- Email: [email protected]
Conservative Management of Pneumatosis Intestinalis and Portal Venous Gas After Pediatric Liver Transplantation
Conservative Management of Pneumatosis Intestinalis and Portal Venous Gas After Pediatric Liver Transplantation Jamie L. Ryana,b, Laura M. Dandridgea,b, Walter S. Andrewsc, James F. Daniela, Ryan T. Fischera, Douglas C. Rivardd, Andrea B. Wieserc, Bartholomew J. Kanee, and Richard J. Hendricksonc,* a Division of Pediatric Gastroenterology, Children’s Mercy Kansas City, Kansas City, Missouri, USA; bDivision of Developmental and Behavioral Sciences, Children’s Mercy Kansas City, Kansas City, Missouri, USA; cDepartment of Surgery, Children’s Mercy Kansas City, Kansas City, Missouri, USA; dDepartment of Radiology, Children’s Mercy Kansas City, Kansas City, Missouri, USA; eDepartment of Transplantation, Lahey Hospital & Medical Center, Burlington, Massachusetts, USA
ABSTRACT Background. Pneumatosis intestinalis (PI) is a rare pathologic finding in pediatric liver transplant (PLT) recipients. The presentation and course of PI can range from asymptomatic and clinically benign to life threatening, with no consensus regarding management of PI in children. We aim to review the clinical presentation and radiologic features of PLT recipients with PI and to report the results of conservative management. Methods. A retrospective medical chart review was conducted on PLT recipients between November 1995 and May 2016. Parameters evaluated at PI diagnosis included pneumatosis location, presence of free air or portal venous gas (PVG), symptoms, laboratory findings, and medication regimen. Results. PI developed in 10 of 130 PLT patients (7.7%) between 8 days and 7 years (median: 113 days) posttransplant. Five of the patients were male, and the median age was 2 years (range, 1-17 years). PI was located in 1 to 2 abdominal quadrants in 6 patients, and 3 patients had PVG. At diagnosis, all patients were on steroids and immunosuppressant medication and 6 patients had a concurrent infection. Laboratory findings were unremarkable. Symptoms were present in 7 patients. Nine patients were managed conservatively, and 1 patient received observation only. All patients had resolution of PI at a median of 7 days (range, 2-14 days). Conclusions. PI can occur at any time after PLT and appears to be associated with steroid use and infectious agents. If PI/PVG is identified and the patient is clinically stable, initiation of a standard management algorithm may help treat these patients conservatively, thus avoiding surgical intervention.
P
NEUMATOSIS intestinalis (PI), characterized by accumulation of gas in the bowel wall, is a rare radiographic finding most commonly identified in neonatal necrotizing enterocolitis [1]. Outside the neonatal period, the incidence of PI is even less recognized, with a recent review identifying only 13 reported cases in pediatric liver transplant (PLT) recipients [2]. The presentation and course of PI can range from asymptomatic and clinically benign to life-threatening, depending on the underlying etiology [1e3]. Although the exact mechanism has yet to be fully elucidated, PI has been associated with steroids, infectious agents, and mucosal disruption in pediatric patients 0041-1345/20 https://doi.org/10.1016/j.transproceed.2020.01.010
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after solid organ and bone marrow transplantation [3,4]. Moreover, the presence of portal venous gas (PVG) may be the result of either migration of air into the portal system from PI or gas-forming organisms in the setting of sepsis. In light of PI being a rare and poorly understood phenomenon, there is currently no consensus or clinical practice
*Address correspondence to Richard J. Hendrickson, Children’s Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. Tel: þ1 (816) 983-6335 (ext. 56335); Fax: þ1 (816) 983-6885. E-mail: [email protected] ª 2020 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 52, 938e942 (2020)
CONSERVATIVE MANAGEMENT OF PNEUMATOSIS INTESTINALIS AND PORTAL VENOUS GAS
guidelines regarding the appropriate management of PI/ PVG in children [5], including pediatric solid organ transplant recipients [4]. Although prompt surgical intervention is paramount in cases of bowel ischemia or obstruction, conservative treatment strategies such as bowel rest, total parenteral nutrition, and antibiotic therapy have also been described [1e5]. Taking into consideration the clinical signs and symptoms of PI/PVG, along with radiographic workup and laboratory findings, we present the results of conservative management of PI/PVG at our liver transplant center over the past 20 years.
MATERIALS AND METHODS Study Design This single-center retrospective study included PLT recipients followed at a pediatric transplant center between November 1995 and May 2016. The study was approved by the hospital’s institutional review board (No. 15070282), and waivers of informed consent and Health Insurance Portability and Accountability Act authorization were obtained.
Data Collection To identify patients with PI during the study period, a search of electronic medical records for the terms pneumatosis and/or portal venous gas/air was completed for each patient. Radiographic imaging for identified cases was then reviewed by a pediatric radiologist (D.C.R.) to confirm PI and determine its location. The diagnosis was established by abdominal radiography (n ¼ 5), abdominal ultrasound (US; n ¼ 3), or computed tomography (CT; n ¼ 2). The presence of free intraperitoneal air or PVG, intestinal perforation or pneumoperitoneum, and bowel obstruction or ascites was also noted. Other parameters extracted from the electronic medical record included patient sex, primary liver diagnosis, immunosuppressive regimen, steroid therapy, clinical findings, laboratory tests done on the day of diagnosis, and results of stool samples that were collected up to 2 weeks before or after diagnosis. The management of PI, including treatment duration and outcome, were also recorded. Time to resolution was defined as the number of days between initiation of PI treatment and resolution of pneumatosis on followup imaging.
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Statistical Analysis Descriptive statistics were used to summarize all variables, including means and standard deviations for approximately normally distributed variables, median and interquartile ranges for ordinal/continuous data that were not normally distributed, and frequencies and percentages for dichotomous variables.
