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Table 3 Some complications of articial nutrition
Enteral nutrition Parenteral nutrition
Tube insertion
• Nasal/oesophageal injury
• Oesophagitis
• Oesophageal erosions
• Oesophageal stricture
• Tube misplacement
• Tube displacement/withdrawal
• Tube blockage
Regurgitation and aspiration Catheter-related sepsis
Gastrointestinal
• Diarrhoea
• Abdominal distension
• Abdominal pain
Metabolic
• Hyperglycaemia
• Hypokalaemia
• Hypomagnesaemia
• Hypocalcaemia
• Hypophosphataemia
• Low zinc
• Low RBC folate
• Refeeding syndrome
Abnormal liver function tests Hepatic dysfunction
Intravenous administration of enteral feed Fluid and electrolyte abnormalities
Catheter-related or catheter insertion-related
• Pneumothorax
• Haemothorax
• Hydrothorax (intrapleural infusion of feed)
• Arterial injuries
• Nerve injuries
• Air embolism
• Catheter/central venous thrombosis
• Arrhythmias
Gastrointestinal
• Increased gastric acid secretion
• Intestinal stasis
• Bacterial overgrowth
Metabolic
• Hyperglycaemia
• Rebound hypoglycaemia and hyperkalaemia
• Hypokalaemia
• Hyponatraemia
• Hypomagnesaemia
• Hypocalcaemia
• Hypophosphataemia
• Low zinc
• Low RBC folate
• Vitamin/trace element deciencies
• Osteomalacia
• Metabolic acidosis
• Hyperammonaemia
• Refeeding syndrome
• Abnormal liver function tests
• Jaundice
• Intrahepatic cholestasis
• Biliary sludge
• Fatty liver
J. Barrie and D. N. Lobo
7 Refeeding Syndrome
Refeeding syndrome is a life-threatening metabolic complication that results from rapid feeding
in combination with inadequate provision of
micronutrients and electrolytes (e.g. phosphate,
potassium, magnesium and vitamin B1) [14]. The
syndrome can occur with oral, enteral or PN [67],
and is often not recognised or treated appropriately [68]. The National Institute for Health and
Care Excellence (NICE) criteria (low BMI; signicant unintentional weight loss; insufcient
nutritional intake; low concentrations of potassium, phosphate or magnesium prior to feeding;
or a history of alcohol abuse or drugs including
insulin, chemotherapy, antacids or diuretics) are
helpful for identication of patients at high risk
of refeeding syndrome, with starvation being the
predominant risk factor [69].
Patients with acute pancreatitis who have not
been fed, particularly those with alcohol-induced
pancreatitis and pre-existing malnutrition, are at
high risk of developing refeeding syndrome.
Diagnostic criteria for imminent refeeding syndrome have been dened as decrease in phosphate concentrations from baseline by >30% or
to <0.6 mmol/L or any two other electrolyte
shifts below the normal range (phosphate, mag-
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171
nesium, potassium) within 72h of starting nutritional therapy [70]. In addition, manifest
refeeding syndrome is diagnosed when any electrolyte shifts occur in combination with clinical
symptoms (e.g. oedema, tachycardia, tachypnoea, neurological symptoms, etc.) [70]. Risk
assessment, establishment of a care plan and
monitoring of patients throughout nutritional
therapy are important to reduce refeeding
syndrome- related morbidity. Patients at risk
should receive generous prophylactic provision
of electrolytes unless plasma concentrations are
high (potassium 2–4 mmol/kg/day, phosphate
0.3–0.6mmol/kg/day, magnesium 0.2–0.4mmol/
kg/day) [69]. Patients should also receive vitamin
B1 (thiamine, 200–300mg daily) and multivitamin supplements immediately before and during
the rst 10days of feeding [69]. There are also
dangers of excess provision of sodium and uid
in patients at risk of the refeeding syndrome, and
an intake of <1mmol/kg/day sodium and 20ml/
kg/day uid is recommended in the early phase
of refeeding [67, 71]. Nutritional therapy should
be started with reduced energy goals and
increased slowly to the full caloric requirements
over 5–10days according to the individual risk
classication [70]. Electrolyte concentrations
should be monitored daily during the vulnerable
refeeding period alongside additional clinical
examination, with special attention to hydration
status as well as vital parameters to detect signs
and symptoms of uid overload and/or micronutrient deciency.
