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Antibiotic prophylaxis in acute necrotizing pancreatitis
Abstract
To evaluate the role of prophylactic antibiotic therapy in the prevention of superimposed infection in acute necrotizing pancreatitis, Sharma and Howden conducted a meta-analysis that included the only three randomized, controlled trials published between 1996 and 2000. The selected studies compared supportive treatment plus antibiotic prophylaxis and supportive treatment alone in patients with clinical and radiographic evidence of acute necrotizing pancreatitis. The primary endpoints were occurrence of pancreatic infection, sepsis, and overall mortality. The pooled data consisted of 84 patients in the treatment group and 76 patients in the control group. Absolute and relative risk reduction as well as number needed to treat were calculated for each of the outcomes. Only one of the three trials demonstrated a significant benefit of antibiotic therapy in the prevention of sepsis and death. However, the analysis of the pooled data suggested that sepsis and death were less likely to occur in patients enrolled in the antibiotic arm. The numbers needed to treat to prevent one episode of sepsis and death were five and eight, respectively. Interestingly, the analysis failed to show a significant benefit of prophylactic antibiotics in preventing pancreatic infections. The authors concluded that antibiotics should be given to patients with sterile necrosis because both overall morbidity and mortality can be reduced.
... P = 0.002) in contrast with those under quinolones with metronidazole [106]. Antibiotic prophylaxis is superior to antibiotic treatment in NP, and it does not result in an increased incidence of fungal infections [107][108][109]. ...
The patients with acute pancreatitis are at risk to develop different complications from ongoing pancreatic inflammation. Often, there is no correlation between the degree of structural damage to pancreas and clinical manifestation of the disease. The effectiveness of any treatment is related to the ability to predict severity accurately, but there is no ideal predictive system or biochemical marker. Severity assessment is indispensable to the selection of proper initial treatment in the management of acute pancreatitis. The use of multiparametric criteria and the evaluation of severity index permit us to select high-risk patients. Furthermore, contrast-enhanced computed tomographic scanning and contrast-enhanced MRI play an important role in severity assessment. The adoption of multiparametric criteria proposed together with morphological evaluation consents the formulation of a discreetly reliable prognosis on the evolution of the disease a few days from onset.
Background:
In people with acute pancreatitis, it is unclear what the role should be for medical treatment as an addition to supportive care such as fluid and electrolyte balance and organ support in people with organ failure.
Objectives:
To assess the effects of different pharmacological interventions in people with acute pancreatitis.
Search methods:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 9), MEDLINE, Embase, Science Citation Index Expanded, and trial registers to October 2016 to identify randomised controlled trials (RCTs). We also searched the references of included trials to identify further trials.
Selection criteria:
We considered only RCTs performed in people with acute pancreatitis, irrespective of aetiology, severity, presence of infection, language, blinding, or publication status for inclusion in the review.
Data collection and analysis:
Two review authors independently identified trials and extracted data. We did not perform a network meta-analysis as planned because of the lack of information on potential effect modifiers and differences of type of participants included in the different comparisons, when information was available. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) for the binary outcomes and rate ratios with 95% CIs for count outcomes using a fixed-effect model and random-effects model.
Main results:
We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin plus ulinastatin, thymosin, ulinastatin, and inactive control. Apart from the comparison of antibiotics versus control, which included a large proportion of participants with necrotising pancreatitis, the remaining comparisons had only a small proportion of patients with this condition. Most trials included either only participants with severe acute pancreatitis or included a mixture of participants with mild acute pancreatitis and severe acute pancreatitis (75 trials). Overall, the risk of bias in trials was unclear or high for all but one of the trials.
Source of funding:
seven trials were not funded or funded by agencies without vested interest in results. Pharmaceutical companies partially or fully funded 21 trials. The source of funding was not available from the remaining trials.Since we considered short-term mortality as the most important outcome, we presented only these results in detail in the abstract. Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-term mortality in any of the comparisons (very low-quality evidence). With regards to other primary outcomes, serious adverse events (number) were lower than control in participants taking lexipafant (rate ratio 0.67, 95% CI 0.46 to 0.96; N = 290; 1 study; very low-quality evidence), octreotide (rate ratio 0.74, 95% CI 0.60 to 0.89; N = 770; 5 studies; very low-quality evidence), somatostatin plus omeprazole (rate ratio 0.36, 95% CI 0.19 to 0.70; N = 140; 1 study; low-quality evidence), and somatostatin plus ulinastatin (rate ratio 0.30, 95% CI 0.15 to 0.60; N = 122; 1 study; low-quality evidence). The proportion of people with organ failure was lower in octreotide than control (OR 0.51, 95% CI 0.27 to 0.97; N = 430; 3 studies; very low-quality evidence). The proportion of people with sepsis was lower in lexipafant than control (OR 0.26, 95% CI 0.08 to 0.83; N = 290; 1 study; very low-quality evidence). There was no evidence of differences in any of the remaining comparisons in these outcomes or for any of the remaining primary outcomes (the proportion of participants experiencing at least one serious adverse event and the occurrence of infected pancreatic necrosis). None of the trials reported heath-related quality of life.
