Goal-directed fluid therapy (GDFT) has been compared with liberal fluid administration in non-optimized perioperative settings. It is not known whether GDFT is of value within an enhanced recovery protocol incorporating fluid restriction. This study evaluated GDFT under these circumstances in patients undergoing elective colectomy.
Patients undergoing elective laparoscopic or open colectomy within an established enhanced recovery protocol (including fluid restriction) were randomized to GDFT or no GDFT. Bowel preparation was permitted for left colonic operations at the surgeon's discretion. Exclusion criteria included rectal tumours and stoma formation. The primary outcome was a patient-reported surgical recovery score (SRS). Secondary endpoints included clinical outcomes and physiological measures of recovery.
Eighty-five patients were randomized, and there were 37 patients in each group for analysis. Nine patients in the GDFT and four in the fluid restriction group received oral bowel preparation for either anterior resection (12) or subtotal colectomy (1). Patients in the GDFT group received more colloid during surgery (mean 591 versus 297 ml; P = 0·012) and had superior cardiac indices (mean corrected flow time 374 versus 355 ms; P = 0·018). However, no differences were observed between the GDFT and fluid restriction groups with regard to surgical recovery (mean SRS after 7 days 47 versus 46 respectively; P = 0·853), other secondary outcomes (mean aldosterone/renin ratio 9 versus 8; P = 0·898), total postoperative fluid (median 3750 versus 2400 ml; P = 0·604), length of hospital stay (median 6 versus 5 days; P = 0·570) or number of patients with complications (26 versus 27; P = 1·000).
Modern perioperative care in colorectal surgery—termed enhanced recovery after surgery (ERAS)—has encouraged renewed scrutiny of intravenous fluid administration. Several randomized trials have demonstrated that fluid excess contributes to surgical morbidity1–4. As a result, fluid restriction has been incorporated into ERAS protocols for patients undergoing elective colectomy5, 6. Although the term is defined heterogeneously7, fluid restriction is essentially the avoidance of fluid overload, the latter being a historical norm following extrapolation of resuscitation practices from trauma care at the time of the Korean war.
Excessive fluid ‘restriction’ can risk hypovolaemia and tissue hypoperfusion8, so individualized management guided by cardiovascular measures of responsiveness, termed goal-directed fluid therapy (GDFT), has been proposed9. Trials and a meta-analysis of GDFT have shown clinical benefits over traditional liberal fluid administration10–14. These studies were not conducted within an ERAS environment, and the control groups received the liberal perioperative fluid therapy of the time. Thus the role of GDFT, within an otherwise optimized environment in which patients are usually subjected to fluid restriction, is undefined.
This was a prospective double-blind single-centre randomized clinical trial with a 1:1 patient allocation ratio. The study received both regional and institutional ethical approval before commencement and was registered prospectively at http://www.clinicaltrials.gov (trial identifier NCT00911391).
Consecutive consenting patients undergoing elective open or laparoscopic colectomy for any indication were enrolled, and randomized to either GDFT or fluid restriction. Exclusion criteria were: severe oesophageal disease, recent oesophageal or upper airway surgery, moderate or severe aortic valve disease on echocardiography, bleeding diathesis, regular use of corticosteroids or mineralocorticoids, cognitive impairment, American Society of Anesthesiologists grade IV or V, rectal tumour (less than 15 cm from the anal verge), stoma formation and patient choice.
The intervention was implemented in the intraoperative phase. Any time before this was defined as the preoperative period and any subsequent period (including in the postanaesthetic care unit) was defined as the postoperative phase.
Patients randomized to fluid restriction were allowed to receive up to 1500 ml crystalloid solution (Plasma-Lyte™ 148; Baxter Healthcare, Sydney, New South Wales, Australia) during surgery. They were also permitted to receive a total of 500 ml succinylated gelatine colloid solution (Gelofusine®; Braun, Sydney, New South Wales, Australia) titrated by heart rate, blood pressure, urine output and invasive measures (arterial lines) when used. Blood loss could be corrected for in a 1:1 ratio using colloid, and hospital transfusion guidelines (haemoglobin level less than 10 g/dl in patients with cardiac co-morbidities, and below 7 g/dl in those without cardiac disease) were used to determine whether blood products were necessary in either group.
Patients randomized to GDFT were also treated with baseline fluid restriction and a limit of 1500 ml crystalloid solution. A weight-based bolus of colloid was permitted based on cardiac function measured by means of an oesophageal Doppler monitor (ODM) (CardioQ™, DP12 probe; Pharmaco NZ, Auckland, New Zealand). The machine was calibrated to provide data averaged over ten cycles15. The algorithm for fluid administration based on ODM measurements is shown in Fig.1.
