Evolution of nutritional support in acute pancreatitis
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Review
Evolution of nutritional support in acute pancreatitis
D. N. Lobo, M. A. Memon, S. P. Allison* and B. J. Rowlands
Section of Surgery and *Clinical Nutrition Unit, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK
Correspondence to: Mr D. N. Lobo
Background: Acute pancreatitis is a catabolic illness and patients with the severe form have high
metabolic and nutrient demands. Arti®cial nutritional support should therefore be a logical component
of treatment. This review examines the evidence in favour of initiating nutritional support in these
patients and the effects of such support on the course of the disease.
Methods: Medline and Science Citation Index searches were performed to locate English language
publications on nutritional support in acute pancreatitis in the 25 years preceding December 1999.
Manual cross-referencing was also carried out. Letters, editorials, older review articles and most case
reports were excluded.
Results and conclusion: There is no evidence that nutritional support in acute pancreatitis affects the
underlying disease process, but it may prevent the associated undernutrition and starvation, supporting
the patient while the disease continues and until normal and suf®cient eating can be resumed. The
safety and feasibility of enteral nutrition in acute pancreatitis have been established; enteral nutrition
may even be superior to parenteral nutrition. Some patients, however, cannot tolerate enteral feeding
and this route may not be practical in others. Parenteral nutrition still has a role, either on its own or in
combination with the oral and enteral routes, depending on the stage of the illness and the clinical
situation.
Paper accepted 7 February 2000 British Journal of Surgery 2000, 87, 695±707
however, that there is no mention of nutritional support
Introduction
in the recent UK guidelines8 for the management of acute
Acute pancreatitis, a disease of varying severity, has been pancreatitis.
de®ned as an acute in¯ammatory process of the pancreas, This review examines the indications for arti®cial
with variable involvement of other regional tissues or nutritional support, identi®es which patients may require
remote organ systems1. Mild disease is associated with it, evaluates the available evidence on the relative merits of
minimal organ dysfunction and an uneventful recovery, the enteral and parenteral routes, and assesses the potential
while severe disease is associated with organ failure and local role of novel nutritional substrates.
complications such as necrosis, abscess and pseudocyst
formation1. Mild attacks account for 70±80 per cent of
Search strategy
hospital admissions for this condition and usually resolve in
5±7 days2±5. The 20±30 per cent of patients with severe An internet-based search of the Medline and Science
disease pose a clinical challenge in critical care, requiring a Citation Index databases was undertaken using the key
multidisciplinary approach that includes arti®cial nutri- words acute, chronic, pancreatitis, nutrition, nutritional
tional support. support, enteral and parenteral in various combinations
Studies on the use of nutritional support are con¯icting with the Boolean operators AND, OR and NOT. Emphasis
and, in recent years, the pendulum has swung from was placed on human studies. Manual cross-referencing was
favouring parenteral nutrition to highlighting the feasibility also performed. Articles published in the English language
and safety of enteral nutrition whenever possible6. within the 25 years preceding December 1999 were
Guidelines published by the American College of selected. This decision was in¯uenced by the need to study
Gastroenterology7 recommend that parenteral nutrition the evolution of nutritional support in acute pancreatitis
should be used for patients with severe disease who will be and the associated controversies. Review articles published
without oral nutrition for 7±10 days. It is interesting, before 1992, editorials, letters and most case reports have
ã 2000 Blackwell Science Ltd British Journal of Surgery 2000, 87, 695±707 695696 Nutritional support in acute pancreatitis · D. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands
been excluded. Abstracts are cited only when full papers patients also have diminished muscle protein synthesis.
addressing a given issue are unavailable. The resultant negative nitrogen balance is, therefore, a net
effect of both these changes. Free fatty acid kinetics are
similar in both groups. Exogenous glucose infusion causes
Need for nutritional support in acute
almost complete suppression of gluconeogenesis from
pancreatitis
protein in normal subjects but not in patients with acute
Especially in its severe form, acute pancreatitis is associated pancreatitis. These metabolic changes are consistent with a
with a systemic in¯ammatory response causing increased state of hepatic insulin resistance23 and are similar to those
metabolic demands which may progress to multiple organ observed in patients with sepsis24.
dysfunction syndrome. The disease and its complications The effects of increased metabolic demands are com-
are associated with the release of proin¯ammatory media- pounded by an inability or reluctance to maintain an
tors such as interleukin (IL) 1, IL-6, IL-8, tumour necrosis adequate oral intake, so that patients become malnourished
factor (TNF) a and platelet-activating factor9±12. In during the course of their illness. Some with alcoholic
addition, there is activation of the complement cascade, pancreatitis may also be premorbidly malnourished25,26 and
release of oxygen-derived free radicals and nitric oxide, and malnutrition may be especially apparent in those who have
generation of prostaglandin E2, thromboxane A2 and acute on chronic pancreatitis. Micronutrient and vitamin
leukotriene4 from the metabolism of arachidonic acid. If de®ciencies may also be present on admission or develop
prolonged and combined with starvation, these changes during hospitalization. In addition to hypocalcaemia, which
lead to a rapid loss of lean body mass with its associated is seen in up to 25 per cent of patients with severe acute
morbidity and death13. Increased intestinal permeability in pancreatitis, de®ciencies of magnesium, zinc, folate and
animals14±16 and humans17, along with an associated thiamin have been described4,27.