Authors' conclusions:
Very low-quality evidence suggests that none of the pharmacological treatments studied decrease short-term mortality in people with acute pancreatitis. However, the confidence intervals were wide and consistent with an increase or decrease in short-term mortality due to the interventions. We did not find consistent clinical benefits with any intervention. Because of the limitations in the prognostic scoring systems and because damage to organs may occur in acute pancreatitis before they are clinically manifest, future trials should consider including pancreatitis of all severity but power the study to measure the differences in the subgroup of people with severe acute pancreatitis. It may be difficult to power the studies based on mortality. Future trials in participants with acute pancreatitis should consider other outcomes such as complications or health-related quality of life as primary outcomes. Such trials should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).
The aim of the study was to verify whether antibiotics excreted by the normal pancreas are also excreted in human necrotizing pancreatitis, reaching the tissue sites of the infection. Twelve patients suffering from acute necrotizing pancreatitis were treated with imipenem-cilastatin (0.5 g), mezlocillin (2 g), gentamicin (0.08 g), amikacin (0.5 g), pefloxacin (0.4 g), and metronidazole (0.5 g). Serum and necrotic samples were collected simultaneously at different time intervals after parenteral drug administration by computed tomography-guided needle aspiration, intraoperatively, and from surgical drainages placed during surgery. Drug concentrations were determined by microbiological and high-performance liquid chromatography assays. All antibiotics reached the necrotic tissues, but with varying degrees of penetration, this being low for aminoglycosides (13%) and high in the case of pefloxacin (89%) and metronidazole (99%). The concentrations of pefloxacin (13.0 to 23 micrograms/g) and metronidazole (8.4 micrograms/g) in the necrotic samples were distinctly higher than the MICs for the organisms most commonly isolated in this disease; the concentrations in tissue of imipenem (3.35 micrograms/g) and mezlocillin (8.0 and 15.0 micrograms/g) did not always exceed the MICs for 90% of strains tested, whereas the aminoglycoside concentrations in necrotic tissue (0.5 microgram/g) were inadequate. Repeated administration of drugs (for 3, 7, 17, and 20 days) seems to enhance penetration of pefloxacin, imipenem, and metronidazole into necrotic pancreatic tissue. The choice of antibiotics in preventing infected necrosis during necrotizing pancreatitis should be based on their antimicrobial activity, penetration rate, persistence, and therapeutic concentrations in the necrotic pancreatic area. These requisites are provided by pefloxacin and metronidazole and to a variable extent by imipenem and mezlocillin.
Necrotizing pancreatitis is the most serious form of pancreatic inflammatory disease leading to multiorgan failure and a high (15-20%) mortality rate. The poor nutritional and metabolic conditions and secondary bacterial translocation raise the mortality rate even more.
The aim of the study was to evaluate the effect of jejunal feeding in cases of chronic pancreatitis with extended necrosis.
In our institution, over a five-year period, 86 patients with severe necrotizing pancreatitis were treated for extended necrosis. In 19 patients, chronic calcifying pancreatitis was demonstrated by computed tomography showing more than 20% necrosis in the residual pancreas as well.
In 12 cases, nutrition was provided by jejunal feeding using an endoscopically placed nasojejunal feeding tube, whereas in 7 cases, hypocaloric parenteral nutrition was used.
Retrospective unicenter study.
The rate of healing with conservative treatment.
Two of the 12 jejunally fed patients were operated on because of complications of pancreatitis. Five patients required intervention in the hypocaloric parenteral nutrition group: 4 were operated on and one more needed endoscopic intervention. The healing rate was significantly higher (P=0.045) in the jejunal feeding group (83.3%) than in the parenteral nutrition (28.6%) patients.
In cases of chronic calcifying pancreatitis serious necrosis can develop in the residual pancreas resulting in a severe acute pancreatitis-like disease. A better healing rate was achieved and less interventions became necessary using nasojejunal tube feeding than in the parenteral nutrition group and this was analogous to what was observed in severe necrotizing pancreatitis This form of pancreatitis has not yet been described in the literature in detail. The authors suggest that it be regarded as a separate entity.
