Does extended infusion piperacillin-tazobactam (Zosyn) improve clinical outcomes?

Introduction

Piperacillin-tazobactam (Zosyn), an extended-spectrum β-lactam/β-lactamase inhibitor combination, is widely used in the United States to treat a variety of infections such as nosocomial pneumonia, skin and soft-tissue infections, intra-abdominal infections, and febrile neutropenia.1,2 Beta-lactam antibiotics, including piperacillin-tazobactam, are time-dependent anti-infective therapies, meaning that their bactericidal activity depends on the time (T) that the free drug concentration (f) remains above the minimum inhibitory concentration (MIC).3 Per the product labeling, piperacillin-tazobactam should be administered by intravenous infusion over 30 minutes.4 However, because piperacillin-tazobactam exhibits time-dependent killing, recent studies suggest that an extended infusion over 4 hours may optimize therapy.3

Pharmacodynamic and Pharmacokinetic Evidence

In vitro and animal studies have shown that for penicillins, bactericidal effects are maximized when the fT>MIC exceeds 50% of the dosing interval (50% fT>MIC).5 Several studies have utilized a Monte Carlo simulation to determine optimal dosing of piperacillin-tazobactam to achieve maximal bactericidal activity.

Lodise et al. used a Monte Carlo simulation to compare extended infusion (EI) piperacillin-tazobactam (3.375 g over 4 hours every 8 hours) with traditional infusion (TI) piperacillin-tazobactam (30 minute infusion every 4 or 6 hours) to assess the probability of achieving 50% fT>MIC against Pseudomonas aeruginosa.5 The probability of target attainment (PTA) using EI was 92% for MICs of 16 mg/L and 100% for lower MICs. For the TI administered every 4 hours, the PTA was greater than 90% only for MIC values of 8 mg/L or less. The authors concluded that the EI dosing strategy offered a superior pharmacodynamic profile.

Kim et al. also evaluated the probability of achieving 50% fT>MIC against P.aeruginosa in TI over 30 minutes, EI over 3 or 4 hours, and a continuous infusion (CI) over 24 hours.6 Both the EI and CI dosing strategies had a higher PTA than the traditional group. At an MIC of 16 mg/L, the PTA was nearly 100% for both the EI and CI groups while the PTA for the TI group (3.375 g over 30 minutes every 6 hours) was only 67.8%. Similar to the previous study, the PTA for the TI groups were greater than 90% only for MIC values of 8 mg/L or less.

Shea et al. compared the pharmacodynamics of 4 TI and 4 EI dosing strategies.7 Unlike the previous studies that only evaluated MICs against P.aeruginosa, this study calculated the PTA for a broad range of MICs against 5 gram-negative pathogens in addition to P.aeruginosa. The study showed that at a MIC of 16 mg/L, PTA was greater than 90% for one of the TI regimens (3.375 g every 4 hours) and 3 of the EI regimens (≥ 3.375 g every 8 hours), but no regimen achieved a PTA greater than 90% at an MIC of 64 mg/L. The authors stated that based on these pharmacodynamic data, piperacillin-tazobactam should be used with caution, if at all, for MICs above 16 mg/L.

Clinical Evidence

Three recent trials evaluated the clinical outcomes of EI piperacillin-tazobactam. These studies were all retrospective and are summarized below with specific results (Table 1). Lodise et al conducted a retrospective cohort study evaluating EI versus TI piperacillin-tazobactam in 194 critically ill patients with P.aeruginosa infections.8 Results showed a significant reduction in 14 day mortality in a subgroup analysis of critically ill patients with Acute Physiological and Chronic Health Evaluation (APACHE) II scores ≥ 17 in the EI versus TI group (12.2% vs. 31.6%, p=0.04). However, this subgroup analysis was not pre-specified and it is not known if p values were adjusted for multiple comparisons. Hospital length of stay (LOS) was also evaluated and differences were only found in the subgroup analysis of patients with APACHE II scores ≥ 17 in the EI versus TI group (21 days vs. 38 days, p=0.02). Of note, the TI group of patients who were dosed every 6 hours (96% of patients in the TI group) as opposed to every 4 hours may have been underdosed, which would favor the EI group. Those who received infusions every 6 hours received a total daily dose of 13.5 g per day. The package insert recommendation is a total daily dose of 18 g for nosocomial infections.

