hypothermia were implemented, including the use of hot air warming blankets and thermic mattresses. Standard monitoring of vital signs was applied in all patients and it was implemented by the applicaiton of BIS for hypnosis depth and TOF for the depth of miorisolulution in EPC. Anesthesia was inducted by the administration of

Propofol 1–2 mg/kg, Rocuronium 1.2 mg/kg and Fentanyl 3 mcg/kg, followed by continuous administration of desflurane

and remifentanil for the maintenance. Sugammadex

100–200 mg was administered at the end of intervention, based on TOF monitoring, to prevent a Post-Operative Residual Curarisation syndrome. It was provided for a “protective” One Lung of the dependent lung in the E.P.C. group characterized by a tidal volume of 4–5 ml/kg, respiratory rate of 10 Breaths/min and a PEEP of 5

cmH2O.

Perioperative and operative protocols for opioid-free pain management

were systematically adopted in the E.P.C. group,

based on specific loco-regional anesthetic techniques such as paravertebral thoracic (T5) erector spinae plane block by the anesthetist associated with local wound infiltration with

ropivacaine 0.75% by the surgeon. Monitoring by urinary and arterial catheter was exclusively reserved to patients undergoing anatomical resections and removed the morning

after surgery. All patients were extubated at the end of the procedure and transferred to thoracic surgery ward if clinically stable after a 30 min period of monitoring in the

preoperative room.

- postoperative: Early mobilization of the patients and postoperative chest

physiotherapy program started 4–6 h after surgery as well as the oral intake of fluid and solid foods. Opioid-free pain

management was maintained during the postoperative phase,

switching from fractionated intravenous to oral painkillers administration as soon as possible. The use of paravertebral or peri-dural catheters were avoided. In the early first post

operative day, any form of monitoring was suspended unless for complicated patients. Twice daily the expected goals and

the achievements of each day were discussed among patients and all the components of the multidisciplinary team. The

single tube was removed in the second postoperative day if no air leak was registered during the previous 12 h by a

digital chest drainage system and pleural effusion was less than 400 ml/24 h. In case of persistent air leak during the third postoperative day, the patient was discharged with a chest tube connected to a portable chest drainage device, as previously discussed and agreed during the preoperative

counseling.

Describe  control (treatment/procedure/test):

Pre-ERAS

Not described.

Length of follow-up:

30 days after the operation

Loss-to-follow-up:

Not reported.

Incomplete outcome data:

Not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

Not reported.

Overall complications

Not reported, only cardiopulmonary complications.

Postoperative length of stay mean (SD)

Not reported.

Readmissions

I: 3 (1.6%)

C: 9 (4.9%)

quality of life

not reported.

functional recovery

not reported

Bellas-Cotán (2021)

Type of study: cohort

Setting and country: ambispective (prospective ERAS, retrospective control), Spain

Funding and conflicts of interest: The authors declare no conflict of interest.

Inclusion criteria:

patients undergoing lobectomy

Exclusion criteria:

Patients who refused to take part or were under 18 years of age.

N total at baseline:

Intervention: 50

Control: 50

Important prognostic factors²:

For example

age (IQR)

I: 64 (57 – 70.8)

C: 64.5 (53.5 – 70)

Sex:

I: 50% M

C: 62% M

Groups comparable at baseline? A higher number of patients in the standard cohort had hypertension and COPD.

Describe intervention (treatment/procedure/test):

ERAS

Our center’s ERAS program includes different strate-

gies for the preoperative, intraoperative, and postoperative

periods. During the preoperative period, the patients and their families received comprehensive multidisciplinary

information about the protocol, the steps to be taken during each day of hospitalization, and the expected discharge date. Patients were taught a series of pulmonary expan-

sion exercises to be performed until surgery by a team specialized in treating lung diseases. Smoking cessation

interventions and nutritional screening were also performed

at this stage.

Patients underwent

VATS whenever possible, placing a chest tube for

drainage at the end of the surgery. All subjects received antibiotics and antithrombotic prophylaxis.

We performed general anesthesia combined with

regional techniques for pain control, avoiding benzodi-

azepines and opioids. The anesthesiologist was free to

choose between thoracic epidural analgesia, intercostal block, and erector spinae block. If a thoracic epidural

catheter was placed, it was left in for postoperative

patient-controlled analgesia. We also used a hot air system to warm patients during surgery to maintain normothermia.

