cho loading bjs

Randomized clinical trial

Randomized controlled trial of preoperative oral carbohydratetreatment in major abdominal surgery

S. Mathur1, L. D. Plank1, J. L. McCall2, P. Shapkov1, K. McIlroy3, L. K. Gillanders3,A. E. H. Merrie1, J. J. Torrie4, F. Pugh4, J. B. Koea5, I. P. Bissett1 and B. R. Parry1

1Department of Surgery, University of Auckland, 2New Zealand Liver Transplant Unit, and 3Nutrition Services, 4Department of Anaesthesia and5Hepatobiliary and Upper Gastrointestinal Unit, Auckland City Hospital, Auckland, New ZealandCorrespondence to: Dr L. D. Plank, Department of Surgery, University of Auckland, Private Bag 92019, Auckland, New Zealand(e-mail: [email protected])

Background: Major surgery is associated with postoperative insulin resistance which is attenuated bypreoperative carbohydrate (CHO) treatment. The effect of this treatment on clinical outcome aftermajor abdominal surgery has not been assessed in a double-blind randomized trial.Methods: Patients undergoing elective colorectal surgery or liver resection were randomized to oralCHO or placebo drinks to be taken on the evening before surgery and 2 h before induction of anaesthesia.Primary outcomes were postoperative length of hospital stay and fatigue measured by visual analoguescale.Results: Sixty-nine and 73 patients were evaluated in the CHO and placebo groups respectively.The groups were well matched with respect to surgical procedure, epidural analgesia, laparoscopicprocedures, fasting period before induction and duration of surgery. Postoperative changes in fatiguescore from baseline did not differ between the groups. Median (range) hospital stay was 7 (2–35) daysin the CHO group and 8 (2–92) days in the placebo group (P = 0·344). For patients not receivingepidural blockade or laparoscopic surgery (20 CHO, 19 placebo), values were 7 (3–11) and 9 (2–48) daysrespectively (P = 0·054).Conclusion: Preoperative CHO treatment did not improve postoperative fatigue or length of hospitalstay after major abdominal surgery. A benefit is not ruled out when epidural blockade or laparoscopicprocedures are not used. Registration number: ACTRN012605000456651 (http://www.anzctr.org.au).

Presented in part to meetings of the European Society for Clinical Nutrition and Metabolism, Istanbul, Turkey, October2006, and the Association of Coloproctology of Great Britain and Ireland, Glasgow, UK, July 2007; and published inabstract form as Colorectal Dis 2007; 9(Suppl 1): 17

Paper accepted 18 December 2009Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.7026

Introduction

Many national anaesthesiology societies now recommendintake of clear fluids (water, tea or coffee without milk,juices without pulp) up to 2 h before induction ofanaesthesia for most patients undergoing elective surgery1.This change to the traditional practice of overnight fasting,while reducing thirst in the hours before surgery2, doesnot provide the metabolic preparation that may potentiallyattenuate the response to the stress that results from a major

The Editors are satisfied that all authors have contributed significantlyto this publication

operation. This response is characterized by activation ofendocrine and inflammatory systems which leads to tissuecatabolism and insulin resistance.

Reduction of postoperative hyperglycaemia by insulintreatment is associated with reduced infectious compli-cations in diabetic patients after cardiac surgery3 andin non-diabetic patients requiring intensive care aftersurgery4,5. It remains unclear whether these benefits ofintensive glycaemic control in patients receiving intensivecare extend to general surgical patients6. However, theseresults support the hypothesis that the improved post-operative insulin sensitivity that results from preoperative

Copyright ! 2010 British Journal of Surgery Society Ltd British Journal of Surgery 2010; 97: 485–494Published by John Wiley & Sons Ltd

486 S. Mathur, L. D. Plank, J. L. McCall, P. Shapkov, K. McIlroy, L. K. Gillanders et al.

carbohydrate (CHO) treatment7,8 may lead to improvedclinical outcome. Postoperative immune function may alsobe better preserved9. CHO-rich drinks at the appropri-ate concentration and osmolality empty from the stomachwithin 90 min and cause a rise in insulin to levels seenafter a normal meal10. They provide a simple and practicalintervention that may improve outcome for many patientsundergoing major surgery.

A number of randomized controlled trials have examinedwhether preoperative CHO treatment results in animprovement in postoperative recovery11–16. In majorabdominal surgery only two small unblinded studieshave been conducted11,12. Before CHO treatment canbe recommended as routine preoperative management forthese patients, larger studies are needed to demonstrate abeneficial effect on postoperative recovery.

This randomized double-blind placebo-controlled trialof preoperative CHO treatment in patients undergoingmajor elective abdominal surgery investigated whether thistreatment reduced early postoperative fatigue and durationof hospital stay. Secondary outcomes were postoperativeinfections, postoperative insulin resistance, and changes inmuscle mass and function.