Patel et al. conducted a retrospective, multicenter study that evaluated 129 patients with gram-negative infections.9 Patients received piperacillin-tazobactam either as an EI over 4 hours or TI over 30 minutes. The primary endpoints were 30 day mortality rate and median hospital LOS. Unlike the study by Lodise et al., results were not significantly different between the 2 groups in either of the primary endpoints. The 30 day mortality rate was 5.7% in the EI group versus 8.5% in the TI group (p=0.54). The authors delineated several explanations for this observation including: lower MIC values for most patients (< 8 mg/L) in which case TI achieves sufficient time above MIC, a higher piperacillin-tazobactam dose (4.5 g every 6 hours) often used in the TI group, and lower disease severity in this study population compared to the previous study (lower mean APACHE II scores). Although the study was not powered to detect modest differences, the authors concluded that the benefits from optimization of piperacillin-tazobactam exposure may only be significant among critically ill patients with P.aeruginosa infections.

Most recently, Yost et al. conducted a retrospective review at 14 US hospitals of 359 patients with gram-negative infections.10 Patients were treated with piperacillin-tazobactam as an EI over 4 hours or a TI with piperacillin-tazobactam or a comparator β-lactam antibiotic. The primary outcome was in-hospital mortality, which was significantly decreased in the EI versus TI treatment groups (9.7% vs. 17.9%, p=0.02). Results were still significant when only comparing patients who received piperacillin-tazobactam; however, when the EI was compared to a TI of other β-lactams, such as cephalosporins or carbapenems, the results were not significant. When only looking at patients who had APACHE II scores ≥ 17, the EI group had lower mortality rates but results were not significant. Secondary outcomes included hospital LOS, intensive care unit LOS, and duration of antibiotic exposure; none of these outcomes were significantly different between the groups. Unlike the previous 2 studies, baseline characteristics were not balanced between the groups.

Table 1. Clinical evidence for extended infusion piperacillin-tazobactam.

EI, extended infusion; TI, traditional infusion; LOS, length of stay; ICU, intensive care unit; MIC, minimum inhibitory concentration; APACHE-II, Acute Physiological and Chronic Health Evaluation.

Implementation

Two recent articles describe the implementation of an EI piperacillin-tazobactam program for adult patients at their institution. These studies do not describe clinical outcomes, but report on administration issues. The first article describes EI piperacillin-tazobactam implementation at an urban teaching hospital where the administration was converted from a 30-minute infusion every 4 to 6 hours to an EI over 4 hours of 3.375 g every 8 or 12 hours. 11 During 11 observation days post-implementation, 90% of the doses were infused at the appropriate rate. By day 6 of observation, all observed doses were administered at the appropriate rate with none of them being omitted due to incompatibilities. This study also reported a decrease in the number of doses per 1000 patient-days after implementation (mean difference 116 doses, p<0.001).

The second study described EI piperacillin-tazobactam implementation at a 500-bed academic medical center where the administration was converted from a 30-minute infusion to a 4-hour infusion of 3.375 g every 8 hours to 12 hours (12 hours being utilized if patient’s creatinine clearance is less than 20 mL/min).12 Over a course of 5 weeks, 1215 doses were prospectively monitored to ensure accurate administration and identify barriers to guideline adherence. Of these doses, 98% were administered at the appropriate rate and 94% were administered on time. Common barriers to guideline adherence included either the patient not being on the nursing unit or dose not being available at the scheduled administration time. Other reported barriers included administration errors and intravenous drug incompatibilities.

