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Pentoxifylline Treatment in Severe Acute Pancreatitis: A Pilot, Double-Blind, Placebo-Controlled, Randomized Trial Santhi Swaroop Vege,1 Tegpal Atwal,1 Yan Bi,1 Suresh T. Chari,1 Magdalen A. Clemens,1 and Felicity T. Enders2 1
Division of Gastroenterology and Hepatology, Department of Medicine, 2Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota In acute pancreatitis (AP) tumor necrosis factor-a mediates multi-organ failure; in animal models its blockade with pentoxifylline ameliorates AP. The efficacy of pentoxifylline in predicted severe AP (pSAP) was tested in a double-blinded, randomized, control trial. Twenty-eight patients with pSAP were randomized within 72 hours of symptom onset to pentoxifylline or placebo. Baseline characteristics were similar in both groups. The pentoxifylline group had fewer intensive care unit admissions and shorter intensive care unit and hospital stays of longer than 4 days (all P < .05). Patients receiving pentoxifylline had no adverse effects. Pentoxifylline within 72 hours of pSAP is safe; a larger study of pentoxifylline in AP is needed to confirm efficacy. ClinicalTrials.gov number: NCT01292005.
Keywords: Tumor Necrosis Factor-a; Pentoxifylline; IL6; IL8.
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espite the high morbidity and mortality associated with severe acute pancreatitis (SAP), there is no specific drug to treat acute pancreatitis (AP). Tumor necrosis factor-a (TNF-a) plays a central role in the pathogenesis of SAP including1 pancreatic and peripancreatic necrosis, systemic inflammatory response syndrome, and persistent organ failure. Pentoxifylline, a nonselective phosphodiesterase inhibitor, has well-established clinical efficacy and safety in other TNF-a–mediated diseases, notably acute alcoholic hepatitis.2 In experimental models of AP, pentoxifylline reduced the severity of the disease.3–8 However, human data regarding its efficacy in AP are limited.9–11 By using multiple institutional resources, we have developed mechanisms to identify AP patients within 24 hours of admission to the hospital. We conducted a double-blinded, allocation-concealed, placebo-controlled, pilot trial of oral pentoxifylline vs placebo in patients with predicted SAP (pSAP). The study was approved by the Mayo Clinic’s Institutional Review Board. From 2009 to 2012 a total of 717 AP patients were identified and 226 showed at least one of the predictors of SAP (Supplementary Materials and Methods section and Supplementary Figure 1). A total of 102 of 132 patients approached to discuss the study declined to participate; 74 provided no reason, 20 were fearful of drug interactions or side effects, and 8 reported feeling better. Twenty-eight patients were allocated randomly to either the
pentoxifylline or control group. Pentoxifylline 400 mg or placebo tablets were administered by mouth at enrollment and 3 times a day for 72 hours thereafter. None of the patients had any difficulty with oral intake of tablets. All other treatments for SAP (fluid resuscitation, antibiotics, pain control, and so forth) were implemented according to the standard of care. All authors had access to the study data and reviewed and approved the final manuscript. On admission, the 2 groups were similar with regard to age, sex, body mass index, Acute Physiology and Chronic Health Evaluation, systemic inflammatory response syndrome score, and pancreatic necrosis or organ failure or baseline TNF-a, interleukin-6 (IL6), and C-reactive protein (CRP) levels (Supplementary Table 1). The median length of hospitalization was 3 days (range, 1–5 days) in the pen- Q9 toxifylline group and 5 days (range, 1–30 days) in the control group (P ¼ .06) (Table 1). Prolonged hospital stay (>4 days) was significantly less frequent in the pentoxifylline group (P ¼ .046). No patient in the pentoxifylline group but 4 patients in the placebo group required intensive care unit (ICU) transfer: 3 patients owing to respiratory failure and 1 patient owing to severe hypophosphatemia and hypocalcaemia. The median length of ICU stay was 0 days, and the maximum stay was 13 days in the control group. Although no patient in the pentoxifylline group developed new necrosis or organ failure after receiving the drug, 2 patients in the placebo group developed pancreatic necrosis and 3 patients developed organ failure during hospitalization. Changes of serum levels of TNF-a, IL6, IL8, and CRP from days 0 to 1 and from days 0 to 3 of enrollment showed no difference between the 2 groups. There were no deaths in either of the groups. One patient was re-admitted twice within 1 year in placebo group and no patient was readmitted in the pentoxifylline group. We report a single-institution, randomized, placebocontrolled drug trial to determine the safety and efficacy of pentoxifylline in patients with pSAP. We found that pentoxifylline was well tolerated and patients receiving
