Indian J Gastroenterol DOI 10.1007/s12664-013-0437-8
REVIEW ARTICLE
India’s first successful intestinal transplant: The road traveled and the lessons learnt A. S. Soin & R. Mohanka & N. Saraf & A. Rastogi & S. Goja & B. Menon & V. Vohra & S. Saigal & R. Sud & D. Kumar & P. Bhangui & S. Ramachandra & P. Singla & G. Shetty & K. Raghvendra & Kareem M. Abu Elmagd
Received: 11 October 2013 / Accepted: 14 December 2013 # Indian Society of Gastroenterology 2014
R. Sud Medanta Institute of Hepato-biliary Diseases and Digestive Disorders, Medanta-The Medicity, Sector 38, Gurgaon, Haryana 122 001, India
he was on parenteral nutrition (PN) through chemoport. Over the next 2 years, he had seven episodes of line sepsis, two of which were potentially life threatening. Over 4 years, he lost 36 kg, had poor quality of life, loss of self-esteem, and developed suicidal tendencies. He was evaluated (Table 1) and found suitable for an isolated intestinal transplant. The donor was a 21-year-old man who had head injury in a road accident in the same city. He was hemodynamically stable with normal hematology, serology, and biochemistry except raised sodium of 162 mmol/L. The small intestinal graft was accepted after confirmation of negative T and B cell lymphocytic crossmatch and correction of sodium and retrieved in the standard fashion. In the recipient, adhesiolysis was performed; the distal ileal remnant and the proximal half of the colon were resected. Under thymoglobulin (ATG) induction, intestinal graft was implanted with inflow from infra-renal aorta and outflow into portal vein using vascular conduits, resulting in uniform reperfusion. Bowel continuity was established by jejunojejunal and ileocolic two-layer anastomoses, leaving a 20-cm “chimney ileostomy”. He was given enteral feeds at 2 weeks and oral diet at 3 weeks after transplant when PN was stopped. He had two episodes of rejection in the first 6 weeks, which responded to ATG and steroids, respectively. After discharge, he developed chylous ascites, and required three re-admissions for intercurrent problems, all of which settled on conservative management. He is well 10 months after the transplant.
D. Kumar Department of Pathology, Medanta-The Medicity, Sector 38, Gurgaon, Haryana 122 001, India
Conclusions
K. M. A. Elmagd Division of Transplantation, Department of Surgery, Cleveland Clinic, Cleveland, OH, USA
This is the first reported case of successful intestinal transplantation from India. Dedicated teams to manage long-term PN,
Abstract Intestinal transplant is a therapeutic challenge not just surgically but also logistically because of the multidisciplinary expertise and resources required. A large proportion of patients who undergo massive bowel resection and develop intestinal failure have poor outcome, because of inability to sustain long-term parenteral nutrition and limited availability of intestinal and multi-visceral transplantation facilities. We report the first successful isolated intestinal transplant from India. Keywords Isolated intestinal transplant . Line infection . Long-term parenteral nutrition . Short gut syndrome
Case A 27-year-old software engineer underwent massive bowel resection of the entire intestine except about 30 cm of small bowel due to mesenteric vein thrombosis 4 years ago. After resection, A. S. Soin (*) : R. Mohanka : N. Saraf : A. Rastogi : S. Goja : B. Menon : V. Vohra : S. Saigal : P. Bhangui : S. Ramachandra : P. Singla : G. Shetty : K. Raghvendra Medanta Institute of Liver Diseases and Transplantation, Medanta-The Medicity, Sector 38, Gurgaon, Haryana 122 001, India e-mail: [email protected]
Bowel anatomical and functional assessment Motility studies (gastric emptying and colonic transit) using nuclear medicine studies Barium/gastrograffin swallow, meal, and enema Endoscopy (upper GI endoscopy and colonoscopy) Manometry (esophageal, antroduodenal, and rectal) Intestinal biopsy