In both groups, no more than 2 mL.kg-1.h-1fluids were administered. Extubation was performed as soon as possible

after the end of the surgery, and we encouraged early

removal of the urinary catheter.

After extubation, patients started oral intake, respira-

tory physiotherapy exercises, and early ambulation. Patients

were discharged when they were free of complications,

without severe pain, and the urinary catheter or chest tube had been removed.

Describe  control (treatment/procedure/test):

Standard care (not specified)

None of the patients in either group fasted for more than 2 hours before

surgery.

Length of follow-up:

We followed up patients for 30 days after surgery using

hospital and primary care medical records.

Loss-to-follow-up:

Not reported.

Incomplete outcome data:

Not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I: 0 (0%)

C: 2 (4%)

Overall complications

Not reported, surgical complications and other complications are reported separately. unknown whether this is in different patients.

Postoperative length of stay not reported.

readmissions

I: 6 (12%)

C: 15 (30%)

quality of life

not reported

functional recovery

not reported

Del Calvo, 2020

Type of study: case-control

Setting and country: retrospective, USA

Funding and conflicts of interest: No funding. The other authors have no conflicts of interest

to declare.

Inclusion criteria:

All patients who underwent

elective minimally invasive pulmonary resection.

Exclusion criteria:

diagnostic wedge procedures, emergent or

urgent pulmonary resections, and pulmonary resections as

part of the “two-step” procedure for cardiac sarcoma with pulmonary resection.

N total at baseline:

Intervention: 90

Control: 221

Important prognostic factors²:

For example

age (IQR)

I: 67 (58-73)

C: 67 (57-73)

Sex:

I: 60% F

C: 52.5% F

Groups comparable at baseline? There was a higher number of patients with diabetes in the control group. There was a significant higher number of patients in the ERS group compared to control who underwent robot assisted surgery.

Describe intervention (treatment/procedure/test):

ERAS protocol

The pre-operative stage was developed to get the patient ready for surgery, with an emphasis on

quitting smoking, learning to use the incentive spirometer, and walking 1 mile per day.

The operative stage included intravenous anesthesia, minimizing fluids and minimally

invasive surgery. In addition, all patients received a direct

injection of undiluted liposomal bupivacaine block of the 2nd to 10th intercostal nerves from inside of the chest

cavity.

The post-operative stage included an around-the

Clock scheduled analgesic and emphasis on early mobility, including an incentive spirometer. We also transitioned

to prescribing tramadol as a default discharge pain

medication for all patients at discharge from hydrocodone/

acetaminophen.

Describe  control (treatment/procedure/test):

Control

No pre-operative regimen

No intra-operative regimen

Post-operative regimen: hydromorphone PCA

Default discharge medication: hydrocodone / acetaminophen.

Length of follow-up:

4 weeks after surgery

Loss-to-follow-up:

Not reported.

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

Not reported

Overall complications

I: 21 (23.3%)

C: 84 (38%)

Postoperative length of stay not reported.

readmissions

I: 3 (3.3%)

C: 25 (11.3%)

quality of life

not reported

functional recovery

not reported

Wu, 2020

Type of study: cohort

Setting and country: retrospective, China

Funding and conflicts of interest: Funding is not reported. The authors declare no conflict of interest.

Inclusion criteria:

1) patients definitely diagnosed with lung cancer through preoperative fiberopti

bronchoscopy or intraoperative frozen pathology and receiving no radiotherapy or chemotherapy; 2) those who could tolerate surgery based on the physical status,

with the Karnofsky Performance Score (KPS) score =70 points; 3) those who were able to tolerate surgery

according to heart and lung functions and had basically

normal liver and kidney functions; and 4) those who had no metastases or severe diseases of other organ

systems as indicated by whole-body PET or CT

examinations.

Exclusion criteria:

1) patients with tumors which were too large or involved the vessels and trachea; 2) those with cancer cells found in the pleural effusion; 3) those who encountered conversion to thoracotomy

since extensive pleural adhesions were found

intraoperatively; 4) those for whom single-hole thoracoscopic

surgery was converted to thoracotomy due to

uncontrolled intraoperative bleeding; 5) those with distant

metastases or severe anemia; 6) those complicated

with severe heart, lung, liver or kidney dysfunction; 7)

those complicated with other malignancies; or 8) those with poor compliance.