Grundproblematik und Fragestellung: Bei der akuten nekrotisierenden Pankreatitis werden der klinische Verlauf und die Letalität maßgeblich durch septische Komplikationen im Rahmen einer bakteriellen Besiedlung der Nekrosen bestimmt. Bisher ist nicht geklärt, ob durch eine antibiotische Prophylaxe die Keimbesiedlung der Nekrosen verringert oder septische Komplikationen vermieden werden können. Es sollte deshalb in der vorliegenden Studie der Einfluß von prophylaktisch verabreichten Antibiotika bei Patienten mit akuter nekrotisierender Pankreatitis untersucht werden.
Patienten und Methodik: In einer prospektiven randomisierten Studie wurden Patienten mit akuter nekrotisierender Pankreatitis und sterilen Nekrosen (n = 13) mit täglich zweimal 200 mg Ofloxacin und zweimal 500 mg Metronidazol intravenös behandelt. Die Ergebnisse wurden mit Daten einer zunächst nicht antibiotisch behandelten Kontrollgruppe (n = 13) verglichen. Bei allen 26 Patienten wurden regelmäßig Feinnadelpunktionen der nekrotischen Areale am Tag 1, 3, 5, 7 und 10 durchgeführt. Bei nachgewiesener Infektion erfolgte auch in der Kontrollgruppe eine antibiotische Therapie.
Ergebnisse: Das Nekroseausmaß betrug in beiden Gruppen im Median 40 %. Die Nekrosen waren im Median nach 9,5 bzw. 10 Tagen in der Therapiegruppe bzw. in der Kontrollgruppe infiziert. Der klinische Verlauf, dokumentiert anhand des APACHE-II-Scores, zeigte eine signifikante Verbesserung unter antibiotischer Prophylaxe (Tag 1-5-10: Score 15-13,0-9,5). In der primär nicht mit Antibiotika behandelten Kontrollgruppe zeigt sich hingegen eine Verschlechterung des klinischen Verlaufs (Tag 1-5-10: Score 11,5-15,0-16). Die Veränderungen des Scores von Tag 1 zu Tag 5, Tag 5 zu Tag 10 und Tag 1 zu Tag 10 waren hochsignifikant (Wilcoxon-Test, P < 0,01). Innerhalb der ersten 3 Wochen starb in der Antibiotika-Gruppe kein Patient. Die Letalität in der Kontrollgruppe betrug 15 % (2 von 13).
Folgerung: Die antibiotische Prophylaxe kann die bakterielle Infektion des nekrotischen Pankreas weder verhindern noch verzögern. Sie kann jedoch den klinischen Verlauf signifikant verbessern, vorausgesetzt, sie wird begonnen, bevor die Infektion der Pankreasnekrosen erfolgt ist.
Prophylactic antibiotics are helpful in decreasing the incidence of septic complications in acute pancreatitis. The aim of this study was to compare the efficacy of meropenem, a new carbapenem antibiotic, with that of imipenem, which is the standard prophylactic treatment in patients with severe acute pancreatitis.
One hundred seventy-six patients with necrotizing pancreatitis were prospectively randomized to prophylactic treatment with 0.5 g meropenem t.i.d. intravenously or 0.5 g imipenem q.i.d. intravenously. The occurrence of infection of pancreatic necrosis, rate of extrapancreatic infections, systemic and local complications, need for surgery, mortality rate, and length of hospitalization were recorded for each group. When a septic complication of pancreatic necrosis was suspected, fine needle aspiration with cultures of the sample was performed. Surgery was performed in cases of verified infected necrosis.
No difference was observed between patients treated with meropenem and those treated with imipenem in terms of incidence of pancreatic infection (11.4% versus 13.6%) and extrapancreatic infections (21.6% versus 23.9%) and clinical outcome. Meropenem is as effective as imipenem in preventing septic complications of patients with severe acute pancreatitis.
This study is a double "blind" prospective evaluation of the efficacy of antibiotics (Ampicillin) in the treatment of acute alcohol-induced and idiopathic pancreatitis. Fifty-eight patients with acute pancreatitis were randomly divided into antibiotic and non-antibiotic treatment groups. The two groups were comparable clinically at the onset of the study and other than for antibiotics received identical therapy. The patients without antibiotics had a clinical course equal or slightly more favorable than the antibiotic treatment group in all parameters examined. These data indicate that prophylactic use of Ampicillin is not indicated in patients with routine acute alcohol-induced or idiopathic pancreatitis. The role of prophylactic antibiotics in patients with pancreatitis related to biliary calculi and those with more severe varieties of acute hemorrhagic or necrotizing pancreatitis remains to be more clearly defined.