Vascular mapping Systemic veins (IJV, subclavian, and femoral) using Doppler or venogram USG abdomen and pelvis with mesenteric Doppler Triphasic CT abdomen angiogram for mesenteric veins (PV, SMV, SV, and SMA)
Pulmonary assessment Chest X-ray function test Arterial blood gases (pH, pO2, pCO2, HCO3, BE, and lactate)
Cardiac assessment ECG ECHO cardiogram Dobutamine stress ECHO Contrast (bubble) ECHO Micro-aggregated albumin scan Stress thallium CT coronary angiogram Coronary angiogram
Evaluation is done in a phased manner where the more invasive and expensive tests are reserved for later phases. This is a comprehensive list of evaluation tests that may be required. In a particular patient, not all tests will be required
Pancreatitis profile and fat malabsorption studies Amylase Lipase Serum citrullin D Xylose Fecal fat
Virology/serology Hematology/iron studies Renal profile Endocrine/metabolic profile Urea nitrogen Hepatitis A Ab (total) ABO with Rh typing Blood sugar—fasting/postCreatinine Hepatitis B profile (HBsAg, HBsAb titre, CBC with total and prandial Sodium (Na) HBcAb (total), HBeAb, HBeAg, and HBV differential leukocyte HbA1C Potassium DNA PCR) counts C peptide Calcium Hepatitis C profile (HCV Ab and HCV RNA T lymphocyte panel Insulin level Phosphate PCR) Platelet count Thyroid profile (total T3/free T3, Magnesium Hepatitis D Prothrombin time (PT; total T4/free T4, and TSH) 24-h urine (volume, creatinine, urea nitrogen, VDRL INR) Ceruloplasmin creatinine clearance, Na (mmol/ day) and protein HIV I and II Activated partial Parathyroid hormone (g/day)) Cytomegalovirus (IgM/IgG) thromboplastin time Estrogen level (females) DTPA scan Epstein–Barr virus (IgM/IgG) Fibrin degradation Testosterone level (males) Varicella Zoster Virus (IgM/IgG) products Lipid profile (total cholesterol, Hepatic profile Herpes Zoster (IgM/IgG) Fibrinogen HDL, LDL, VLDL, and Bilirubin (total/direct/indirect) Iron triglycerides) AST/SGOT Total iron binding Hemochromatosis genetic testing Infection screen ALT/SGPT Urine (R/M (Sp. gravity, cells (RBC/WBC), capacity Total protein and bacteria/pus), culture, and sensitivity) Ferritin Vitamin and trace elements Albumin Ascitic fluid (total and differential cell count, Transferrin Vitamin A Pre-albumin culture, and sensitivity) Vitamin B1 Vitamin B2 Alkaline phosphatase Blood culture and sensitivity Hypercoagulable workup Vitamin B6 Gammaglutamyl (GGTP) Stool microscopy for ova and cysts Antithrombin-III Vitamin B12 Arterial ammonia Cryptococcal antigen Protein C Vitamin C Liver biopsy Stool culture and sensitivity Protein S 25 hydroxy vitamin D Central line culture and sensitivity (one from Homocysteine Vitamin E Immunological profile each line) Factor V leiden Folic acid HLA DR A/B/DR typing Sputum for culture and sensitivity Lupus anticoagulant Copper Quick PRA Sputum for Aspergillus Anticardiolipid Selenium Tissue typing and T and B cell cross match antibody Zinc Immunoglobulin profile (IgG (total), IgA (total), Tumor screen Prothrombin mutation Chromium and IgM (total)) Αlpha fetoprotein dAPC resistance Manganese Anti-nuclear antibody Carcinoembryonic antigen Total homocysteine Carnitine (total, free, and esters) Anti-microsomal antibody CA 19.9 MTHFR C667T Anti-smooth muscle antibody Prostate-specific antigen gene variant Liver–kidney microsomal antibody Mammogram Jack 2 mutation Anti-thyroid globulin Pap smear Factor X APCR-V ratio
Table 1 Small intestine evaluation protocol
Indian J Gastroenterol
Indian J Gastroenterol
with expertise in intestinal transplantation, standardization of perioperative management protocols, and sensitization of surgeons performing massive resection about intestinal transplant, and of organ retrieval centers about suitable intestine donors are essential for future success in this field.
