Restricted Fluid Therapy in Colorectal Surgery
Restricted Fluid Therapy in Colorectal Surgery
This is a protocol for a trial carried out from 1999 to 2002. At that time, surgical patients
 received a large volume of intravenous saline during operations on the colon or the rectum,
 often so much fluid that their bodyweight increased by 4-6 kilograms. We hypothesized; that a
 restricted fluid regimen could prevent the development of cardiopulmonary complications and
 improve wound healing including the healing of an anastomosis of the gut.

 We designed a clinical randomized assessor blinded multi-center trial comparing a restricted
 fluid regimen to a standard fluid regimen, the difference being the volume of saline
 administered to the patients. Patients undergoing surgery on the colon or the rectum were
 included after informed oral and written consent.

 The restricted regimen aimed at zero-fluid balance with allowance for a body weight increase
 of 1 kg. The standard regimen was a bit "dryer" than the actual standard; our patients in the
 standard group received saline causing a body weight increase of only 3-4 kg. The fluid
 therapy started at midnight the day of operation, went on through the operation and continued
 on the wards until discharge. The patients were encouraged to eat and drink as much and as
 soon as possible after the operation.

 The primary outcome was the number of patients who died or suffered a complication measured
 within 30 days of surgery. We looked at all complications, but especially heart and lung
 complications and complications related to the healing of wounds and anastomosis.

 The patients was examined in the outpatient clinic after 30 days, and in addition, blinded
 assessors were reviewing the medical files for registration of postoperative complications.

 The results are published in The Annals of Surgery 2003; 238(5)641-48. The restricted regimen
 nearly halved the number of patients with complications, and heart and lung complications
 were almost eliminated.

 Other investigators confirmed the results, and a more restricted approach to fluid therapy to
 surgical patients has been implemented worldwide.
Aim:

 To show the effect of a restrictive fluid regime compared to a standard regime by the
 frequency of complications in patients undergoing colorectal surgery.

 Background:

 Previous studies have risen suspicions of fluid balance, and especially a large amount of
 water and NaCl administration, can be a significant factor in developing postoperative
 complications (1, 2).

 In 1990 in Critical Care Magazine, Lowell et al. described patients who in transferring to
 intensive therapy had an increased weight of > 10% of their preoperative weight, had a
 significantly higher mortality rate of 31.6 % than patients with an increased weight of <
 10%, who only had a mortality rate of 10.3 %.

 Some studies, have described, how all patients undergoing gastroenterological operations
 increase their body weight by 2-4% of the preoperative weight during the first 24 hours
 following surgery due to the perioperative saline intravenously (2, 3). The patients have
 been given a median of 6-7 L saline intravenously during the day of operation. This is fully
 comparable to other studies (3, 5).

 Based on previous guidelines in anesthesiological departments, a volume of saline of 15 ml/kg
 bodyweight was administered during the first hour of surgery, and 7.5 ml/kg during the
 following hours. Furthermore, any blood loss was replaced by 2.5 ml saline per ml blood lost
 (6-9).

 The patients in the study by Beier-Holgersen et al. returned to their preoperative weight
 after 4-5 days. In this material of 60 patients, six patients developed leakage of the bowel
 anastomosis, and two patients died from AMI and ARDS. Nine patients with severe complications
 had a weight gain of 6-14%.

 The increased postoperative fluid retention results in increased universal edema, which can
 significantly affect the tissue's microcirculation and oxygenation. This may have influenced
 the healing of intestinal anastomoses and the development of cardiovascular and pulmonary
 complications, which typically occurred during the third postoperative day. Based on this, it
 is therefore relevant to investigate whether perioperative intervention against fluid
 administration can improve the postoperative course.

 Design:

 Prospective randomized multicenter study with stratification for each center. Block
 randomization with four patients per block. It is necessary to incorporate several centers
 for the investigation to be finished within a reasonable time.

 Material:

 Two x 70 patients scheduled for colorectal resection. The number is determined from previous
 works (1, 2) finding a total complication rate of at least 30% after colorectal resection in
 post-operatively early-nourished patients. The investigators wish to reduce this to 10%
 (MIREDIF = 20%). The risk of Type 1 error (5%) is set low to avoid overlooking a possible
 gain. The risk of Type 2 error is set at 20% (power at 80%).