Abbreviations used in this paper: AP, acute pancreatitis; CRP, C-reactive protein; ICU, intensive care unit; IL, interleukin; pSAP, predicted severe acute pancreatitis; SAP, severe acute pancreatitis; TNF-a, tumor necrosis factor a. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.019
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Table 1.Clinical and Laboratory Outcomes of Patients in the Pentoxifylline and Placebo Groups Pentoxifylline (N ¼ 14)
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Length of hospitalization, days Length of hospitalization >4 days, n (%) Length of ICU stay, days Need for ICU, n (%) New-onset necrosis during hospitalization, n (%)a New-onset organ failure during hospitalization, n (%) Change in SIRS score from baseline to day 3 Change in APACHE II baseline to day 3 Death Laboratory outcomes Inflammatory markersb (change day 0 to 1) TNF-a, pg/mL IL6, pg/mL4 IL8, pg/mL CRP, mg/L Inflammatory markers‡ (change day 0 to 3) TNF-a, pg/mL IL6, pg/mL IL8, pg/mL CRP, mg/L
3 2 0 0 0 0 0 -1
(1–5) (14) (0–0) (0) (0) (0) (-2 to 1) (-7 to 5) 0
Placebo (N ¼ 14) 5 8 0 4 2 3 0 0
P value
(1–30) (57) (0–13) (28) (20) (21) (-2 to 2) (-1 to 5) 0
.06 .046 .03 .098 .18 .22 .96 .08
0 2 -3 48.4
(-1.2 to 0.5) (-37 to 25) (-7.2 to 30.8) (-37.1 to 207.3)
-0.1 0.9 -2.1 60.6
(-0.9 to 49.2) (-62 to 152) (38.2–49.2) (-71 to 283.2)
.74 .58 .90 .62
0 1.75 -1.7 30.7
(-1 to 0.5) (-61 to 18) (-10.3 to 6.4) (-157.4 to 255.3)
0 0.95 -2 122.2
(-3.5 to 17.2) (-340 to 65.8) (-43.6 to 18.2) (-170 to 394.4)
.98 .45 .60 .30
NOTE. Data are presented as median (range) unless otherwise indicated. APACHE, Acute Physiology and Chronic Health Evaluation; SIRS, systemic inflammatory response syndrome. a Patients with necrosis on admission were excluded for the analysis of necrosis after admission. b Normal value range for TNF-a, 0–22 pg/mL; IL6, 0–5 pg/mL; IL8, 0–5 pg/mL; and CRP, 0–10 mg/L.
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pentoxifylline showed improvements in outcomes of morbidity, as measured by the need for a hospital stay longer than 4 days and a reduced need for ICU transfer. However, there were no significant differences in the levels of inflammatory markers, including circulating TNF-a levels, between the 2 groups. Differences in levels of TNF-a, IL6, IL8, and CRP may be significant if the sample size is larger. Pentoxifylline has been proposed to reduce the systemic inflammation by reducing TNF-a, IL6, and CRP levels12; therefore, the exact mechanism of benefit of pentoxifylline in pSAP remains unclear. In an alcoholic hepatitis study, pentoxifylline did not decrease the TNF-a levels despite improvement in short-term survival and the investigators postulated the benefit was the result of improvement in microcirculation.2 It also may blunt the deleterious vascular factors similar to angiopoietin-2,13 and reduce the complications that correlate with severity. Our study was limited by its small sample size. Also, drug administration earlier than 72 hours after diagnosis may be preferable because experimental models have suggested that giving the drug within a few hours of disease onset is effective. Pancreatic TNF-a production peaks at 24–36 hours and, hence, prophylactic administration of pentoxifylline has been shown to be useful in experimental animals but a randomized controlled trial to prevent post– endoscopic retrograde cholangiopancreatography pancreatitis failed to show benefit.10 Another experimental study showed that delaying treatment until “AP is manifest” is more protective than prophylactic use.14 Initiating drug therapy within a few hours is challenging although a 24-hour cut-off time may be feasible in appropriate settings.
Despite these limitations, we showed that a singleinstitution drug trial for AP is feasible and that pentoxifylline is safe, cheap, and might have efficacy. This sets the stage for a larger trial of this drug in all patients with AP, to realize the goal of finding an effective drug that can be given within 24 hours of diagnosis in any setting.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/ j.gastro.2015.04.019.