impaired gut barrier function, may lead to translocation of Severe disease usually manifests at onset or within a few
bacteria and bacterial products from the gut lumen into the days of onset28±30 and usually follows a protracted course.
circulation18. While experimental animal work has indi- On the other hand, it is common experience that mild
cated that enteral nutrition may prevent bacterial transloca- disease resolves in less than a week. The UK guidelines8
tion in acute pancreatitis, this does not necessarily translate recommend that strati®cation of the severity of pancreatitis
into a survival advantage19. should be made within 48 h using the Glasgow score31 and
Mass spectrometry demonstrates that total energy plasma C-reactive protein (CRP) level32. Severe disease is
expenditure is 1´49 times the predicted resting energy identi®ed by the presence of three or more positive Glasgow
expenditure using the Harris±Benedict equation in patients criteria on both initial admission and subsequent tests over
with severe acute pancreatitis20. There is no signi®cant 48 h. CRP concentrations above 210 mg/l in the ®rst 4 days
difference when patients with and without sepsis are of the attack have a similar predictive value8,32. Some
compared. Calculation of nutrient oxidation rate suggests authors have found that CRP concentrations reach a peak
a high rate of protein catabolism, with increased gluconeo- only 48 h after onset of pancreatitis33 and others argue that
genesis and lipolysis. The total : resting energy expenditure concentrations above 120 mg/l may also predict severe
ratio correlates inversely with nitrogen balance (r = ± 0´63, disease34. The Ranson criteria28 are popular with American
P = 0´01). Indirect calorimetry shows that the mean workers7 and, like the Glasgow score, three or more positive
total : resting energy expenditure ratio is signi®cantly criteria indicate severe disease. The Acute Physiology And
higher in patients with acute pancreatitis complicated by Chronic Health Evaluation (APACHE) II scoring system35
sepsis than in patients with chronic pancreatitis (1´20 versus is also useful in stratifying disease severity and has the
1´05; P < 0´02)21. The mean ratio for patients with acute advantage of being suitable for continuous monitoring.
pancreatitis without sepsis was 1´12. The same study also APACHE II scores of 8 or more indicate severe disease, but
showed that, although 82 per cent of patients with acute a few patients with scores of 6±7 may also have severe acute
pancreatitis and sepsis have a ratio above 1´10, 61 per cent of pancreatitis. Any patient who has severe acute pancreatitis,
patients with non-septic acute pancreatitis and 33 per cent de®ned by any of the above scoring systems, should be
of those with chronic pancreatitis are hypermetabolic. considered for nutritional support.
Isotope techniques demonstrate that patients with severe
disease have an impaired ability to oxidize glucose
Physiology of exocrine pancreatic function and
compared with controls22. This is associated with a
the need for pancreatic rest
signi®cantly higher urea production, indicating increased
protein catabolism. This increase is not as high as predicted The secretions of the exocrine pancreas total 1±2 litres per
from nitrogen balance studies, suggesting that these day and the normal response to a meal contains twice the
British Journal of Surgery 2000, 87, 695±707 www.bjs.co.uk ã 2000 Blackwell Science LtdD. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands · Nutritional support in acute pancreatitis 697
minimal enzyme requirement for normal digestion36. evidence is that the bene®t of pancreatic rest in patients with
There is, therefore, some redundancy in the system. acute pancreatitis is unproven.
Recently, it has been shown that protein energy malnutri-
tion is associated with gross reduction in pancreatic enzyme
Effect of enteral feeding on pancreatic
secretion and that this is restored to normal as body tissue is
secretions
regained during refeeding37. The electrolyte-rich pancrea-
tic juice is iso-osmotic with plasma and contains a number of The presence of food in the stomach and duodenum elicits
digestive enzymes that include inactive zymogenic proteo- gastropancreatic and duodenopancreatic re¯exes that result
lytic enzymes and active amylase and lipase. Pancreatic in stimulation of pancreatic exocrine secretions. However,
secretions are under complex neurohumoral control and, as these effects are not as pronounced when nutrients are
with other gastrointestinal secretions, have a cephalic, delivered directly into the jejunum.
gastric and intestinal phase. The release of digestive A study in dogs50 showed that intragastric delivery of
enzymes is mainly under the control of cholecystokinin nutrients causes an increase in the volume, and protein and
and vagal cholinergic stimulation, while vasoactive intest- bicarbonate content, of pancreatic secretions compared
inal polypeptide in¯uences bicarbonate secretion. with those in saline-infused controls. Intraduodenal feeding
Pancreatic polypeptide, calcitonin gene-related peptide, increases the volume of pancreatic secretions but does not
peptide YY, somatostatin and neuropeptide Y have affect protein or bicarbonate secretion. Other studies in
inhibitory effects38,39. dogs51±53 also show that the intraduodenal administration
The concept of pancreatic rest stems from the belief that of elemental diets or pure amino acid solutions signi®cantly
stimulation of pancreatic exocrine function in patients with increases pancreatic secretions, suggesting that the amino
acute pancreatitis releases large quantities of proteolytic acid content of elemental diets is responsible for the
enzymes which results in autodigestion of the in¯amed stimulatory effects. In contrast, intrajejunal delivery of
pancreas and peripancreatic tissues, causing a deterioration nutrients is not associated with a signi®cant change in the
in the patient's condition. In a study40 of eight patients with volume, or protein or bicarbonate content, of pancreatic
acute pancreatitis it was found that interdigestive secretions secretions compared with controls50. These authors50 also
of the exocrine pancreas, within 72 h of the onset of mild to found in one human subject that avoidance of cephalic,
moderate disease, were no different from those in 26 normal gastric and duodenal stimuli by jejunal tube feeding using
controls. On this evidence the authors propose early neutral amino acids did not result in pancreatic stimulation.