The penetration of ciprofloxacin in pancreatic juice was investigated in 5 patients with pancreatic fistula. The drug was administered as a single oral dose of 500 mg after which serial samples of pancreatic juice and serum were collected for ciprofloxacin assay. The following pharmacokinetic parameters (mean +/- SD) were estimated from the serum level versus time curves: clearance 11.51 +/- 2.85 (ml/min/kg); Vd area 3.08 +/- 1.20 ml/kg; terminal half-life 3.10 +/- 0.92 h; mean residence time 5.64 +/- 1.40 h. Ciprofloxacin serum levels declined rapidly after the third hour, whereas concentrations in pancreatic juice remained elevated (above 1 mg/1) for nearly 12 h. The pancreatic juice/serum ciprofloxacin concentration ratio increased gradually fom 0.63 +/- 0.45 after 0.5 h to 6.18 +/- 4.59 after 12 h (mean +/- SD). Our data indicate that while the drug elimination half-life from the serum is short, the time-course of ciprofloxacin levels in the pancreatic juice conforms to a much slower disappearance rate. In particular, the ciprofloxacin levels achieved in pancreatic juice are constantly greater than the MICs of the bacteria generally responsible for pancreatic infections.
In a prospective clinical study including 114 patients with acute necrotizing pancreatitis, but excluding patients with a pancreatic abscess, necrotic material obtained at surgery was tested bacteriologically. Intestinal microorganisms were cultured in 39.4% of the cases. The contamination rate was 23.8% in patients operated on during the first 7 days of the attack; it rose to 71.4% in the third week and decreased to 32.5% after the fourth week. Intra- and extrapancreatic necrosis was more widespread and pancreatitis-associated ascites was more frequent in patients with proven contamination. The number of objective signs was 4.5 (median) and postoperative mortality was 37.8% in bacteriologically positive subjects, whereas the number was 3.5 (median) and mortality was 8.7% in bacteriologically negative patients. Morphologic and clinical alterations were more severe, and the mortality rate was significantly elevated, in patients with a short history of disease and bacterial contamination of necrotic tissue. All 5 patients with pancreatic sepsis who were operated on in the first 7 days of the disease, as compared with 2 of 16 patients with sterile necrosis, died. Thus, it is demonstrated that bacterial contamination of pancreatic necrosis occurs early and frequently, causing a significant increase in morbidity and mortality, particularly when it develops in the initial stages of the attack.
In 83 patients with acute pancreatitis, the initial computed tomographic (CT) examinations were classified by degree of disease severity (grades A-E) and were correlated with the clinical follow-up, objective prognostic signs, and complications and death. The length of hospitalization correlated well with the severity of the initial CT findings. Abscesses occurred in 21.6% of the entire group, compared with 60.0% of grade E patients. Pleural effusions were also more common in grade E patients. Grades A and B patients did not have abscesses, and none died, regardless of the number of prognostic signs. Abscesses were seen in 80.0% of patients with six to eight prognostic signs, compared with 12.5% of those with zero to two. The use of prognostic signs with initial CT findings results in improved prognostic accuracy. Early CT examination of patients with acute pancreatitis is a useful prognostic indicator of morbidity and mortality.
Despite improvements in surgical treatment and intensive care, mortality from severe acute pancreatitis remains high. We have carried out a randomised study of 60 consecutive patients with alcohol-induced necrotising pancreatitis to find out whether early antibiotic treatment can improve outcome. 30 patients were assigned cefuroxime (4.5 g/day intravenously) from admission. In the second group, no antibiotic treatment was given until clinical or microbiologically verified infection or after a secondary rise in C-reactive protein. The inclusion criteria were C-reactive protein concentration above 120 mg/L within 48 h of admission and low enhancement (< 30 Hounsfield units) on contrast-enhanced computed tomography. There were more infectious complications in the non-antibiotic than in the antibiotic group (mean per patient 1.8 vs 1.0, p = 0.01). The most common cause of sepsis was Staphylococcus epidermidis; positive cultures were obtained from pancreatic necrosis or the central venous line in 14 of 18 patients with suspected but blood-culture-negative sepsis. Mortality was higher in the non-antibiotic group (seven vs one in the antibiotic group; p = 0.03). Four of the eight patients who died had cultures from pancreatic necrosis positive for Staph epidermidis. We conclude that cefuroxime given early in necrotising pancreatitis is beneficial and may reduce mortality, probably by decreasing the frequency of sepsis.
• Acute pancreatitis is a protean disease capable of wide clinical variation, ranging from mild discomfort to apocalyptic prostration. Moreover, the inflammatory process may remain localized in the pancreas, spread to regional tissues, or even involve remote organ systems. This variability in presentation and clinical course has plagued the study and management of acute pancreatitis since its original clinical description. In the absence of accepted definitions for acute pancreatitis and its complications, it has not been possible to devise a clinical classification system useful for case management. Following 3 days of group meetings and open discussions, unanimous consensus on a series of definitions and a clinically based classification system for acute pancreatitis was achieved by a diverse group of 40 international authorities from six medical disciplines and 15 countries. The proposed classification system will be of value to practicing clinicians in the care of individual patients and to academicians seeking to compare interinstitutional data.