References 1. Malleo G, et al. Shock 2007;28:130–140. 2. Akriviadis E, et al. Gastroenterology 2000;119: 1637–1648. 3. Coelho AM, et al. Acta Cir Bras 2012;27:487–493. 4. Hughes CB, et al. Am Surg 1996;62:8–13. 5. Le Campion ER, et al. HPB (Oxford) 2013;15:588–594. 6. Oruc N, et al. Pancreas 2004;28:e1–e8. 7. Pereda J, et al. Ann Surg 2004;240:108–116. 8. Szentkereszty Z, et al. Clin Hemorheol Microcirc 2013. 9. Farkas G, et al. Surgery 2006;10:278–285. 10. Kapetanos D, et al. Gastrointest Endosc 2007;66: 513–518. 11. Vakhrushev IM, et al. Ter Arkh 1988;60:129–132. 12. Gonzalez-Espinoza L, et al. Nephrol Dial Transplant 2012;27:2023–2028.
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13. Buddingh KT, et al. J Am Coll Surg 2014;218:26–32. 14. Norman JG, et al. Surgery 1996;120:515–521.
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Acknowledgment Santhi Swaroop Vege was involved in the concept, planning, and execution of this research, and writing the manuscript; Tegpal Atwal contributed to writing the manuscript and the analysis; Suresh Chari and Yan Bi were involved in manuscript writing; Magdalen Clemens recruited the patients and managed the study protocol; and Felicity Enders was responsible for data analysis and manuscript writing.
Received January 12, 2015. Accepted April 23, 2015.
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Reprint requests Address requests for reprints to: Santhi Swaroop Vege, MD, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-0350.
Conflicts of interest The authors disclose no conflicts.
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Funding Supported by a scholarly opportunity award from the Mayo Clinic (grant Q4 Q5 18023).
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Supplementary Materials and Methods This study was approved by the Mayo Clinic Institutional Review Board. Identification of AP patients used different sets of programs, including the Mayo Clinic Emergency Department Admission Board, the Mayo Clinic Life Sciences System/Data Discovery and Query Builder, and the Hospital Admission Board. The Mayo Clinic Emergency Department Admission Board is a program designed by the Emergency Department for tracking all patient admissions. The Mayo Clinic Life Sciences System/Data Discovery and Query Builder program was developed through a collaborative effort of the Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, and the Department of Information Technology. This program runs queries that will identify patients who are admitted to the hospital who meet certain preset parameters, such as 3-fold increased values of amylase and/or lipase. For this study, the query was run by the study coordinator every morning and early afternoon, as well as on weekends and off-hours to capture patients with AP. The Hospital Admission Board is a live program that is viewable on all work stations and used several times a day to identify patients with AP. In our study, the definition of AP required at least 2 of the following criteria: (1) characteristic abdominal pain, (2) amylase and/or lipase more than 3 times the upper limit of normal, or (3) positive results of characteristic crosssectional imaging. All consecutive adult patients (age, 18 y) with AP, admitted to our institution from 2009 through 2012, who showed any one of the following predictors of SAP were approached within the first 72 hours of onset: (1) age older than 60 years, (2) body mass index greater than 30, (3) Acute Physiology and Chronic Health Evaluation II score of 8 or higher, (4) admission hematocrit level greater than 45, (5) systemic inflammatory response syndrome score greater than 2, (6) abnormal admission (pleural effusion, infiltrates, atelectasis) chest radiograph, (7) admission computed tomography scan indicating necrosis of more than 30% of total gland size, or (8) Balthazar grade D (single fluid collection) or E (2 fluid collections) on admission computed tomography scan. In the absence of a single criterion or scoring system that accurately predicts severe or moderately severe AP, we chose to use any one of the earlier-mentioned criteria, all of which have been reported to be of some use. The patients who agreed to participate were enrolled by the study coordinator and then randomly allocated 1:1 to a treatment or placebo/control group, using a computerized random number generator by the statistician (F.T.E.). The randomization sequence was implemented by the research pharmacist. Study participants, care providers, and all members of the study team except for the statistician and pharmacist were blinded to allocation. The treatment group received pentoxifylline 400 mg 3 times a day by mouth from the time of enrollment until 72 hours after enrollment. Subjects received up to a maximum of 9 doses of this medication. The control group received similar-looking placebo tablets at similar intervals. All other
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treatment for SAP (fluid resuscitation, antibiotics, surgical intervention, pain control, and so forth) was implemented according to the standard of care. The levels of TNF-a, IL6, IL8, and CRP were obtained at the time of enrollment, and every other day until 7 days or until the dismissal date, whichever occurred earlier. The subjects were not considered withdrawals if they were discharged before 7 days. The clinical outcomes recorded were as follows: length of hospital stay, need for ICU care and length of ICU stay, development of organ failure, persistent organ failure, daily systemic inflammatory response syndrome and Acute Physiology and Chronic Health Evaluation II scores, computed tomography findings of pancreatic necrosis and fluid collections, the need for intervention, and death. A length of hospital stay of longer than 4 and 10 days was recorded for all patients as a Q13 binary variable. The median duration of hospitalization for AP has been reported to be 4 days.1 Hence, we decided to look at the number of patients needing more than a 4-day stay in both groups. Changes in the levels of TNF-a, IL6, IL8, and CRP on days 1 and 3 were compared with baseline values.