Methods

Patients undergoing major elective colorectal surgeryor hepatic resection at Auckland City Hospital orMercy Hospital, Auckland, were eligible for inclusionin this trial. Exclusion criteria were age below 18 orabove 80 years, pregnancy, inability to consume clearfluids, gastrointestinal obstruction, liver cirrhosis, diabetesmellitus, corticosteroid treatment exceeding 5 mg/day andAmerican Society of Anesthesiologists (ASA) grade IV orhigher. The trial was approved by the Auckland RegionalEthics Committee, and all patients gave written informedconsent before randomization.

Study protocol

The study design is summarized in Fig. 1. Patientswere enrolled at preadmission clinics and assigned toa CHO or placebo group based on variable block sizerandomization and sequential allocation using opaquesealed envelopes. Randomization was stratified by typeof surgery (colorectal or hepatic resection). Patients andinvestigators were blinded to the treatment allocation,and the CHO and placebo products were packagedidentically in coded tetrapaks prepared by NumicoCorporate Research (Zoetermeer, The Netherlands). The

Insulin, glucose, cortisol, C-reactive protein

Fatigue score, discomfort score, grip strength, MAMC

Time to oral diet, length of stay, complications

Baseline

Randomization

Study day

0 1 2 3 4 5 6 7 28

OperationCarbohydrate or placebo (800 ml, 19.00–24.00 hours;400 ml, 2 h before anaesthesia)

Fig. 1 Study design. MAMC, mid-arm muscle circumference

code was released to the investigators by Numico followingcompletion of all data entry and locking of the database.

The evening before surgery, between 19.00 and24.00 hours, patients in the CHO group consumed 800 mlNutricia PreOp" solution (Numico; 12·5 per cent CHO,50 kcal per 100 ml, 290 mOsm/kg, pH 5·0). Those in theplacebo group consumed the same quantity of flavouredwater with artificial sweetener (acesulfame-K, 0·64 g per100 ml citrate, 0 kcal per 100 ml, 107 mOsm/kg, pH 5·0),identical in taste and appearance to the CHO drink17.On the day of surgery patients received 400 ml CHO orplacebo solution 2 h before scheduled induction of anaes-thesia, to be taken over 20 min. To facilitate compliancewith this, patients were generally scheduled first on themorning list for surgery. Water was allowed freely aftermidnight. Patients were asked to record the time of con-sumption and any side-effects caused by the drink. On themorning before surgery they were asked to assess the tasteusing a five-point scale: 1, disliked; 2, moderately disliked;3, neutral opinion; 4, moderately liked; and 5, liked.

All patients received general anaesthesia and wereactively warmed using forced air blankets. Before inductionof anaesthesia, patients having open surgery received athoracic epidural catheter, between T7 and T12, unlessthis was contraindicated or the patient refused. Generalanaesthesia was induced with propofol and fentanyl, andmaintenance achieved with infusion or bolus injectionsof these agents. Atracurium, rocuronium or vecuroniumwas given as a muscle relaxant according to anaesthetistpreference. Epidural anaesthesia was established duringoperation with bupivacaine, with doses at the discretion ofthe anaesthetist. At the end of surgery, an epidural infusionof 0·125 per cent bupivacaine and 2 µg/ml fentanyl wasmaintained at 2–10 ml/h for at least 48 h. In addition,patient-controlled epidural analgesia could be used with2-ml boluses every 20 min. Patient-controlled analgesiawith morphine (1 mg/ml) and/or tramadol was prescribedfor patients who did not have epidural anaesthesia.

Copyright ! 2010 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2010; 97: 485–494Published by John Wiley & Sons Ltd

Preoperative oral carbohydrate treatment in major abdominal surgery 487

Supplemental paracetamol was used if required. Urinarycatheters were used routinely and peritoneal drains placedat the discretion of the surgeon.

Patients were mobilized out of bed for a short periodof sitting and/or walking on the day of surgery or within24 h for laparoscopic and non-laparoscopic proceduresrespectively. Free oral fluids were permitted immediatelyafter surgery and oral diet was allowed from day 1after operation, as tolerated. Time to intake of oral dietafter surgery was recorded and patients were monitoredfor 28 days for infectious complications. Infection wasdefined as the presence of clinical sepsis (two or more of:temperature exceeding 38·5°C, heart rate more than 100beats/min, arterial partial pressure of carbon dioxide below32 mmHg or respiratory rate above 20 per min, white cellcount greater than 12 ! 109/l or more than 10 per centimmature forms) or temperature exceeding 38°C for 24 hand no alternative source for the fever, and antibiotics werecommenced.

Fatigue, general discomfort, grip strength, tricepsskinfold thickness and mid-arm muscle circumference(MAMC) were measured in the preadmission clinic (base-line), approximately 1 h before initiation of anaesthesia, ondays 1–7 after surgery or until discharge if earlier, and onday 28. Before the scheduled day of surgery patients pro-vided an overnight-fasted blood sample for measurementof glucose, insulin, cortisol and C-reactive protein (CRP)at a local laboratory between 08.00 and 09.30 hours. Thesemeasurements were repeated at the time of induction ofanaesthesia (day 0), in hospital on days 1, 3, 5 and 7, andafter discharge on day 28. Additional measurements wereintroduced part-way through this study; patients scheduledfor operation at Auckland City Hospital were asked to con-sent to comprehensive body composition analysis beforesurgery, and on days 7 and 28.