Recent evidence of pancreatic penetration of several antibiotics active against the usual flora found in pancreatic sepsis, at therapeutic minimal inhibitory concentration, prompted the authors to perform a randomized, multicenter, clinical trial on imipenem prophylaxis in acute pancreatitis. Seventy-four patients with computed tomographic (CT) scans demonstrating necrotizing pancreatitis within 72 hours of onset were randomly assigned to two groups receiving no antibiotic treatment or 0.5 gram of prophylactic imipenem administered intravenously every eight hours for two weeks. Pancreatic sepsis was always detected by means of cultures (percutaneous CT or ultrasound-guided needle aspiration and intraoperative samples). The incidence of pancreatic sepsis was much less in treated patients (12.2 versus 30.3 percent, p < 0.01). Therefore, the authors recommend prophylactic use of imipenem in patients with acute necrotizing pancreatitis.
It is still unproven whether prophylactic antibiotics can reduce mortality from acute necrotizing pancreatitis (ANP). The aim of this study was to investigate whether antibiotic therapy can influence long-term outcome in ANP and how appropriate this therapy is.
ANP was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptide levels were used to verify comparable disease severity. Starting 6 hours after induction, animals randomly received saline (n = 60), 20 mg/kg imipenem (n = 62), or 10 mg/kg ciprofloxacin (n = 60) every 8 hours for 7 days. On day 7, half of each group was killed so a quantitative pancreatic bacteriology could be conducted. The other half was analyzed at 21 days for long-term mortality, late bacteriologic changes, abscesses, and pseudocysts.
Comparable trypsinogen activation peptide increases confirmed equally severe ANP in each group before treatment. Imipenem and ciprofloxacin significantly reduced the number of infected pancreatic specimens, bacterial counts, and identified species at 1 week. At 3 weeks, pancreatic infection prevalence was lower in animals treated with antibiotics; abscess formation was reduced and pseudocysts were smaller and less frequently infected. Survival was significantly improved by imipenem and ciprofloxacin.
Antibiotic treatment reduces early and late septic pancreatic complications and improves survival from experimental ANP.
Infectious complications currently account for 80% of deaths from acute pancreatitis. The aim of this study was to evaluate the necessity for prophylactic antibiotics in patients with severe acute pancreatitis. Twenty-three consecutive patients suffering from acute alcoholic pancreatitis with computed tomography demonstrating two or more fluid collections were randomly assigned to one of two groups receiving either nonantibiotic treatment or prophylactic antibiotics (ceftazidime, amikacine, and metronidazole for 10 days). Sepsis was always diagnosed by positive cultures. Seven episodes of severe sepsis occurred (pancreatic infection and septic shock) in the nonantibiotic group, and no infection occurred in the prophylactic antibiotic group (p < 0.03). In conclusion, the use of prophylactic antibiotics in severe alcoholic acute pancreatitis significantly reduces the incidence of severe infection.
The clinical course and death rate in acute necrotizing pancreatitis (ANP) are largely determined by septic complications as part of bacterial invasion of the necrotic tissues. It remains unclear whether antibiotic prophylaxis reduces bacterial invasion of the necroses or septic complications. It was, therefore, the aim of this study to evaluate the effect of prophylactic administration of antibiotics to patients with ANP.
In a prospective randomized study 13 patients with ANP and sterile necroses (quantified by contrast-enhanced computed tomography) were given twice daily 200 mg ofloxacin and twice daily 500 mg metronidazole intravenously. The results were compared to those in a control group of patients with ANP (n = 13) who had not initially received antibiotics. In both patient groups fine-needle biopsies of the necrotic areas were performed on days 1, 3, 5, 7 and 10. If there was evidence of infection, antibiotics were then also given to patients of the control group.
The extent of the necroses was the same, 40%, in both groups. These necroses became infected in a median of 9.5 (treated group) and 10 days (untreated group). The clinical course, documented by the APACHE II score, showed significant improvement under antibiotic treatment (days 1-5-10: scores 15-13.0-9.5). In the (initially untreated) control group the clinical condition deteriorated significantly (days 1-5-10: score 11.5-15.0-16.0). The changes from days 1 to 5, 5 to 10 and 1 to 10 were highly significant (Wilcoxon test, P < 0.01). None of the patients in the antibiotic group died within the first 3 weeks, but 2 of the 13 in the control group died.
Antibiotic prophylaxis neither prevented nor delayed bacterial infection of the necrotic pancreas. But it significantly improved the clinical course if started before the onset of infection of the pancreatic necroses.
Parenteral nutrition is well established for providing nutritional support in acute pancreatitis while avoiding pancreatic stimulation. However, it is associated with complications and high cost. Benefits of enteral feeding in other disease states prompted a comparison of early enteral feeding with total parenteral nutrition in this clinical setting.