Statistical Methods Because no preliminary data were available, we developed the sample size using a 2-sided, 5% type I error to have 80% power to detect a difference of 1 SD for the change in CRP, TNF-a, IL6, and IL8 (separately) between the intervention and control arms. Categoric variables were presented as percentages and numeric variables were presented as medians and ranges. Continuous data were compared between the study groups with the Wilcoxon rank-sum test. Categoric data were compared between the study groups with the Fisher exact test. P values of less than .05 were considered statistically significant. For the analysis of necrosis after admission to the hospital, patients with baseline necrosis on admission were excluded. For the change from baseline to day 3, data are presented using the last value carried forward for patients who were discharged before day 3. A sensitivity analysis also was performed to assess whether the results differed significantly if discharged patients were excluded from the analyses using day 3 data (results not shown). All analyses were performed using Stata version 11.2 (StataCorp LP, College Station, TX) according to the assigned study groups. All of the authors had access to the data and analyses results.
Patient Recruitment A total of 717 patients were admitted with AP at the Mayo Clinic (Rochester, MN) between 2009 and 2012 (Figure 1). Of these, 491 were not eligible and 226 were Q14 eligible. We missed contacting 94 patients within the available time period of 72 hours. The study was discussed with 132 patients, of whom 102 declined and 30 consented to participate. One patient was excluded in each group because they were later found not to have AP; the remaining 28 patients were enrolled and received study medication.
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Of the 94 patients who could not be consented within the 72-hour window, the principal investigator and/or study coordinator were not available within the available time in 90 patients and 4 patients were unable to consent because they were medicated too heavily. Of 102 patients who declined to participate, 74 provided no reason, 20 were fearful of drug interactions or side effects, and 8 reported feeling better and therefore were not inclined to take another drug.
Baseline Characteristics There was no difference in age, sex, body mass index, Acute Physiology and Chronic Health Evaluation II score on admission, systemic inflammatory response syndrome score on admission, and pancreatic necrosis or organ failure on admission in the 2 groups. Baseline TNF-a, IL6, and CRP
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levels did not differ between the 2 study groups. IL8 approached statistical significance with a P value of .06, but was greater among placebo patients at baseline (median, 21.1 vs 12.3) (Supplementary Table 1).
Pentoxifylline Treatment In the pentoxifylline group, 4 patients received at least 3 doses, 5 patients received at least 6 doses, and 5 patients received 9 doses of the drug. In the placebo group, 6 patients received at least 3 doses, 3 patients received at least 6 doses, and 5 patients received 9 doses. Dosage was 1 tablet given 3 times a day.
Reference 1. Peery AF, et al. Gastroenterology 2012;143:1179–1187. e1-3.
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Supplementary Figure 1. Enrollment data for the study.
Supplementary Table 1.Baseline Characteristics of Patients in Pentoxifylline and Placebo Groups Pentoxifylline (N ¼ 14) Age, y Male sex, n (%) BMI, kg/m2 APACHE II SIRS scorea Necrosis on admission, n (%) Organ failure on admission TNF-a IL6 IL8 CRP
69 8 30.2 8.5 1 1 1.75 14 12.3 30.7
(34–87) (57) (20.6–42.9) (3–13) (0–2) (7) 0 (0.83–4.6) (1.5–74) (5–37.3) (3–237.9)
Placebo (N ¼ 14) 58 9 32.5 7 1 4 1.65 7.45 21.1 26.65
(24–82) (64) (16.7–50.1) (1–13) (0–2) (29) 0 (0.83–48.8) (1.8–500) (5–108) (3–400)
P value .20 >.99 .31 .25 >.99 .33 – .76 .41 .06 .98
NOTE. Data are presented as median (range) unless otherwise indicated. BMI, body mass index; SIRS, systemic inflammatory response syndrome. a Temperature greater than 38.5 C or less than 35.0 C, heart rate of greater than 90 beats/min, respiratory rate of more than 20 breaths/min or PaCO2 of less than 32 mm Hg, white blood cell count of more than 12,000 cells/mL or less than 4000 cells/mL, or more than 10% immature (band) forms.
