Background
Recent developments in large bowel surgery are the introduction of laparoscopic surgery and the implementation of multimodal fast track perioperative care programs. Both focus on enhanced recovery and shorter hospital stay as compared to open surgery and traditional care. Laparoscopic colectomy was first described in 1991
At the same time, enthusiasm was raised for the so-called fast track perioperative care program, also referred to as Enhanced Recovery After Surgery (ERAS®), which essentially is a modification of the program initially developed by the Danish surgeon Henrik Kehlet
As these new developments have been introduced in clinical practice, time has come to evaluate their feasibility, safety, and cost-effectiveness in large bowel surgery in a randomized controlled setting. It can be hypothesized that fast track and/or laparoscopy are associated with less attenuation of the patient's condition after surgery resulting in a shorter postoperative hospital stay, a faster recovery to full activity at home, and a better quality of life.
Since it has not been established which combination of perioperative management and surgical approach
Methods/design
Study objectives
The objective of this study is to determine whether laparoscopic surgery, fast track perioperative care or a combination of both is to be preferred over open surgery with standard care in patients undergoing segmental colectomy for malignant disease. The objective is subdivided in three research questions; first, how laparoscopic surgery compares to open surgery in terms of hospital stay, quality of life and costs? Second, how fast track perioperative care compares to standard care in terms of hospital stay, quality of life, and costs? Finally, what is the added benefit of fast track perioperative care program in laparoscopic surgery in terms of hospital stay, quality of life and costs?
Study design
The LAFA-trial is a randomized multicenter trial, designed as a 2 × 2 balanced factorial design. Patients are blinded for the type of intervention
LAFA-study Flowchart
LAFA-study Flowchart. R = randomization, SF-36 = Short Form 36, GIQLI = Gastro-Intestinal Quality of Life Index, POSSUM score = Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity.
Randomization is performed by an Internet randomization module. Block-randomization is used and the randomization is stratified for the randomizing centers.
Primary and secondary endpoint
The primary endpoint of the LAFA-study is total postoperative hospital stay in days, including hospital stay of patients who are readmitted within 30 days after surgery.
Secondary endpoints are quality of life at two and four weeks after surgery. Quality of life will be measured by two validated questionnaires; Short Form 36 (SF-36) and the Gastro-Intestinal Quality of Life Index (GIQLI). Further secondary endpoints are; medical and non medical costs, morbidity, and mortality within 30 days after surgery, patient satisfaction measured by standardized questionnaires, and readmission rate.
Participating centers
Seven Dutch hospitals of the LAFA-study group, including three academic centers and four non-academic centers, will enroll patients.
Study population
The study population consists of patients eligible for segmental colectomy for malignant colorectal disease viz. right and left colectomy and anterior resection.
Inclusion criteria are; age between 40 and 80 years, colorectal cancer including colon and recto sigmoid cancers, ASA I-III, and informed consent.
Exclusion criteria are; prior midline laparotomy, ASA IV, laparoscopic surgeon not available, emergency surgery and a planned stoma.
Ethics
This study is conducted in accordance with the principles of the Declaration of Helsinki and 'good clinical practice' guidelines. The independent medical ethics committees of the participating hospitals have approved the study protocol. Prior to randomization, written informed consent will be obtained from all patients.
Study outline
Informed consent will be obtained at the outpatient department if the patient fulfills the inclusion and exclusion criteria. Randomization is performed instantly through the study website.
The randomization produces four treatment groups; open colectomy with standard care (a), open colectomy with fast track perioperative care (b), laparoscopic colectomy with standard care (c), and laparoscopic surgery with fast track perioperative care (d) (see Figure
Patients that are randomized to fast track perioperative care will be informed by a "fast track" trial nurse and by the anesthesiologist about the essence of the fast track program. Appointments for these consultations will be made after consulting the surgeon and randomization has been done. All patients randomized to have a fast track perioperative treatment will be admitted to a separate "fast track" ward, where the nurses and medical staff are trained in fast track perioperative management.
Patients who will receive standard treatment are not counseled by the fast track nurse and will have a standard preassessment by the anesthesiologist.
Patient and medical staff will be blinded for the surgical approach until the day of discharge by applying a covering abdominal bandage.