RESULTS Patient Characteristics
PI developed in 10 of 130 PLT patients (7.7%) between 8 days and 11 years (median ¼ 113 days) posttransplant (Table 1). Five patients were male, and the median age of patients with PI was 2 years (range, 1-17 years). The primary diagnosis and indication for liver transplant was biliary atresia (n ¼ 4), hepatoblastoma (n ¼ 3), congenital hepatic fibrosis (n ¼ 1), alpha-1 antitrypsin deficiency (n ¼ 1), and Wilson’s disease (n ¼ 1). At the time PI was diagnosed, 7 patients (70%) were receiving tacrolimus (TAC) and mycophenolate mofetil, 2 patients (20%) were on TAC alone, and 1 patient (10%) was receiving sirolimus with mycophenolate mofetil. In addition, all 10 patients were receiving corticosteroids (prednisone n ¼ 3, prednisolone n ¼ 7), either perioperatively or for treatment of rejection. Indications for obtaining radiographic examinations (radiography, US, or CT scan) included the following: surveillance imaging (n ¼ 2), abdominal distension (n ¼ 2), abdominal pain (n ¼ 1), possible intussusception (n ¼ 1), possible vascular stricture (n ¼ 1), blood in stool (n ¼ 1), vomiting (n ¼ 1), and constipation (n ¼ 1). Imaging, Clinical, and Laboratory Findings
PI was located in 1 abdominal quadrant in 7 patients (70%), 2 quadrants in 2 patients (20%), and all 4 quadrants in 1 patient (10%; Table 2). The cecum and ascending and transverse colon were most commonly involved. Three patients (30%) had PVG. None of the patients had signs of secondary complications, such as bowel obstruction, perforation, or peritonitis. Of the 10 patients, 3 were asymptomatic and 7 presented with mild to moderate gastrointestinal symptoms, including diarrhea (n ¼ 6),
Table 1. Patient and Clinical Characteristics and Laboratory Findings at the Onset of PI in 10 PLT Recipients Pt
Sex
1 2 3 4 5 6 7 8 9 10
F M F F M M F F M M
Age, y
Liver Diagnosis
2.45 Hepatoblastoma 1.51 Hepatoblastoma 1.47 Biliary atresia 2.29 Biliary atresia 17.59 Wilson’s disease 0.97 Biliary atresia 1.14 Biliary atresia 17.77 CHF 7.09 A1A 1.68 Hepatoblastoma
Months to PI Onset
Immunosuppressive Therapy (Drug Level, ng/mL)
Steroid Dose (mg/kg/d)
Concurrent Infection
1.63 2.80 4.73 10.47 52.23 0.27 0.90 84.47 42.70 2.33
TAC (5.7), MMF (NA)* TAC (8.3), MMF (NA) TAC (11.2), MMF (1.0) TAC (2.3) TAC (8.4), MMF (2.4) TAC (12.5), MMF (NA) TAC (4.6), MMF (NA) TAC (7.9) SRL (44.5), MMF (2.0) TAC (11.2), MMF (NA)
7.5 5 10 20 30 10 10 10 2.5 2.5
ENC, STAHO CD CMV, ADV, RV, NV CD d KP NV d d d
Abbreviations: A1A, alpha-1 antitrypsin deficiency; ADV, adenovirus; CD, clostridium difficile; CHF, congenital hepatic fibrosis; CMV, cytomegalovirus; ENC, Enterobacter cloacae; KP, Klebsiella pneumonia; LT, liver transplantation; MMF, mycophenolate mofetil; NV, norovirus; PI, pneumatosis intestinalis; Pt, patient; RV; rotavirus; SRL, sirolimus; STAHO, Staphylococcus hominis bacteremia; TAC, tacrolimus. * NA (not applicable) indicates the serum drug level was not obtained at the time of PI diagnosis.
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RYAN, DANDRIDGE, ANDREWS ET AL Table 2. Pneumatosis Intestinalis Diagnostic and Treatment Data Treatment Duration, d
Pt
Presenting Symptoms
PI Location
PVG
NPO
TPN
Antibiotics
Days to Resolution
1 2 3 4 5 6 7 8 9 10
Diarrhea, emesis, fever Diarrhea, fever Diarrhea Bloody stool Asymptomatic Asymptomatic Diarrhea Abdominal pain, diarrhea Asymptomatic Diarrhea, emesis
RUQ RLQ, RUQ RUQ RLQ, LLQ RUQ RLQ LLQ RUQ RLQ All quadrants
No No Yes No No Yes No Yes No No
7 5 2 6 2 6 18 25 NA 19
9 NA 5 9 NA 7 22 11 NA 19
Metronidazole, 10 Metronidazole, 14 Metronidazole, 5; cefepime, 7 Metronidazole, 21; cefepime, 7 Metronidazole, 14 Cefepime, 10 Metronidazole, 14; cefepime, 7 Metronidazole, 14; cefepime, 12 NA, observation only Metronidazole, 17; cefepime, 19
7 6 2 9 8 5 7 14 NA 6
Abbreviations: LLQ, left lower quadrant; LUQ, left upper quadrant; NA, not applicable; NPO, nothing by mouth; PI, pneumatosis intestinalis; Pt, patient; PVG, portal venous gas; RLQ, right lower quadrant; RUQ, right upper quadrant; TPN, total parenteral nutrition.