In both groups an extra 500 ml crystalloid was allowed every hour if the operation extended beyond 3 h. A consultant anaesthetist (1 of 10) was present for every operation. Vasopressors were permitted at discretion of the anaesthetist in both groups.
Preoperative fluid administration
Oral bowel preparation was used at the discretion of the operating surgeon in patients having left-sided colonic operations (Fleet® Phospho-soda®; Pharmaco NZ), but was otherwise avoided. Patients who received bowel preparation received 1 litre crystalloid before surgery.
Postoperative fluid administration
All intravenous fluids were stopped by default when patients arrived on the ward (typically 1–3 h after surgery), and oral intake of food, fluids and supplements was encouraged. The patient was formally assessed by a blinded ward doctor to decide whether any intravenous fluid was necessary based on the criteria described below. Clinicians were required to see the patient and document their findings, and were not allowed to make decisions over the telephone. Examination findings consistent with volume deficit were required for intravenous fluid to be prescribed. Intravenous fluid was administered if patients were oliguric (less than 0·5 ml per kg per h averaged over 4 h) or had deranged physiological parameters suggestive of volume deficit: tachycardia exceeding 90 beats per min or low blood pressure (systolic blood pressure below 90 mmHg in the presence of a functioning epidural; less than 100 mmHg without an epidural). Intravenous fluid was also administered for resuscitative purposes in the event of complications, to compensate for losses or for prolonged poor oral intake such as in the event of paralytic ileus. The only colloid used after surgery was succinylated gelatine solution. Crystalloid as described previously was used after operation in the high-dependency unit, and dextrose–saline solution (Dex Saline™, 0·18 per cent sodium chloride, 4 per cent glucose, 20 mmmol/l potassium; Baxter Healthcare) was used as maintenance crystalloid on the ward, when required to replenish extracellular fluid and total body water respectively and to limit sodium overload.
Patients were cared for within an established ERAS programme6, 16. Patients received 400 ml oral carbohydrate loading on the morning of surgery up to 2 h before operation (preOp™; Nutricia, Auckland, New Zealand). Nutritional supplementation (Fortisip™; Nutricia) was also provided before surgery if deemed necessary. Oral bowel preparation was used selectively as described above. Prophylactic nasogastric tubes and abdominal drains were not used. All patients received volatile general anaesthesia and mid or low thoracic epidural analgesia (combination of local anaesthetic and opioid) unless contraindicated. Successful epidural analgesia was defined as that not requiring an intravenous morphine pump for the first 48 h after surgery. Eight milligrams of intravenous dexamethasone (DBL® Dexamethasone Sodium Phosphate Injection; Hospira NZ, Wellington, New Zealand) was administered at induction17.
Mobilization from 4 h after surgery was encouraged and urinary catheters were removed on the day after surgery. Epidural analgesia was continued for 48 h. Simple oral analgesia was provided regularly; oral or parenteral opioid analgesia was avoided unless required for breakthrough pain. Non-steroidal analgesia was used from day 2 (20 mg oral tenoxicam). The ERAS protocol is summarized in Table16.
Table 1. Enhanced recovery after surgery protocol
Details of fluid management are explained in text. NSAID, non-steroidal anti-inflammatory drug.
Prophylactic use of antiemetics at
Short-acting anaesthetic agents
Social situation explored
Prevention of hypothermia, warming blanket
Avoidance of drains/nasogastric tubes
Milestone and goal setting
Laparoscopic/transverse incisions when
Conservative fluid regimen
Ward visit/meet nursing staff
High inspired oxygen
Careful medical assessment
Functional assessment, activities of daily living
Early oral feeding with
Avoidance of fasting
Avoidance of bowel preparation except in patients
‘Balanced analgesia’ ladder
with left-sided colonic pathology (see text)
Early removal of urinary catheter
Structured nursing pathway
Timed removal of epidural
Early mobilization and physiotherapy
Predefined discharge criteria
Outside the intraoperative phase all data were collected prospectively by a single blinded investigator.
The primary outcome of the study was the surgical recovery score (SRS) on day 7 after surgery. This score assesses fatigue, vigour, mental function, impact on patient activity and activities of daily living. The SRS (range 17–100) is derived from the validated Identity-Consequence Fatigue Scale, which measures surgical recovery by incorporating measures of postoperative fatigue and quality of life, and has been correlated with postoperative inflammation, as evidenced by cytokine release18, 19. The SRS was also registered before surgery, and on days 1, 3, 14 and 30 after the procedure.