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Pentoxifylline Treatment in Severe Acute Pancreatitis: A Pilot, Double-Blind, Placebo-Controlled, Randomized Trial Santhi Swaroop Vege,1 Tegpal Atwal,1 Yan Bi,1 Suresh T. Chari,1 Magdalen A. Clemens,1 and Felicity T. Enders2 1
Division of Gastroenterology and Hepatology, Department of Medicine, 2Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota In acute pancreatitis (AP) tumor necrosis factor-a mediates multi-organ failure; in animal models its blockade with pentoxifylline ameliorates AP. The efficacy of pentoxifylline in predicted severe AP (pSAP) was tested in a double-blinded, randomized, control trial. Twenty-eight patients with pSAP were randomized within 72 hours of symptom onset to pentoxifylline or placebo. Baseline characteristics were similar in both groups. The pentoxifylline group had fewer intensive care unit admissions and shorter intensive care unit and hospital stays of longer than 4 days (all P < .05). Patients receiving pentoxifylline had no adverse effects. Pentoxifylline within 72 hours of pSAP is safe; a larger study of pentoxifylline in AP is needed to confirm efficacy. ClinicalTrials.gov number: NCT01292005.
Keywords: Tumor Necrosis Factor-a; Pentoxifylline; IL6; IL8.
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espite the high morbidity and mortality associated with severe acute pancreatitis (SAP), there is no specific drug to treat acute pancreatitis (AP). Tumor necrosis factor-a (TNF-a) plays a central role in the pathogenesis of SAP including1 pancreatic and peripancreatic necrosis, systemic inflammatory response syndrome, and persistent organ failure. Pentoxifylline, a nonselective phosphodiesterase inhibitor, has well-established clinical efficacy and safety in other TNF-a–mediated diseases, notably acute alcoholic hepatitis.2 In experimental models of AP, pentoxifylline reduced the severity of the disease.3–8 However, human data regarding its efficacy in AP are limited.9–11 By using multiple institutional resources, we have developed mechanisms to identify AP patients within 24 hours of admission to the hospital. We conducted a double-blinded, allocation-concealed, placebo-controlled, pilot trial of oral pentoxifylline vs placebo in patients with predicted SAP (pSAP). The study was approved by the Mayo Clinic’s Institutional Review Board. From 2009 to 2012 a total of 717 AP patients were identified and 226 showed at least one of the predictors of SAP (Supplementary Materials and Methods section and Supplementary Figure 1). A total of 102 of 132 patients approached to discuss the study declined to participate; 74 provided no reason, 20 were fearful of drug interactions or side effects, and 8 reported feeling better. Twenty-eight patients were allocated randomly to either the
pentoxifylline or control group. Pentoxifylline 400 mg or placebo tablets were administered by mouth at enrollment and 3 times a day for 72 hours thereafter. None of the patients had any difficulty with oral intake of tablets. All other treatments for SAP (fluid resuscitation, antibiotics, pain control, and so forth) were implemented according to the standard of care. All authors had access to the study data and reviewed and approved the final manuscript. On admission, the 2 groups were similar with regard to age, sex, body mass index, Acute Physiology and Chronic Health Evaluation, systemic inflammatory response syndrome score, and pancreatic necrosis or organ failure or baseline TNF-a, interleukin-6 (IL6), and C-reactive protein (CRP) levels (Supplementary Table 1). The median length of hospitalization was 3 days (range, 1–5 days) in the pen- Q9 toxifylline group and 5 days (range, 1–30 days) in the control group (P ¼ .06) (Table 1). Prolonged hospital stay (>4 days) was significantly less frequent in the pentoxifylline group (P ¼ .046). No patient in the pentoxifylline group but 4 patients in the placebo group required intensive care unit (ICU) transfer: 3 patients owing to respiratory failure and 1 patient owing to severe hypophosphatemia and hypocalcaemia. The median length of ICU stay was 0 days, and the maximum stay was 13 days in the control group. Although no patient in the pentoxifylline group developed new necrosis or organ failure after receiving the drug, 2 patients in the placebo group developed pancreatic necrosis and 3 patients developed organ failure during hospitalization. Changes of serum levels of TNF-a, IL6, IL8, and CRP from days 0 to 1 and from days 0 to 3 of enrollment showed no difference between the 2 groups. There were no deaths in either of the groups. One patient was re-admitted twice within 1 year in placebo group and no patient was readmitted in the pentoxifylline group. We report a single-institution, randomized, placebocontrolled drug trial to determine the safety and efficacy of pentoxifylline in patients with pSAP. We found that pentoxifylline was well tolerated and patients receiving