emesis (n ¼ 2), fever (n ¼ 2), abdominal pain (n ¼ 1), and/ or bloody stool (n ¼ 1). More than half of the patients (n ¼ 6) had a concurrent infection at the time PI was identified. Two patients had stool positive for Clostridium difficile; 1 patient had systemic cytomegalovirus, rotavirus, and adenovirus; 2 patients had norovirus; 1 patient was noted to have Staphylococcus hominis and Enterobacter cloacae bloodstream infections; and 1 patient had Klebsiella pneumoniae. For the 9 patients receiving TAC, the mean (standard deviation; SD) trough concentration was 8.00 ng/mL (SD ¼ 3.34) at the time of diagnosis, and no patients were above the target range (3-15 ng/mL). In addition, all 10 patients were receiving steroid therapy at a dose of 2.5 mg/ kg/d (mean ¼ 10.75, SD ¼ 8.42), with 4 of those patients more than 3 months posttransplant and being treated for acute or chronic rejection. Treatment and Outcomes
Nine patients were managed conservatively with broadspectrum antibiotics (median ¼ 13 days; range, 5-19 days), bowel rest (n ¼ 9; median ¼ 6 days; range, 2-25 days), intravenous fluids, and/or total parenteral nutrition (n ¼ 7; median ¼ 8 days; range, 5-22 days; Table 2). In addition, 6 of the 10 patients received a reduced dose of steroid treatment until PI resolved. One patient was monitored clinically without any bowel rest, intravenous fluids, parental nutrition, or antibiotics after a bowel clean out for severe constipation. Nine patients had resolution of PI on serial imaging at a median of 7 days (range, 2-14 days) after diagnosis, and no patient had more than 1 episode of PI. DISCUSSION
Beyond the neonatal period, PI is a rare radiologic finding. Although there have been several case reports of PI developing in pediatric solid organ transplant recipients [2,6e9], to our knowledge, this is the largest case series, consisting of 10 pediatric patients presenting with PI and/or PVG after liver transplantation. The incidence of PI in our cohort was 7%, a finding notably higher than the 1% incidence rate reported in adult liver transplant studies [10,11].
This difference may be due, in part, to differences in radiographic interrogation practices or immunosuppression protocols at our program. It also could be related to anatomic or microbiological differences in pediatric patients compared with adults. Because the true incidence of PI is unknown, reported cases may not accurately reflect actual numbers [4]. Although the exact mechanism causing PI in PLT recipients is unknown, several theories have been proposed, with the mechanical and bacterial theories being the most notable. According to the mechanical theory, injury to the mucosa or its immune barrier may allow gas to enter the bowel wall or mesenteric veins, leading to PI or PVG [7,12]. Increased intraluminal pressure may also permit gas to penetrate an intact mucosa, as in the case of bowel obstruction or severe vomiting or constipation. At the time of PI diagnosis, 5 of the 10 PLT patients in our series were receiving high-dose steroids for the treatment of acute rejection. Consistent with the mechanical theory, steroids may result in atrophy of lymphoid tissue, which can lead to bowel compromise and subsequent intramural gas [7]. However, additional research is needed to understand the association between the intensity and duration of steroid therapy and the risk of developing PI. Concurrent bacterial (C difficile, E cloacae, S hominis, K pneumonia) or viral infections (cytomegalovirus, rotavirus, adenovirus, norovirus) were seen in 6 of our 10 patients, and each has been associated with the development of PI [1,13,14]. Based on the bacterial theory, inflammation caused by the infectious agent can disrupt the structural integrity of the bowel mucosa, allowing intramural gas to invade the bowel wall [14]. That said, the signs and symptoms of PI are diverse and nonspecific. Patients can present with abdominal pain, distention, diarrhea, fever, or other mild gastrointestinal symptoms [2,10,13], as was the case for 7 patients (70%) in our series, whereas the other 3 cases of PI were found incidentally in asymptomatic patients. Similarly, laboratory studies are usually normal in patients with PI. However, laboratory studies that might indicate more severe disease (eg, necessitating surgical intervention) include an elevated
CONSERVATIVE MANAGEMENT OF PNEUMATOSIS INTESTINALIS AND PORTAL VENOUS GAS
white blood cell count, lactic acidosis, and a base deficit [15]. Conditions underlying many severe cases of PI include sepsis, thermal injury, or recent complex surgery [15,16]. The diagnosis of PI is usually made by abdominal radiography in symptomatic patients, as was the case for half of our patients. In 2 asymptomatic patients, PI/PVG was an incidental finding on US and CT obtained for other reasons. Because of their increased sensitivity, US and CT may help in detecting PI/PVG when plain radiography is inconclusive and can also be used to determine the extent of PI and its underlying etiology [17]. A CT scan may be obtained to rule out further pathology, if clinically indicated. However, we do not recommend this type of further imaging in asymptomatic or mildly symptomatic patients and believe that these patients may be monitored with close clinical followup and repeat abdominal radiography. In our series, PVG was identified on US in 2 symptomatic patients, one with bloody diarrhea and diagnosed as having C difficile infection 10 months postoperation and the other with abdominal pain and diarrhea with normal abdominal radiography findings and no infectious diagnosis at 7 years postoperation. In light of the diverse clinical presentation of PI and the severity of outcomes, treatment can vary greatly and should be focused on the underlying cause. One patient in our series was monitored only clinically after imaging demonstrating PI was obtained after a bowel clean out for significant constipation. This patient was asymptomatic, and further workup was not needed. The remaining 9 patients were managed conservatively with a combination of bowel rest, total parenteral nutrition, and