Fatigue and discomfort

Postoperative fatigue was measured using a 100-mmhorizontal visual analogue scale (VAS)17. Subjectivediscomfort was determined as the mean VAS score of 11items including anxiety, depression, hunger, thirst, inabilityto concentrate, malaise, nausea, pain at rest, pain withcough, unfitness and irritability17.

Duration of hospital stay

Postoperative length of hospital stay was determined bothfrom the actual date of discharge (LOS) and from a ‘fit-for-discharge’ date (LOSFD), which was not affected bysocial and rehabilitation issues delaying discharge. Patients

were deemed fit for discharge if they met all the followingcriteria: passing flatus, stool and urine; eating satisfactorily;managing on oral analgesia; afebrile; mentally clear andcooperative; mobilizing independently to shower andtoilet; requiring wound dressing changes less than twicedaily; and without drains requiring inpatient management.

Biochemistry

Glucose was measured by the hexokinase method(Roche Diagnostics, Mannheim, Germany) and insulinby microparticle enzyme immunoassay on an IMx"

analyser (Abbott Diagnostics, Abbott Park, Illinois, USA).Insulin resistance was estimated by the homeostaticmodel assessment of insulin resistance (HOMA-IR)using the computer model HOMA2 Calculator version2.2.218. Electrochemiluminescence immunoassay (RocheDiagnostics) was used for measurement of serum cortisol,and an immunoturbidimetric method (Roche Diagnostics)for high-sensitivity CRP assay.

Grip strength and mid-arm muscle circumference

Grip strength was measured in the dominant handas the maximum of three attempts using a hand-helddynamometer (Lafayette Instrument Company, Lafayette,Indiana, USA). MAMC was derived from triceps skinfoldthickness (TSF) and mid-arm circumference (MAC) asMAC " !TSF.

Total body protein

Total body nitrogen was measured at baseline, and ondays 7 and 28 by in vivo neutron activation analysis19

with a precision of 2·7 per cent20 and an accuracy ofwithin 4 per cent21. Briefly, the supine patient was scannedfrom the shoulders to the knees through two opposedneutron fields and the prompt " radiation resulting fromthermal neutron reactions with hydrogen and nitrogenwas monitored. The method assumes that the ratio ofnitrogen to hydrogen counts over the region scannedis representative of the whole-body ratio. Total bodynitrogen is calculated from this ratio, after correction forbody habitus and background counts, using the knownconcentrations of hydrogen in the body compartmentstogether with body mass and the masses of fat and bonemineral measured by dual-energy X-ray absorptiometry(model DPX+, software version 3.6y; GE-Lunar, Madison,Wisconsin, USA). Total body protein was calculated as6·25 times total body nitrogen.



Assessed for eligibilityn = 209

Randomizedn = 162

Enr

olm

ent

Allo

catio

nF

ollo

w-u

pA

naly

sis

Lost to follow-up n = 0 Lost to follow-up n = 0

Excluded n = 47Did not meet inclusion criteria n = 38Refused to participate n = 5Other reason n = 4

Allocated to placebo n = 82Received intervention n = 79Did not receive intervention n = 3

Patient withdrew from trial n = 2No surgery n = 1

Allocated to carbohydrate n = 80Received intervention n = 76Did not receive intervention n = 4

Patient withdrew from trial n = 2No surgery n = 1Acute presentation n = 1

Analysed n = 69Excluded from analysis n = 7

Open–close surgery n = 5Intraoperative steroids n = 2

Analysed n = 73Excluded from analysis n = 6

Open–close surgery n = 5Intraoperative steroids n = 1

Fig. 2 CONSORT diagram for the trial

Statistical analysis

The primary endpoints for this study were postoperativefatigue and LOS. It was calculated that 65 patients wouldbe required in each group to detect a 50 per cent reductionin the increase in VAS score for fatigue from baselineto day 4 after surgery as a result of CHO treatment(# = 0·05, power = 90 per cent), based on the findings ofBuxton and colleagues22 in general surgical patients andallowing for a 10 per cent dropout rate. Limited data wereavailable regarding LOS after CHO treatment in patientshaving colorectal surgery, but a small study7 indicated amean(s.d.) reduction of 2·1(2·3) days. The sample size of65 patients per group had more than 95 per cent power todetect a reduction in hospital stay of this magnitude.