Limitations

Pediatrics

Data are limited for the use of EI piperacillin-tazobactam in pediatrics. Therefore, pediatric patients were excluded from the 2 studies describing implementation. A recently published prospective observational study evaluated the feasibility of using EI piperacillin-tazobactam as the standard of care in a children’s hospital.13 After protocol implementation, 92% of patients received EI piperacillin-tazobactam for the duration of therapy while 8% received a traditional infusion over 30 minutes. The most common reasons for not using EI were coadministration of vancomycin, lack of compatibility data, and concern for limited intravenous access.

Renal dose adjustments

There is limited evidence to examine the effect of a patient’s renal function on the PTA for TI and EI piperacillin-tazobactam. One study by Patel et al examined the effect of various levels of renal impairment on the probability of achieving 50% fT>MIC for TI and EI dosing strategies through pharmacokinetic modeling.14 Although only 3 of the 150 patients evaluated had a creatinine clearance less than 40 mL/min, the authors did not believe this to be a major issue since the clearance of piperacillin in the presence of tazobactam was demonstrated to be linear. Their findings support dose adjustment recommendations when creatinine clearance is below 20 mL/min. They concluded that EI improved the pharmacodynamic profile of piperacillin-tazobactam, especially with MICs ≥ 8 mg/L. For MICs of 32 mg/L, however, none of the EI or TI regimens effectively reached PTA; therefore, alternative agents to piperacillin-tazobactam should be considered. Although this study shows that dose adjustments are recommended when creatinine clearance is below 20 mL/min, the actual dose adjustment is not well defined. Yost et al. described that dose adjustments for patients with creatinine clearance less than 20 mL/min were not consistent among the 14 institutions in their trial.10 The optimal dose for patients with renal dysfunction is yet to be determined.

Compatibility

Compatibility of piperacillin-tazobactam with other medications is an important consideration. With the EI piperacillin-tazobactam over 4 hours every 8 hours, the use of an intravenous line is restricted for 12 hours per day, which can be challenging in the intensive care unit or in patients with limited intravenous access.15 Multiple medications are incompatible with piperacillin-tazobactam via Y-site administration.16,17 Of note, the compatibility of vancomycin and piperacillin-tazobactam is concentration dependent and therefore, if these antibiotics are being administered together, clinicians should be aware of specific concentrations.17

Infusion Volume and Pump Characteristics

Another important consideration is incomplete administration of the drug if volume and pump characteristics have not been taken into account. One hospital implemented an EI piperacillin-tazobactam protocol and observed that if the line was not flushed after antibiotic infusion, there was a 40% loss of dose after infusion line replacement.18 They were, however, administering the antibiotic in a smaller volume of 50 mL to enable hospital-wide implementation to include fluid restricted patients. Both studies that described the implementation of an EI program increased the volume in which piperacillin-tazobactam was administered from 50 to 100 mL to minimize the amount of drug left in the tubing after administration.11,12

Conclusion

Optimizing antibiotic exposure is important in the health-care setting as antimicrobial resistance is a major concern. For piperacillin-tazobactam, bactericidal effects are maximized when the fT>MIC exceeds 50% of the dosing interval. Pharmacodynamic and pharmacokinetic evidence shows that TI over 30 minutes is sufficient to achieve this goal of 50% fT>MIC for MIC values of 8 mg/L or less. However, for higher MICs, the probability of target attainment is achieved more frequently in EI groups. As the MIC exceeds 16 mg/L, alternatives to piperacillin-tazobactam should be considered. The clinical evidence shows a mortality benefit and decreased hospital LOS for EI piperacillin-tazobactam in critically ill patients infected with P.aeruginosa. These improved clinical outcomes were not observed in other patient populations and there is a lack of evidence in pediatrics and patients with renal insufficiency. Prospective, randomized controlled trials are needed to further investigate the benefits of EI that have been reported in these retrospective trials.

References

1. Pakyz AL, MacDougall C, Oinonen M, Polk RE. Trends in antibacterial use in US academic health centers: 2002 to 2006. Arch Intern Med. 2008;168(20):2254-2260.