inhibition of pancreatic secretion with somatostatin in the They concluded that bypassing the stomach, minimizing
acute phase of the illness. It can equally be argued, however, acid secretion, plays an important role in keeping the
as these patients secrete normal quantities of pancreatic pancreas at rest.
enzymes, that the gut should be capable of digesting Pancreatic exocrine secretion is less, both in volume and
nutrients given enterally into the jejunum. Still, some enzyme content, in dogs fed orally with an elemental diet
animal studies41,42 suggest that both basal and stimulated than in those fed commercial dog food54. However, these
pancreatic secretions are impaired in experimental pan- changes are apparent only a month after the commence-
creatitis, even before the development of major necrosis. ment of feeding. Another canine study55, in which an
Oral and nasogastric feeding do, however, increase elemental diet was fed into the proximal jejunum, demon-
pancreatic secretion by stimulation of the cephalic and strated a brisk pancreatic secretory response. However, the
gastric phase, and it is suggested that early oral feeding may pancreatic juice collected was watery and enzyme poor.
lead to recurrence of symptoms and delayed complica- A study56 on volunteers fed either an elemental diet or a
tions43. Although animal studies44±46 show that `pancreatic food homogenate via a nasoenteral tube placed at the
rest' reduces pancreatic synthetic activity and basal proteo- duodenojejunal ¯exure indicates that the latter has a greater
lytic and bicarbonate secretions, evidence from human stimulatory effect on the secretion of pancreatic lipase and
studies is less certain. A retrospective review of 330 patients chymotrypsin than the former. The authors suggest that
with pancreatitis suggests that early oral feeding predis- this difference might be related to the greater nitrogen
poses to major peripancreatic infections, while prolonged content of the food homogenate. Osmolality of the feeds
nasogastric suction and avoidance of early operation does not seem to have an effect.
reduces the incidence of these infections47. Randomized A study on a single patient with a duodenal ®stula, tube-
controlled studies48,49 in patients with mild to moderate fed into the efferent limb of a gastrojejunostomy, demon-
acute pancreatitis have, however, failed to establish the strated that although enteral feeding does not alter the
value and ef®cacy of fasting or nasogastric suction. The only volume of secretions into the duodenum there is a decrease
®rm conclusion that can be drawn from such con¯icting in bicarbonate and amylase secretion, and an increase in
ã 2000 Blackwell Science Ltd www.bjs.co.uk British Journal of Surgery 2000, 87, 695±707698 Nutritional support in acute pancreatitis · D. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands
lipase and nitrogen content of the duodenal ®stula produce a signi®cant change. These ®ndings con®rm those
ef¯uent57. of an earlier study61 showing that intravenous infusion of
Bodoky et al.58 randomized 12 patients undergoing amino acids in a canine ®stula model does not result in any
pylorus-preserving pancreaticoduodenectomy for chronic change in volume or protein content of pancreatic secre-
pancreatitis to receive enteral nutrition via a needle catheter tions. All these studies52,53,60 compared parenteral with
feeding jejunostomy (seven patients) or parenteral nutrition intraduodenal feeding, which is known to stimulate the
(®ve patients). A catheter placed during operation in the pancreas. No direct comparison has yet been made between
pancreatic duct was used to collect pancreatic secretions. the secretory effects of parenteral and jejunal feeding.
The authors believed that the disease was mainly in the A case report62 suggests that the parenteral infusion of
pancreatic head and that the function of the pancreatic concentrated glucose solutions produces a decrease in
remnant was near normal. They did not ®nd any difference volume and amylase content of pancreatic secretions, while
in the volume of pancreatic secretions or the content of fat has the opposite effect and amino acids cause no change.
bicarbonate, protein, chymotrypsin or amylase between the Variyam et al.63 have shown that parenteral amino acids do
two groups. not stimulate pancreatic enzyme secretion in healthy young
A recent study59 compared the effects of a jejunally men. Another study64 of pancreatic secretion in 31 normal
administered elemental diet with those of an immune- volunteers recorded a rise in response to parenteral amino
enhancing formula on exocrine pancreatic secretions after acid infusions, a fall with glucose infusions and no change
Whipple pancreaticoduodenectomy. The authors found a with infusion of lipids alone or a mixture of all three
small but signi®cant increase in pancreatic enzyme and substrates, suggesting that in normal practice parenteral
bicarbonate secretion after jejunal feeding compared with nutrition has no signi®cant effect on pancreatic secretion.
the fasting state, but there was no signi®cant difference in
pancreatic enzyme output when the effects of the elemental
Parenteral nutrition in acute pancreatitis
and immune-enhancing feeds were compared.