N total at baseline:

Intervention: 76

Control: 76

Important prognostic factors²:

For example

age ± SD:

I: 65.11 (10.43)

C: 63.94 (10.59)

Sex (M/F):

I: 41/35

C: 46/30

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

- preoperative health education and mental support were completed.

- before operation, patients were informed, physical exercise and respiratory function exercise were performed, malnourished patients were given appropriate nutritional support, all patients were fasted for food 6h before operation, allowed to drink 300-500 ml of water 4h before operation and IV dripped with antibiotics 30 min before operation.

- intraoperative: The patients were kept warm during routine

disinfection and generally anesthetized using drugs with a short half-life. The incision was protected by an incision protection sleeve, and the operations should be gentle to avoid excessively pulling and squeezing lung tissues.

Moreover, restricted fluid infusion was conducted,

with the fluid volume <1,000 mL, and vasoactive drugs were used to raise the blood pressure. Finally, a pleural drainage catheter was indwelled and led out from the incision.

- postoperative: On the day of operation, the patients were instructed to do sit-ups on the bed for 2-3 times. Additionally, they were encouraged to

actively move their lower limbs or their family members massaged the patients’ lower limb muscles, combined

with the adjutant pneumatic pump therapy, to prevent deep-vein thrombosis. At 6 h after operation, the patients

were given water and liquid food

- day 1 postoperative: the patients ate normally eat in the morning, and they were encouraged to get off bed and ambulate for 4-6 times (about 10 min/time). The ambulation time was extended 2 days after operation. Additionally, the

patient-controlled analgesia pump was applied to ease

pain, and the patients were encouraged to cough and

expectorate.

- extubation indications: The chest tube was squeezed once every 30 min to avoid blocking tube opening

and ensure the smooth drainage of intrapleural fluid thereby accelerating the recovery of pulmonary function. Finally, the tube was removed when there was no air leak of the closed thoracic drainage bottle, and no bloody, chylous or purulent pleural effusion, X-ray chest imaging indicated favorable lung recruitment, with the 24 h-pleural drainage volume <200 mL, and the postoperative

daily intravenous fluid infusion was controlled

to be <800 mL.

Describe  control (treatment/procedure/test):

- patients and their family members were informed of the preoperative smoking cessation and breathing exercise.

- day 1 before operation: patients and family were routinely informed and on the evening the patients ate liquid food.

- 10h before operation patients deprived of food and water.

- intraoperatively: blood volume was routinely enlarged to increase BP.

- 24h after surgery: patients were given food and water, analgesics and provided with rehabilitation guidance.

- extubation indications: no air leak, pleural effusion was not bloody, chylous or purulent, chest x-ray imaged indicated complete lung recruitment, pleural drainage volume <100 ml.

Length of follow-up:

Not reported.

Loss-to-follow-up:

Unknown, not reported.

Incomplete outcome data:

Unknown, not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

Not reported.

Overall complications

not reported, complications are reported separately. However unknown if they occurred in the same patients.

Length of stay (postoperative)

I: 5.2 (+/-0.8)

C: 7.2 (+/-1.1)

Readmissions

Not reported

Quality of life

Not reported

Functional recovery

Not reported.

Author, year

Selection of participants

Was selection of exposed and non-exposed cohorts drawn from the same population?

Exposure

Can we be confident in the assessment of exposure?

Outcome of interest

Can we be confident that the outcome of interest was not present at start of study?

Confounding-assessment

Can we be confident in the assessment of confounding factors? 

Confounding-analysis

Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these confounding variables?

Assessment of outcome

Can we be confident in the assessment of outcome?

Follow up

Was the follow up of cohorts adequate? In particular, was outcome data complete or imputed?

Co-interventions

Were co-interventions similar between groups?

Overall Risk of bias

Definitely yes, probably yes, probably no, definitely no

Definitely yes, probably yes, probably no, definitely no

Definitely yes, probably yes, probably no, definitely no

Definitely yes, probably yes, probably no, definitely no

Definitely yes, probably yes, probably no, definitely no

Definitely yes, probably yes, probably no, definitely no

Definitely yes, probably yes, probably no, definitely no

Definitely yes, probably yes, probably no, definitely no

Low, Some concerns, High

Wang, 2021

Definitely no

Reason: Participants were selected from different time periods.

Definitely yes

Reason: Protocols differed significantly, washout period was applied.

Probably yes

Reason: however patients with previous lung resections were not excluded on beforehand.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Probably yes

Reason: multivariable analyses were performed to assess the risk to postoperative pulmonary comlications.