2. Mah GT, Mabasa VH, Chow I, Ensom MH. Evaluating outcomes associated with alternative dosing strategies for piperacillin/tazobactam: a qualitative systematic review. Ann Pharmacother. 2012;46(2):265-275.

3. Kaufman SE, Donnell RW, Hickey WS. Rationale and evidence for extended infusion of piperacillin-tazobactam. Am J Health Syst Pharm. 2011;68(16):1521-1526.

4. Zosyn (piperacillin and tazobactam) [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2009.

5. Lodise TP, Lomaestro BM, Drusano GL. Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on beta-lactam antibiotics: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2006;26(9):1320-1332.

6. Kim A, Sutherland CA, Kuti JL, Nicolau DP. Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion? Pharmacotherapy. 2007;27(11):1490-1497.

7. Shea KM, Cheatham SC, Smith DW, et al. Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients. Ann Pharmacother. 2009;43(11):1747-1754.

8. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44(3):357-363.

9. Patel GW, Patel N, Lat A, et al. Outcomes of extended infusion piperacillin/tazobactam for documented Gram-negative infections. Diagn Microbiol Infect Dis. 2009;64(2):236-240.

10. Yost RJ, Cappelletty DM. The Retrospective Cohort of Extended-Infusion Piperacillin-Tazobactam (RECEIPT) study: a multicenter study. Pharmacotherapy. 2011;31(8):767-775.

11. Xamplas RC, Itokazu GS, Glowacki RC, et al. Implementation of an extended-infusion piperacillin-tazobactam program at an urban teaching hospital. Am J Health Syst Pharm. 2010;67(8):622-628.

12. Heinrich LS, Tokumaru S, Clark NM, et al. Development and implementation of a piperacillin-tazobactam extended infusion guideline. J Pharm Pract. 2011;24(6):571-576.

13. Nichols KR, Knoderer CA, Cox EG, Kays MB. System-wide implementation of the use of an extended-infusion piperacillin/tazobactam dosing strategy: feasibility of utilization from a children's hospital perspective. Clin Ther. 2012;34(6):1459-1465.

14. Patel N, Scheetz MH, Drusano GL, Lodise TP. Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients. Antimicrob Agents Chemother. 2010;54(1):460-465.

15. Rotschafer JC, Ullman M. Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulation and steady-state pharmacokinetic data from hospitalized patients. Ann Pharmacother.2009;43(11):1887-1889.

16. Trissel LA, Martinez JF. Compatibility of piperacillin sodium plus tazobactam with selected drugs during simulated Y-site injection. Am J Hosp Pharm. 1994;51(5):672-678.

17. Trissel LA. Handbook on Injectable Drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011.

18. Claus B, Buyle F, Robays H, Vogelaers D. Importance of infusion volume and pump characteristics in extended administration of ß-lactam antibiotics. Antimicrob Agents Chemother. 2010;54(11):4950.

Written by:
Shadi Ghaibi, PharmD
University of Illinois at Chicago
November 2012

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What are the most recent antimicrobial prophylaxis guidelines from the Medical Letter?

The Medical Letter released updated guidelines in October 2012 for antimicrobial prophylaxis for surgery.1 These guidelines update the previous version from June 2009. Several other organizations also provide guidelines for antimicrobial surgical prophylaxis. The Infectious Diseases Society of America is projected to update their 1994 antimicrobial prophylaxis for surgery guidelines, with a tentative release date of Spring 2013. The Medical Letter also updated guidelines for endocarditis prophylaxis for dental procedures in September 2012. This review will focus on key differences between the 2009 and 2012 guidelines from The Medical Letter. A summary of the recommendations, with doses, is given in Table 1.