broad-spectrum antibiotics (unless a causative agent was identified) to decrease anaerobic bowel flora [18,19]. In addition, immunosuppression was reduced in 6 patients, given its association with PI formation. Once symptoms resolved and there was no evidence of PI/PVG on follow-up imaging, oral intake was slowly advanced and patients were weaned off total parenteral nutrition. Patients generally continued with a 2-week course of antibiotic therapy. Fortunately, no patient deteriorated clinically or had signs of ischemia, peritonitis, or perforation to warrant an operation. Among the patients in whom PI/PVG was identified incidentally, 1 underwent observation only after a bowel clean out, whereas the other 2 patients had reduction in TAC and suspension of mycophenolate mofetil. All 3 of these patients received antibiotics. We believe that most, if not all, patients should receive antibiotics and an individualized reduction in immunosuppression even if laboratory values are normal. The duration of antibiotic therapy and reduction in immunosuppression must take into consideration the patient’s history, physical examination, imaging findings, and laboratory values. There are a few interesting correlations that should be mentioned as well. Three patients had neutropenia at or around the time of the PI/PVG diagnosis. Interestingly, all 3 of these patients had unresectable hepatoblastoma and therefore underwent liver transplantation. Three different patients were on lactulose before transplantation, ranging
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from 1 to 4 months before transplant, with PI/PVG diagnosed 8 days to several months after transplant. Finally, we only identified hypotension in 1 patient who was on dialysis and admitted 2 days before the diagnosis of PI/PVG. PVG is a rare radiologic finding and historically is associated with a high mortality rate [20,21]. However, more recent studies note that venous gas detected early in the course of disease may not be associated with mortality [22,23]. This may be due to the increased use and sensitivity of current imaging technologies. In light of this, we note that Nelson et al [24] developed an algorithm that depends on the patient’s condition to determine whether surgical or conservative intervention is necessary. Evidence of bowel ischemia or necrosis would prompt more aggressive surgical intervention, something that was not noted in our patients. CONCLUSION
The presentation and course of PI/PVG in PLT recipients can range from asymptomatic and clinically benign to life threatening. Identifying patients who require immediate surgical intervention relies on a combination of radiologic, laboratory, and clinical findings. Although our study is limited in that it is retrospective and a single-center study, it consists of a large cohort of patients followed over a 20-year period. As such, we recommend that conservative management be considered in most PLT patients with PI or PVG even when symptomatic, with surgical intervention reserved for those with peritonitis, signs of ischemia, or compatible underlying histories. We believe that most, if not all, patients should receive antibiotics and an individualized reduction in immunosuppression even if laboratory values are normal. The duration of antibiotic therapy and reduction in immunosuppression must take into consideration the patient’s history, physical examination, imaging findings, and laboratory values. REFERENCES [1] Kurbegov AC, Sondheimer JM. Pneumatosis intestinalis in non-neonatal pediatric patients. Pediatrics 2001;108:402e6. [2] Abdel-Aziz O, Elaffandi AH, El Shazly M, Hosny A, ElKaraksy H. Pneumatosis intestinalis following pediatric live-related liver transplant: a case report and successful conservative approach. Pediatr Transplant 2014;18:e18e21. [3] Wu L, Yang Y, Dou Y, Liu Q. A systematic analysis of pneumatosis cystoids intestinalis. World J Gastroenterol 2013;19: 4973e8. [4] Gemma V, Mistrot D, Row D, Gagliano RA, Bremner RM, Walia R, et al. Pneumatosis intestinalis in solid organ transplant recipients. J Thorac Dis 2018;10:1984e97. [5] Nellihela L, Mutalib M, Thompson D, Jochen K, Upadhyaya M. Management of pneumatosis intestinalis in children over the age of 6 months: a conservative approach. Arch Dis Child 2018;103:352e5. [6] Chelimsky G, Blanchard S, Sivit C, Davis I, Czinn S. Pneumatosis intestinalis and diarrhea in a child following renal transplantation. Pediatr Transpl 2003;7:236e9. [7] Fleenor JT, Hoffman TM, Bush DM, Paridon SM, Clark BJ, Spray TL, et al. Pneumatosis intestinalis after pediatric thoracic organ transplantation. Pediatrics 2002;109:E78e82.
942 [8] King S, Shuckett B. Sonographic diagnosis of portal venous gas in two pediatric liver transplant patients with benign pneumatosis intestinalis. Pediatr Radiol 1992;22:577e8. [9] Varma S, Dumitriu D, Stephenne X, Smets F, Clapuyt P, Sokal E. Pneumatosis intestinalis and portal venous gas in pediatric liver transplant recipient. J Pediatr Gastroenterol Nutr 2016;62:e14. [10] Kwon HJ, Kim KW, Song GW. Pneumatosis intestinalis after liver transplantation. Eur J Radiolol 2011;80:629e36. [11] Park CS, Hwang S, Jung DH, Song GW, Moon DB, Ahn CS, et al. Pneumatosis intestinalis after adult living donor liver transplantation: report of three cases and collective literature review. Korean J Hepatobiliary Pancreat Surg 2015;19:25e9. [12] Peter SD, Abbas MA, Kelly KA. The spectrum of pneumatosis intestinalis. Arch Surg 2003;138:68e75. [13] Kim MJ, Kim YJ, Lee JH, Lee JS, Kim JH, Cheon DS, et al. Norovirus: a possible cause of pneumatosis intestinalis. J Pediatr Gastroenterol Nutr 2011;52:314e8. [14] Yale CE, Balish E, Wu JP. The bacterial etiology of pneumatosis cystoides intestinalis. Arch Surg 1974;109:89e94. [15] Huzar TF, Oh J, Renz EM, Wolf SE, King BT, Chung KK, et al. Pneumatosis intestinalis in patients with severe thermal injury. J Burn Care Res 2011;32:e37e44. [16] Shah A, Al Furajii H, Cahill RA. Symptomatic pneumatosis intestinalis (including portal venous gas) after laparoscopic total colectomy. World J Gastrointest Endosc 2014;6:564e7.