Thirty-eight patients with acute severe pancreatitis were randomized into two groups. The first (n = 18) received enteral nutrition through a nasoenteric tube with a semi-elemental diet, while the second group (n = 20) received parenteral nutrition through a central venous catheter. Safety was assessed by clinical course of disease, laboratory findings and incidence of complications. Efficacy was determined by nitrogen balance. The cost of nutritional support was calculated.
Enteral feeding was well tolerated without adverse effects on the course of the disease. Patients who received enteral feeding experienced fewer total complications (P < 0.05) and were at lower risk of developing septic complications (P < 0.01) than those receiving parenteral nutrition. The cost of nutritional support was three times higher in patients who received parenteral nutrition.
This study suggests that early enteral nutrition should be used preferentially in patients with severe acute pancreatitis.
In patients with major trauma and burns, total enteral nutrition (TEN) significantly decreases the acute phase response and incidence of septic complications when compared with total parenteral nutrition (TPN). Poor outcome in acute pancreatitis is associated with a high incidence of systemic inflammatory response syndrome (SIRS) and sepsis.
To determine whether TEN can attenuate the acute phase response and improve clinical disease severity in patients with acute pancreatitis.
Glasgow score, Apache II, computed tomography (CT) scan score, C reactive protein (CRP), serum IgM antiendotoxin antibodies (EndoCAb), and total antioxidant capacity (TAC) were determined on admission in 34 patients with acute pancreatitis. Patients were stratified according to disease severity and randomised to receive either TPN or TEN for seven days and then re-evaluated.
SIRS, sepsis, organ failure, and ITU stay, were globally improved in the enterally fed patients. The acute phase response and disease severity scores were significantly improved following enteral nutrition (CRP: 156 (117-222) to 84 (50-141), p < 0.005; APACHE II scores 8 (6-10) to 6 (4-8), p < 0.0001) without change in the CT scan scores. In parenterally fed patients these parameters did not change but there was an increase in EndoCAb antibody levels and a fall in TAC. Enterally fed patients showed no change in the level of EndoCAb antibodies and an increase in TAC.
TEN moderates the acute phase response, and improves disease severity and clinical outcome despite unchanged pancreatic injury on CT scan. Reduced systemic exposure to endotoxin and reduced oxidant stress also occurred in the TEN group. Enteral feeding modulates the inflammatory and sepsis response in acute pancreatitis and is clinically beneficial.
Antibiotic prophylaxis in severe pancreatitis has recently yielded promising clinical results, with imipenem significantly reducing the incidence of infected necrosis compared with an untreated control group. On the bases of pefloxacin's spectrum of action and pancreatic penetration, we investigated whether such drugs represent a valid alternative to imipenem.
In a multicenter study, 60 patients with severe acute pancreatitis with necrosis affecting at least 50% of the pancreas were randomly allocated to receive intravenous treatment for 2 weeks with pefloxacin, 400 mg twice daily (30 patients), or imipenem, 500 mg three times daily (30 patients), within 120 hours of onset of symptoms. Age, sex, body weight, Ranson and Apache II scores, C-reactive protein, etiology, and time from onset of symptoms to treatment were well matched in the two groups.
The incidences of infected necrosis and extrapancreatic infections were 34% and 44%, respectively, in the pefloxacin group and 10% and 20% in the imipenem group. Imipenem proved significantly more effective in prevention of pancreatic infections (P </= 0.05). Mortality was not significantly different in the two groups.
Despite its theoretical potential, pefloxacin is inferior to imipenem in the prevention of infections associated with severe pancreatitis.
Acute pancreatitis may be clinically mild or severe. Severe acute pancreatitis is usually a result of pancreatic glandular necrosis. The morbidity and mortality associated with acute pancreatitis are substantially higher when necrosis is present, especially when the area of necrosis is also infected.1 It is important to identify patients with pancreatic necrosis so that appropriate management can be undertaken. In recent years, the treatment of these patients has shifted away from early surgical debridement (“necrosectomy”) to aggressive intensive medical care, with specific criteria for operative and nonoperative intervention.2,3 Advances in radiologic imaging and aggressive medical management with emphasis on . . .
In severe AP, infected necrosis is the leading cause of death. Prevention of pancreatic infection is the major goal in the treatment of patients with necrotizing pancreatitis. Adequate early antibiotic therapy seems to be promising in these patients. Their role and the optimal timing of the antibiotic therapy (e.g., benefit of prophylactic application) are discussed. Preliminary results of a study in patients with infected pancreatic necrosis and exclusively or primarily conservative treatment also are presented.
To find out whether postoperative enteral feeding is safe and effective in patients with severe pancreatitis.
Prospective randomised trial.
Teaching hospital, Latvia.