Intraoperative cardiac indices obtained from the ODM were registered at 15-min intervals in both groups. Fluid volumes administered, and intraoperative and early postoperative (first 24 h after surgery) urine output were measured. Vasopressor use was noted. Bodyweight was recorded before surgery and daily for the first 3 days after operation. Serum concentrations of brain natriuretic peptide, renin and aldosterone were measured before operation and on the day after surgery. Serum concentrations of sodium and creatinine were measured before surgery and daily for the first 3 days after the procedure.
Maximum voluntary grip strength using a hand-held dynamometer (hydraulic hand dynamometer; Jamar, Chicago, Illinois, USA) and peak expiratory flow (Mini-Wright peak flowmeter; Clement Clark, Harlow, UK) were measured in the sitting position before surgery and daily for 3 days after the procedure. These outcomes were not part of the SRS.
Complications within 30 days of surgery were categorized according to the Clavien–Dindo classification20. Length of hospital stay was recorded.
Patients were recruited at the preadmission clinic and gave consent to participate in a private room, after being given verbal explanations and information sheets. Consent was reaffirmed verbally on the day of surgery and participants were free to withdraw consent at any time. Randomization was conducted using random numbers obtained from an open-source computer-based random number generator (http://www.random.org). The randomization sequence was generated by a third party not involved in the conduct of the study. Allocation details were concealed in opaque envelopes that were opened on the day of surgery, when patients were randomized. The allocation was performed by a research assistant after insertion of the ODM probe before the start of surgery and before colloid administration.
The patient, study investigators, surgeon and other medical staff responsible for patient care were blinded to patient allocation. All patients had the ODM probe inserted by a trained research assistant. The ODM monitor was covered by a custom-designed plastic casing (Acryform, Auckland, New Zealand) to ensure blinding.
An unblinded research assistant and the consultant anaesthetist were aware of patient allocation. All fluid administration was protocol-driven and delivered by the unblinded research assistant under the supervision of the anaesthetist. Suggested action based on the ODM protocol was reconfirmed every 15 min between the research assistant and anaesthetist for patients in the GDFT group. The research assistant was not involved in any postoperative data collection or perioperative care of the patients. The plastic cover over the monitor prevented the anaesthetist from looking at the readings obtained by the ODM for patients in the fluid restriction group. Intraoperative adherence to the fluid protocol was monitored.
A drape was placed to prevent the surgeons from observing fluid administration, and the research assistant was instructed to attach intravenous fluids periodically for patients in the fluid restriction group without actually administering them, to mimic the anticipated practice of fluid boluses in the GDFT group.
Based on previous data17, a priori power calculations indicated that 37 patients would be required in each group to detect a 20 per cent difference in the SRS with an α of 0·05 and β of 0·2. Thus a sample size of 80 was planned. Owing to a higher than anticipated number of exclusions, the sample size was increased to 85 patients after gaining permission from the ethics committee.
Normality of data was assessed using the Kolmogorov–Smirnov test and visually using the Q-Q plot. Continuous data are presented as mean(s.d.) if distributed normally and as median (range or interquartile range) otherwise. Two-tailed Fisher's exact test, Mann–Whitney U test and t test were used as appropriate for statistical analysis. Repeated measures were analysed by ANOVA with Tukey's correction. No subgroup analyses were planned and no post hoc analyses were conducted. P < 0·050 was considered statistically significant and all data were analysed using intention-to-treat principles. The results were analysed using SPSS® version 17.0 (IBM, Armonk, New York, USA).
This study was conducted between November 2009 and September 2011. Patient recruitment is summarized in Fig.2. Consistent ODM measurements were not available for one patient in the GDFT group. Three patients (2 fluid restriction, 1 GDFT) had intraoperative protocol violations; the two patients allocated to fluid restriction received an extra 500 ml crystalloid each and the patient in the GDFT group received a 3-ml/kg bolus of colloid when not indicated by the protocol. All patients were analysed on an intention-to-treat basis.
The two groups were well matched at baseline (Table2). Nine patients in the GDFT group and four in the fluid restriction arm received oral bowel preparation. All patients receiving bowel preparation were undergoing anterior resection, except for one patient in the GDFT group undergoing subtotal colectomy.
Includes high-grade dysplasia and appendiceal carcinoid that were not included in American Joint Committee on Cancer (AJCC) staging analysis.
GDFT, goal-directed fluid therapy; ASA, American Society of Anesthesiologists; HALS, hand-assisted laparoscopic surgery; POSSUM, Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity.
Values are mean(s.d.). GDFT, goal-directed fluid therapy.