RYAN, DANDRIDGE, ANDREWS ET AL [17] Olson DE, Kim YW, Yink J, Donnelly LF. CT predictors for differentiating benign and clinically worrisome pneumatosis intestinalis in children beyond the neonatal period. Radiol 2009;253:513e9. [18] Ellis BW. Symptomatic treatment of primary pneumatosis coli with metronidazole. Br Med J 1980;280:763e4. [19] Choo-Kang LR, Benson J, Fry T, Schwarz KB. Pneumatosis cystoides intestinalis with labial crepitus in an infant with acute lymphoblastic leukemia. J Pediatr Gastroenterol Nutr 1999;28:442e5. [20] Wolfe JN, Evans WA. Gas in the portal veins of the liver in infants: a roentgenographic demonstration with postmortem anatomical correlation. Am J Roentgenol Radium Ther Nucl Med 1955;74:486e8. [21] Liebman PR, Patten MT, Manny J, Benfield JR, Hechtman HB. Hepatic-portal venous gas in adults: etiology, pathophysiology and clinical significance. Ann Surg 1978;187:281e7. [22] Yoo SK, Park JH, Kwon SH. Clinical outcomes in surgical and non-surgical management of hepatic portal venous gas. J Hepatobiliary Pancreat Surg 2015;19:181e7. [23] Faberman RS, Mayo-Smith WW. Outcome of 17 patients with portal venous gas detected by CT. AJR Am J Roentgenol 1997;169:1535e8. [24] Nelson AL, Millington TM, Sahani D, Chung RT, Bauer C, Hertl M, et al. Hepatic portal venous gas: the ABCs of management. Arch Surg 2009;144:575e81.
ABSTRACT Background. Pneumatosis intestinalis (PI) is a rare pathologic finding in pediatric liver transplant (PLT) recipients. The presentation and course of PI can range from asymptomatic and clinically benign to life threatening, with no consensus regarding management of PI in children. We aim to review the clinical presentation and radiologic features of PLT recipients with PI and to report the results of conservative management. Methods. A retrospective medical chart review was conducted on PLT recipients between November 1995 and May 2016. Parameters evaluated at PI diagnosis included pneumatosis location, presence of free air or portal venous gas (PVG), symptoms, laboratory findings, and medication regimen. Results. PI developed in 10 of 130 PLT patients (7.7%) between 8 days and 7 years (median: 113 days) posttransplant. Five of the patients were male, and the median age was 2 years (range, 1-17 years). PI was located in 1 to 2 abdominal quadrants in 6 patients, and 3 patients had PVG. At diagnosis, all patients were on steroids and immunosuppressant medication and 6 patients had a concurrent infection. Laboratory findings were unremarkable. Symptoms were present in 7 patients. Nine patients were managed conservatively, and 1 patient received observation only. All patients had resolution of PI at a median of 7 days (range, 2-14 days). Conclusions. PI can occur at any time after PLT and appears to be associated with steroid use and infectious agents. If PI/PVG is identified and the patient is clinically stable, initiation of a standard management algorithm may help treat these patients conservatively, thus avoiding surgical intervention.
P
NEUMATOSIS intestinalis (PI), characterized by accumulation of gas in the bowel wall, is a rare radiographic finding most commonly identified in neonatal necrotizing enterocolitis [1]. Outside the neonatal period, the incidence of PI is even less recognized, with a recent review identifying only 13 reported cases in pediatric liver transplant (PLT) recipients [2]. The presentation and course of PI can range from asymptomatic and clinically benign to life-threatening, depending on the underlying etiology [1e3]. Although the exact mechanism has yet to be fully elucidated, PI has been associated with steroids, infectious agents, and mucosal disruption in pediatric patients 0041-1345/20 https://doi.org/10.1016/j.transproceed.2020.01.010
938
after solid organ and bone marrow transplantation [3,4]. Moreover, the presence of portal venous gas (PVG) may be the result of either migration of air into the portal system from PI or gas-forming organisms in the setting of sepsis. In light of PI being a rare and poorly understood phenomenon, there is currently no consensus or clinical practice
*Address correspondence to Richard J. Hendrickson, Children’s Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. Tel: þ1 (816) 983-6335 (ext. 56335); Fax: þ1 (816) 983-6885. E-mail: [email protected] ª 2020 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 52, 938e942 (2020)
CONSERVATIVE MANAGEMENT OF PNEUMATOSIS INTESTINALIS AND PORTAL VENOUS GAS
guidelines regarding the appropriate management of PI/ PVG in children [5], including pediatric solid organ transplant recipients [4]. Although prompt surgical intervention is paramount in cases of bowel ischemia or obstruction, conservative treatment strategies such as bowel rest, total parenteral nutrition, and antibiotic therapy have also been described [1e5]. Taking into consideration the clinical signs and symptoms of PI/PVG, along with radiographic workup and laboratory findings, we present the results of conservative management of PI/PVG at our liver transplant center over the past 20 years.
MATERIALS AND METHODS Study Design This single-center retrospective study included PLT recipients followed at a pediatric transplant center between November 1995 and May 2016. The study was approved by the hospital’s institutional review board (No. 15070282), and waivers of informed consent and Health Insurance Portability and Accountability Act authorization were obtained.
Data Collection To identify patients with PI during the study period, a search of electronic medical records for the terms pneumatosis and/or portal venous gas/air was completed for each patient. Radiographic imaging for identified cases was then reviewed by a pediatric radiologist (D.C.R.) to confirm PI and determine its location. The diagnosis was established by abdominal radiography (n ¼ 5), abdominal ultrasound (US; n ¼ 3), or computed tomography (CT; n ¼ 2). The presence of free intraperitoneal air or PVG, intestinal perforation or pneumoperitoneum, and bowel obstruction or ascites was also noted. Other parameters extracted from the electronic medical record included patient sex, primary liver diagnosis, immunosuppressive regimen, steroid therapy, clinical findings, laboratory tests done on the day of diagnosis, and results of stool samples that were collected up to 2 weeks before or after diagnosis. The management of PI, including treatment duration and outcome, were also recorded. Time to resolution was defined as the number of days between initiation of PI treatment and resolution of pneumatosis on followup imaging.