 As the material is unlikely to meet the normal distribution, the number of participant's
 increases to 70 in each group, i.e. 140 patients must be included. In order to reduce the
 variation, each center must include at least 16 patients (which means that up to nine centers
 have to participate).

 Method:

 1. Patients are included preoperatively after informed consent. An investigator at the
 local center randomize the patients to either standard fluid treatment or restrictive
 perioperative fluid treatment. The main difference between the two regimes is that less
 isotonic saline is administered in the restrictive regime. Anesthesia and postoperative
 nutrition regimes are the same in the two groups. The patients are ASA and Apache 2
 scored.

 2. Weight registration: The patient is weighed on the same set of scales at the time of
 hospitalization (entry weight), after bowel cleansing, and in the morning on the day of
 operation (preoperative weight). Hereafter daily weighing every postoperative morning.

 3. Blood tests: Blood is withdrawn on the day of hospitalization, on the day of operation
 in the morning, on arrival in the recovery ward and the following 7 days (or until
 discharged).

 4. Anesthesia: Patients must fast for food from midnight before surgery, but they can have
 clear fluids up to 2 hours preoperatively, but max. 500 ml from midnight.

 Premedication is a tablet of Triazolam 0.125 mg with 50-100 ml of water by mouth.

 Combined epidural and general anesthesia are used: An epidural catheter is inserted
 corresponding to TH10-12, tested with Lidocaine 2% and adrenaline 3-4 ml. After 3-5
 minutes this is supplemented with refracted doses of Bupivacaine 0.5% until the blockade
 is sufficient (often about 8-12 ml). Continuous infusion of Bupivacain is administered
 0.5%, 4-8 ml/hour. Finally, a bolus injection of 2 mg Morphine is administered. General
 anesthesia is induced with Fentanyl 5μg/kg, Thiopental 3-4 mg/kg and Rocuronium
 (Esmeron®) 0.6 mg/kg (all doses are modified according to each patient's needs and
 cardiovascular condition). Anesthesia is maintained with Isoflurane 0.2-0.4% end-tidal
 concentration in oxygen / atmospheric air (inspiratory oxygen concentration 30-35%). The
 neuromuscular block can be reverted with neostigmine when needed.

 Hypotension Diagnosis and Treatment: Detailed guidelines for clinical treatment and
 handling are given in the case report forms (CRF).

 5. Perioperative fluid treatment: During operation, fluid is submitted and recorded in the
 CRF. Fluid balance is calculated at the end of anesthesia.

 6. Monitoring: Standard anesthesia monitoring as recommended by Danish Anesthesiological
 Society. A central vein catheter (CVK) is placed if needed after the initiation of
 anesthesia to measure central venous pressure (CVP) until the patient is discharged from
 the recovery ward. Arterial blood gases and hematocrit are withdrawn immediately after
 the initiation of anesthesia, immediately after arriving at the recovery ward and before
 the patient is transferred to the surgical ward, in addition to clinical needs.

 7. Surgery: Surgery is performed in accordance with the department's routines. During the
 surgery, a nutritional feeding tube is inserted in the duodenum for postoperative
 enteral nutrition. If the tube cause nausea, the tube is removed and the patient will
 consume nutrition according to ability by mouth.

 Antibiotic prophylaxis, bowel cleansing, physiotherapy, etc. follow the usual guidelines
 of the respective departments.

 8. Postoperative fluid treatment and nutrition during the day of operation: Fluid
 recordings continue from the end of the anesthesia, on the recovery ward and for the
 rest of the day of operation. On the day of operation, 600 ml of Nutri-concentrated 75
 is given in the feeding tube. Nutri-concentrated 75 contains 200 kcal and 7.5 g protein
 per 100 ml. 1000 ml pr. Day cover the recommended daily allowances for vitamins and
 minerals.