8 Conclusion
Nutritional therapy in patients with acute pancreatitis is generally safe, with low risk of complications. EN is useful in the treatment or prevention
of malnutrition in patients with acute pancreatitis
when the gut is functional and when nutritional
requirements cannot be met by oral feeding. PN,
including fat, is well tolerated, does not stimulate
pancreatic secretion and can minimise malnutrition when gastrointestinal dysfunction is prolonged. A diagnosis of acute pancreatitis alone is
not an indication for instituting articial nutrition
as most patients with mild or moderate acute pancreatitis can tolerate an oral diet. Nevertheless, in
severe disease in patients who are hypercatabolic
and/or unable to eat normally, it is prudent to
begin early articial nutrition either parenterally
or via the jejunum, or both, in order to prevent the
clinical consequences of malnutrition. The establishment and maintenance of jejunal access in
patients with severe acute pancreatitis may be
problematic, and it may be difcult to achieve the
targeted intrajejunal nutrient delivery within the
rst few days. A combination of EN and PN is,
therefore, a reasonable way to meet metabolic
demands in these patients, and the amount of
nutrients delivered parenterally can be progressively reduced as larger volumes are tolerated
enterally. Particular attention should be paid to
prevent refeeding syndrome.
Declarations
Conict of Interest None of the authors have a direct
conict of interest to declare.
Funding No external funding was received for this book
chapter.
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Antibiotics andProbiotics
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RupjyotiTalukdar
Key Points
1. Increase in the total leucocyte count and fever
in the rst week of acute pancreatitis (AP) are
usually due to non-septic systemic inammatory response syndrome (SIRS).
2. Prophylactic antibiotics have not shown consistent benet in the higher-quality studies
and are not recommended.
3. Empirical antibiotics in patients with acute
necrotizing pancreatitis should be started
based on clinical and radiological.
4. Choice of empirical antibiotics should be
those which penetrate the necrotic pancreas.
5. Probiotics, prebiotics, and synbiotics are currently not recommended in AP.
1 Introduction
Acute pancreatitis (AP) begins as a sterile inammation within the pancreatic parenchyma, triggered by acinar cell injury. Around 15–20% of
the patients with AP develop pancreatic and/or
extrapancreatic fat necrosis, out of which a proportion of susceptible patients get primary
infected pancreatic necrosis (IPN). The other
potential and occasionally underrecognized
R. Talukdar (*)
Pancreas Research Group and Division of Gut
Microbiome Research, Asian Institute of
Gastroenterology Hospitals, Institute of Translational
Research, Asian Healthcare Foundation,
Hyderabad, Telangana, India
infections seen in patients with AP are urinary
tract infection (UTI), pneumonia, including ventilator-associated pneumonia (VAP), cholangitis,
sepsis, intravenous (IV) catheter site infections,
and secondary IPN [1, 2]. Antibiotics have a role
in the management of complications of AP.While
there is no debate about the use of therapeutic
antibiotics for the septic indications stated above,
there are varying opinions about the use of prophylactic and empirical antibiotics. There
remainsa tendency toward theearly use of prophylactic antibiotics in real-world clinical practice despite most guidelines recommending the
contrary.
This chapter discusses the current pattern of
antibiotic and probiotic use in AP, rationale for its
use, evidence, guidelines, and future
perspectives.
2 Real-World Practice
ofProphylactic Antibiotic
Usage inAP
Several studies that have addressed the subject
of antibiotic usage in AP report a high prevalence of prophylactic antibioticusage. Table1
illustrates this practice based on global data.