Although there is a paucity of human studies on the effects
Uncontrolled studies
of oral feeding and enteral nutrition on pancreatic secretion,
one may reasonably conclude from available evidence from Feller et al.65 were the ®rst to advocate intravenous
both human and canine studies that oral, intragastric and hyperalimentation followed by enteral administration of
intraduodenal feeding produce a signi®cant stimulation of an elemental diet as supportive therapy in acute pancreatitis.
pancreatic secretions. In contrast, intrajejunal feeding has In an uncontrolled retrospective analysis, they showed a
much less stimulatory effect and is therefore the route of decrease in the overall mortality rate from 22 to 14 per cent,
choice for enteral feeding in acute pancreatitis. which they attributed to aggressive nutritional and respira-
tory support. Blackburn et al.25 described another uncon-
trolled retrospective study of 11 patients who had sustained
Effect of parenteral feeding on pancreatic
signi®cant malnutrition secondary to severe acute pancrea-
secretions
titis lasting more than 14 days. Patients received parenteral
Kelly and Nahrwold52 compared the exocrine pancreatic hyperalimentation combined with enteral support in the
secretory response to intravenous saline and parenteral form of a de®ned formula diet before surgical intervention.
nutrition in dogs with chronic gastric ®stulas and found that All were later operated on for control of pancreatitis-related
the latter produced a small but signi®cant increase in the complications with no postoperative death or signi®cant
mean volume of pancreatic juice (2´4 versus 1´8 ml per morbidity. The authors noted a signi®cant improvement
15 min; P < 0´05) with a slight increase in mean protein and over the 62 per cent mortality rate of Ranson et al.28 in this
bicarbonate secretions. These differences are minimal subgroup of patients and the 60 per cent survival rate
compared with the changes found in dogs receiving an recorded by investigators from the Massachusetts General
intraduodenal infusion of an enteral diet. Con¯icting results Hospital66. They concluded that the improved results were
have been reported in canine studies53,60 on the effects of due to proper preoperative assessment and correction of
intraduodenal versus intravenous amino acids and fat on nutritional depletion.
pancreatic secretions. One study53 found that, in the short Goodgame and Fischer67 retrospectively analysed 44
term, both routes of administration stimulated pancreatic patients with acute pancreatitis who were treated with
secretions. A later study60 demonstrated that increasing parenteral nutrition. They concluded that hyperalimenta-
doses of amino acids and fat produce increasing responses in tion should be viewed as a method of support rather than
volume, protein and bicarbonate when administered primary therapy in this disease. They found a higher
intraduodenally, but similar intravenous doses do not incidence of catheter-related septicaemia in the early phase
British Journal of Surgery 2000, 87, 695±707 www.bjs.co.uk ã 2000 Blackwell Science LtdD. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands · Nutritional support in acute pancreatitis 699
of acute pancreatitis and recommended that a feeding Guillou70 proposed that the increased incidence of septic
jejunostomy should be performed as a potential means for complications in patients with acute pancreatitis receiving
long-term nutritional management if the need for lapar- parenteral nutrition may be a result of a complex interaction
otomy arises. They also demonstrated that parenteral of factors which include deranged gut barrier function,
feeding can be accomplished with minimal technical or impaired complement ®xation due to hyperglycaemia
metabolic morbidity and that it may help salvage patients resulting from glucose/lipid-based parenteral feeding, the
with prolonged gut dysfunction secondary to complications immunosuppressive effect of some lipids and even the fact
of acute pancreatitis. These authors, however, concede that that pancreatitis may produce an immunosuppressive state.
the retrospective nature of this study and the absence of any Kalfarentzos et al.71 published their retrospective ®nd-
true control group make de®nitive conclusions dif®cult. ings in 67 patients with severe disease who had three or
Grant et al.68 also analysed data retrospectively on 121 more Ranson criteria. They divided their patients into two
patients with severe pancreatitis (73), chronic pancreatitis groups: patients in group A (38) received parenteral
(23) and pancreatic cancer (25) who received parenteral nutrition within 72 h of admission and in group B (29) it
nutrition. They found that it had no impact on the clinical was delayed until after 72 h. These authors failed to show
course of pancreatic disease. The overall death rate was 20 any alteration in the disease process itself. However, there
per cent, with it being 15 per cent in patients with acute was a signi®cantly lower morbidity (24 versus 96 per cent)
pancreatitis and 18 per cent in patients with complicated and mortality (13 versus 38 per cent) rate for patients in
pancreatitis. As in the previous study, catheter-related sepsis group A compared with group B. There was also a
in patients with acute pancreatitis or its complications was signi®cantly higher rate of catheter-related sepsis in
signi®cantly commoner than in all other patients receiving patients with severe acute pancreatitis compared with that
similar nutrition in the same institution during the same in other groups of patients receiving parenteral nutrition.
time period. Although nutritional status can be maintained Pseudocysts and pancreatic ®stulas also resolved with this
with few metabolic or technical complications and is well regimen. Parenteral feeding, therefore, may be considered
tolerated, these authors concluded that it has no signi®cant safe and effective in maintaining and improving the overall
impact on the clinical outcome of pancreatic disease. nutritional status of such patients; it appears to be associated
Robin et al.69 retrospectively analysed 156 patients with a reduction in local complications and mortality rate.
