brjsurg200895p1387balzano

Original article

Fast-track recovery programme after pancreatico-duodenectomy reduces delayed gastric emptying

G. Balzano, A. Zerbi, M. Braga, S. Rocchetti, A. A. Beneduce and V. Di CarloPancreas Unit, Department of Surgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, ItalyCorrespondence to: Dr G. Balzano (e-mail: [email protected])

Background: Data on enhanced recovery programmes after pancreatic surgery are sparse. Thisretrospective cohort study, using historical controls, aimed to evaluate the impact of a fast-trackprogramme after pancreaticoduodenectomy (PD).Methods: Between 2004 and 2007, 252 patients undergoing PD were treated by a fast-track programmethat included earlier postoperative feeding and mobilization. The patients were compared with an equallysized control group that received a traditional programme from 2000 to 2004. Outcome measures weremorbidity, length of stay and readmission rate.Results: The rates of pancreatic fistula and other intra-abdominal complications were similar in thetwo groups. Delayed gastric emptying (DGE) was significantly reduced in the fast-track group (13·9versus 24·6 per cent; P = 0·004). The independent effect of the fast-track protocol in reducing DGEwas confirmed by the multiple regression analysis (adjusted odds ratio 0·477, P = 0·005). Length of staywas reduced with the fast-track protocol (median 13 versus 15 days; P < 0·001), without increasing thereadmission rate (7·1 versus 6·3 per cent; P = 0·865).Conclusion: A fast-track programme after PD improves gastric emptying and reduces postoperative stay.

Presented to the Seventh Congress of the European Chapter of the International Hepato-Pancreato-Biliary Association,Verona, Italy, June 2007

Paper accepted 6 June 2008Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.6324

Introduction

Novel approaches to the optimization of perioperativecare for elective surgical patients, based on advances insurgical techniques and anaesthetic care, were availableby the end of 1990s. Fast-track surgery (or enhancedrecovery after surgery) is an interdisciplinary, multimodalconcept designed to accelerate postoperative recovery. Itcombines various techniques used in the care of patientsundergoing elective surgery: epidural or regional anaes-thesia, minimally invasive techniques, optimal pain con-trol and aggressive postoperative rehabilitation, includ-ing early enteral or oral feeding and ambulation1. Thedevelopment and improvement of fast-track protocols isa major challenge for surgeons working to achieve apain- and risk-free perioperative course2. Recent stud-ies have demonstrated the feasibility and safety of fast-track protocols in colorectal surgery3, but its role inupper gastrointestinal major surgery is still controver-sial.

Pancreaticoduodenectomy (PD) is a common abdominaloperation with a high risk of postoperative morbidity andmortality. Data on the application of fast-track clinicalprotocols in pancreatic surgery are sparse4,5. The aimof this study was to evaluate the safety and outcome ofa protocol of enhanced recovery after PD in a tertiaryreferral university hospital with a high-volume pancreaticsurgery unit6.

Methods

The protocol of enhanced recovery after PD (Table 1)was introduced in the authors’ department in July 2004.Over a 3-year period, from July 2004 to June 2007, 252patients underwent PD (fast-track group). Compared withthe previous traditional pathway, changes involved earlieroral feeding (removal of nasogastric tube on day 1, liquiddrinks from day 3, solid food from day 4) and standardizedpostoperative mobilization. No further change in the

Copyright 2008 British Journal of Surgery Society Ltd British Journal of Surgery 2008; 95: 1387–1393Published by John Wiley & Sons Ltd

1388 G. Balzano, A. Zerbi, M. Braga, S. Rocchetti, A. A. Beneduce and V. Di Carlo

Table 1 Protocol for early recovery after pancreaticoduodenectomy

Before operation At the time of informed consent to operation patient informed about fast-track rehabilitation programme

Day 0 Placement of thoracic epidural catheter (T7–T9 level) with continuous infusion of bupivacaine 0·125% with fentanyl 2 µg/mlat a rate of 4–6 ml/h until day 5, plus intravenous paracetamol or NSAIDs, or, if epidural catheter is contraindicated,patient-controlled analgesia with morphine, plus intravenous paracetamol or NSAIDs

Day 1 Removal of nasogastric tube if drainage amount < 300 mlMobilization out of bed for >1 hIntravenous fluid administration (30 ml/kg per day of hydroelectrolytic solution plus 5% glucose) continued until adequate

oral fluid intake

Day 2 Enhanced mobilization (> 2 h out of bed)