29 patients who had been operated on for severe pancreatitis.
They were randomised to have either enteral nutrition and conventional intravenous fluids postoperatively (n = 11), or conventional intravenous fluids only (n = 18). 17 additional patients who had had major abdominal operations for other conditions were also given enteral nutrition and intravenous fluids and comprised the control group.
Nutritional intake, duration of stay in intensive care (ICU) and hospital morbidity, mortality, and outcome.
1 patient died of the 11 given enteral nutrition combined with conventional intravenous fluids, compared with 5/18 given fluids only. The pattern of bowel transit in the fed group did not differ from that in the control group.
Postoperative enteral nutrition seems to be safe and effective in patients with severe pancreatitis and may improve survival. Our results suggest that enteral and parenteral nutrition may complement each other in seriously ill patients.
The aim of this study was to evaluate the frequency of Candida infection of pancreatic necrosis in patients suffering from severe acute pancreatitis (SAP) and to analyze its impact on the outcome. Two-hundred and fifty consecutive patients with SAP from January 1986 to December 1998 were studied retrospectively. Their mean APACHE II score at the day of admission was in 16.1 (range 8-35). All patients were in need of operative therapy. Overall mortality was 38.8% (97 patients). One-hundred and eighty-two patients (72.8%) suffered from local infected necrosis. Among these patients, local Candida infection was observed in 31 patients, whereof 23 patients (74%) suffered from local fungal infection detected at first operation. During the course of disease, 12 patients (39%) also revealed fungemia. Local Candida infection as compared to no Candida infection was associated with an increased mortality rate (84% vs. 32%; P 0.0001). Multivariate logistic regression analysis identified APACHE II score (P < 0.0001), age of the patient (P < 0.003), extent of pancreatic necrosis (P < 0.002), and local bacterial (P < 0.04) and fungal infection (P < 0.004) as independent factors significantly contributing to mortality. SAP, requiring surgical treatment, is associated with high in-hospital mortality. Patients suffering from local Candida infection are at high risk of fatal outcome.
Pancreatic infection is the main indication for surgery and the principal determinant of prognosis in acute necrotizing pancreatitis. Previous studies on the effects of antibiotics have not, however, uniformly demonstrated any reduction in the need for surgery or any decrease in mortality among these patients, although the incidence of pancreatic infections was significantly reduced. This single-center randomized study was designed to compare early vs. delayed imipenem treatment for acute necrotizing pancreatitis. Ninety patients with acute necrotizing pancreatitis (C-reactive protein > 150 mg/L, necrosis on CT) were randomized within 48 hours either to a group receiving imipenem (1.0 g plus cilastatin intravenously 3 times a day) or a control group. Not included were those who had been started on antibiotics at the referring clinic, those who were taken directly to the intensive care unit for multiorgan failure, and those who refused antibiotics or might have had adverse reactions. Thirty-two patients were excluded because they were over 70 years of age (not potentionally operable) or for any study violation. There were 25 patients in the imipenem group and 33 patients in the control group. The main end point was the indication for necrosectomy due to infection (i.e., after the initial increase and decrease, there was a second continuous increase in temperature, white blood cell count [> 30%] and C-reactive protein [> 30%], with other infections ruled out, or bacteria were found on Gram stain of the pancreatic fine-needle aspirate). In the control group, imipenem was started when the operative indication was fulfilled. Conservative treatment was continued for at least 5 days before necrosectomy. The study groups did not differ from each other with regard to sex distribution, patient age, etiology, C-reactive protein concentration, and extent of pancreatic necrosis on CT. Two (8%) of 25 patients in the imipenem group compared to 14 (42%) of 33 in the control group fulfilled the operative indications (P = 0.003). Nine patients in the control group responded to delayed antibiotics but five had to undergo surgery. Of those receiving antibiotics, 2 (8%) of 25 in the early antibiotic (imipenem) group needed surgery compared to 5 (36%) of 14 in the delayed antibiotic (control) group (P = 0.04). Two (8%) of 25 patients in the imipenem group and 5 (15%) of 13 patients in the control group died (P = NS [no significant difference]). Seven (28%) of 25 in the imipenem group and 25 (76%) of 33 in the control group had major organ complications (P = 0.0003). Based on the preceding criteria, early imipenem-cilastatin therapy appears to significantly reduce the need for surgery and the overall number of major organ complications in acute necrotizing pancreatitis, and reduces by half the mortality rate; this is not, however, statistically significant in a series of this size.