with acute pancreatitis who received parenteral nutrition Sitzmann et al.26 prospectively studied 73 patients with
over a 3-year period. They divided the patients into two severe acute pancreatitis who received early parenteral
groups: group I with uncomplicated acute pancreatitis (70) feeding. Patients were divided into three groups depending
and group II with local complex disease (pseudocyst, abscess on their ability to tolerate glucose-based (44), lipid-based
or necrosis) (86). The mean Ranson score was below 3 in (20) and lipid-free (nine) nutrition. Most achieved positive
both groups, although more patients in group II tended to nitrogen balance and improved nutritional indices within
have more than three positive Ranson criteria. The duration 2 weeks of commencement of parenteral nutrition. There
of parenteral nutrition was signi®cantly longer in group II. were nine deaths with a signi®cantly higher mortality rate
The mean durations from hospital admission to institution among patients who did not receive fat as a calorie source.
of a liquid oral and full oral diet were signi®cantly less in Furthermore, this trend was also apparent in patients who
group I. However, the number of days spent in the intensive were in negative nitrogen balance and who had a Ranson
therapy unit was similar in both groups. Mean hospital stay score of 3 or more.
was signi®cantly shorter for group I. Metabolic and
electrolyte abnormalities and the requirement for exo-
Controlled studies
genous insulin were signi®cantly higher in group II.
Patients with acute on chronic pancreatitis were more Sax et al.72 carried out the only randomized controlled trial
likely to be malnourished. The authors did not ®nd a higher of the effects of early parenteral nutrition versus no feeding
overall rate of catheter-related sepsis and attributed this to in 54 patients with acute pancreatitis (Table 1). Their
the shorter duration of therapy. They concluded that lack of patients had an average Ranson score of 1 and received
speci®c bene®t in the treated group, compared with a either conventional treatment alone or conventional treat-
random group of ten patients with similar disease who did ment with parenteral feeding within 24 h of admission.
not receive parenteral nutrition, means that there is no role Patients with acute pancreatitis had a signi®cantly higher
for parenteral nutrition in the routine management of rate of catheter-related sepsis than other groups treated
uncomplicated acute pancreatitis. However, they recom- with parenteral feeding in the same hospital (10 versus 1 per
mend early aggressive parenteral feeding for patients with cent). Parenteral nutrition did not affect the number of days
complications or underlying malnutrition. to oral intake, total hospital stay or number of complications
ã 2000 Blackwell Science Ltd www.bjs.co.uk British Journal of Surgery 2000, 87, 695±707700 Nutritional support in acute pancreatitis · D. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands
Table 1 Summary of randomized controlled trials of nutritional support in acute pancreatitis
Reference Inclusion criteria Study groups Main outcome measures Results
Sax et al.72 (1987) Patients with acute Early parenteral nutrition Days to oral intake, No advantage of parenteral
pancreatitis (n = 29) versus conventional total hospital stay and nutrition
therapy with no nutritional number of complications
support (n = 25) of pancreatitis
McClave et al.73 (1997) Patients with acute Enteral (n = 16) versus Days to normal amylase Enteral nutrition group fared
pancreatitis or acute on parenteral (n = 16) and to oral diet, length of better; the only statistically
chronic pancreatitis with nutrition. Two patients ITU and hospital stay, significant difference was
abdominal pain and raised randomized twice on nosocomial infection rate, in cost (enteral cheaper)
lipase and amylase separate admissions mortality rate and cost
Kalfarentzos et al.34 Glasgow score > 3 or APACHE Enteral (n = 18) versus Complications, length of Enteral nutrition well
(1997) II score > 8 or CRP > 120 mg/l parenteral (n = 20) nutrition ITU and hospital stay, tolerated. Patients receiving
or grade D or E Balthazar CT duration of ventilation enteral nutrition had fewer
criteria74 and cost septic (P < 0´01) and total
(P < 0´05) complications.
Cost of parenteral nutrition
was three times greater
Windsor et al.75 (1998) Patients with serum amylase Enteral (n = 16) versus APACHE II score, APACHE II score and CRP
> 1000 units/l (stratified for parenteral (n = 18) CRP, SIRS, sepsis, significantly decreased
Glasgow score > 3 and < 3) nutrition MODS, hospital stay, in enteral group but no
death change seen in parenteral
group at 7 days. No change
in Balthazar CT criteria in
either group. SIRS, sepsis,
MODS, hospital stay and
mortality rate better in
enteral group (P not
significant)
de Beaux et al.76 (1998) Glasgow score > 3 Conventional parenteral DNA synthesis and Trend for glutamine group to
(n = 7) versus glutamine- proinflammatory cytokines have improved lymphocyte
enhanced parenteral (n = 7) (TNF, IL-6 and IL-8) proliferation and reduced
nutrition IL-8 release (P not
significant)
Powell et al.77 (1999) Glasgow score > 3 or Enteral (n = 13) versus Tolerance of enteral No evidence of improved
APACHE II score > 7 no nutritional support nutrition, intestinal outcome with enteral
(n = 14) dysfunction, change in nutrition
inflammatory markers,
organ dysfunction score
ITU, intensive therapy unit; APACHE, Acute Physiology And Chronic Health Evaluation; CRP, C-reactive protein; CT, computed tomography; SIRS,
systemic inflammatory response syndrome; MODS, multiple organ dysfunction syndrome; TNF, tumour necrosis factor; IL, interleukin
of pancreatitis. Patients with a Ranson score of 2 or more nutrition in 18 patients with severe acute pancreatitis. They
took longer to achieve an adequate oral intake than those showed, not surprisingly, an increased mortality rate
with a score of 0±1 and early use of parenteral feeding did in patients with higher Ranson scores. Furthermore,
not appear to improve the eventual outcome. The authors the requirement for various energy substrates and
suggest that the use of parenteral nutrition should be insulin was dictated by disease severity. Persistent hypertri-
reserved for patients with a prolonged period of fasting or glyceridaemia, hyperglycaemia, hypoalbuminaemia and
for the treatment of speci®c complications, such as higher insulin requirements predicted a poor prognosis.