Probably yes

Reason: data was obtained from medical records.

Unclear

Reason:

Nothing was reported on follow-up.

Definitely no

Reason: The surgical approach was different between the groups (more VATS versus open) which may have biased the results.

High (all outcomes)

Tiberi, 2022

Definitely no

Reason: Participants were selected from different time periods.

Probably no

Reason: No transition period was used.

Probably yes

Reason: however patients with previous lung resections were not excluded on beforehand.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Probably yes

Reason: propensity-score matching was used to adjust for confounders. 

Probably yes

Reason: data was obtained from medical records.

Probably yes

Reason:

30-day follow-up.

Probably yes

Reason: patients were matched according to their type of surgery (among other variables). 

High (all outcomes)

Peng, 2021

Definitely no

Reason: Participants were selected from different time periods.

Probably no

Reason: No transition period was used.

Probably yes

Reason: however patients with previous lung resections were not excluded on beforehand.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Definitely no

Reason: adjustment for confounders was not performed.

Probably yes

Reason: data was obtained from medical records.

Probably yes

Reason:

30-day follow-up.

Outcome data was complete.

Definitely no

Reason: The surgical approach was different between the groups (minimal invasive versus open) which may have biased the results.

High (all outcomes)

Forster, 2021

Definitely no

Reason: Participants were selected from different time periods.

Probably no

Reason: No transition period was used.

Probably yes

Reason: however patients with previous lung resections were not excluded on beforehand.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Probably yes

Reason: propensity-score matching was used to adjust for confounders and multivariable analyses were preformed.

Probably yes

Reason: data was obtained from medical records.

Probably yes

Reason:

30-day follow-up.

Outcome data was complete.

Probably yes

Reason: all patients received VATS.

High (all outcomes)

Ni, 2021

Definitely no

Reason: Participants were selected from different time periods.

Probably no

Reason: No transition period was used.

Definitely yes

Reason: patients with previous lung resections were excluded.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Definitely no

Reason: adjustment for confounders was not performed.

Probably yes

Reason: data was obtained from medical records.

Probably yes

Reason:

30-day follow-up.

Outcome data was complete. Incomplete data records were excluded.

Probably yes

Reason: all patients received minimally invasive lobectomy.

High (all outcomes)

Khoury, 2021

Definitely no

Reason: Participants were selected from different time periods.

Probably yes

Reason: a wash-in period was excluded as the ERAS protocol was not fully implemented yet.

Definitely yes

Reason: patients with previous lung resections were excluded.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Probably yes

Reason: multivariable analyses were preformed.

Probably yes

Reason: data was obtained from medical records.

Probably yes

Reason:

30-day follow-up.

Outcome data was complete.

Definitely no

Reason: The surgical approach was different between the groups (more VATS versus open) which may have biased the results.

High (all outcomes)

Bellas-Cotás, 2021

Definitely no

Reason: Participants were selected from different time periods.

Definitely yes

Reason: a transition period was included.

Probably yes

Reason: however patients with previous lung resections were not excluded on beforehand.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Definitely no

Reason: adjustment for confounders was not performed.

Probably yes

Reason: data was obtained from medical records.

Probably yes

Reason:

30-day follow-up.

Probably yes

Reason: The surgical approach was different between the groups (more VATS versus open) which may have biased the results.

High (all outcomes)

Del Calvo, 2020

Definitely no

Reason: Participants were selected from different time periods.

Probably no

Reason: No transition period was used.

Probably yes

Reason: however patients with previous lung resections were not excluded on beforehand.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Definitely no

Reason: adjustment for confounders was not performed.

Probably yes

Reason: data was obtained from medical records.

Unclear

Reason:

Nothing was reported on follow-up.

Probably yes

Reason: all patients received minimal invasive surgery.

High (all outcomes)

Wu, 2020

Definitely no

Reason: Participants were selected from different time periods.

Probably no

Reason: No transition period was used.

Probably yes

Reason: however patients with previous lung resections were not excluded on beforehand.

Probably yes

Reason: data was collected from hospital records, similar data was obtained for both time periods.

Definitely no

Reason: adjustment for confounders was not performed.

Probably yes

Reason: data was obtained from medical records.

Unclear

Reason:

Nothing was reported on follow-up.

Probably yes

Reason: all patients received minimal invasive surgery. 

High (all outcomes)