The analysis of primary outcomes was performedon an intention-to-treat basis. Data were presented asmean(s.e.m.), median (range) or median (interquartilerange). For between-group comparisons, Student’s t testand Mann–Whitney U test were used for normally andnon-normally distributed data respectively; for within-group comparisons, paired t test and Wilcoxon signedranks test for paired observations were employed forparametric and non-parametric data respectively. Fisher’sexact test was used for categorical data. Correlation wasexamined using Spearman rank or Pearson correlationcoefficients as appropriate. HOMA-IR values were log-transformed before analysis and reported as geometric

means. Time-to-event data (duration of hospital stay, timeto intake of oral diet) were compared between groups usingthe log rank test. P < 0·050 was considered statisticallysignificant. Statistical analyses were performed using SAS"

release 9.1 (SAS Institute, Cary, North Carolina, USA).

Results

Between July 2004 and December 2005 a total of162 patients were randomized to either CHO orplacebo (Fig. 2). Twenty patients were excluded afterrandomization for the following reasons: surgery delayedbeyond study termination date (two patients), withdrawalat patient request before ingestion of beverage (four),open–close surgery (ten), intraoperative administration ofsteroids (three), and acute presentation with perforateddiverticular disease between randomization and electivesurgery (one). Baseline characteristics and demographicdata for the remaining 142 patients are summarizedin Table 1. Three patients (two CHO, one placebo)who underwent laparoscopic procedures received spinalanaesthesia and for the purposes of analysis were includedin the epidural groups.

Median (range) scores for taste were 4 (1–5) and 3(1–5) for CHO and placebo respectively (P = 0·636). Side-effects ascribed to the beverages were reported by 20 of69 and seven of 73 patients respectively (P = 0·004), andincluded nausea (seven), bloating (eight), headache (four),



Table 1 Patient characteristics

Carbohydrate(n = 69)

Placebo(n = 73)

Sex ratio (M : F) 29 : 40 44 : 29Age (years)* 60 (27–80) 65 (22–81)Body mass index (kg/m2)* 26 (19–45) 25 (17–37)

ASA gradeI 9 (13) 10 (14)II 42 (61) 51 (70)III 18 (26) 12 (16)

Cancer 39 (57) 48 (66)Type of surgery

Colorectal 47 (68) 50 (68)Liver 22 (32) 23 (32)

ProcedureMajor liver resection 14 (20) 15 (21)

(# 3 segments)Minor liver resection 8 (12) 8 (11)

(< 3 segments)Anterior resection 12 (17) 16 (22)Abdominoperineal 2 (3) 2 (3)

resectionRight 6 (9) 6 (8)

hemicolectomyLeft hemicolectomy 1 (1) 2 (3)Restoration of 9 (13) 10 (14)

intestinal continuitySigmoid colectomy 6 (9) 8 (11)Total colectomy 3 (4) 1 (1)Proctectomy and 2 (3) 2 (3)

pouchIleocolic resection 2 (3) 1 (1)Other 4 (6) 2 (3)

Laparoscopic procedure 15 (22) 13 (18)Epidural 36 (52) 42 (58)Time from ingestion to

induction of anaesthesia(min)*

158 (78–566) 146 (75–312)

Time from ingestion tostart of surgery (min)*

200 (102–618) 191 (110–342)

Duration of surgery (min)* 154 (43–409) 144 (52–420)

Values in parentheses are percentages unless indicated otherwise; *valuesare median (range). ASA, American Society of Anesthesiologists.

taste intolerance (three) and one each of sore throat, light-headedness, vomiting, feeling ‘water-logged’ and increasedurinary frequency.

Postoperative fatigue

The VAS score for fatigue was significantly higher thanbaseline in each group on days 1–5 after surgery (P <

0·005) (Fig. 3) and did not differ significantly between thegroups on any of the study days. For patients who under-went open surgery without epidural blockade (20 CHO, 19placebo) the fatigue score dropped to baseline level within3 days of operation in the CHO-treated group but was still

#100 1 2 3 4

Study day5 6 7 28

0

10

VA

S s

core

diff

eren

ce (

mm

)

20

30CarbohydratePlacebo

Fig. 3 Mean(s.e.m.) changes in fatigue measured by visualanalogue scale (VAS) from baseline to the day of surgery (day 0)and for up to 28 days after operation. *P < 0·050 for change(paired t test)

significantly higher than baseline (P = 0·008) on day 6 inthe placebo group (P = 0·015 versus CHO group).

Clinical outcome

Median (range) LOS was 7 (2–35) days in the CHOgroup and 8 (2–92) days in the placebo group (P = 0.344).LOSFD values were 6 (2–35) and 7 (2–92) days respectively(P = 0·523). After controlling for ASA as an index of co-morbidity, the respective P values were 0·417 and 0·549for LOS and LOSFD. For patients who underwent opensurgery without epidural blockade, median LOS was 7(3–11) days in the CHO group and 9 (2–48) days in theplacebo group (P = 0·054). LOSFD values were 6 (3–10)and 8 (2–48) days respectively (P = 0·059). Median timeto intake of oral diet was 3 (1–33) days in the CHOgroup and 3 (1–31) days in the placebo group (P = 0·968).Postoperative infectious complications were reported in23 patients (33 per cent) in the CHO group and 30(41 per cent) in the placebo group (P = 0·387).