Medical Letter surgical prophylaxis guideline summary

The updated Medical Letter guidelines discuss pre-operative screening and decolonization. Screening patients who are nasal carriers of methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive S. aureus (MSSA) and using intranasal mupirocin ointment for decolonization have been shown to decrease surgical site infections, primarily in cardiac and orthopedic surgeries. A study by Bode et al in 2010 2 found that the combination of nasal mupirocin and chlorhexidine baths within the first 24 hours after hospital admission reduced the risk of hospital-acquired MSSA infections. However, there is also growing concern for mupirocin resistance.

Medical Letter surgical prophylaxis updates from 2009

In the updated guidelines, cefuroxime has been added as an option for prophylaxis prior to cardiac surgery; it is no longer recommended prior to orthopedic procedures or thoracic (non-cardiac) operations. For non-perforated appendectomy surgery, ampicillin/sulbactam is no longer listed as a preferred agent. However, for head and neck surgery and thoracic (non-cardiac) operations, ampicillin/sulbactam has been added to the choices as a recommended antimicrobial.

Parenteral prophylactic antimicrobials should be administered within 60 minutes before the initial surgical incision. This is to ensure adequate serum levels and tissue penetration. If using vancomycin or a fluoroquinolone, which have prolonged infusion times, the infusion should be started 60 to 120 minutes prior to the incision. For procedures that are longer than 3 hours, have major blood loss, or in patients with extensive burns, additional prophylactic doses should be given. The timing of these antibiotics depends on the half-life of the drug (generally at intervals of 1 to 2 times the drug half-life. Ampicillin/sulbactam and cefoxitin should be given every 2 hours, cefazolin and cefuroxime every 4 hours, clindamycin every 6 hours, and vancomycin every 12 hours. The duration of prophylactic antibiotics should be <24 hours for most procedures.

For indications with cefazolin as a preferred agent, the recommended dose is 1 g for patients who weigh < 80 kg and 2 g for patients ≥80 kg. Vancomycin can be considered if MRSA frequently causes postoperative wound infections at the hospital, in patients with a history of MRSA colonization, or for patients with a penicillin or cephalosporin allergy. Clindamycin can also be used in patients with a penicillin or cephalosporin allergy. When using vancomycin in a procedure in which enteric gram-negative bacilli are common pathogens, the addition of an aminoglycoside, aztreonam, or a fluoroquinolone may be recommended. Fluoroquinolones should not be used for prophylaxis in cesarean section. Prior to using a fluoroquinolone or ampicillin/sulbactam, local sensitivity profiles should be reviewed due to increasing resistance of Escherichia coli.

Table 1. Summary of antimicrobial prophylaxis for surgery recommendations

Medical Letter endocarditis prophylaxis guideline summary

The Medical Letter also published recommendations for endocarditis prophylaxis for dental procedures in September 2012.3 Antimicrobial prophylaxis for dental procedures is indicated for patients at high risk of severe consequences from endocarditis. These patients include those with a history of previous infective endocarditis, prosthetic heart valves, unrepaired cyanotic congenital heart disease, repair of congenital heart defects with prosthetic material within 6 months, residual defect of prosthetic device after congenital heart repair, or development of valvulopathy after cardiac transplant. In these high risk patients, only procedures involving manipulation of gingival tissues (such as cleaning, tooth extraction, or biopsy) or perforation of oral mucosa warrant prophylaxis. Amoxicillin 2 g (or 50 mg/kg for pediatric patients) given 30 to 60 minutes prior to the dental procedure is the drug of choice for endocarditis prophylaxis. Cephalexin, clindamycin, or azithromycin are options for patients with penicillin allergies.

References

1. The Medical Letter. Antimicrobial prophylaxis for surgery. Treat Guide Med Lett. 2012; 10(122):73-78.
2. Bode LG et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med. 2010; 362(1):9-17.
3. The Medical Letter. Endocarditis prophylaxis for dental procedures. Med Lett On Drugs and Therapuetics 2012; 54:74-75.

Written by:
Melanie Martinez, PharmD
University of Illinois at Chicago
November 2012

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What is the efficacy of rectal NSAIDs for prevention of pancreatitis post-ERCP?