Prophylactic antibiotics were used not only in
patients with moderately severe AP (MSAP)
and severe AP (SAP) but also in patients with
mild AP (MAP) [13, 14]. Evaluation of the
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024
J. A. Windsor et al. (eds.), Acute Pancreatitis, https://doi.org/10.1007/978-981-97-3132-9_12
175
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Table 1 Prophylactic antibiotic usage in different parts of the world
Author (year) Country/continent Proportion of use of prophylactic antibiotics
Powell etal. (1999) [3] United Kingdom;
Ireland
King etal. (2004) [4] Pan-Europe • 73% used antibiotic prophylaxis
Lankisch etal. (2005) [5] Germany • 47% used antibiotic prophylaxis
Foitzik etal. (2007) [6] Germany • 44% prescribe prophylactic antibiotics in all patients with SAP
Sekimoto etal. (2010) [7] Japan Before guidelines
Hutan etal. (2010) [8] Slovak Republic • 41.2% of wards use prophylactic antibiotics
Murata etal. (2011) [9] Japan • 80% with MAP received
Rebours etal. (2012) [10] France In 2001
Sun etal. (2013) [11] North America • 1% use in >75% of all AP
Talukdar etal. (2014) [12] India • 66.4% patients overall received prophylactic antibiotics
Thong etal. (2020) [13] Vietnam • 31.1% of MAP patients received antibiotics
Abbreviations: AP acute pancreatitis, MAP mild acute pancreatitis, MSAP moderately severe acute pancreatitis, SAP
severe acute pancreatitis
• 24% used prophylactic antibiotics for all patients with AP
• 81% used prophylactic antibiotics for severe disease
• 65% used prophylactic antibiotics for pancreatic necrosis
• 34% selectively prescribed prophylactic antibiotics in SAP
• 59% received for MAP and 98% for SAP
After guidelines
• 43% received for MAP and 100% for SAP
• 91% with SAP received
• 19% used for all patients and 57% used for pancreatic necrosis
In 2008
• 8% used for all patients and 20% used for pancreatic necrosis
• 69% use in >50% of SAP
• 46.1% of MAP patients received prophylactic antibiotics
• 55.8% of MSAP patients received prophylactic antibiotics
• 34.5% of SAP patients received prophylactic antibiotics
• 73.6% of MSAP patients received antibiotics
• 100% of SAP patients received antibiotics
R. Talukdar
type of antibiotics used for prophylaxis
revealed carbapenems, third- and fourth-generation cephalosporins, nitroimidazoles, and quinolones alone, or in combinations [12]. Further
international surveys reported varied indications for starting antibiotics in the rst week,
the most frequent being high total leucocyte
count (TLC) and C-reactive protein (CRP),
fever, and presence of necrosis on contrastenhanced computed tomography (CECT).
There exist geographic differences in the use
of prophylactic antibiotics (higher frequency
of prophylactic antibiotic use in Asia/Oceania),
including differences in physician characteristics (for instance, higher proportion of surgeons, clinicians from nonacademic institution,
and those from institutions with lower case
volume opting to use prophylactic antibiotics)
[15, 16].
3 Is there aRationale forEarly
Antibiotic Use inAP?
The vast majority of studies on the early pathophysiology of AP were conducted in animal
models. Recent studies using human pancreatic
tissue have shown that biliary and alcohol-related
acinar injuries result in the release of proinammatory cytokines from the acinar cells to the
local pancreatic milieu [17, 18]. These cytokines
activate circulating mononuclear cells that traverse the pancreas which then disseminate into
the systemic circulation, releasing cytokines.
This results in a cascade that eventually leads to
elevation of the TLC, and/or an increase in heart
and respiratory rates, and/or increase in body
temperature, all of which are components of systemic inammatory response syndrome (SIRS).
Other potential factors that could contribute to
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177
SIRS are the damage-associated molecular patterns (DAMPs) that are liberated in response to
acinar injury/necrosis. This explains that fever
and high TLC during this stage of the disease are
related to sterile systemic inammation and not
bacterial infection (Fig. 1). Hence, there is no
rationale for using prophylactic or empirical antibiotics in this early stage of AP.
Therapeutic antibiotics in the early stage of
the disease (rst week) will nd rationale only in
the presence of documented extrapancreatic
infection including UTI, pneumonia, cholangitis,
and IV catheter site infections, which will produce infectionand organ-specic signs.
4 Evidence andPitfalls
ofProphylactic Antibiotic
Usage
Several observational studies and randomized
controlled trials have so far been conducted to
determine the efcacy of prophylactic systemic
antibiotics in AP.Though many of these RCTs
were unblinded, four were double-blinded
placebo- controlled studies. These showed no
reduction in the incidence of IPN and extrapancreatic infections (Table2) [19–22]. The antibiotics used in these randomized controlled trials
(RCTs) were meropenem, imipenem-cilastatin,
ciprooxacin, and ciprooxacin with metronidazole. Meta-analysis of RCTs have failed to demonstrate arole for prophylactic antibiotics in the
prevention of IPN, mortality, and intervention,
while there were variable results in relation to the
prevention of extrapancreatic infections. In an
earlier meta-analysis, a subgroup analysis performed appeared to suggest that carbapenems
may have a role in mortality prevention.
Subsequently, it was shown that there was an
inverse relationship of the quality of the study
and the efcacy of prophylactic antibiotics
[23–25].