We evaluated the usefulness of continuous regional arterial infusion (CRAI) of protease inhibitors and antibiotics in 156 patients with acute necrotizing pancreatitis (ANP) collected in a cooperative survey carried out in 1997 in Japan. The overall mortality rate was 18.6%, and the frequency of infected pancreatic necrosis was 12.8%. There was no significant difference in mortality rates between patients who received the protease inhibitor via CRAI and the antibiotics intravenously (group A) and patients who received both the protease inhibitor and the antibiotics via CRAI (group B), but the frequency of infected pancreatic necrosis was significantly lower in group B (7.6%) than in group A (23.5%). The mortality rate in patients in whom CRAI therapy was initiated within 48 h after the onset of ANP (11.9%) was significantly lower than that in patients in whom CRAI therapy was initiated more than 48 h after the onset (23.6%). These results suggested that CRAI of both protease inhibitors and antibiotics was effective in reducing mortality and preventing the development of pancreatic infection in ANP when initiated within 48 h after the onset of ANP.
Data from an 8-year period for 46 patients with severe acute pancreatitis and infected pancreatic necrosis were analyzed to
determine the incidence of fungal infection, to identify risk factors for the development of fungal infection, and to assess
the use of early fluconazole treatment. Intraabdominal fungal infection was found in 17 (37%) of 46 patients. Candida albicans was isolated most frequently (15 patients); Candida tropicalis and Candida krusei were found in 1 patient each. Characteristics of patients with fungal infection were not different from patients without
fungal infection. The difference in mortality was not statistically significant between patients with fungal infection and
patients without fungal infection. Early antifungal therapy (prophylactic or preemptive antifungal therapy) was administered
to 18 patients, and only 3 of them developed fungal infection. In this cohort of critically ill patients, no risk factors
for fungal infection could be demonstrated, and mortality among patients who received early antifungal therapy was not different.
Early treatment with fluconazole seems to prevent fungal infection in these high-risk patients.
We compared two imipenem regimens for prevention of septic complications in patients with severe acute necrotizing pancreatitis (ANP).
Prospective, randomized open clinical trial involving intensive care units of 14 Spanish Hospitals.
92 patients with ANP.
Imipenem/cilastatin was administered at 500 mg four times daily starting at the time of diagnosis of ANP, within the first 96 h from the onset of symptoms. Patients were randomized to receive antibiotic prophylaxis either for 14 days (group 1) or at least for 14 days and as long as major systemic complications of the disease persisted (group 2).
Antibiotic was maintained in group 2 for 19.7+/-10.9 days. The incidence of infected pancreatic necrosis, pancreatic abscess, and extrapancreatic infections was 11%, 17%, and 28% in group 1 and 17.4%, 13%, and 35% in group 2 (n.s.). Pancreatic or extrapancreatic infection by Candida albicans occurred in 7% and 22% of patients. Global mortality was 18.5% (10.9% secondary to septic complications), without differences between groups. In patients with persisting systemic complications at day 14 mortality was almost always secondary to septic complications and decreased from 25% (group 1) to 8.8% (group 2) by maintaining antibiotic prophylaxis.
Compared to a 14-day imipenem prophylaxis, a longer antibiotic administration in patients with ANP is not associated with a reduction in the incidence of septic complications of the disease. However, prolonged imipenem administration in patients with persisting systemic complications tends to reduce mortality in ANP compared to a 14-days regimen.
Antibiotic prophylaxis in necrotizing pancreatitis remains controversial. Until now, there have been no double-blind studies dealing with this topic.
A total sample size of 200 patients was calculated to demonstrate with a power of 90% that antibiotic prophylaxis reduces the proportion of patients with infected pancreatic necrosis from 40% placebo (PLA) to 20% ciprofloxacin/metronidazole (CIP/MET). One hundred fourteen patients with acute pancreatitis in combination with a serum C-reactive protein exceeding 150 mg/L and/or necrosis on contrast-enhanced CT scan were enrolled and received either intravenous CIP (2 x 400 mg/day) + MET (2 x 500 mg/day) or PLA. Study medication was discontinued and switched to open antibiotic treatment when infectious complications, multiple organ failure sepsis, or systemic inflammatory response syndrome (SIRS) occurred. After half of the planned sample size was recruited, an adaptive interim analysis was performed, and recruitment was stopped.
Fifty-eight patients received CIP/MET and 56 patients PLA. Twenty-eight percent in the CIP/MET group required open antibiotic treatment vs. 46% with PLA. Twelve percent of the CIP/MET group developed infected pancreatic necrosis compared with 9% of the PLA group (P = 0.585). Mortality was 5% in the CIP/MET and 7% in the PLA group. In 76 patients with pancreatic necrosis on contrast-enhanced CT scan, no differences in the rate of infected pancreatic necrosis, systemic complications, or mortality were observed.
This study detected no benefit of antibiotic prophylaxis with respect to the risk of developing infected pancreatic necrosis.
Sainio, V, Kemppainen, E, Puolakkainen, P, et al. Early antibiotic treatment in acute necrotizing pancreatitis. Lancet 1995;346:663-667