Introduction Long-term parenteral nutrition (PN) and intestinal transplant (ITx) are the cornerstones of management of intestinal failure. The latter develops when inadequate physical or functional length of small bowel fails to adapt enough to maintain electrolyte, nutrient, and fluid balance without PN. Intestinal failure in adults usually results from short gut syndrome because of repeated/massive resections in Crohn’s disease, superior mesenteric artery, or venous thrombosis or trauma, whereas in children, intestinal atresia, gastroschisis, Crohn’s disease, or microvillus involution disease [1] are the main causes. Short bowel syndrome may manifest as massive diarrhea, high stoma output, electrolyte abnormalities, fat and vitamin B 12 malabsorption, gastric hypersecretion, hyperbilirubinemia, or hepatic steatosis [2]. Altough PN has been the first line of therapy for such patients, it is expensive, cumbersome, and commonly associated with potentially life-threatening complications, such as catheter-related sepsis and/or venous thrombosis, stenosis or occlusion, metabolic derangements, and liver dysfunction, especially in the long-term. The intestine is capable of significant adaptation as a result of villous hypertrophy leading to increased absorptive surface. This may lead to a complete or partial independence from PN in patients with more than 50 cm of small bowel, especially those with a preserved ileocecal valve [3, 4]. In those who fail to adapt and cannot maintain on PN, ITx is the next logical step. Although the results of ITx have recently improved, the requisite expertise and experience in the complex perioperative management of these chronically sick and malnourished patients remains restricted to only a few centers worldwide. We hereby report India’s first successful deceased donor isolated intestinal transplant.
Case report A 27-year-old previously healthy male, a software engineer by profession, presented in December 2009 with continuous, nonradiating, severe, central abdominal pain, tachycardia, generalized abdominal tenderness, absent bowel sounds, progressive abdominal distension, and leukocytosis. A CT scan of the abdomen revealed a distended small and large intestine and pneumatosis intestinalis. Laparotomy revealed extensive small intestine gangrene due to superior mesenteric vein
thrombosis for which he underwent resection of the entire small intestine except the first 12 cm of jejunum and last 16 cm of terminal ileum, with primary jejuno-ileal anastomosis. He recovered well and was discharged on peripheral PN and limited oral liquids. He did not thrive well with peripheral PN, lost 36 kg (74 kg to 38 kg), and stopped going to work. A chemoport was inserted and central PN was given, with which he gained about 5 kg, but soon he had three episodes of central line-related sepsis necessitating chemoport removal. He came to us a year after his initial bowel resection, with history of line sepsis, poor tolerance to oral diet, and significant weight loss. He was counseled, evaluated and listed for an isolated small bowel transplant. A fresh chemoport was dedicated for PN and the peripherally inserted central catheter (PICC) line was used for blood sampling and medications. He developed familial intentional ataxia, which resolved with trace element supplementation. Over the next 3 years, he had several periods of absence (total, 20 months) from work due to PN, which improved with institution of weekend PN. He was hospitalized 11 times, had a poor social life, and developed feelings of low self-esteem and suicidal tendencies for which he needed professional help. He also had four further episodes of line sepsis, with the last one being 4 months before the transplant, requiring chemoport removal. His home PN regimen consisted of 4–5 L/week of Kabiven® (each liter containing 900 kcal, 100 kcal protein, 800 kcal nonprotein calories, 100 g carbohydrates, and 40 g 20 % fat; Fresenius Kabi AG, Hamburg, Germany) which he took from Friday to Sunday nights. Additionally, he needed 500 to 1,500 mL intravenous (IV) fluid every day to achieve normal hydration. He also received calcium, magnesium, vitamins D3, E, B complex, and B12, folic acid daily, and Inj Celecel® (trace elements include: chromium chloride, copper, manganese, zinc, and selenium; Claris Lifesciences Limited, Ahmadabad, India) twice a week. He was monitored with complete blood count, liver and kidney function tests, and cultures at clinic visits every 15 days.
The operation The operative and postoperative protocols were adapted from those successfully used by the last author (AK) for over 500 cases of bowel transplant at UPMC [5]. The donor was a blood group-matched 21-year-old, 70-kg, lean man who had head injury in a road traffic accident at another hospital in the city. He had been in the ICU for 80 hours, and there was no history of cardiac respiratory arrest. His hematological, liver and kidney function tests were normal and hepatitis and HIV serology were negative. His peak serum sodium was 162 mmol/L 8 hours prior to organ retrieval, which was brought down to 152 at the time of retrieval. The T and B cell flow-cytometry lymphocytic crossmatch were negative.