pseudocyst or ascites. Silberman et al.79 retrospectively reviewed 11 patients
with acute pancreatitis who received lipid-based parenteral
feeding. All patients showed improvement or no change in
Special formulations for parenteral nutrition
serum amylase concentrations during such feeding and
The use of intravenous lipid formulations in patients with urinary diastase concentrations improved in the majority.
acute pancreatitis remains controversial despite evidence There was no major change in serum lipid pro®le in any
that they are not harmful. Van Gossum et al.78 published a patient and nutritional indices either improved or were
retrospective experience with lipid-associated parenteral maintained in all. They concluded that lipid-based formulas
British Journal of Surgery 2000, 87, 695±707 www.bjs.co.uk ã 2000 Blackwell Science LtdD. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands · Nutritional support in acute pancreatitis 701
are safe and nutritionally effective but do not affect the Simpson et al.87 retrospectively reviewed an experience of
natural history of the disease. Although intravenous lipids nasoenteral feeding in ®ve patients with acute alcoholic
are usually safe and well tolerated when given at the pancreatitis with a mean Ranson score of 1´8. None needed
recommended rate, there are case reports in which lipid parenteral nutrition and the disease and its complications
infusions were the cause of pancreatitis, presumably because resolved in all. Nakad et al.88 described an experience of
of the resultant hypertriglyceridaemia80±82. It may therefore early enteral nutrition in severe disease using the same
be recommended that hypertriglyceridaemia (greater than technique, starting 36 h after admission. One patient
4 g/l) should be avoided when lipid infusions are used in required parenteral feeding because of failure to achieve
acute pancreatitis83, and that lipid clearance should be nutritional goals. No patient developed relapse, hypertri-
monitored by measurement of plasma triglycerides after glyceridaemia or abnormalities of liver function, indicating
feeding. that jejunal feeding can be used safely in severe acute
pancreatitis without reactivation of the in¯ammatory
process.
Enteral nutrition in acute pancreatitis
Controlled studies
Uncontrolled studies
The only randomized controlled trial of enteral nutrition
The concept of enteral nutrition in patients with acute versus conventional therapy (i.e. no nutritional support) in
pancreatitis goes back to the 1970s when Voitk et al.84 severe disease77 (Table 1) provides no evidence of improved
demonstrated the bene®cial effects of an elemental diet in outcome in patients receiving nutritional support in terms
six patients with closure of ®stulas, resolution of sepsis and of organ dysfunction score or in¯ammatory markers such as
ascites, achievement of positive nitrogen balance and weight antiendotoxin core antibody, IL-6, TNF receptor 1 and
gain. After almost two decades of dormancy stemming from CRP. Patients receiving enteral feeding had signi®cantly
the advocacy of pancreatic rest, there is now renewed worse intestinal function on day 4 (P = 0´026). However, this
interest in enteral feeding. Kudsk et al.85 reviewed an phase II trial, which has as yet been published only in
experience of feeding jejunostomies in 11 patients who abstract form, involved a total of only 27 patients and the
underwent exploratory laparotomy for complications of results may be attributable to the small sample size.
pancreatitis. Two died, but the remaining nine patients
gradually improved on enteral feeding with none showing
Parenteral versus enteral nutrition in acute
any increase in serum amylase concentration. Glycosuria
pancreatitis
and hyperglycaemia were common, but were easily
managed with insulin. No catheters were lost and mild McClave et al.73 conducted the ®rst prospective randomized
diarrhoea was encountered only during the ®rst week of trial comparing early enteral nutrition with parenteral
therapy. This study shows that prolonged jejunal feeding nutrition in 30 patients with mild acute or acute on chronic
may be provided safely in patients with severe acute pancreatitis (Table 1). Enteral feeding was via an endosco-
pancreatitis without aggravating the disease. pically placed nasojejunal tube and parenteral feeding was
Parekh et al.86 showed similar bene®cial effects of enteral via a central or peripheral line, both within 48 h of
nutrition in nine patients with acute pancreatitis in whom admission. Ef®cacy was measured by the percentage of
enteral nutrition was commenced at a mean of 11 days after goal energy intake (25 kcal per kg per day) achieved, days to
admission and continued for a mean of 16 days. This not oral diet and length of hospital stay. Although enterally fed
only improved nutritional status but was also accompanied patients lagged 1 day behind the other group in achieving
by successful resolution of complications in seven of the energy goals, this difference disappeared by the fourth day.