Despite studies demonstrating the futility of
antibiotic prophylaxis in AP, a closer look into
the meta-analyses reveals substantial heterogeneity among the individual studies. Table 3 illustrates the areas of heterogeneity among the
studies. This could be one of the reasons for the
varying recommendations on the use of prophylactic antibiotics in the rst week of AP. For
instance, the American Gastroenterological
Association (AGA) 2018 guidelines provide a
conditional recommendation based on lowquality evidence, while the American College of
Gastroenterology (ACG) 2019 guidelines suggest a strong recommendation based on moderatequality evidence against the use of prophylactic
antibiotics [26, 27].
It is now clearly shown from experimental and
clinical research that there is an alteration in the
intestinal permeability barrier which supports bacterial translocation and colonization in the necrotic
tissue, thereby resulting in IPN.Studies conducted
on experimental models and patients over the past
few years have also demonstrated gut microbial
dysbiosis in patients with AP [28, 29]. For instance,
studies have reported an increase in the phylum
Bacteroidetes, Escherichia-Shigella complex, and
the genus Enterococcus, with a reduction in the
abundance of benecial organisms such as
Bidobacterium. Dysbiosis correlated with inammation [interleukin- 6 (IL-6)], multiorgan failure,
infectious complications, and intestinal barrier
function. Therefore, it is plausible that selective
gut decontamination with antibiotics could be
another form of prophylactic approach.
Unfortunately, results from studies performed in
Fig. 1 Schematic representation of the events on how initial acinar injury leads to sterile inammation in the rst
week of acute pancreatitis. Abbreviations: FAEE fatty acid
ethyl ester, MNC mononuclear cell, SIRS systemic inammatory response syndrome, MODS multiorgan dysfunction syndrome. (Adapted from references [17, 18])
178
https://t.me/med1917
Table 2 Double-blind randomized placebo-controlled studies that evaluated the role of prophylactic antibiotics for
acute pancreatitis
Study details Outcomes (treated vs. placebo)
Infected
Author (year) N Antibiotics used
Isenmann etal. (2004) [19] 114 Ciprooxacin+metronidazole 12 vs. 14% 23 vs. 15% 36 vs. 42%
Dellinger etal. (2007) [20] 100 Meropenem 17 vs. 11% 23 vs. 24% 50 vs. 42%
Garcia-Barrasa etal. (2009)
[21]
Poropat etal. (2019) [22] 98 Imipenem-cilastatin 6.1 vs. 4.8% 14.2 vs.
41 Ciprooxacin 12 vs. 9% 20 vs. 18% 18 vs. 11%
necrosis
Need for
surgery Mortality
R. Talukdar
16.3%
Table 3 Areas of heterogeneity in clinical trials evaluating the role prophylactic antibiotics
1. Variable methodology (single-blind, double-blind,
single/multicenter)
2. Nonuniform selection criteria
3. Sample size variation
4. Different treatment duration
(1week or less to 3weeks)
5. Selection of antibiotics
(Imipenem, meropenem, ciprooxacin, ooxacin,
cefuroxime, metronidazole)
6. Outcome measures
(Infected necrosis, extrapancreatic infection,
fungal infections, need for interventions, mortality)
this regard over the past several years have been
unclear. While a multicenter randomized study
from Netherlands in 1995 demonstrated signicant reduction of gram-negative bacterial colonization and infected pancreatic necrosis by selective
decontamination with noroxacin, amphotericin,
and colistin, a subsequent study from 2007 failed
to show any benet [30, 31]. On the contrary, a
more recent study reported a signicant reduction
in the hospitalization duration and IPN with selective decontamination by rifaximin [32]. However,
this was a non-randomized retrospective study,
and patients with different modalities were
enrolled over different time periods. Therefore, in
the absence of supportive data from large and
high- quality RCTs, there is no role for selective
gut decontamination in the current management
armamentarium of AP [33].However it would be
prudent tohold off on a denitive position regarding selective gut decontamination until more evidence is available from adequately powered RCTs.
Since only a proportion of patients with acute
necrotizing pancreatitis (ANP) develop IPN, it is
plausible that there could be susceptibility factors
that determine the development of infections.