Indian J Gastroenterol Fig. 1 Operative pictures. a Packing of intestinal graft. b Graft inflow-arterial conduit. c Graft outflow-venous conduit. d Graft reperfusion. e Diagrammatic representation of the intestinal graft after implantation showing vascular inflow, outflow, proximal, and distal bowel anastomoses and chimney ileostomy
a
c
b d
e
SMV outflow into the portal vein
Jejunojenunal anastomosis
Chimney ileostomy
SMA inflow from Aorta
ileo-transverse colic anastomosis
Prior to organ recovery, the donor was given IV meropenem, fluconazole, teicoplanin, metronidazole, and bowel decontamination with colistimethate, amphotericin, and tobramycin via a nasogastric tube. The graft was perfused with 8 L of UW (University of Wisconsin, Belzer UW®, Bridge to Life Ltd, Columbia, SC, USA) solution through the aorta. The entire
small bowel from proximal jejunum to distal ileum was retrieved based on the superior mesenteric vein (SMV), up to just beyond the SMV-splenic vein junction and superior mesenteric artery (SMA). The ends of the bowel graft were stapled (Proximate GIA TLC 75 Ethicon Endosurgery LLC, Somerville, NJ, USA). The graft was “triple bagged”
Indian J Gastroenterol Table 2 Postoperative monitoring protocol after intestinal transplant
Disposition Nutrition Routine tests CBC LFT RFT Amylase, lipase Arterial blood gases Infection surveillance Chest X-ray Urine C/S Blood C/S Endotracheal secretion/sputum C/S C-reactive protein and procalcitonin Rejection monitoring Tacrolimus level CD3 count Ileoscopy and biopsy
POD 1–5
POD 6–14
POD 15–21
POD 22–24
POD 25–29
POD 30–discharge
ICU PN
Ward PN/NJ feeds
PN/NJ/oral
NJ feeds/oral diet
Oral diet
BD BD BD BD BD
OD OD OD OD As required
OD Twice a week OD Twice a week As required
OD Twice a week OD Once a week As required
Twice a week Once a week Twice a week As required As required
Twice a week Once a week Twice a week As required As required
BD OD OD OD OD
OD Twice a week Twice a week Twice a week Twice a week
Twice a week Once a week Once a week Once a week Once a week
Twice a week Once a week Once a week Once a week Once a week
Once a week Once a week Once a week Once a week Once a week
As required As required As required As required As required
OD OD
OD OD
Twice a week Twice a week
Twice a week Once a week
Twice a week Once a week
Once a week Once a week
Thrice a week
Twice a week
Once a week
Once a week
Once a week
OD once a day, BD twice a day, POD postoperative day, ICU intensive care unit, PN parenteral nutrition, NJ nasojejunal, LFT liver function test, RFT renal function test, ABG arterial blood gases
and transported in cold UW solution at 4 deg C (Fig. 1a). Meanwhile, upon inspection and approval of the graft quality by the donor surgeon, recipient surgery was begun. Dense adhesions in the abdominal cavity were lysed. The remnant small bowel and proximal half of colon were mobilized off the retroperitoneum, inferior vena cava (IVC) and aorta, and resected to make space for the intestinal graft. The infra-renal aorta was exposed 5 cm below the origin of the right renal artery and a 5-cm long and 8-mm wide donor iliac artery conduit was anastomosed end-to-side to it (Fig. 1b). Since the SMV was thrombosed, portal vein (PV) was exposed in the hepato-duodenal ligament and a 6-cm long and 1.5 cm wide venous conduit (cryopreserved external iliac vein) was anastomosed end-to-side to it. Immunosuppression induction was done with anti-thymocyte globulin (ATG) 5 mg/kg and methylprednisolone (MP) 15 mg/kg intravenously. The intestinal graft was orientated appropriately, and implanted by anastomosing the graft SMA to the aortic conduit and the graft portal vein to the recipient PV conduit (Fig. 1c). The cold and warm ischemia times were 256 and 28 minutes, respectively. On reperfusion, the graft ‘pinked up’ immediately (Fig. 1d). Both ends of graft bowel were oversewn using interrupted silk sutures. Proximal bowel continuity was established by a graft-recipient side-to-side, double-layered jejunojejunostomy (inner continuous PDS and outer interrupted silk sutures). Distally, a side-to-side, double-layered ileo-
transverse colic anastomosis (inner continuous PDS and outer interrupted silk sutures) was done leaving 20 cm of the graft distal ileum, which was fashioned into a ‘chimney ileostomy’ (Fig. 1e). A nasojejunal (NJ) tube (Freka® Trelumina, Fresenius Kabi AG, Hamburg, Germany) was kept beyond the proximal bowel anastomosis.