nine patients. The authors suggest that stable patients who Mean Ranson, APACHE III and multiorgan failure scores
are unable eat bene®t from enteral nutrition. Some patients decreased in the enteral group and increased in the
in this study86 were fed either orally or by nasogastric tube, parenteral nutrition group, but these differences were not
and ®ve of the six patients in the study of Voitk et al.84 were statistically signi®cant. Patients in the latter group had
tube-fed into the stomach without problems. In both signi®cantly higher stress-induced hyperglycaemia over the
studies, however, feeding was commenced after the acute ®rst 5 days. There was a statistically insigni®cant trend
phase of the illness, when the in¯ammatory process may towards earlier normalization of serum amylase, progres-
have been subsiding. These studies therefore do not provide sion to oral diet, and decrease in hospital and intensive
evidence that oral or nasogastric feeding is safe or advisable therapy unit stay in the enteral group compared with the
in severe acute pancreatitis. parenteral group. The mean cost of parenteral feeding was
ã 2000 Blackwell Science Ltd www.bjs.co.uk British Journal of Surgery 2000, 87, 695±707702 Nutritional support in acute pancreatitis · D. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands
four times higher than that of enteral feeding. There are critically ill patients in the maintenance of mucosal integrity
some dif®culties with this study, including the fact that it and immune status89. Acute in¯ammation and injury are
was restricted solely to patients with mild pancreatitis with a associated with a reduction in plasma concentrations of
mean Ranson score of only 1´3 in both arms, and that it glutamine90. It is postulated that, under these circum-
contained a group of patients with mild attacks of recurrent stances, glutamine may become conditionally essential and
pancreatitis. The study, however, does provide evidence rate limiting for gut mucosal and immune cell metabolism.
that enteral nutrition is both feasible and safe. Although glutamine is present in enteral feeds as a
In another prospective randomized trial34, comparing constituent of protein, its instability in solution makes it
parenteral with enteral feeding in 38 consecutive patients more dif®cult to provide in parenteral feeds unless it is
with severe necrotizing pancreatitis (Table 1), there was no added shortly before administration or as a stable dipeptide.
statistically signi®cant difference between the two groups Signi®cantly improved survival (P = 0´049) at 6 months has
with regard to intensive therapy unit support, use of been demonstrated in critically ill patients receiving
antibiotics, hospital stay and number of days of nutritional glutamine-supplemented parenteral feeding compared with
support. Nitrogen balance improved equally in both groups, controls receiving standard parenteral nutrition91 but,
but severe hyperglycaemia requiring insulin therapy was until recently, the bene®ts of enteral glutamine were
twice as frequent in the parenteral group compared with the unproven in terms of outcome92. A recent study compar-
enteral group. Total complications and septic complications ing a glutamine-enhanced enteral feed with a standard
were signi®cantly more common in the parenteral group, isocaloric, isonitrogenous enteral feed in critically ill
suggesting that enteral feeding should be preferred for patients has demonstrated a decreased (albeit not statistic-
nutritional support in patients with severe acute pancreatitis. ally signi®cant) median intensive therapy unit stay and later
Windsor et al.75 recently published a randomized con- hospital stay in the former group93. The authors also
trolled trial of enteral versus parenteral nutrition in 34 document a signi®cant reduction in postintervention costs;
consecutive patients with acute pancreatitis who had a mean the cost per survivor was 30 per cent less in the glutamine-
Glasgow score of 2 and APACHE II score of 8. None of the fed group.
patients in the enteral group needed parenteral feeding. De Beaux et al.76 randomized 14 patients with severe
After 7 days of nutritional support, the enteral group fared acute pancreatitis (Table 1) to standard parenteral feeding or
better than the parenteral group with respect to CRP isocaloric, isonitrogenous, glutamine-enriched parenteral
concentrations and APACHE II scores (Table 1). feeding. Thirteen patients completed the study protocol
Furthermore, the serum level of immunoglobulin M and, although the patient numbers were small and there was
endotoxin core antibodies increased in the parenteral group large individual variation, there was a trend for the
whereas it remained unchanged in the enteral group. The glutamine-fed group to show improved lymphocyte pro-
total antioxidant capacity also fell in the former group and liferation, increased T-cell DNA synthesis and decreased
increased in the latter. There was a reduction, albeit not release of the proin¯ammatory cytokine IL-8. The authors
statistically signi®cant, in the requirement for intensive feel that this improvement in immune function may have
care, incidence of intra-abdominal sepsis and multiple implications in the prevention of septic complications.