Heart rate (beats/min)
Mean during operation
Cardiac index (l per min
Mean during operation
Corrected flow time (ms)
Mean during operation
Perioperative fluid administration is shown in Fig.3. Patients randomized to GDFT received significantly more colloid during surgery than those randomized to fluid restriction (mean 591(471) versus 297(275) ml; P = 0·012) and an overall greater volume of intravenous fluid (1994(590) versus 1614(420) ml; P = 0·010). There were no other statistically significant differences between the two groups. A similar number of patients required blood transfusions (GDFT 13, fluid restriction 12; P = 1·000). Median (interquartile range) total postoperative fluid administered in the GDFT and fluid restriction groups was 3750 (8808) and 2400 (9513) ml respectively (P = 0·604). There were no differences in bodyweight, urine output, serum electrolytes and vasoactive hormones (Tables5 and 6).
There were no differences between the GDFT and fluid restriction groups at any point in surgical recovery as measured by the SRS (mean SRS after 7 days 47 versus 46 respectively; P = 0·853) (Fig.4). Clinical outcomes are summarized in Table7.
In this randomized trial GDFT did not provide any measurable benefit to patients undergoing elective colectomy within an ERAS protocol incorporating fluid restriction. Patients randomized to GDFT received more intraoperative colloid and a larger volume of intravenous fluid overall, and had greater aortic flow. However, this did not translate into any differences in surgical recovery, physiological variables, serum electrolytes, vasoactive hormones or clinical outcomes.
This study is dissimilar to previous trials as it explored the efficacy of GDFT alongside intraoperative fluid restriction. Moreover, this is one of the few trials to have been conducted in an otherwise optimized perioperative environment. It is notable that the most recent trials exploring GDFT within an ERAS protocol, but without fluid restriction, showed either equivalent or inferior outcomes for patients randomized to GDFT21, 22. Thus, the proposed benefits of GDFT may be offset by the other advances in perioperative care; either that or avoidance of overload using fluid restriction may be an equally valid intraoperative fluid administration strategy. In the present trial, absolute weight gain was minimal in both groups and hence unlikely to be associated with adverse outcomes.
Patients randomized to GDFT had a superior corrected aortic flow time but there were no differences in cardiac index between the groups. It is possible that higher values of cardiac indices are a measure of physiological reserve rather than therapeutic targets23, 24. It is also important to note that the patients randomized to fluid restriction alone in this trial showed acceptable intraoperative cardiac indices. It is possible that observed cardiac indices in all patients were adequate, and correction of occult hypovolaemia as seen in previous trials was not required10, such that fluid optimization had no demonstrable benefit. This may be a result of some of the elements of optimized perioperative care including free oral fluid until 2 h before surgery and preoperative carbohydrate loading25. Although bowel preparation was used in some patients with left-sided pathology in this trial, no statistically significant difference was observed between the two groups. It is, however, acknowledged that a type II error cannot be excluded.
This study was powered for an index of surgical recovery in contrast to previous trials that were powered for length of hospital stay. Although this is a limitation, it has been recognized previously that a single intervention is unlikely to reduce hospital stay in an otherwise optimized setting4, 21, 26. As such, a sensitive measure such as the SRS, which also correlates with postoperative inflammation as evidenced by cytokine release18, is ideal for detection of any clinically meaningful benefits from interventions even if they do not result in a shorter hospital stay17. The congruence between all measured endpoints also suggests a lack of benefit from GDFT in this setting. Nonetheless, it is acknowledged that this trial was not powered to detect differences in postoperative complications specifically.
Although GDFT allows individualized titration of intraoperative intravenous fluids, it is possible that simply aiming for a neutral perioperative fluid balance is adequate for patients with physiological reserve able to correct minor disturbances of homeostasis4. The results of this study therefore may not be generalizable to patients who are physiologically compromised. However, in a recent trial, patients with greater co-morbidities undergoing colorectal surgery experienced adverse outcomes following GDFT22. It is also possible that any benefits gained from careful titration of fluids in the intraoperative setting are offset by postoperative fluid administration, which is usually based on clinical assessment alone.
This randomized trial has demonstrated no effect of GDFT on recovery in patients undergoing elective colectomy within an ERAS protocol incorporating fluid restriction.
S.S. and P.P.S. are recipients of the Auckland Medical Research Foundation Ruth Spencer Medical Research Fellowship. T.-C.Y. is a recipient of a New Zealand Health Research Council Clinical Training Scholarship. The ODM was lent by Pharmaco NZ for the duration of the study. All disposable probes were purchased at regular cost, and Pharmaco NZ had no input into the study design, data collection, interpretation of results or decision to publish.
Disclosure: The authors declare no conflict of interest.