Identication of these susceptibility factors could
result in a rational use of prophylactic antibiotic in
targeted populations that might show potential
benecial effects. A few earlier studies that
attempted to identify predictors of IPN reported
that procalcitonin [34], low admission systolic
blood pressure [35], rising blood urea nitrogen
[36], and low lymphocyte count [37] could be
potential predictors of IPN. However, it was not
clear what cutoff values of procalcitonin and measurement in which timepoint was predictive of
IPN, the other markers were not specic for infections. Another recent study demonstrated that persistent downregulation of HLA-DR, which is a
marker of immunosuppression, till the second
week of illness increases the risk of developing
IPN by 4.5 (1.2–16.9) [38]. However, this study
had a small sample size and a larger multicenterstudyis required. Studies have also implicated the altered kynurenine pathway metabolites,
including reduction of circulating tryptophan with
organ failure and development of IPN [39, 40].
The predictive capability of these also needs to be
validated in large multicenter cohorts of patients.
In conclusion, there is lack of substantial evidence and the use of prophylactic antibiotics in
AP is not recommended.
5 Use ofTherapeutic
Antibiotics inAP
Infected pancreatic necrosis should ideally be
treated with therapeutic antibiotics based on culture sensitivity from the necrotic uid collection.
However, it may be difcult to conrm the presence of infection in necrotic pancreatic tissue
Antibiotics andProbiotics
https://t.me/med1917
179
until a drainage procedure is conducted. Fine
needle aspiration (FNA) used to be advised to
conrm IPN. However, it is no longer used in
routine clinical practice due to false negative
results of 12–25% and the risk of secondary
infection of pancreatic necrosis. Therefore,
empirical antibiotics can be started in these
patients with an indication of infection, includingclinical markers such as persistent fever inthe
second week of illness or beyond, progressive
increase in the TLC, increased inammatory
markers, and imaging evidence of free air within
the necrotic collections/WON [27]. Another
recent study has suggested that empirical antibiotics can be started/continued or stopped based
on a serum procalcitonin value of greater than or
equal to 1.0ng/mL or lower, respectively [41]. It
is important to select antibiotics that have been
shown to have good penetration into necrotic
pancreatic tissue such as imipenem, ciprooxacin, ooxacin, metronidazole, and cefoperazone
[42, 43]. Once drainage of the infected pancreatic
necrosis is done, then therapeutic antibiotics can
be directed according to the culture and sensitivity of the drained uid. Blood culture- and
sensitivity- directed therapeutic antibiotics can be
used if the patient develops secondary sepsis
resulting from IPN.
(PROPATRIA trial) from the Dutch Pancreatitis
Research Group, mortality was signicantly
higher in the probiotics group compared to that in
the placebo group [44]. It was subsequently
reported that even though the probiotic strains
used in this trial reduced bacterial translocation
overall, there were increased enterocyte damage
and bacterial translocation in the patients with
organ failure [45].There was also a signicant
increase in gastrointestinal ischaemia and mortality. It was argued that the elevated lactic acid
level due to the bacterial fermentation of carbohydrates was the primary factor responsible for
higher mortality [46]. While this is still a subject
of scrutiny, it can also be inferred that probiotic
therapy could still have a place if the appropriate
strain is used, treatment is initiated at the correct
time, and diet is modied to include a lower volume of fermentable carbohydrates. A subsequent
meta-analysis conrmed divergent results, i.e.,
failed to show neither benet of probiotics, prebiotics, and synbiotics in preventing IPN nor any
harm to the patients sufcient to result in an
increased frequency of organ failure and hospital
stay [47]. Nevertheless, in the absence of highquality evidence and potential harm, means there
is no role for probiotics and/or synbiotics in
patients with ANP/IPN.
6 Use ofProbiotics inAP
Probiotics with, or without, prebiotics, in general, have been shown to confer immunomodulatory, anti-inammatory, and gut mucosal health
benets. In the context of AP, since the alteration
in the gut barrier integrity and bacterial translocation are established pathophysiologic events,
treating patients especially with ANP with prophylactic probiotics or synbiotics appears to be a
plausible option. However, RCTs that evaluated
the protective role of probiotics against IPN
failed to demonstrate a protective role. In a welldesigned and adequately powered RCT
7 Conclusion
In view of the absence of high-quality studies and
theheterogeneous data from the existing studies,
prophylactic antibiotics and probiotics/synbiotics
should not be used in patients with AP.Figure2
depicts the current approach to antibiotic therapy
in patients with AP. Empirical pancreaspenetrating antibiotics should be used when the
patient is suspected to have an IPN based on clinical and radiological criteria. Further placebocontrolled RCTs examining the roles of
prophylactic antibiotics and probiotics using targeted predictors of IPN are warranted.
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