organ failure, need for operative intervention and mortality At present there are no available reports on the effects of
rate in the enterally fed group compared with the immune-enhancing feeds on patients with acute pancrea-
parenterally fed group. There was, however, no difference titis although bene®cial effects are found in other groups of
in hospital stay. The authors conclude that enteral nutrition critically ill patients. Randomized controlled studies of the
is not only feasible, but may reduce disease severity and effects of proprietary immune-enhancing enteral feeds
improve clinical and physiological parameters compared containing arginine, nucleotides and w-3 fatty acids (®sh
with parenteral nutrition. However, patients in the enteral oil) in patients after operation and trauma demonstrate a
group received less non-protein energy per day and it may lower rate of postoperative infections and wound complica-
be hypothesized that this group tended to fare better tions compared with patients receiving isocaloric, isoni-
because of the superior effects of hypocaloric feeds in the trogenous control feeds94,95. Similar studies on critically ill
acute phase of critical illness. patients fed with treatment and control feeds of the same96
or differing97 energy and nitrogen content demonstrate a
reduction in hospital stay and a signi®cantly lower rate of
Role for novel substrates and immune-
acquired infections and morbidity in the immunonutrition
enhancing feeds
group. Two recent meta-analyses98,99 of randomized
Novel nutrient substrates, such as glutamine, arginine, w-3 controlled trials comparing patients receiving standard
fatty acids and nucleotides, play important roles in some enteral nutrition with those receiving commercially
British Journal of Surgery 2000, 87, 695±707 www.bjs.co.uk ã 2000 Blackwell Science LtdD. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands · Nutritional support in acute pancreatitis 703
available immune-enhancing feeds show that, although Conclusions
immunonutrition has no effect on mortality rate, there is a
signi®cant reduction in infection rates, ventilator duration Parenteral nutrition, including fat, is well tolerated, does
and length of hospital stay in these patients. not stimulate pancreatic secretion and can minimize
malnutrition when gastrointestinal dysfunction is pro-
longed. Similarly, nasojejunal or jejunostomy feeds are well
tolerated and, unlike nasogastric or nasoduodenal feeding,
Critique of studies on nutritional support in
do not stimulate the pancreas. Like parenteral feeding, this
acute pancreatitis
form of nutrition may be useful in the treatment or
Most of the clinical studies of nutrition in acute pancreatitis prevention of malnutrition in patients with acute pancrea-
are retrospective and include heterogeneous groups of titis. This leaves two questions. First, whether or not the
patients with varying disease severity and sometimes routine use of parenteral or enteral nutrition has bene®t in
patients with acute on chronic pancreatitis or exacerbation terms of clinical outcome and the natural history of the
of symptoms of chronic pancreatitis; this limits the disease, or whether or not arti®cial nutrition should be
conclusions that may be drawn. This criticism of patient restricted to those who would otherwise suffer the
selection is also applicable to some of the prospective consequences of malnutrition. Second, if routine nutri-
randomized trials. Moreover, in none of the randomized tional support is effective, is enteral feeding better than
trials is a primary endpoint identi®ed or a sample size and parenteral?
power calculation performed. The number of patients At present there is no de®nite evidence that arti®cial
included in these studies is small and a type II error may well nutritional support alters outcome in most patients with
be the reason for apparent lack of bene®t from nutritional acute pancreatitis, unless malnutrition is also a problem. A
support or of bene®t from one form of nutritional support diagnosis of acute pancreatitis is not, therefore, itself an
over the other. It is well known that patients with mild acute indication for instituting arti®cial nutrition. Nevertheless,
pancreatitis do not need nutritional support and addition of in severely affected patients who are hypercatabolic and/or
such patients to the trials is both a waste of resources and unable to eat normally for more than 7±10 days, it is prudent
dilutes the results of the studies. Patients with acute on to begin arti®cial nutrition either parenterally or via the
chronic pancreatitis form a distinct population group as jejunum, or both, in order to prevent the clinical
they may be signi®cantly malnourished premorbidly; consequences of malnutrition. In those with acute on
inclusion of these patients in trials without strati®cation chronic pancreatitis and who are for this or other reasons
further confounds the analysis. malnourished on admission, nutritional support should be
Parenteral nutrition has no statistically signi®cant bene®t introduced as early as possible. This is not a disease-speci®c
in mild disease72, but it may be associated with an increased treatment but a supportive one aimed at maintaining
incidence of catheter-related sepsis if its duration is physiology as near normal as possible while the underlying
prolonged. On the other hand, it does not have a negative pathology resolves.
effect on outcome in severe disease and provides essential Jejunal feeding may be preferred where practical and
nutrients. At the same time, the results of the studies tolerated, although for some patients parenteral feeding
claiming superiority of enteral over parenteral nutrition may be necessary, particularly in the early stages. The
must be interpreted with caution, as the theoretical bene®ts establishment and maintenance of jejunal access in patients
of enteral feeding have not yet translated into improved with severe disease may be problematic, and it may be
outcome in patients with severe acute pancreatitis. Two of dif®cult to achieve the targeted intrajejunal nutrient
the studies73,75 that included patients with mild pancreatitis delivery within the ®rst few days, not least because of
show only a trend towards better outcome in patients fed impaired upper gastrointestinal motility. A combination of
enterally, while the study34 that included only patients with enteral and parenteral nutrition is therefore a reasonable
severe disease demonstrates a statistically signi®cant way to meet metabolic demands in these patients; the
reduction in total and septic complications in the enterally amount of nutrients delivered parenterally can be progres-
fed group. These results contrast with those of the phase II sively reduced as larger volumes are tolerated enterally100.
trial77 which was unable to demonstrate an advantage of Larger, well conducted trials that include only patients
enteral nutrition over no nutritional therapy in patients with with severe acute pancreatitis and stratify patients for
severe disease. What is clearly demonstrated by these trials disease severity, nutritional status and aetiology of pan-
is that enteral feeding is feasible and practical in these creatitis before randomization are needed before any
patients, apart from being much cheaper than parenteral conclusive statement on the bene®ts of nutritional support
feeding. on outcome can be made.
ã 2000 Blackwell Science Ltd www.bjs.co.uk British Journal of Surgery 2000, 87, 695±707704 Nutritional support in acute pancreatitis · D. N. Lobo, M. A. Memon, S. P. Allison and B. J. Rowlands
experimental pancreatitis. Journal of Gastrointestinal Surgery
Acknowledgements
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