Day 3 Clear fluid intake (free amount)Enhanced mobilization (> 4 h out of bed, with personal hygiene care in bathroom)

Day 4 Solid food intake

Day 5 Diet increase on daily basis (given as five to six small meals) until reaching a calorie intake of 1000 kcal on day 8Drain removal (if no pancreatic or biliary fistula, when daily amount < 200 ml)Epidural catheter removal

Discharge criteria Absence of fever (< 37·5°C for > 48 h), adequate pain control with oral analgesics, ability to take solid foods (at least 1000kcal/day), passage of stools, adequate mobilization and acceptance of discharge by patient

NSAID, non-steroidal anti-inflammatory drug.

perioperative approach was made: epidural analgesia hadbeen performed routinely in the department since 1996 andno modification of the epidural regimen was introducedduring the study period; in addition, the protocol forperioperative infusions did not change over the years. Toevaluate the effect of enhanced recovery after PD, thefast-track group was compared with a historical controlgroup of equal size, comprising 252 patients operatedon consecutively between May 2000 and June 2004. Thetraditional protocol included nasogastric decompressionuntil day 5, liquid drinks from day 6 and solid food fromday 7; no specific action on mobilization was defined.

Data for all patients were collected prospectively inan electronic pancreatic surgery database and evaluatedretrospectively; however, data for postoperative nauseaand vomiting were retrospective for the control group,whereas they were recorded prospectively for the fast-trackgroup, on days 3, 5 and 7 after surgery. Outcome measureswere postoperative complications (in-hospital and within30 days of discharge), length of stay and readmission rate(within 30 days of discharge). Complications were definedas: mortality (in-hospital death, irrespective of durationof stay, or death occurring within 30 days of discharge);pancreatic fistula (PF; according to the definition of theInternational Study Group on Pancreatic Fistula (ISGPF)7,defined as any measurable amount of drainage fluid,with amylase three times the normal level, on or afterpostoperative day 3); delayed gastric emptying (DGE;need for nasogastric decompression or vomiting occurringafter day 10, according to the definition proposed inprevious studies8–11), stratified into two classes (primary

DGE, when not associated with other intra-abdominalcomplications, and secondary DGE, when associated withsuch complications); and intra-abdominal complication(any complication associated with the abdominal cavity,excluding DGE, such as relaparotomy, pancreatic, biliaryor digestive fistula, intra-abdominal fluid collection(infected or not), intra-abdominal or digestive bleeding,intestinal or liver ischaemia, acute pancreatitis, etc.).

The same team of six surgeons performed the opera-tions, routinely through a right subcostal incision, slightlyextended to the left side, with pylorus preservation, stan-dard lymphadenectomy, end-to-side two-layer pancreati-cojejunostomy and retrocolic duodenojejunostomy. If thepylorus was preserved, so was the right gastric artery,unless it was damaged or hindered adequate gastric mobi-lization. No prokinetic agent was administered routinely,but intravenous metoclopramide was given on demand(10 mg intravenously, three times daily). Prophylaxis con-sisted of octreotide (0·1 mg three times daily from day 0to 7), low molecular weight heparin and a single dose ofantibiotic (cefazolin 2 g). Early postoperative analgesia wasobtained by means of epidural or, when contraindicated,patient-controlled analgesia.

Statistical analysis

All patients operated on after introduction of the protocolfor early recovery following PD were considered to belongto the fast-track group even if they did not accomplish theprotocol (intent-to-treat analysis). Categorical variableswere compared with the χ2 test, quantitative variables with

Copyright 2008 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2008; 95: 1387–1393Published by John Wiley & Sons Ltd

Recovery after pancreaticoduodenectomy 1389

Student’s t test and length of stay with the non-parametricMann–Whitney U test. Univariable and multivariableanalysis was performed, by logistic regression, to assessthe independent value of the fast-track programme inreducing DGE; variables with P < 0·100 were consideredin the multivariable analysis. The level of significance wasset at 0·050. Data analysis was performed with SPSS

version 13.0 (SPSS, Chicago, Illinois, USA).