Abbreviations used in this paper: AP, acute pancreatitis; CRP, C-reactive protein; ICU, intensive care unit; IL, interleukin; pSAP, predicted severe acute pancreatitis; SAP, severe acute pancreatitis; TNF-a, tumor necrosis factor a. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.019
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Table 1.Clinical and Laboratory Outcomes of Patients in the Pentoxifylline and Placebo Groups Pentoxifylline (N ¼ 14)
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Length of hospitalization, days Length of hospitalization >4 days, n (%) Length of ICU stay, days Need for ICU, n (%) New-onset necrosis during hospitalization, n (%)a New-onset organ failure during hospitalization, n (%) Change in SIRS score from baseline to day 3 Change in APACHE II baseline to day 3 Death Laboratory outcomes Inflammatory markersb (change day 0 to 1) TNF-a, pg/mL IL6, pg/mL4 IL8, pg/mL CRP, mg/L Inflammatory markers‡ (change day 0 to 3) TNF-a, pg/mL IL6, pg/mL IL8, pg/mL CRP, mg/L
3 2 0 0 0 0 0 -1
(1–5) (14) (0–0) (0) (0) (0) (-2 to 1) (-7 to 5) 0
Placebo (N ¼ 14) 5 8 0 4 2 3 0 0
P value
(1–30) (57) (0–13) (28) (20) (21) (-2 to 2) (-1 to 5) 0
.06 .046 .03 .098 .18 .22 .96 .08
0 2 -3 48.4
(-1.2 to 0.5) (-37 to 25) (-7.2 to 30.8) (-37.1 to 207.3)
-0.1 0.9 -2.1 60.6
(-0.9 to 49.2) (-62 to 152) (38.2–49.2) (-71 to 283.2)
.74 .58 .90 .62
0 1.75 -1.7 30.7
(-1 to 0.5) (-61 to 18) (-10.3 to 6.4) (-157.4 to 255.3)
0 0.95 -2 122.2
(-3.5 to 17.2) (-340 to 65.8) (-43.6 to 18.2) (-170 to 394.4)
.98 .45 .60 .30
NOTE. Data are presented as median (range) unless otherwise indicated. APACHE, Acute Physiology and Chronic Health Evaluation; SIRS, systemic inflammatory response syndrome. a Patients with necrosis on admission were excluded for the analysis of necrosis after admission. b Normal value range for TNF-a, 0–22 pg/mL; IL6, 0–5 pg/mL; IL8, 0–5 pg/mL; and CRP, 0–10 mg/L.
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pentoxifylline showed improvements in outcomes of morbidity, as measured by the need for a hospital stay longer than 4 days and a reduced need for ICU transfer. However, there were no significant differences in the levels of inflammatory markers, including circulating TNF-a levels, between the 2 groups. Differences in levels of TNF-a, IL6, IL8, and CRP may be significant if the sample size is larger. Pentoxifylline has been proposed to reduce the systemic inflammation by reducing TNF-a, IL6, and CRP levels12; therefore, the exact mechanism of benefit of pentoxifylline in pSAP remains unclear. In an alcoholic hepatitis study, pentoxifylline did not decrease the TNF-a levels despite improvement in short-term survival and the investigators postulated the benefit was the result of improvement in microcirculation.2 It also may blunt the deleterious vascular factors similar to angiopoietin-2,13 and reduce the complications that correlate with severity. Our study was limited by its small sample size. Also, drug administration earlier than 72 hours after diagnosis may be preferable because experimental models have suggested that giving the drug within a few hours of disease onset is effective. Pancreatic TNF-a production peaks at 24–36 hours and, hence, prophylactic administration of pentoxifylline has been shown to be useful in experimental animals but a randomized controlled trial to prevent post– endoscopic retrograde cholangiopancreatography pancreatitis failed to show benefit.10 Another experimental study showed that delaying treatment until “AP is manifest” is more protective than prophylactic use.14 Initiating drug therapy within a few hours is challenging although a 24-hour cut-off time may be feasible in appropriate settings.
Despite these limitations, we showed that a singleinstitution drug trial for AP is feasible and that pentoxifylline is safe, cheap, and might have efficacy. This sets the stage for a larger trial of this drug in all patients with AP, to realize the goal of finding an effective drug that can be given within 24 hours of diagnosis in any setting.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/ j.gastro.2015.04.019.