Surgery
Both open and laparoscopic surgery is done according to the technique applied by the local surgeon. Antibiotic prophylaxis is done according to hospital protocol. All patients will have two enemas before surgery (evening before and morning before). After surgery the surgical wounds are covered with a abdominal dressing in order to blind the medical staff for the type of approach. A requirement for the participating laparoscopic surgeons to perform laparoscopic colectomy for cancer is a minimum of 20 laparoscopic colectomies for benign disease as indicated by the proclamation of the American Society of the Colon and Rectum Surgeons in 2004
Fast track and standard care
Comparison of the different strategies is only possible when a fast track program is running sufficiently and patients are nursed separately depending on the results of randomization either on a standard care or fast track ward in order to avoid a bias towards fast track treatment by the nursing and medical staff. Patients that have standard care cannot be nursed by nurses that have experience with fast track care. Fast track multimodal management is done according to the protocol summarized in Table
The essence of the fast track care program and standard care program.
- Scheduling of operation
-Information about the fast track program
-Informed consent
- Scheduling of operation
-Informed consent
- Pre-assessment for risk adjustment
-Discussion focusing on placement of thoracic epidural catheter for management of perioperative analgesia
-Discussion of the essence of the fast track program
- Pre-assessment for risk adjustment
-Open discussion about different possibilities for management of perioperative analgesia
- Yes
- No
- Additional fast track information
- Routine
- Only enema
- Only enema
- 4 units (preOp®)
- No
- Last meal 6 h before operation
- Last meal until midnight
- Lorazepam, 1 mg the evening before operation,
- Lorazepam, 1 mg or Temazepam 10 or 20 mg
- No, 2 units CHL 2 h before surgery
- Yes
- No
- Lorazepam 1 mg, or Midazolam 7.5 mg
- Placement of thoracic epidural catheter (T6–T10, depending on the surgical resection);
-Combined with balanced general anesthesia
-Restricted per-operative fluid infusion regime (Ringers lactate 20 ml.kg-1 in the 1st h followed by 6 ml.kg-1.h-1)
-Use of vasopressor drugs as 1st choice for management of mean blood pressure drop > 20% of baseline
-Forced body heating (Bair hugger system and warmed IV fluids)
-Removal of naso-gastric tube before extubation
-Prophylactic use of Odansetron (4 mg) to prevent PONV
- Placement of thoracic epidural conform fast track group, or lower level, or PCA-pump.
-Combined with balanced general anesthesia
-Standard per-operative fluid infusion regime (Ringers lactate 20 ml.kg-1 in the 1st h followed by 10–12 ml.kg-1.h-1)
-Use of extra fluid challenge as 1st choice for management of mean blood pressure drop > 20% below baseline
-Forced body heating (Bair hugger system and warmed IV fluids)
-Removal of naso-gastric tube before extubation
-Use of Odansetron, Dexamethason or Droperidol for PONV management according to attending anesthesiologist
- Minimal invasive incisions/laparoscopy
-Supra-pubic urine catheter
-Infiltration of surgical wounds with Bupivacaine
-No standard use of abdominal drains
- Median laparotomy approach/laparoscopy
-Urine catheter according to attending surgeon
-No infiltration of surgical wounds with local anesthetic drugs
-No standard use of abdominal drains
- Use of epidural catheter as mentioned before to which Paracetamol 4 × 1 g.d-1 is added
-First oral drinks at 2 h post-surgery, supplemented with CHL liquids, 2 units (Nutridrink®)
-IV infusion of Ringers lactate 1.5 l.d-1
-Mobilization in the evening (>2 h out of bed)
-First semi-solid food intake in the evening
- Epidural or PCA-morphine to which Paracetamol 4 × 1 g.d-1 and/or Diclofenac 3 × 50 mg.d-1 are added
-Small amount of water orally
-IV infusion of Ringers lactate 2.5 l.d-1
-No mobilization scheme
- Oral intake > 2 l (including 4 units CHL liquids)
-Normal diet
-Stop IV fluid administration (leave canulla)
-Start laxative (MgO, 2 × 1 g.d-1)
-Close supra-pubic urine catheter and remove when residue < 50 ml
-Expand mobilization (> 6 h out of bed)
- Diet increased on daily basis
-IV fluid administration (2.5 l.d-1) is continued till adequate oral fluid intake
-Mobilization according to attending surgeon
DAY 2 AFTER SURGERY
- Remove epidural add Diclofenac 3 × 50 mg.d-1
-Remove IV cannula
-Continue Paracetamol 4 × 1000 mg and laxative
-Normal diet
-Expand mobilization (> 8 hours)
-Plan discharge
- Epidural removed according to attending anesthesiologist
-Continue as on day 1 untill discharge criteria are fulfilled
DAY 3 AFTER SURGERY
- Continue as on day 2 untill discharge criteria are fulfilled
Continue as on day 2 untill discharge criteria are fulfilled
CHL: CarboHydrate Loaded, PCA: Patient Controlled Anesthetics, IV: Intra Venous, PONV: PostOperative Nauseaand Vomiting, MgO: Magnesium Oxide
Discharge criteria
Since hospital stay is a primary efficacy parameter, the discharge criteria are defined. Every postoperative day will be noted whether the discharge criteria are met, and other reasons of prolonged hospital stay
Statistical analysis
Intention to treat
The analysis will be performed in accordance with the intention to treat principle.