Results

The two groups were similar with regard to alldemographic and clinical factors, including preservationof the pylorus and postoperative use of opioids (Table 2).In 20 patients (7·9 per cent) in the fast-track group thenasogastric tube was not removed on day 1 because theamount of drainage fluid was greater than 300 ml (16patients) or because of early reoperation (four). However,the tube could be withdrawn in nine of these patients bythe third postoperative day, so that overall 241 patients(95·6 per cent) had no nasogastric decompression by day3. Most of these patients (203 patients, 84·2 per cent) didnot need subsequent replacement of the tube. Reasonsfor reinsertion were relaparotomy (23 patients, includingthose who had died) and repeated emesis (15). Allpatients without a nasogastric tube commenced liquidintake on day 3 and resumption of oral food on day4; however, nausea, gastric distension and/or emesisprevented most patients from resuming the planneddaily dietary calorie intake (1000 kcal) within the first

8 days. Of 241 orally refed patients, nausea and vomitingoccurred in 23 (9·5 per cent) and three (1·2 per cent)patients respectively on day 3, in 94 (39 per cent) and eight(3·3 per cent) on day 5, and in 141 (58.5 per cent) and 19(7·9 per cent) on day 7. Metoclopramide was administeredto a total of 164 patients (65·1 per cent) in the fast-trackgroup.

In traditionally treated patients, after resumption oforal food (from the seventh postoperative day onwards)nausea and vomiting were recorded in 106 (42·1 per cent)and 43 (17·1 per cent) of patients respectively. In boththe traditional and fast-track groups, the median dayfor first flatus was day 3, whereas first passage ofstools occurred earlier in fast-track patients than incontrols (median 5 versus 6 days; P < 0·001) (Table 3).The programme of mobilization was accomplishedby 199 patients (79·0 per cent) on day 1, by 176(69·8 per cent) on day 2 and by 151 (59·9 per cent) onday 3.

Postoperative complications are shown in Table 3. Theoverall mortality rate was 3·2 per cent (16 of 504 patients),with no significant difference between the two groups.The incidence and grading of PF, as well as of other intra-abdominal complications, was similar in the two cohorts,but the DGE rate was significantly reduced in patientsin the fast-track programme (13·9 versus 24·6 per cent;P = 0·004). The occurrence of secondary DGE was similarin the two groups, but fewer patients in the fast-trackgroup experienced primary DGE (5·6 versus 13·9 per cent;P = 0·003).

Table 2 Demographic and perioperative factors in patients having traditional care and those in the fast-track programme

Traditional (n = 252) Fast track (n = 252) P

Mean age (years)* 62·9 (26–84) 64·3 (33–88) 0·181‡No. of women 104 (41·3) 97 (38·5) 0·594§Pathology

Pancreatic cancer 145 (57·5) 151 (59·9) 0·652§Periampullary cancer 51 (20·2) 42 (16·7) 0·373§Endocrine neoplasm 15 (6·0) 12 (4·8) 0·730§Chronic pancreatitis 20 (7·9) 24 (9·5) 0·636§Other 21 (8·3) 23 (9·1) 0·879§

Preoperative jaundice 166 (65·9) 154 (61·1) 0·305§Preoperative diabetes 71 (28·2) 66 (26·2) 0·280§Wirsung duct ≤ 3 mm 135 (53·6) 127 (50·4) 0·532§Fibrotic remnant 106 (42·1) 100 (39·7) 0·651§Median duration of surgery (min)* 390 (200–730) 402 (200–780) 0·112‡Median operative blood loss (ml)* 500 (50–5700) 550 (75–2600) 0·194‡No. of patients transfused 116 (46·0) 96 (38·1) 0·091§Median volume transfused (ml)* 500 (200–8700) 540 (180–2550) 0·480‡Pylorus preservation 211 (83·7) 221 (87·7) 0·090§Analgesia with opioids† 42 (16·7) 35 (13·9) 0·386§

Values in parentheses are percentages unless indicated otherwise; *values are ranges. †Patient-controlled analgesia with morphine. ‡Student’s t test; §χ2

test.