 9. Fluid treatment and nutrition in the following days: Nutri-concentrated 75® 1000 ml/day
 is continued the first three postoperative days. Thereafter the patient is expected to
 eat normally. The fluid regime in the restrictive group assessed based on the patient's
 weight, ability to drink independently and blood samples. The standard regime follows
 the department's usual postoperative regime.

 10. Postoperative analgesia: The basis is an epidural infusion of the standard mixture of
 Bupivacain-Morphine (5 mg Morphine + 250 mg Bupivacain in NaCl to the volume of 100 ml),
 4-8 ml/hour. In addition, Morphine 5-10 mg p.n. If there are no contraindications,
 Paracetamol or NSAID can be administered (orally or rectally). The epidural pain
 treatment is continued postoperatively for a maximum of 4 days, after which the epidural
 catheter is removed. If the patient need analgesics hereafter, opioid is given by mouth
 or intravenously as well as Paracetamol and/or NSAIDs.

 11. For the treatment of nausea the following may be given: Ondansetron (Zofran®), Cisapride
 (Prepulsid®), Metoclopramide (Primperan®) or DHB.

 12. A postoperative outpatient visit with the investigating doctor is planned 4 weeks after
 the surgery. Postoperative complications are registered.

 Ethics:

 Participation in the project is voluntary and inclusion is after informed consent. Consent
 can be withdrawn at any time without further explanation, and without this affecting the
 patient's treatment in any way.

 There is no risk associated with participation in the project, but discomfort associated with
 additional blood sampling for the project, no more than 4-5 times. However, these blood
 samples will preferably be taken from the CVK, so the patient avoids being stabbed
 unnecessarily.

 In the long term, a treatment benefit is possible and this appears to outweigh the discomfort
 mentioned above.

 The project is registered with the Scientific Ethics Committee (multicenter study) and The
 Danish Data registration agency in accordance with applicable guidelines. All
 person-identifiable data is destroyed after the project is completed.

 Addendum to the protocol written during the patient inclusion and before the trial was
 completed.

 Hypothesis:

 Both too little and too much fluid administered intravenously may be harmful to the cardiac
 function (low oxygen supply and congestion) and cause cardiovascular complications:
 Postoperatively developed arrhythmias, AMI, pneumonia, pulmonary congestion, postoperatively
 developed pleural exudate, pulmonary edema or ARDS.

 Both too little and too much fluid administered intravenously may be harmful to tissue
 healing (low oxygen supply and interstitial edema) and cause complications related to tissue
 healing and infection: Infections of the wound, bursting of the wound (superficial and
 deeper), leakage from the anastomosis and separation of stoma.

 Randomization:

 The investigating surgeon or anesthesiologist perform the randomization by opening
 consecutively numbered opaque envelopes. The randomization is stratified for each center and
 for colonic and rectal surgery the latter by opening an envelope with highest number for
 rectal surgical patients, and with lowest number for colonic patients.

 Blinding:

 Specialist surgeons reading the medical journals censored for all information about
 randomization group, fluid therapy given or bodyweight measurements will perform a blinded
 assessment for the primary outcome.

 Two doctors will evaluate each patient file, and in case of disagreement, a third will decide
 the outcome.

 Plan for analysis:

 An intention to treat analysis will be performed for the primary outcome for all patients
 included in the trial whether or not they met a post randomization exclusion criterion, and
 therefore did or did not receive the allocated treatment.

 A per protocol analysis will be performed for the primary outcome for all patients fulfilling
 the in- and exclusion criteria whether or not they adhered to the protocol.

 Subgroup analysis will be performed for the patients with Major-, Minor-, Cardio-pulmonic-
 and tissue-healing complications.
Inclusion Criteria:

 -  Patients scheduled for planned surgery on the colon or the rectum

 -  ASA group 1-3

 Exclusion Criteria:

 • Patients unable to give informed consent (mental disorders, dementia, language problems)

 Patients with:

 -  Diabetes mellitus

 -  Renal insufficiency

 -  Disseminated cancers or secondary cancers

 -  Inflammatory bowel disease

 -  Diseases hindering epidural analgesia

 -  Alcohol consumption more than 35 drinks pr. Week

 -  Pregnant and lactating woman.