Postoperative course Postoperatively, the patient was managed in an isolation room in the intensive care unit (ICU) for 6 days following which he was shifted to the ward. Both the ICU and ward rooms were positive pressure isolation rooms equipped with high efficiency particulate air filter and UV radiation. His monitoring protocol is outlined in Table 2. He was extubated 14 hours after the surgery and administered IV antibacterials, antifungals, antivirals and NJ gut decontamination. He was ambulated on postoperative day (POD) 4. PN (Kabiven) was given at 85 mL/hours in addition to calcium, magnesium, phosphate and trace element supplementation. NJ feeding was started on POD 15 and slowly increased over 10 days. PN was commensurately reduced from POD 15 and was stopped by POD 25. Oral feeding was started with liquids, followed by semi-solids and then normal diet from POD 22 onwards. By POD 30, he was completely on oral diet, with occasional need to supplement fluid intake of 500–1,000 mL every day.
Indian J Gastroenterol
Fig. 2 Histological findings: a POD 14 graft biopsy (10×10 magnification) showing moderate acute cellular rejection. Goblet cell apoptosis (black arrow) 8–10/10 crypts. Lamina propria infiltrated by mixed inflammatory infiltrate is composed of lymphocytes, plasma cells, and eosinophils (white arrow). b Pattern of CD3 counts over postoperative
course. c POD 24 graft biopsy (40×10 magnification) showing mild acute cellular rejection with goblet cell apoptosis (black arrows) 6/10 crypts. d Normal ileal mucosa after intestinal transplant—(10×10 magnification) normal crypt villous ratio, no denudation or ulceration. Apoptotic bodies,
REVIEW ARTICLE
India’s first successful intestinal transplant: The road traveled and the lessons learnt A. S. Soin & R. Mohanka & N. Saraf & A. Rastogi & S. Goja & B. Menon & V. Vohra & S. Saigal & R. Sud & D. Kumar & P. Bhangui & S. Ramachandra & P. Singla & G. Shetty & K. Raghvendra & Kareem M. Abu Elmagd
Received: 11 October 2013 / Accepted: 14 December 2013 # Indian Society of Gastroenterology 2014
R. Sud Medanta Institute of Hepato-biliary Diseases and Digestive Disorders, Medanta-The Medicity, Sector 38, Gurgaon, Haryana 122 001, India
he was on parenteral nutrition (PN) through chemoport. Over the next 2 years, he had seven episodes of line sepsis, two of which were potentially life threatening. Over 4 years, he lost 36 kg, had poor quality of life, loss of self-esteem, and developed suicidal tendencies. He was evaluated (Table 1) and found suitable for an isolated intestinal transplant. The donor was a 21-year-old man who had head injury in a road accident in the same city. He was hemodynamically stable with normal hematology, serology, and biochemistry except raised sodium of 162 mmol/L. The small intestinal graft was accepted after confirmation of negative T and B cell lymphocytic crossmatch and correction of sodium and retrieved in the standard fashion. In the recipient, adhesiolysis was performed; the distal ileal remnant and the proximal half of the colon were resected. Under thymoglobulin (ATG) induction, intestinal graft was implanted with inflow from infra-renal aorta and outflow into portal vein using vascular conduits, resulting in uniform reperfusion. Bowel continuity was established by jejunojejunal and ileocolic two-layer anastomoses, leaving a 20-cm “chimney ileostomy”. He was given enteral feeds at 2 weeks and oral diet at 3 weeks after transplant when PN was stopped. He had two episodes of rejection in the first 6 weeks, which responded to ATG and steroids, respectively. After discharge, he developed chylous ascites, and required three re-admissions for intercurrent problems, all of which settled on conservative management. He is well 10 months after the transplant.