Discomfort

Preoperative VAS scores for discomfort did not differsignificantly between groups at baseline (P = 0·926) or1 h before induction (P = 0·357). Discomfort scores weresignificantly higher than baseline in both groups on days1–6 after surgery (P < 0·007) but did not differ betweengroups (data not shown). By day 7 the scores were notsignificantly different from baseline values.



Table 2 Plasma glucose, insulin, C-reactive protein and cortisol levels during the study

Study day

Baseline 0 1 3 5 7 28

Glucose (mmol/l)Carbohydrate 5·0(0·1) 5·3(0·2) 6·6(0·3)‡ 5·8(0·2)† 5·9(0·2)‡ 5·8(0·2)† 5·0(0·2)Placebo 5·1(0·1) 5·4(0·1)‡ 6·5(0·2)§ 5·7(0·2)† 6·1(0·2)§ 5·7(0·2)† 5·1(0·1)

Insulin (munits/l)*Carbohydrate 9 (6–14) 7 (3–16) 11 (7–19)† 9 (6–16) 8 (4–19) 11 (6–18) 10 (6–13)Placebo 8 (6–11) 5 (3–9)† 12 (6–20)† 8 (5–13) 11 (7–19)† 12 (5–20)† 10 (7–12)

C-reactive protein(mg/l)*

Carbohydrate 3 (3–4) 3 (1–7) 73 (36–98)§ 99 (46–192)§ 66 (32–140)§ 56 (36–112)§ 3 (3–4)Placebo 3 (3–5) 3 (2–8)† 73 (37–117)§ 93 (56–155)§ 82 (33–145)§ 42 (27–104)§ 3 (3–7)

Cortisol (nmol/l)Carbohydrate 444(23) 416(27) 219(34)†¶ 495(40) 540(22) 575(36) 407(36)Placebo 443(24) 445(24) 473(44) 511(26) 524(33) 591(56) 417(25)

Values are mean(s.e.m.) except *median (interquartile range). †P < 0·050, ‡P < 0·010, §P < 0·001 versus baseline (paired t test if normally distributed;otherwise Wilcoxon signed ranks test); ¶P < 0·001 versus placebo (Student’s t test).

0Baseline 1

Study day3 5 7 28

0·5

1·0

HO

MA

insu

lin r

esis

tanc

e 0·5

2·0

CarbohydratePlacebo

Fig. 4 Mean(s.e.m.) insulin resistance assessed by homeostaticmodelling (HOMA; geometric) over the study period in patientsreceiving preoperative carbohydrate treatment or placebo.*P < 0·050 versus baseline (paired t test)

Biochemistry

No significant differences in glucose, insulin and CRPwere seen between the groups on any study day (Table 2).Glucose and CRP levels were significantly higher thanbaseline on days 1, 3, 5 and 7 in both groups. The insulinlevel was significantly higher than baseline on days 1, 5 and7 in the placebo group but only on day 1 in the CHO group.The cortisol concentration was significantly lower in theCHO than in the placebo group on day 1 after surgeryonly. HOMA-IR did not differ between groups during

84Baseline 0 1 2 3 4 5

Study daya Grip strength

b MAMC

6 7 28

86

88

90

92

94

96

98

100

102

104

106 Carbohydrate

Grip

str

engt

h (%

)

96Baseline 0 1 2 3 4 5

Study day

6 7 28

97

98

99

100

101

102

103

104

MA

MC

(%

)

Placebo

Fig. 5 a Grip strength and b mid-arm muscle circumference(MAMC) expressed as mean(s.e.m.) percentage of baselinevalues. *P < 0·050 versus baseline (paired t test)



Table 3 Characteristics of 31 patients who underwent total bodyprotein measurements

Carbohydrate(n = 14)

Placebo(n = 17)

Sex ratio (M : F) 8 : 6 11 : 6Age (years)* 64·5 (27–76) 65 (38–80)

ASA gradeI 1 2II 10 13II 3 2

Cancer 11 12Type of surgery

Colorectal 5 6Liver 9 11

ProcedureMajor liver resection 7 8

(# 3 segments)Minor liver resection 2 3

(< 3 segments)Anterior resection 2 0Abdomino-perineal 0 1

resectionRight 1 1

hemicolectomyLeft hemicolectomy 0 1Restoration of 0 3

intestinalcontinuity

Total colectomy 1 0Ileocolic resection 1 0

Laparoscopicprocedure

3 2

Epidural 9 13Time from ingestion to

induction ofanaesthesia (min)*

154 (87–566) 144 (85–202)

Time from ingestion tostart of surgery(min)*

213 (125–618) 201 (136–251)

Duration of surgery(min)*

212 (139–409) 148 (67–420)