Table 3 Postoperative course in patients having traditional care and those in the fast-track programme

Traditional (n = 252) Fast track (n = 252) P

Mortality 7 (2·8) 9 (3·6) 0·798§Morbidity 148 (58·7) 119 (47·2) 0·014§Relaparotomy (deaths excluded) 20 (7·9) 17 (6·7) 0·733§Percutaneous drainage (deaths and relaparotomy excluded) 6 (2·4) 9 (3·6) 0·598§Intra-abdominal complications 106 (42·1) 93 (36·9) 0·236§Pancreatic fistula 65 (25·8) 60 (23·8) 0·315§

Type A† 31 (12·3) 29 (11·5) 0·892§Type B† 19 (7·5) 20 (7·9) 0·999§Type C† 15 (6·0) 11 (4·4) 0·578§

DGE 62 (24·6) 35 (13·9) 0·004§Primary 35 (13·9) 14 (5·6) 0·003§Secondary 27 (10·7) 21 (8·3) 0·447§

Time to passage of flatus (days)* 3 (1–7) 3 (1–6) 0·172‡Time to passage of stool (days)* 6 (1–10) 5 (1–9) < 0·001‡Postoperative stay (days)*

All patients 15 (7–102) 13 (7–110) < 0·001¶Patients with no complications 13 (7–17) 11 (7–15) < 0·001¶

Readmission 16 (6·3) 18 (7·1) 0·865§

Values in parentheses are percentages unless indicated otherwise; *values are median (range). †According to stratification of the International StudyGroup on Pancreatic Fistula7. DGE, delayed gastric emptying. ‡Student’s t test; §χ2 test; ¶Mann–Whitney U test.

Table 4 Odds ratios for overall delayed gastric emptying

Odds ratio P† Adjusted odds ratio* P†

Age 1·004 (0·984, 1·021) 0·687Female sex 1·008 (0·636, 1·507) 0·974Malignancy 1·011 (0·805, 1·955) 0·316Preoperative jaundice 1·059 (0·782, 1·457) 0·823Preoperative diabetes 1·171 (0·598, 1·874) 0·845Octreotide prophylaxis 0·786 (0·587, 2·336) 0·655Duration of surgery 1·000 (0·997, 1·002) 0·780Pylorus preservation 0·786 (0·410, 1·507) 0·469Transfusions 1·744 (1·062, 2·864) 0·028 1·526 (0·914, 2·549) 0·106Pancreatic fistula 1·522 (0·946, 2·449) 0·084 1·188 (0·523, 2·699) 0·680Intra-abdominal complication 1·661 (1·063, 2·594) 0·026 1·495 (0·687, 3·250) 0·310Fast-track programme 0·494 (0·313, 0·781) 0·003 0·477 (0·285, 0·797) 0·005

Values in parentheses are 95 per cent confidence intervals. *Reported only for co-variables with P < 0·100 in the univariable analysis. †Logistic regressionanalysis.

In univariable analysis, DGE was significantly associatedwith blood transfusions, intra-abdominal complicationsand the fast-track programme (Table 4). In a multivariablelogistic regression analysis, the only significant indepen-dent factor influencing DGE was the fast-track programme(adjusted odds ratio 0·477, P = 0·005) (Table 4).

The length of postoperative hospital stay was signif-icantly shorter in the fast-track group (P < 0·001), as aresult of both a decrease in the DGE rate and a shorterstay in patients with no complications (median 11 ver-sus 13 days; P < 0·001) (Table 3). The readmission ratefor patients in the fast-track group was low (7·1 per cent)and similar to that of patients in the traditional group(6·3 per cent) (Table 3).

Discussion

Fast-track perioperative care programmes aim to obtaina reduction in morbidity, a faster recovery and a shorterhospital stay. In colonic surgery, these protocols haveproved to be safe, reducing complications and length ofstay3. Fast-track pathways have also been proposed inother surgical settings, such as aortic aneurysm repair12,prostatectomy13 and thoracic surgery14,15, but few data areavailable.

PD is one of the most complex abdominal operations.In recent decades, the progressive establishment of high-volume pancreatic surgery hospitals worldwide has led tothe achievement in these institutions of mortality rates



consistently lower than 5 per cent4,5,8,16–19. However,the morbidity rate is still around 50 per cent19,20, andpostoperative hospital stay outside the USA averages14–28 days21. A programme of enhanced recovery afterPD could improve these results. The fear that earlyfeeding could increase the complication rate by stimulatingpancreatic secretion led surgeons traditionally to maintainpatients on long fasting periods after PD. Recently,the feasibility of fast-track programmes after pancreaticresection4 and the decrease in both postoperative stay andhospital costs of PD through enhanced clinical pathways5

have been reported. The present study compared alarge group of patients treated according to a fast-trackprogramme with a conventionally treated group. Despitethe possible selection bias due to historical controls, the twocohorts were similar for all demographic and perioperativefactors. The introduction of the fast-track programme wasthe only change in the management of patients undergoingPD, and any differences in outcome between the groups cantherefore be attributed to this variable. Hospital volume ofPD increased slightly over the years, although it was alreadyaround 50 PDs per year at the beginning of the study,warranting an absence of a learning curve. The protocolis simple: it includes early postoperative oral feeding andearly mobilization, two mainstays of a multimodal fast-track programme. Pain control was effected by continuousepidural analgesia, but as this had also been administeredin patients in the traditional group it did not influence thechanges observed in the study group.