939
Statistical Analysis Descriptive statistics were used to summarize all variables, including means and standard deviations for approximately normally distributed variables, median and interquartile ranges for ordinal/continuous data that were not normally distributed, and frequencies and percentages for dichotomous variables.
RESULTS Patient Characteristics
PI developed in 10 of 130 PLT patients (7.7%) between 8 days and 11 years (median ¼ 113 days) posttransplant (Table 1). Five patients were male, and the median age of patients with PI was 2 years (range, 1-17 years). The primary diagnosis and indication for liver transplant was biliary atresia (n ¼ 4), hepatoblastoma (n ¼ 3), congenital hepatic fibrosis (n ¼ 1), alpha-1 antitrypsin deficiency (n ¼ 1), and Wilson’s disease (n ¼ 1). At the time PI was diagnosed, 7 patients (70%) were receiving tacrolimus (TAC) and mycophenolate mofetil, 2 patients (20%) were on TAC alone, and 1 patient (10%) was receiving sirolimus with mycophenolate mofetil. In addition, all 10 patients were receiving corticosteroids (prednisone n ¼ 3, prednisolone n ¼ 7), either perioperatively or for treatment of rejection. Indications for obtaining radiographic examinations (radiography, US, or CT scan) included the following: surveillance imaging (n ¼ 2), abdominal distension (n ¼ 2), abdominal pain (n ¼ 1), possible intussusception (n ¼ 1), possible vascular stricture (n ¼ 1), blood in stool (n ¼ 1), vomiting (n ¼ 1), and constipation (n ¼ 1). Imaging, Clinical, and Laboratory Findings
PI was located in 1 abdominal quadrant in 7 patients (70%), 2 quadrants in 2 patients (20%), and all 4 quadrants in 1 patient (10%; Table 2). The cecum and ascending and transverse colon were most commonly involved. Three patients (30%) had PVG. None of the patients had signs of secondary complications, such as bowel obstruction, perforation, or peritonitis. Of the 10 patients, 3 were asymptomatic and 7 presented with mild to moderate gastrointestinal symptoms, including diarrhea (n ¼ 6),
Table 1. Patient and Clinical Characteristics and Laboratory Findings at the Onset of PI in 10 PLT Recipients Pt
Sex
1 2 3 4 5 6 7 8 9 10
F M F F M M F F M M
Age, y
Liver Diagnosis
2.45 Hepatoblastoma 1.51 Hepatoblastoma 1.47 Biliary atresia 2.29 Biliary atresia 17.59 Wilson’s disease 0.97 Biliary atresia 1.14 Biliary atresia 17.77 CHF 7.09 A1A 1.68 Hepatoblastoma
Months to PI Onset
Immunosuppressive Therapy (Drug Level, ng/mL)
Steroid Dose (mg/kg/d)
Concurrent Infection
1.63 2.80 4.73 10.47 52.23 0.27 0.90 84.47 42.70 2.33
TAC (5.7), MMF (NA)* TAC (8.3), MMF (NA) TAC (11.2), MMF (1.0) TAC (2.3) TAC (8.4), MMF (2.4) TAC (12.5), MMF (NA) TAC (4.6), MMF (NA) TAC (7.9) SRL (44.5), MMF (2.0) TAC (11.2), MMF (NA)
7.5 5 10 20 30 10 10 10 2.5 2.5
ENC, STAHO CD CMV, ADV, RV, NV CD d KP NV d d d
Abbreviations: A1A, alpha-1 antitrypsin deficiency; ADV, adenovirus; CD, clostridium difficile; CHF, congenital hepatic fibrosis; CMV, cytomegalovirus; ENC, Enterobacter cloacae; KP, Klebsiella pneumonia; LT, liver transplantation; MMF, mycophenolate mofetil; NV, norovirus; PI, pneumatosis intestinalis; Pt, patient; RV; rotavirus; SRL, sirolimus; STAHO, Staphylococcus hominis bacteremia; TAC, tacrolimus. * NA (not applicable) indicates the serum drug level was not obtained at the time of PI diagnosis.
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RYAN, DANDRIDGE, ANDREWS ET AL Table 2. Pneumatosis Intestinalis Diagnostic and Treatment Data Treatment Duration, d
Pt
Presenting Symptoms
PI Location
PVG
NPO
TPN
Antibiotics
Days to Resolution
1 2 3 4 5 6 7 8 9 10
Diarrhea, emesis, fever Diarrhea, fever Diarrhea Bloody stool Asymptomatic Asymptomatic Diarrhea Abdominal pain, diarrhea Asymptomatic Diarrhea, emesis
RUQ RLQ, RUQ RUQ RLQ, LLQ RUQ RLQ LLQ RUQ RLQ All quadrants
No No Yes No No Yes No Yes No No
7 5 2 6 2 6 18 25 NA 19
9 NA 5 9 NA 7 22 11 NA 19
Metronidazole, 10 Metronidazole, 14 Metronidazole, 5; cefepime, 7 Metronidazole, 21; cefepime, 7 Metronidazole, 14 Cefepime, 10 Metronidazole, 14; cefepime, 7 Metronidazole, 14; cefepime, 12 NA, observation only Metronidazole, 17; cefepime, 19
7 6 2 9 8 5 7 14 NA 6
Abbreviations: LLQ, left lower quadrant; LUQ, left upper quadrant; NA, not applicable; NPO, nothing by mouth; PI, pneumatosis intestinalis; Pt, patient; PVG, portal venous gas; RLQ, right lower quadrant; RUQ, right upper quadrant; TPN, total parenteral nutrition.