Total body protein (kg)†At baseline 9·50(0·51) 9·83(0·53)Change from "0·67(0·10)‡ "0·60(0·15)‡

baseline to day 7Change from "0·49(0·15)§ "0·52(0·20)¶

baseline to day 28

Values are *median(range) and †mean(s.e.m.). ASA, American Society ofAnesthesiologists. ‡P < 0·001 (paired t test); §P = 0·020 (n = 6),¶P = 0·031 (n = 9) (paired t test).

the study but was significantly higher than baseline in theplacebo group on days 1, 5 and 7, and not significantlydifferent from baseline in the CHO group after surgery(Fig. 4). Insulin and glucose concentrations at inductionwere inversely correlated with time from ingestion of thebeverage (r = "0·44, P = 0·001 and r = "0·34, P = 0·009respectively) in the CHO group but not in the placebo

group (r = "0·10, P = 0·472 and r = "0·22, P = 0·084respectively).

Grip strength and mid-arm muscle circumference

Compared with baseline, grip strength was reduced inboth groups on day 0 and over the first week after surgery(P < 0·010), returning to baseline levels by day 28. Thepercentage change from baseline was no different betweenthe groups on any of these days (Fig. 5a). The percentagechange in MAMC from baseline was no different betweenthe groups on any study day (Fig. 5b).

Total body protein

Total body protein decreased after surgery in both groupsbut did not differ significantly between groups (Table 3).

Discussion

This study is the largest double-blind placebo-controlledtrial to date investigating the effects of preoperative CHOloading on clinical outcome after major abdominal surgery.Intention-to-treat analysis showed no significant benefitof this treatment on postoperative fatigue or LOS inpatients undergoing colorectal surgery or hepatic resection.Postoperative infectious complications, time to intake oforal diet, and postoperative changes in patient discomfort,grip strength and MAMC did not differ between theplacebo and CHO groups. Using the HOMA-IR approachit was not possible to prove that patients in the CHOgroup were significantly less insulin resistant over the earlypostoperative period. Preoperative CHO loading was lesswell tolerated than the placebo product, but no adverseevents were recorded.

This study focused on the potential clinical benefits ofCHO treatment in patients undergoing major abdominalsurgery in a traditional care setting. No attempt wasmade to restrict the study, for example to non-laparoscopic procedures or to patients having epiduralanaesthesia/analgesia. Heterogeneity in terms of surgicalprocedure, surgical access and anaesthetic protocolsintroduces a number of potential variables and maytherefore have reduced the likelihood of detecting anyclinical benefit of CHO treatment. The trend observedtowards reduced LOS in the subgroup of patientshaving non-epidural, non-laparoscopic procedures tendsto support this view and may imply that the study is notable to rule out a clinical benefit in particular subgroups ofpatients.

Although there are clear merits in conducting a studysuch as this in more homogeneous groups of patients, the



intention was to examine efficacy across a range of generalsurgical patients. Indeed CHO loading has been advocatedas part of enhanced recovery protocols for an even broaderrange of patients and procedures than those included inthe present study, and it would be impractical to test eachof these situations independently.

Several randomized trials in patients undergoing uppergastrointestinal13–15 or cardiac16 surgery also failed toshow improved clinical outcome with preoperative CHO.Median duration of hospital stay was 17 days in the CHOgroup and 16 days in the placebo group for the cardiacsurgery study16, and 8 and 10 days respectively in the studyreported by Yuill and colleagues15. In contrast, Noblett andco-workers11 showed, in a small unblinded study of patientsundergoing colorectal surgery, that median hospital staybased on fit-for-discharge criteria (administered by blindedpersonnel) was significantly lower in patients takingpreoperative CHO than in those receiving water (7·5versus 13 days).

The CHO loading formulation used in the presentstudy was designed to be taken on the evening beforesurgery and 2 h before induction of anaesthesia. In general,investigators have targeted 2–3 h as the interval betweenCHO ingestion and induction. Although insulin levelshave returned to near-basal values 2 h after the 400-mlmorning CHO dose (50 g)10,23, insulin action is neverthe-less enhanced beyond this time. Kingston and colleagues24

showed that around 1 h after glucose and insulin concen-trations had returned to stable baseline levels followinga 25-g glucose load, whole-body insulin action was sig-nificantly increased for a couple of hours. Similarly, 3 hafter the 50-g dose of PreOp" Svanfeldt and co-workers23

showed that insulin action was enhanced by approximately50 per cent. This increased insulin sensitivity at 3 h ormore after CHO treatment, coinciding with the time ofsurgery, may be at least partly responsible for the reducedpostoperative insulin resistance in these patients23.