D. Kumar Department of Pathology, Medanta-The Medicity, Sector 38, Gurgaon, Haryana 122 001, India
Conclusions
K. M. A. Elmagd Division of Transplantation, Department of Surgery, Cleveland Clinic, Cleveland, OH, USA
This is the first reported case of successful intestinal transplantation from India. Dedicated teams to manage long-term PN,
Abstract Intestinal transplant is a therapeutic challenge not just surgically but also logistically because of the multidisciplinary expertise and resources required. A large proportion of patients who undergo massive bowel resection and develop intestinal failure have poor outcome, because of inability to sustain long-term parenteral nutrition and limited availability of intestinal and multi-visceral transplantation facilities. We report the first successful isolated intestinal transplant from India. Keywords Isolated intestinal transplant . Line infection . Long-term parenteral nutrition . Short gut syndrome
Case A 27-year-old software engineer underwent massive bowel resection of the entire intestine except about 30 cm of small bowel due to mesenteric vein thrombosis 4 years ago. After resection, A. S. Soin (*) : R. Mohanka : N. Saraf : A. Rastogi : S. Goja : B. Menon : V. Vohra : S. Saigal : P. Bhangui : S. Ramachandra : P. Singla : G. Shetty : K. Raghvendra Medanta Institute of Liver Diseases and Transplantation, Medanta-The Medicity, Sector 38, Gurgaon, Haryana 122 001, India e-mail: [email protected]
Bowel anatomical and functional assessment Motility studies (gastric emptying and colonic transit) using nuclear medicine studies Barium/gastrograffin swallow, meal, and enema Endoscopy (upper GI endoscopy and colonoscopy) Manometry (esophageal, antroduodenal, and rectal) Intestinal biopsy
Vascular mapping Systemic veins (IJV, subclavian, and femoral) using Doppler or venogram USG abdomen and pelvis with mesenteric Doppler Triphasic CT abdomen angiogram for mesenteric veins (PV, SMV, SV, and SMA)
Pulmonary assessment Chest X-ray function test Arterial blood gases (pH, pO2, pCO2, HCO3, BE, and lactate)
Cardiac assessment ECG ECHO cardiogram Dobutamine stress ECHO Contrast (bubble) ECHO Micro-aggregated albumin scan Stress thallium CT coronary angiogram Coronary angiogram
Evaluation is done in a phased manner where the more invasive and expensive tests are reserved for later phases. This is a comprehensive list of evaluation tests that may be required. In a particular patient, not all tests will be required
Pancreatitis profile and fat malabsorption studies Amylase Lipase Serum citrullin D Xylose Fecal fat
Virology/serology Hematology/iron studies Renal profile Endocrine/metabolic profile Urea nitrogen Hepatitis A Ab (total) ABO with Rh typing Blood sugar—fasting/postCreatinine Hepatitis B profile (HBsAg, HBsAb titre, CBC with total and prandial Sodium (Na) HBcAb (total), HBeAb, HBeAg, and HBV differential leukocyte HbA1C Potassium DNA PCR) counts C peptide Calcium Hepatitis C profile (HCV Ab and HCV RNA T lymphocyte panel Insulin level Phosphate PCR) Platelet count Thyroid profile (total T3/free T3, Magnesium Hepatitis D Prothrombin time (PT; total T4/free T4, and TSH) 24-h urine (volume, creatinine, urea nitrogen, VDRL INR) Ceruloplasmin creatinine clearance, Na (mmol/ day) and protein HIV I and II Activated partial Parathyroid hormone (g/day)) Cytomegalovirus (IgM/IgG) thromboplastin time Estrogen level (females) DTPA scan Epstein–Barr virus (IgM/IgG) Fibrin degradation Testosterone level (males) Varicella Zoster Virus (IgM/IgG) products Lipid profile (total cholesterol, Hepatic profile Herpes Zoster (IgM/IgG) Fibrinogen HDL, LDL, VLDL, and Bilirubin (total/direct/indirect) Iron triglycerides) AST/SGOT Total