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure performed in over 500,000 patients in the United States annually for both diagnostic and therapeutic purposes.1,2 The procedure is often used for management of common bile duct stones, bile and pancreatic duct strictures, and pancreatic malignancies. A serious concern is the risk for post-ERCP pancreatitis (PEP), which affects approximately 3.5% of patients who undergo ERCP. Post-ERCP elevations in pancreatic enzymes are often mistaken for PEP, especially given that up to 75% of post-ERCP patients experience this. However, PEP is diagnosed when additional factors are present, such as pancreatic-type abdominal pain, prolongation of hospitalization, or imaging confirmation. 1,3 Significant morbidity and mortality may accompany PEP, and multivariate analyses have been performed to identify risk factors.1,2 Table 1 lists patient-specific and procedure-specific factors correlated with risk for and protection from PEP. Risk factors are additive; patients with multiple risk factors are at an increasingly higher risk of developing PEP.

Table 1. Risk and protective factors for development of post-ERCP pancreatitis .1,2

Given the risk of pancreatitis, ERCP should only be performed in a patient who is truly likely to benefit from it.2 Alternatives to ERCP include magnetic resonance cholangiopacreatography (MRCP) and endoscopic ultrasound (EUS), which are noninvasive techniques that are not associated with an increased risk for pancreatitis. Both procedural techniques and pharmacologic methods have been studied to reduce the risk of PEP.1,2 Prophylactic stent placement has been shown to reduce the odds of developing PEP in high-risk patients, and guidewire cannulation also reduces the incidence of PEP. Over 35 pharmacologic agents have been studied for prevention of PEP, most of which have shown little or no benefit.4,5 Nitroglycerin prior to ERCP has conflicting evidence for benefit, but its use is limited by adverse effects of hypotension and headache.2 Somatostatin and gabexate (a protease inhibitor not approved for use in the United States) have shown minimal benefit for PEP prevention in meta-analyses, and interleukin 10, octreotide, corticosteroids, allopurinol, platelet-activating factor inhibitors, heparin, and use of non-ionic contrast have been determined ineffective. 4

NSAIDS and prevention of pancreatitis

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly studied agents for PEP prevention.5 Because acute pancreatitis is characterized by inflammation, NSAID efficacy is likely due to attenuation of the inflammatory process through inhibition of prostaglandin, an inflammatory process mediator. Evidence for use of NSAIDs for PEP prevention was first published a decade ago.6 Since then, the majority of clinical trials assessed diclofenac (rectal, oral, and intramuscular routes) and indomethacin (rectal route).11-15 Intravenous valdecoxib, a cyclooxygenase 2 inhibitor, was also studied, but found to be ineffective.7 Evidence has not shown oral NSAIDs to be effective for PEP prevention, but evidence for rectal NSAIDs is more promising.1 A possible explanation for this is that bioavailability of NSAIDs is reduced greatly when administered orally, but when administered rectally first-pass metabolism is bypassed and absorption is complete.8 Three meta-analyses of rectally administered NSAIDs support their efficacy in PEP prevention and have since been recommended by the European Society of Gastrointestinal Endoscopy. 9 Interestingly, despite these guidelines, a survey of endoscopists in Europe revealed that approximately 84% did not use NSAIDs for PEP prevention given the lack of evidence.10 The European guidelines are not accepted in the United States.