Patients in the present study (49 placebo, 43 CHO)who were fully compliant with beverage consumptionand underwent induction of anaesthesia within 3 h afterthe morning drink were analysed as a subgroup andthe pattern of results was similar to that found for thestudy as a whole (data not shown). In this subgroup,as for the whole group, no evidence was found ofreduced postoperative insulin resistance in the patientswho received CHO. This treatment has been shown, usinghyperinsulinaemic–euglycaemic clamp methodology, toreduce insulin resistance in patients having abdominalsurgery7 and in those undergoing total hip replacement25.Although regarded as the ‘gold standard’ for assessinginsulin sensitivity, the clamp approach is clearly limited

to small-scale investigations from a practical standpoint.In the present study the HOMA-IR approach, based onfasting glucose and insulin, was used and it should berecognized that this basal test, essentially reflecting hepaticinsulin resistance, may yield results that differ markedlyfrom those of the clamp method in which insulin is atnon-basal, active levels, which reflect primarily peripheralinsulin resistance26.

Enhanced insulin action by preoperative CHO treat-ment may reduce protein breakdown after surgery27.Improved nitrogen economy early after operation wasobserved following preoperative intravenous28 and oral27

glucose loading. A recent study showed that intravenousglucose with amino acids started 20 h before colorectalsurgery resulted in a positive net protein balance 2 daysafter surgery29. The present study did not detect greaterpreservation of muscle mass assessed by the anthropomet-ric technique (MAMC) in the CHO group. Furthermore,direct measurement of total body protein in a subgroupof patients did not show that CHO treatment amelio-rated postoperative loss of nitrogen. This subgroup wasbroadly representative of the complete cohort althoughwith a greater proportion undergoing hepatic resection.Both the CHO and placebo groups sustained losses of6–7 per cent of protein stores over the first week afteroperation. Interestingly, Yuill and colleagues15 found thatthe postoperative decrease in MAMC was significantly lessin patients taking CHO than in those receiving placebo.

The changes in VAS scores for fatigue (as a measure offunctional recovery) were comparable with those foundin a previous study of patients undergoing colorectalsurgery12, in which there was no difference between oralCHO and overnight-fasted groups. In the subgroup ofcompliant patients in the present study, the increase infatigue score from baseline to days 4–5 after surgery was50 per cent lower in the CHO group than in the placebogroup, although this difference did not reach statisticalsignificance.

Hausel and colleagues17 showed in 252 patients, usingVAS scales similar to those in the present study, thatpatients taking PreOp" were less hungry and less anxiousthan those receiving placebo at 40 and 90 min after takingthe drinks. Measurements taken in the present study,typically 30–60 min after the morning drink, showed nodifferences in these variables between the groups, nor inthe other measures of discomfort. The present findingthat PreOp" was tolerated less well than the placebo isin contrast to a report of more side-effects in the placebogroup13.

Limited data are available on the relationship betweenpreoperative CHO treatment and the stress hormone



response to surgery. In the present study, the serumcortisol concentration was significantly lower in the CHOthan in the placebo group on day 1 after surgery butthis appeared to be transitory and not evident on day 3.Epidural anaesthesia/analgesia is associated with a reducedcortisol response after major surgery, as observed on days1–3 after elective gastrectomy30. On the day after surgeryin the present study serum cortisol concentrations weresignificantly lower in those receiving epidural blockade(mean(s.e.m.) 297(262) versus 431(308) nmol/l; P = 0·037).CHO-treated patients had significantly lower serumcortisol levels than those receiving placebo on the dayafter operation whether on epidural blockade (P = 0·002)or not (P < 0·001).

A traditional overnight-fasted group was not includedso it was not possible to determine whether CHOtreatment or water may be beneficial compared withovernight fasting. Although the aim was to demonstratethe benefits, if any, of preoperative CHO in a standardhospital setting, a special effort was made to control theinterval between ingestion of the last drink and induction,given the understanding that this interval should not beprolonged, by scheduling patients first on the morningsurgery list. Rescheduling of operating lists and patientcancellations made this difficult to achieve in an acute-care hospital and a third of the patients had a fastingperiod of more than 3 h before induction. This proportionis likely to be substantially higher in routine clinicalpractice in such a hospital. Randomization resulted in asex imbalance between the groups, but there appeared tobe no difference in the results for men and women analysedseparately.

This study has shown that CHO drinks taken upto 2 h before anaesthesia are safe for non-diabeticpatients undergoing a variety of major abdominal surgicalprocedures. However, no significant beneficial effectson clinical outcome were observed in the context ofcurrent standards of care for these patients. For patientsundergoing major open abdominal surgery withoutepidural anaesthesia and analgesia in the same traditional-care setting, a benefit is not ruled out in terms ofduration of hospital stay and postoperative fatigue butconfirmation of this would require an appropriatelydesigned clinical trial in a more homogeneous patientgroup.

Acknowledgements

The authors thank Numico Corporate Research, Zoeter-meer, The Netherlands, for providing CHO and placebobeverages in coded packaging. Financial support for this

study was provided by Nutricia (NZ) Ltd. S.M. is therecipient of a Health Research Council Clinical TrainingFellowship and a Foundation New Zealand Research Fel-lowship of the Royal Australasian College of Surgeons.The authors declare no conflict of interest.

References

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5 Krinsley JS. Effect of an intensive glucose managementprotocol on the mortality of critically ill adult patients. MayoClin Proc 2004; 79: 992–1000.