iron binding Hemochromatosis genetic testing Infection screen ALT/SGPT Urine (R/M (Sp. gravity, cells (RBC/WBC), capacity Total protein and bacteria/pus), culture, and sensitivity) Ferritin Vitamin and trace elements Albumin Ascitic fluid (total and differential cell count, Transferrin Vitamin A Pre-albumin culture, and sensitivity) Vitamin B1 Vitamin B2 Alkaline phosphatase Blood culture and sensitivity Hypercoagulable workup Vitamin B6 Gammaglutamyl (GGTP) Stool microscopy for ova and cysts Antithrombin-III Vitamin B12 Arterial ammonia Cryptococcal antigen Protein C Vitamin C Liver biopsy Stool culture and sensitivity Protein S 25 hydroxy vitamin D Central line culture and sensitivity (one from Homocysteine Vitamin E Immunological profile each line) Factor V leiden Folic acid HLA DR A/B/DR typing Sputum for culture and sensitivity Lupus anticoagulant Copper Quick PRA Sputum for Aspergillus Anticardiolipid Selenium Tissue typing and T and B cell cross match antibody Zinc Immunoglobulin profile (IgG (total), IgA (total), Tumor screen Prothrombin mutation Chromium and IgM (total)) Αlpha fetoprotein dAPC resistance Manganese Anti-nuclear antibody Carcinoembryonic antigen Total homocysteine Carnitine (total, free, and esters) Anti-microsomal antibody CA 19.9 MTHFR C667T Anti-smooth muscle antibody Prostate-specific antigen gene variant Liver–kidney microsomal antibody Mammogram Jack 2 mutation Anti-thyroid globulin Pap smear Factor X APCR-V ratio
Table 1 Small intestine evaluation protocol
Indian J Gastroenterol
Indian J Gastroenterol
with expertise in intestinal transplantation, standardization of perioperative management protocols, and sensitization of surgeons performing massive resection about intestinal transplant, and of organ retrieval centers about suitable intestine donors are essential for future success in this field.
Introduction Long-term parenteral nutrition (PN) and intestinal transplant (ITx) are the cornerstones of management of intestinal failure. The latter develops when inadequate physical or functional length of small bowel fails to adapt enough to maintain electrolyte, nutrient, and fluid balance without PN. Intestinal failure in adults usually results from short gut syndrome because of repeated/massive resections in Crohn’s disease, superior mesenteric artery, or venous thrombosis or trauma, whereas in children, intestinal atresia, gastroschisis, Crohn’s disease, or microvillus involution disease [1] are the main causes. Short bowel syndrome may manifest as massive diarrhea, high stoma output, electrolyte abnormalities, fat and vitamin B 12 malabsorption, gastric hypersecretion, hyperbilirubinemia, or hepatic steatosis [2]. Altough PN has been the first line of therapy for such patients, it is expensive, cumbersome, and commonly associated with potentially life-threatening complications, such as catheter-related sepsis and/or venous thrombosis, stenosis or occlusion, metabolic derangements, and liver dysfunction, especially in the long-term. The intestine is capable of significant adaptation as a result of villous hypertrophy leading to increased absorptive surface. This may lead to a complete or partial independence from PN in patients with more than 50 cm of small bowel, especially those with a preserved ileocecal valve [3, 4]. In those who fail to adapt and cannot maintain on PN, ITx is the next logical step. Although the results of ITx have recently improved, the requisite expertise and experience in the complex perioperative management of these chronically sick and malnourished patients remains restricted to only a few centers worldwide. We hereby report India’s first successful deceased donor isolated intestinal transplant.