Sample size calculation
Since both, fast track care and laparoscopy focus on earlier recovery resulting in a reduction of hospital stay, the latter is used as primary efficacy parameter. The mean postoperative hospital stay for segmental bowel resection with standard care is 9 days with a standard deviation of 2.5 days in the Academic Medical Center Amsterdam. Using a 5% significance level, a total sample size of 400 would have a power of >95% to detect a minimum reduction of 1 day in hospital stay between laparoscopic surgery and open surgery, a 1 day reduction in hospital stay between fast track care and standard care, and a power of 80% to detect the same difference between the combination of fast track care with laparoscopic surgery and current treatment.
A much larger difference can be expected between the treatment groups, for instance open surgery and standard care compared to fast track perioperative care and laparoscopic surgery. In order to obtain results with adequate precision we have calculated group size using a difference of 1 day rather than the expected 2–4 days. With a group size of one hundred patients per arm it is possible to find a significant difference (alfa = 0.05, beta = 0.1) of at least 10% in subscales of the SF-36, a validated Quality of life Questionnaire, at two weeks after surgery
Economic evaluation
The marginal direct medical, non-medical and time cost differences will be calculated for the four treatment strategies. These will include the additional costs of laparoscopy, of fast track care, as well as the differences due to complications and readmissions.
Data collection and monitoring
Data are collected via a secured Internet module which is specially designed for the LAFA-study. Data are collected daily until the day of discharge. Preoperatively, and at two and four weeks postoperatively the questionnaires (SF-36/GIQLI) are filled in by the patient. One month postoperatively, the general practitioner is contacted to inform whether he/she was contacted by the patient for problems related to the operation.
There will be regular contact between the study coordinators and the participating centers. One research fellow will monitor the included data of every patient.
Discussion
Fast track programs in colonic surgery have been introduced more than a decade ago with favorable early results. Many elements of these fast track programs are based on solid evidence derived from randomized trials and systematic reviews. However, it is quite surprising, that implementation in daily practice has so far stayed behind
Both, laparoscopic surgery and fast track programs are costly and require extensive expertise. Laparoscopic surgery is costly due to expensive disposables and additional operating time. Furthermore, a considerable learning curve must be mastered. Only 5–8% of the colectomies are therefore done laparoscopically in the Netherlands. Fast track multimodal perioperative care requires additional personnel trained in several aspects of the fast track program to make the program work. It is clear that both, laparoscopic surgery and fast track programs enhance recovery and thereby reduce hospital stay
The largest reduction in hospital stay can probably be achieved by a combination of fast track programs and laparoscopic surgery. However, it is not known what the additional costs of laparoscopic surgery or fast track programs are compared to the reduction in hospital stay that can be achieved with these programs. Since the average postoperative hospital stay after segmental colectomy is still considerable in the Netherlands as well as throughout Europe, an enormous improvement can be expected applying fast track programs and/or laparoscopy. What the relative contribution is in reduction in hospital stay of both methods is unknown. This must be assessed in a setting where patients are blinded for the approach of surgery. The randomized controlled LAFA-trial was conceived to determine whether laparoscopic surgery, fast track perioperative care or a combination of both is to be preferred over open surgery with standard care in patients undergoing segmental colectomy for malignant disease.
Abbreviations
LAFA-trial: LAparoscopy and/or Fast track multimodal management versus standard care trial
ASA: American Society of Anaesthesiologists
ERAS®: Enhanced Recovery After Surgery
GIQLI: Gastro-Intestinal Quality of Life Index
SF-36: Short Form-36
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
JW drafted the manuscript. WAB co-authored the writing of the manuscript. All other authors participated in the design of the study during several meetings and are local investigators at the participating centers.
All authors edited the manuscript and read and approved the final manuscript.