6 Krinsley J. Perioperative glucose control. Curr OpinAnaesthesiol 2006; 19: 111–116.

7 Nygren J, Soop M, Thorell A, Efendic S, Nair KS,Ljungqvist O. Preoperative oral carbohydrate administrationreduces post-operative insulin resistance. Clin Nutr 1998; 17:65–71.

8 Soop M, Nygren J, Myrenfors P, Thorell A, Ljungqvist O.Preoperative oral carbohydrate treatment attenuatesimmediate post-operative insulin resistance. Am J PhysiolEndocrinol Metab 2001; 280: E576–E583.

9 Melis GC, van Leeuwen PA, von Blomberg-van derFlier BME, Goedhart-Hiddinga AC, Uitdehaag BM, Strackvan Schijndel RJ et al. A carbohydrate-rich beverage prior tosurgery prevents surgery-induced immunodepression: arandomized, controlled, clinical trial. JPEN J ParenterEnteral Nutr 2006; 30: 21–26.

10 Nygren J, Thorell A, Jacobsson H, Larsson S, Schnell PO,Hylen L et al. Preoperative gastric emptying. Effects ofanxiety and oral carbohydrate administration. Ann Surg 1995;6: 728–734.

11 Noblett SE, Watson DS, Huong H, Davison B,Hainsworth PJ, Horgan AF. Pre-operative oral carbohydrateloading in colorectal surgery: a randomized controlled trial.Colorectal Dis 2006; 8: 563–569.

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15 Yuill KA, Richardson RA, Davidson HIM, Garden OJ,Parks RW. The administration of an oralcarbohydrate-containing fluid prior to major electiveupper-gastrointestinal surgery preserves skeletal muscle masspost-operatively – a randomised clinical trial. Clin Nutr 2005;24: 32–37.

16 Breuer J-P, von Dossow V, von Heymann C, Griesbach M,von Schickfus M, Mackh E et al. Preoperative oralcarbohydrate administration to ASA III–IV patientsundergoing elective cardiac surgery. Anesth Analg 2006; 103:1099–1108.

17 Hausel J, Nygren J, Lagerkranser M, Hellstrom PM,Hammarqvist F, Almstrom C et al. A carbohydrate-rich drinkreduces preoperative discomfort in elective surgery patients.Anesth Analg 2001; 93: 1344–1350.

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Commentary

Randomized controlled trial of preoperative oral carbohydrate treatmentin major abdominal surgery (Br J Surg 2010; 97: 485–494)

Preoperative oral carbohydrate loading has been shown to be safe, to attenuate postoperative insulin resistance, and todecrease thirst, nausea and anxiety. Although part of the enhanced recovery after surgery (ERAS) protocol1, the effectsof this intervention alone on patients undergoing major abdominal surgery have not been tested in the context of arandomized double-blind controlled trial. Dr Mathur and co-workers have done this and, although they did not show astatistically significant difference in outcome between the two groups (notwithstanding a 1-day shorter hospital stay in thetreatment group), they were able to demonstrate that postoperative insulin and cortisol responses were attenuated in the



treatment group. In addition, although the homoeostatic model (HOMA-IR) is not the ‘gold standard’ for quantifyinginsulin resistance, the authors did confirm a significant decrease in insulin resistance in the treatment group on the first dayafter surgery. The lack of a statistically significant difference in length of hospital stay may have been because the projected2-day difference was rather ambitious. Multimodal interventions under the ERAS pathway have led to a 2·5-day reductionin hospital stay in patients undergoing colorectal surgery compared with those managed with traditional care2 and it isunlikely that the single intervention of carbohydrate loading would have reduced hospital stay by a similar magnitude.

K. Lassen1 and D. N. Lobo2

1Department of Gastrointestinal Surgery, University Hospital Northern Norway, 9038 Tromsø, Norway, and 2Division ofGastrointestinal Surgery, Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham University Hospitals,

Queen’s Medical Centre, Nottingham NG7 2UH, UK (e-mail: [email protected]; [email protected])DOI: 10.1002/bjs.7049

Potential conflict of interest

K.L. and D.N.L. are members of the Enhanced Recovery After Surgery (ERAS) Group, which has received funding inthe form of unrestricted grants from Nutricia Clinical Care in the past and from Fresenius Kabi currently. D.N.L. hasreceived research grants, travel bursaries and speaker’s honoraria from Fresenius Kabi and Nutricia Clinical Care.

References

1 Lassen K, Soop M, Nygren J, Cox PBW, Hendry PO, Spies C et al. Consensus review of optimal perioperative care in colorectalsurgery. Arch Surg 2009; 144: 961–969.

2 Varadhan KK, Neal KR, Dejong CHC, Fearon KCH, Ljungqvist O, Lobo DN. The enhanced recovery after surgery (ERAS)pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials. Clin Nutr2010; [Epub ahead of print 27 January 2010].


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