The first NSAID for PEP prevention trial was performed by Murray and colleagues.6 It was a single-center, double-blind, randomized, placebo-controlled trial of rectal diclofenac in high-risk patients post-ERCP. Patients who received diclofenac 100 mg per rectum immediately after ERCP were less likely to develop pancreatitis compared to those who received placebo (6.4% versus 15.5%; p<0.05). Rectal diclofenac was assessed in 3 more randomized controlled trials, all of which found benefit for its use.11-13 Khoshbaten and colleagues discontinued their trial early due to statistically significant efficacy with diclofenac 100 mg per rectum compared to placebo immediately after ERCP in high-risk patients.11 Of 100 patients, 2 developed pancreatitis in the diclofenac group compared to 13 in the placebo group (p<0.01). Another trial assessed diclofenac 100 mg per rectum immediately prior to ERCP in combination with somatostatin 0.25 mg/h for 6 hours in a double-blind, double-dummy fashion.12 Pancreatitis was significantly reduced in the diclofenac/somatostatin group compared to the placebo group in the overall study population (4.7% vs. 10.4%; p=0.015). Subgroup analyses revealed that high-risk patients also benefitted significantly from diclofenac/somatostatin (5.8% vs. 12.3%; p=0.027), but low-risk patients did not (1.5% vs. 3.5%; p=0.594). However, it should be considered that because the study was not designed to detect differences within subgroups and there were fewer low-risk patients than high-risk patients, a lack of power may be an explanation for no difference seen between groups in the low-risk patients. The authors concluded that further trials on the combination of diclofenac/somatostatin should be performed before making definitive conclusions on their efficacy for prevention of PEP. The most recent trial assessing rectal diclofenac was also terminated early due to significantly fewer cases of pancreatitis in patients receiving diclofenac 50 mg with a saline infusion immediately before ERCP compared to those only receiving saline (the control group).13 The study took place in Japan and investigated the lower dose since that is what is commercially available to them. Pancreatitis occurred in 3.9% of patients in the diclofenac group compared to 18.9% of patients in the control group (p=0.017). It was also found that in patients who received diclofenac 25 mg (administered to patients <50 kg), the incidence of pancreatitis was significantly lower than in the control group. The authors concluded that lower rectal doses of diclofenac can prevent PEP.

Rectal indomethacin has also been studied in PEP prevention. A double-blind randomized trial including 490 patients assessed indomethacin 100 mg per rectum immediately before ERCP.14 While there were fewer cases of pancreatitis in the indomethacin group compared to placebo, this difference was not statistically significant. However, in a subgroup analysis of patients receiving a pancreatic duct injection (a high-risk population), use of indomethacin significantly lowered the incidence of pancreatitis in comparison to placebo (relative risk reduction=88%; 95% confidence interval [CI]: 21 to 100%; p=0.01). It should be noted that pancreatic stents, which are known to reduce the risk for pancreatitis, were not placed in these patients. Most recently, Elmunzer and colleagues conducted a double-blind randomized controlled trial assessing rectal indomethacin 100 mg compared to placebo immediately after ERCP in 602 patients at high risk for PEP (a majority having suspicion of sphincter of Oddi dysfunction).15 Significantly fewer patients in the indomethacin group compared to the placebo group developed pancreatitis (9.2% vs. 16.9%; p=0.03). The authors calculated a number needed to treat of 13, meaning 13 patients need to be treated with rectal indomethacin 100 mg in order to prevent one episode of PEP. The secondary outcome of the study was the incidence of moderate or severe pancreatitis, and indomethacin was also significantly better than placebo at reducing these rates (4.4% vs. 8.8%; p=0.03). Patients in the indomethacin group had a significantly shorter hospital length of stay than those in the placebo group (3.5 vs. 4.0 days; p<0.001). Post hoc subgroup analyses led the authors to conclude that the benefit of indomethacin appeared to be consistent regardless of placement of pancreatic stents. The authors concluded that rectal indomethacin is an effective prevention method for PEP for patients at high risk for PEP, including those with suspicion for sphincter of Oddi dysfunction.