emesis (n ¼ 2), fever (n ¼ 2), abdominal pain (n ¼ 1), and/ or bloody stool (n ¼ 1). More than half of the patients (n ¼ 6) had a concurrent infection at the time PI was identified. Two patients had stool positive for Clostridium difficile; 1 patient had systemic cytomegalovirus, rotavirus, and adenovirus; 2 patients had norovirus; 1 patient was noted to have Staphylococcus hominis and Enterobacter cloacae bloodstream infections; and 1 patient had Klebsiella pneumoniae. For the 9 patients receiving TAC, the mean (standard deviation; SD) trough concentration was 8.00 ng/mL (SD ¼ 3.34) at the time of diagnosis, and no patients were above the target range (3-15 ng/mL). In addition, all 10 patients were receiving steroid therapy at a dose of 2.5 mg/ kg/d (mean ¼ 10.75, SD ¼ 8.42), with 4 of those patients more than 3 months posttransplant and being treated for acute or chronic rejection. Treatment and Outcomes
Nine patients were managed conservatively with broadspectrum antibiotics (median ¼ 13 days; range, 5-19 days), bowel rest (n ¼ 9; median ¼ 6 days; range, 2-25 days), intravenous fluids, and/or total parenteral nutrition (n ¼ 7; median ¼ 8 days; range, 5-22 days; Table 2). In addition, 6 of the 10 patients received a reduced dose of steroid treatment until PI resolved. One patient was monitored clinically without any bowel rest, intravenous fluids, parental nutrition, or antibiotics after a bowel clean out for severe constipation. Nine patients had resolution of PI on serial imaging at a median of 7 days (range, 2-14 days) after diagnosis, and no patient had more than 1 episode of PI. DISCUSSION
Beyond the neonatal period, PI is a rare radiologic finding. Although there have been several case reports of PI developing in pediatric solid organ transplant recipients [2,6e9], to our knowledge, this is the largest case series, consisting of 10 pediatric patients presenting with PI and/or PVG after liver transplantation. The incidence of PI in our cohort was 7%, a finding notably higher than the 1% incidence rate reported in adult liver transplant studies [10,11].
This difference may be due, in part, to differences in radiographic interrogation practices or immunosuppression protocols at our program. It also could be related to anatomic or microbiological differences in pediatric patients compared with adults. Because the true incidence of PI is unknown, reported cases may not accurately reflect actual numbers [4]. Although the exact mechanism causing PI in PLT recipients is unknown, several theories have been proposed, with the mechanical and bacterial theories being the most notable. According to the mechanical theory, injury to the mucosa or its immune barrier may allow gas to enter the bowel wall or mesenteric veins, leading to PI or PVG [7,12]. Increased intraluminal pressure may also permit gas to penetrate an intact mucosa, as in the case of bowel obstruction or severe vomiting or constipation. At the time of PI diagnosis, 5 of the 10 PLT patients in our series were receiving high-dose steroids for the treatment of acute rejection. Consistent with the mechanical theory, steroids may result in atrophy of lymphoid tissue, which can lead to bowel compromise and subsequent intramural gas [7]. However, additional research is needed to understand the association between the intensity and duration of steroid therapy and the risk of developing PI. Concurrent bacterial (C difficile, E cloacae, S hominis, K pneumonia) or viral infections (cytomegalovirus, rotavirus, adenovirus, norovirus) were seen in 6 of our 10 patients, and each has been associated with the development of PI [1,13,14]. Based on the bacterial theory, inflammation caused by the infectious agent can disrupt the structural integrity of the bowel mucosa, allowing intramural gas to invade the bowel wall [14]. That said, the signs and symptoms of PI are diverse and nonspecific. Patients can present with abdominal pain, distention, diarrhea, fever, or other mild gastrointestinal symptoms [2,10,13], as was the case for 7 patients (70%) in our series, whereas the other 3 cases of PI were found incidentally in asymptomatic patients. Similarly, laboratory studies are usually normal in patients with PI. However, laboratory studies that might indicate more severe disease (eg, necessitating surgical intervention) include an elevated
CONSERVATIVE MANAGEMENT OF PNEUMATOSIS INTESTINALIS AND PORTAL VENOUS GAS
white blood cell count, lactic acidosis, and a base deficit [15]. Conditions underlying many severe cases of PI include sepsis, thermal injury, or recent complex surgery [15,16]. The diagnosis of PI is usually made by abdominal radiography in symptomatic patients, as was the case for half of our patients. In 2 asymptomatic patients, PI/PVG was an incidental finding on US and CT obtained for other reasons. Because of their increased sensitivity, US and CT may help in detecting PI/PVG when plain radiography is inconclusive and can also be used to determine the extent of PI and its underlying etiology [17]. A CT scan may be obtained to rule out further pathology, if clinically indicated. However, we do not recommend this type of further imaging in asymptomatic or mildly symptomatic patients and believe that these patients may be monitored with close clinical followup and repeat abdominal radiography. In our series, PVG was identified on US in 2 symptomatic patients, one with bloody diarrhea and diagnosed as having C difficile infection 10 months postoperation and the other with abdominal pain and diarrhea with normal abdominal radiography findings and no infectious diagnosis at 7 years postoperation. In light of the diverse clinical presentation of PI and the severity of outcomes, treatment can vary greatly and should be focused on the underlying cause. One patient in our series was monitored only clinically after imaging demonstrating PI was obtained after a bowel clean out for significant constipation. This patient was asymptomatic, and further workup was not needed. The remaining 9 patients were managed conservatively with a combination of bowel rest, total parenteral nutrition, and broad-spectrum antibiotics (unless a causative agent was identified) to decrease anaerobic bowel flora [18,19]. In addition, immunosuppression was reduced in 6 patients, given its association with PI formation. Once symptoms resolved and there was no evidence of PI/PVG on follow-up imaging, oral intake was slowly advanced and patients were weaned off total parenteral nutrition. Patients generally continued with a 2-week course of antibiotic therapy. Fortunately, no patient deteriorated clinically or had signs of ischemia, peritonitis, or perforation to warrant an operation. Among the patients in whom PI/PVG was identified incidentally, 1 underwent observation only after a bowel clean out, whereas the other 2 patients had reduction in TAC and suspension of mycophenolate mofetil. All 3 of these patients received antibiotics. We believe that most, if not all, patients should receive antibiotics and an individualized reduction in immunosuppression even if laboratory values are normal. The duration of antibiotic therapy and reduction in immunosuppression must take into consideration the patient’s history, physical examination, imaging findings, and laboratory values. There are a few interesting correlations that should be mentioned as well. Three patients had neutropenia at or around the time of the PI/PVG diagnosis. Interestingly, all 3 of these patients had unresectable hepatoblastoma and therefore underwent liver transplantation. Three different patients were on lactulose before transplantation, ranging
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from 1 to 4 months before transplant, with PI/PVG diagnosed 8 days to several months after transplant. Finally, we only identified hypotension in 1 patient who was on dialysis and admitted 2 days before the diagnosis of PI/PVG. PVG is a rare radiologic finding and historically is associated with a high mortality rate [20,21]. However, more recent studies note that venous gas detected early in the course of disease may not be associated with mortality [22,23]. This may be due to the increased use and sensitivity of current imaging technologies. In light of this, we note that Nelson et al [24] developed an algorithm that depends on the patient’s condition to determine whether surgical or conservative intervention is necessary. Evidence of bowel ischemia or necrosis would prompt more aggressive surgical intervention, something that was not noted in our patients. CONCLUSION
The presentation and course of PI/PVG in PLT recipients can range from asymptomatic and clinically benign to life threatening. Identifying patients who require immediate surgical intervention relies on a combination of radiologic, laboratory, and clinical findings. Although our study is limited in that it is retrospective and a single-center study, it consists of a large cohort of patients followed over a 20-year period. As such, we recommend that conservative management be considered in most PLT patients with PI or PVG even when symptomatic, with surgical intervention reserved for those with peritonitis, signs of ischemia, or compatible underlying histories. We believe that most, if not all, patients should receive antibiotics and an individualized reduction in immunosuppression even if laboratory values are normal. The duration of antibiotic therapy and reduction in immunosuppression must take into consideration the patient’s history, physical examination, imaging findings, and laboratory values. REFERENCES [1] Kurbegov AC, Sondheimer JM. Pneumatosis intestinalis in non-neonatal pediatric patients. Pediatrics 2001;108:402e6. [2] Abdel-Aziz O, Elaffandi AH, El Shazly M, Hosny A, ElKaraksy H. Pneumatosis intestinalis following pediatric live-related liver transplant: a case report and successful conservative approach. Pediatr Transplant 2014;18:e18e21. [3] Wu L, Yang Y, Dou Y, Liu Q. A systematic analysis of pneumatosis cystoids intestinalis. World J Gastroenterol 2013;19: 4973e8. [4] Gemma V, Mistrot D, Row D, Gagliano RA, Bremner RM, Walia R, et al. Pneumatosis intestinalis in solid organ transplant recipients. J Thorac Dis 2018;10:1984e97. [5] Nellihela L, Mutalib M, Thompson D, Jochen K, Upadhyaya M. Management of pneumatosis intestinalis in children over the age of 6 months: a conservative approach. Arch Dis Child 2018;103:352e5. [6] Chelimsky G, Blanchard S, Sivit C, Davis I, Czinn S. Pneumatosis intestinalis and diarrhea in a child following renal transplantation. Pediatr Transpl 2003;7:236e9. [7] Fleenor JT, Hoffman TM, Bush DM, Paridon SM, Clark BJ, Spray TL, et al. Pneumatosis intestinalis after pediatric thoracic organ transplantation. Pediatrics 2002;109:E78e82.
942 [8] King S, Shuckett B. Sonographic diagnosis of portal venous gas in two pediatric liver transplant patients with benign pneumatosis intestinalis. Pediatr Radiol 1992;22:577e8. [9] Varma S, Dumitriu D, Stephenne X, Smets F, Clapuyt P, Sokal E. Pneumatosis intestinalis and portal venous gas in pediatric liver transplant recipient. J Pediatr Gastroenterol Nutr 2016;62:e14. [10] Kwon HJ, Kim KW, Song GW. Pneumatosis intestinalis after liver transplantation. Eur J Radiolol 2011;80:629e36. [11] Park CS, Hwang S, Jung DH, Song GW, Moon DB, Ahn CS, et al. Pneumatosis intestinalis after adult living donor liver transplantation: report of three cases and collective literature review. Korean J Hepatobiliary Pancreat Surg 2015;19:25e9. [12] Peter SD, Abbas MA, Kelly KA. The spectrum of pneumatosis intestinalis. Arch Surg 2003;138:68e75. [13] Kim MJ, Kim YJ, Lee JH, Lee JS, Kim JH, Cheon DS, et al. Norovirus: a possible cause of pneumatosis intestinalis. J Pediatr Gastroenterol Nutr 2011;52:314e8. [14] Yale CE, Balish E, Wu JP. The bacterial etiology of pneumatosis cystoides intestinalis. Arch Surg 1974;109:89e94. [15] Huzar TF, Oh J, Renz EM, Wolf SE, King BT, Chung KK, et al. Pneumatosis intestinalis in patients with severe thermal injury. J Burn Care Res 2011;32:e37e44. [16] Shah A, Al Furajii H, Cahill RA. Symptomatic pneumatosis intestinalis (including portal venous gas) after laparoscopic total colectomy. World J Gastrointest Endosc 2014;6:564e7.
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