References 1. Malleo G, et al. Shock 2007;28:130–140. 2. Akriviadis E, et al. Gastroenterology 2000;119: 1637–1648. 3. Coelho AM, et al. Acta Cir Bras 2012;27:487–493. 4. Hughes CB, et al. Am Surg 1996;62:8–13. 5. Le Campion ER, et al. HPB (Oxford) 2013;15:588–594. 6. Oruc N, et al. Pancreas 2004;28:e1–e8. 7. Pereda J, et al. Ann Surg 2004;240:108–116. 8. Szentkereszty Z, et al. Clin Hemorheol Microcirc 2013. 9. Farkas G, et al. Surgery 2006;10:278–285. 10. Kapetanos D, et al. Gastrointest Endosc 2007;66: 513–518. 11. Vakhrushev IM, et al. Ter Arkh 1988;60:129–132. 12. Gonzalez-Espinoza L, et al. Nephrol Dial Transplant 2012;27:2023–2028.
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13. Buddingh KT, et al. J Am Coll Surg 2014;218:26–32. 14. Norman JG, et al. Surgery 1996;120:515–521.
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Acknowledgment Santhi Swaroop Vege was involved in the concept, planning, and execution of this research, and writing the manuscript; Tegpal Atwal contributed to writing the manuscript and the analysis; Suresh Chari and Yan Bi were involved in manuscript writing; Magdalen Clemens recruited the patients and managed the study protocol; and Felicity Enders was responsible for data analysis and manuscript writing.
Received January 12, 2015. Accepted April 23, 2015.
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Reprint requests Address requests for reprints to: Santhi Swaroop Vege, MD, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-0350.
Conflicts of interest The authors disclose no conflicts.
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Funding Supported by a scholarly opportunity award from the Mayo Clinic (grant Q4 Q5 18023).
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Supplementary Materials and Methods This study was approved by the Mayo Clinic Institutional Review Board. Identification of AP patients used different sets of programs, including the Mayo Clinic Emergency Department Admission Board, the Mayo Clinic Life Sciences System/Data Discovery and Query Builder, and the Hospital Admission Board. The Mayo Clinic Emergency Department Admission Board is a program designed by the Emergency Department for tracking all patient admissions. The Mayo Clinic Life Sciences System/Data Discovery and Query Builder program was developed through a collaborative effort of the Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, and the Department of Information Technology. This program runs queries that will identify patients who are admitted to the hospital who meet certain preset parameters, such as 3-fold increased values of amylase and/or lipase. For this study, the query was run by the study coordinator every morning and early afternoon, as well as on weekends and off-hours to capture patients with AP. The Hospital Admission Board is a live program that is viewable on all work stations and used several times a day to identify patients with AP. In our study, the definition of AP required at least 2 of the following criteria: (1) characteristic abdominal pain, (2) amylase and/or lipase more than 3 times the upper limit of normal, or (3) positive results of characteristic crosssectional imaging. All consecutive adult patients (age, 18 y) with AP, admitted to our institution from 2009 through 2012, who showed any one of the following predictors of SAP were approached within the first 72 hours of onset: (1) age older than 60 years, (2) body mass index greater than 30, (3) Acute Physiology and Chronic Health Evaluation II score of 8 or higher, (4) admission hematocrit level greater than 45, (5) systemic inflammatory response syndrome score greater than 2, (6) abnormal admission (pleural effusion, infiltrates, atelectasis) chest radiograph, (7) admission computed tomography scan indicating necrosis of more than 30% of total gland size, or (8) Balthazar grade D (single fluid collection) or E (2 fluid collections) on admission computed tomography scan. In the absence of a single criterion or scoring system that accurately predicts severe or moderately severe AP, we chose to use any one of the earlier-mentioned criteria, all of which have been reported to be of some use. The patients who agreed to participate were enrolled by the study coordinator and then randomly allocated 1:1 to a treatment or placebo/control group, using a computerized random number generator by the statistician (F.T.E.). The randomization sequence was implemented by the research pharmacist. Study participants, care providers, and all members of the study team except for the statistician and pharmacist were blinded to allocation. The treatment group received pentoxifylline 400 mg 3 times a day by mouth from the time of enrollment until 72 hours after enrollment. Subjects received up to a maximum of 9 doses of this medication. The control group received similar-looking placebo tablets at similar intervals. All other
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treatment for SAP (fluid resuscitation, antibiotics, surgical intervention, pain control, and so forth) was implemented according to the standard of care. The levels of TNF-a, IL6, IL8, and CRP were obtained at the time of enrollment, and every other day until 7 days or until the dismissal date, whichever occurred earlier. The subjects were not considered withdrawals if they were discharged before 7 days. The clinical outcomes recorded were as follows: length of hospital stay, need for ICU care and length of ICU stay, development of organ failure, persistent organ failure, daily systemic inflammatory response syndrome and Acute Physiology and Chronic Health Evaluation II scores, computed tomography findings of pancreatic necrosis and fluid collections, the need for intervention, and death. A length of hospital stay of longer than 4 and 10 days was recorded for all patients as a Q13 binary variable. The median duration of hospitalization for AP has been reported to be 4 days.1 Hence, we decided to look at the number of patients needing more than a 4-day stay in both groups. Changes in the levels of TNF-a, IL6, IL8, and CRP on days 1 and 3 were compared with baseline values.