Most patients undergoing PD experienced difficulty inadhering to the fast-track programme; nausea, vomitingand postoperative fatigue were the main hindrances.Nausea and vomiting did not appear to be a consequence ofearly removal of the nasogastric tube, as the retrospectiveevaluation of patients receiving traditional care showeda similar proportion suffering from such symptoms;retaining the tube until day 5 did not minimize thesetroubles in control patients, but merely postponed theiroccurrence, with the further discomfort of a long periodof nasogastric intubation. The protocol did not includeprophylactic drugs to prevent nausea and vomiting,although about two-thirds of patients received a standarddose of metoclopramide to treat such symptoms. Aroutine strategy to prevent nausea and vomiting and tosupport bowel recovery might reduce patient discomfortand accelerate gastrointestinal function; higher doses ofmetoclopramide (in association with dexamethasone)22 ornew opioid antagonists23 should be tested in this setting toimprove the present results.

Nevertheless, patients in the fast-track programme hadless DGE than traditionally treated patients. DGE is one

of the most common complications of PD, with reportedrates of 20–30 per cent24. To define DGE, a widely useddefinition was adopted by the present authors: the needfor a nasogastric tube or emesis after day 108–11. Recently,a consensus definition was proposed that stratifies DGEinto grades A, B and C according to its clinical impact21;the definition employed here was similar to grades B andC of this consensus definition (nasogastric tube requiredfor 8 days or more after surgery, inability to tolerate solidoral intake until at least day 14), and therefore included therelevant events. To reduce the clinical impact of DGEafter PD, erythromycin therapy has been suggested8,or, more recently, reconstruction with an antecolicduodenojejunostomy25,26. Early postoperative feeding canbe a further means of improving gastric emptying, as thefasting state impairs the peristaltic activity of the stomachand small intestine, whereas the fed state is characterizedby more forceful peristaltic waves of contraction27. Inthe present study, the programme of enhanced recoveryresulted in a significantly reduced incidence of DGE,from 24·6 to 13·9 per cent, confirming that early feedingcan improve gastric motility even after major pancreaticsurgery. The fast-track programme reduced the rate ofprimary DGE, while, as expected, having only a minoreffect on secondary DGE, which accounts for about halfof all DGE. Early mobilization probably has a secondaryrole in reducing DGE: even though bed rest contributesto slowing gastrointestinal activity, ambulation has littleeffect on postoperative ileus28.

Another important finding was that earlier resumptionof food did not have a negative effect on the incidence ofPF. Patients in the control group, who fasted for 1 weekafter surgery, had a PF rate of 25·8 per cent, compared with23·8 per cent in patients who had earlier feeding. The highincidence of PF is a consequence of the ISGPF definitionapplied7, which has been shown to result in an increased PFrate compared with the standard definition19. In addition,the overall rate of intra-abdominal complications wassimilar in the two groups.

A further major advantage of the fast-track programmewas the significantly decreased postoperative length ofstay, with no increase in the readmission rate. The reducedhospital stay can be attributed both to the decrease in DGEand to the effect of the fast-track programme on patientswith no complications; improved digestive function andearlier mobilization contribute to the acceptance of hospitaldischarge by the patient. Length of stay can be an indicatorof hospital costs29; this protocol involved a shorter hospitalstay with no increase in costs, as the two simple measuresintroduced (early oral feeding and mobilization) did notnecessitate an increase in delivered care.



In summary, a fast-track programme after PD improvesgastric emptying, reduces patient discomfort by enablinga shorter nasogastric intubation, and reduces hospital stay,without affecting patient safety. This protocol can beintroduced easily by surgeons in daily practice, with noincrease in costs. More intensive, multimodal approachesshould be examined in future studies.

Acknowledgements

This study was supported partially by the Italian Ministryof University and Scientific Research.

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