Two meta-analyses were performed in order to assess the efficacy of NSAIDs for prevention of PEP, with results that support the findings of the randomized controlled trials discussed above.8,16 Four randomized controlled trials enrolling 912 patients were included in the 2008 meta-analysis by Elmunzer and colleagues.16 A majority of the patients were at high risk for PEP development. The investigators found that patients receiving periprocedural rectal NSAIDs for prevention of PEP were 64% less likely to develop PEP. They also concluded that patients receiving NSAIDs were 90% less likely to develop moderate to severe pancreatitis, but this statistic was calculated from very limited data. Dai and colleagues performed a meta-analysis on NSAIDs administered by any route for prevention of PEP.8 Unlike the meta-analysis by Elmunzer and colleagues, only a minority of patients were at high risk for PEP development. It was found that overall, NSAIDs reduced the risk for PEP when compared to placebo (odds ratio: 0.46; 95% CI: 0.32 to 0.65; p<0.0001). Indomethacin and diclofenac were the only NSAIDs studied in both meta-analyses and were given either immediately prior or immediately after ERCP. Neither meta-analysis found an increase in adverse events in patients receiving NSAIDs. It should be noted that patients with contraindications to NSAIDs (renal impairment and active peptic ulcer disease) were excluded in these studies. A limitation of the meta-analyses is the possibility of varying pancreatitis diagnostic criteria amongst included trials, which could obscure the true rates of pancreatitis. Another limitation is inconsistent types of ERCP procedures (and varying experience of the endoscopists performing them). Although Elmunzer and colleagues found no statistical heterogeneity within their analysis, it may have not included enough studies to detect a difference if one exists.16 Dai and colleagues did not comment on heterogeneity within their analysis.8 Despite these limitations, both analyses showed efficacy for use of indomethacin or diclofenac for the prevention of PEP.

Summary

Issues that should be addressed in future prospective trials of rectal NSAIDs for prevention of PEP include identification of an appropriate patient population in which they should be used and comparative and additive benefits when rectal NSAIDs are used with other pharmacologic agents and pancreatic stenting. Collectively, evidence supports the use of rectal diclofenac or indomethacin immediately prior to or immediately after ERCP for prevention of pancreatitis. Patients with risk factors for PEP may especially benefit from these agents. Given the low cost and relative safety of diclofenac and indomethacin, as well as the cost of treatment of pancreatitis, rectal NSAIDs should be considered for prevention of pancreatitis in patients undergoing ERCP.

References

1. Anderson MA, Fisher L, Jain R, et al; ASGE Standards of Practice Committee. Complications of ERCP. Gastrointest Endosc. 2012;75(3):467-473.

2. Feurer ME, Adler DG. Post-ERCP pancreatitis: review of current preventive strategies. Curr Opin Gastroenterol. 2012;28(3):280-286.

3. Parsi MA. NSAIDs for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: Ready for prime time? World J Gastroenterol. 2012;18(3):3936-3937.

4. Kahaleh M, Freeman M. Prevention and management of post-endoscopic retrograde cholangiopancreatography complications. Clin Endosc. 2012 Sep;45(3):305-12. Epub 2012 Aug 22.

5. Testoni PA. Can rectal NSAIDs prevent post-ERCP pancreatitis? Nat Rev Gastroenterol Hepatol. 2012;9(8):429-430.

6. Murray B, Carter R, Imrie C, Evans S, O’Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology. 2003;124(7):1786-1791.

7. Bhatia V, Ahuja V, Acharya SK, Garg PK. A randomized controlled trial of valdecoxib and glyceryl trinitrate for the prevention of post-ERCP pancreatitis. J Clin Gastroenterol. 2011;45(2):170-176.

8. Dai HF, Wang XW, Zhao K. Role of nonsteroidal anti-inflammatory drugs in the prevention of post-ERCP pancreatitis: a meta-analysis. Hepatobiliary Pancreat Dis Int. 2009;8(1):11-16.

9. Dumonceau JM, Andriulli A, Deviere J, et al. European Society of Gastrointestinal Endoscopy (ESGE) Guideline: prophylaxis of post-ERCP pancreatitis. Society of Gastrointestinal Endoscopy. Endoscopy. 2010;42(6):503-515.

10. Dumonceau JM, Rigaux J, Kahaleh M, et al. Prophylaxis of post-ERCP pancreatitis: a practice survey. Gastrointest Endosc. 2010;71(6):934-939.

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