Statistical Methods Because no preliminary data were available, we developed the sample size using a 2-sided, 5% type I error to have 80% power to detect a difference of 1 SD for the change in CRP, TNF-a, IL6, and IL8 (separately) between the intervention and control arms. Categoric variables were presented as percentages and numeric variables were presented as medians and ranges. Continuous data were compared between the study groups with the Wilcoxon rank-sum test. Categoric data were compared between the study groups with the Fisher exact test. P values of less than .05 were considered statistically significant. For the analysis of necrosis after admission to the hospital, patients with baseline necrosis on admission were excluded. For the change from baseline to day 3, data are presented using the last value carried forward for patients who were discharged before day 3. A sensitivity analysis also was performed to assess whether the results differed significantly if discharged patients were excluded from the analyses using day 3 data (results not shown). All analyses were performed using Stata version 11.2 (StataCorp LP, College Station, TX) according to the assigned study groups. All of the authors had access to the data and analyses results.
Patient Recruitment A total of 717 patients were admitted with AP at the Mayo Clinic (Rochester, MN) between 2009 and 2012 (Figure 1). Of these, 491 were not eligible and 226 were Q14 eligible. We missed contacting 94 patients within the available time period of 72 hours. The study was discussed with 132 patients, of whom 102 declined and 30 consented to participate. One patient was excluded in each group because they were later found not to have AP; the remaining 28 patients were enrolled and received study medication.
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Of the 94 patients who could not be consented within the 72-hour window, the principal investigator and/or study coordinator were not available within the available time in 90 patients and 4 patients were unable to consent because they were medicated too heavily. Of 102 patients who declined to participate, 74 provided no reason, 20 were fearful of drug interactions or side effects, and 8 reported feeling better and therefore were not inclined to take another drug.
Baseline Characteristics There was no difference in age, sex, body mass index, Acute Physiology and Chronic Health Evaluation II score on admission, systemic inflammatory response syndrome score on admission, and pancreatic necrosis or organ failure on admission in the 2 groups. Baseline TNF-a, IL6, and CRP
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levels did not differ between the 2 study groups. IL8 approached statistical significance with a P value of .06, but was greater among placebo patients at baseline (median, 21.1 vs 12.3) (Supplementary Table 1).
Pentoxifylline Treatment In the pentoxifylline group, 4 patients received at least 3 doses, 5 patients received at least 6 doses, and 5 patients received 9 doses of the drug. In the placebo group, 6 patients received at least 3 doses, 3 patients received at least 6 doses, and 5 patients received 9 doses. Dosage was 1 tablet given 3 times a day.
Reference 1. Peery AF, et al. Gastroenterology 2012;143:1179–1187. e1-3.
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Supplementary Figure 1. Enrollment data for the study.
Supplementary Table 1.Baseline Characteristics of Patients in Pentoxifylline and Placebo Groups Pentoxifylline (N ¼ 14) Age, y Male sex, n (%) BMI, kg/m2 APACHE II SIRS scorea Necrosis on admission, n (%) Organ failure on admission TNF-a IL6 IL8 CRP
69 8 30.2 8.5 1 1 1.75 14 12.3 30.7
(34–87) (57) (20.6–42.9) (3–13) (0–2) (7) 0 (0.83–4.6) (1.5–74) (5–37.3) (3–237.9)
Placebo (N ¼ 14) 58 9 32.5 7 1 4 1.65 7.45 21.1 26.65
(24–82) (64) (16.7–50.1) (1–13) (0–2) (29) 0 (0.83–48.8) (1.8–500) (5–108) (3–400)
P value .20 >.99 .31 .25 >.99 .33 – .76 .41 .06 .98
NOTE. Data are presented as median (range) unless otherwise indicated. BMI, body mass index; SIRS, systemic inflammatory response syndrome. a Temperature greater than 38.5 C or less than 35.0 C, heart rate of greater than 90 beats/min, respiratory rate of more than 20 breaths/min or PaCO2 of less than 32 mm Hg, white blood cell count of more than 12,000 cells/mL or less than 4000 cells/mL, or more than 10% immature (band) forms.
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