Case report A 27-year-old previously healthy male, a software engineer by profession, presented in December 2009 with continuous, nonradiating, severe, central abdominal pain, tachycardia, generalized abdominal tenderness, absent bowel sounds, progressive abdominal distension, and leukocytosis. A CT scan of the abdomen revealed a distended small and large intestine and pneumatosis intestinalis. Laparotomy revealed extensive small intestine gangrene due to superior mesenteric vein
thrombosis for which he underwent resection of the entire small intestine except the first 12 cm of jejunum and last 16 cm of terminal ileum, with primary jejuno-ileal anastomosis. He recovered well and was discharged on peripheral PN and limited oral liquids. He did not thrive well with peripheral PN, lost 36 kg (74 kg to 38 kg), and stopped going to work. A chemoport was inserted and central PN was given, with which he gained about 5 kg, but soon he had three episodes of central line-related sepsis necessitating chemoport removal. He came to us a year after his initial bowel resection, with history of line sepsis, poor tolerance to oral diet, and significant weight loss. He was counseled, evaluated and listed for an isolated small bowel transplant. A fresh chemoport was dedicated for PN and the peripherally inserted central catheter (PICC) line was used for blood sampling and medications. He developed familial intentional ataxia, which resolved with trace element supplementation. Over the next 3 years, he had several periods of absence (total, 20 months) from work due to PN, which improved with institution of weekend PN. He was hospitalized 11 times, had a poor social life, and developed feelings of low self-esteem and suicidal tendencies for which he needed professional help. He also had four further episodes of line sepsis, with the last one being 4 months before the transplant, requiring chemoport removal. His home PN regimen consisted of 4–5 L/week of Kabiven® (each liter containing 900 kcal, 100 kcal protein, 800 kcal nonprotein calories, 100 g carbohydrates, and 40 g 20 % fat; Fresenius Kabi AG, Hamburg, Germany) which he took from Friday to Sunday nights. Additionally, he needed 500 to 1,500 mL intravenous (IV) fluid every day to achieve normal hydration. He also received calcium, magnesium, vitamins D3, E, B complex, and B12, folic acid daily, and Inj Celecel® (trace elements include: chromium chloride, copper, manganese, zinc, and selenium; Claris Lifesciences Limited, Ahmadabad, India) twice a week. He was monitored with complete blood count, liver and kidney function tests, and cultures at clinic visits every 15 days.
The operation The operative and postoperative protocols were adapted from those successfully used by the last author (AK) for over 500 cases of bowel transplant at UPMC [5]. The donor was a blood group-matched 21-year-old, 70-kg, lean man who had head injury in a road traffic accident at another hospital in the city. He had been in the ICU for 80 hours, and there was no history of cardiac respiratory arrest. His hematological, liver and kidney function tests were normal and hepatitis and HIV serology were negative. His peak serum sodium was 162 mmol/L 8 hours prior to organ retrieval, which was brought down to 152 at the time of retrieval. The T and B cell flow-cytometry lymphocytic crossmatch were negative.
Indian J Gastroenterol Fig. 1 Operative pictures. a Packing of intestinal graft. b Graft inflow-arterial conduit. c Graft outflow-venous conduit. d Graft reperfusion. e Diagrammatic representation of the intestinal graft after implantation showing vascular inflow, outflow, proximal, and distal bowel anastomoses and chimney ileostomy
a
c
b d
e
SMV outflow into the portal vein
Jejunojenunal anastomosis
Chimney ileostomy
SMA inflow from Aorta
ileo-transverse colic anastomosis
Prior to organ recovery, the donor was given IV meropenem, fluconazole, teicoplanin, metronidazole, and bowel decontamination with colistimethate, amphotericin, and tobramycin via a nasogastric tube. The graft was perfused with 8 L of UW (University of Wisconsin, Belzer UW®, Bridge to Life Ltd, Columbia, SC, USA) solution through the aorta. The entire
small bowel from proximal jejunum to distal ileum was retrieved based on the superior mesenteric vein (SMV), up to just beyond the SMV-splenic vein junction and superior mesenteric artery (SMA). The ends of the bowel graft were stapled (Proximate GIA TLC 75 Ethicon Endosurgery LLC, Somerville, NJ, USA). The graft was “triple bagged”
Indian J Gastroenterol Table 2 Postoperative monitoring protocol after intestinal transplant
Disposition Nutrition Routine tests CBC LFT RFT Amylase, lipase Arterial blood gases Infection surveillance Chest X-ray Urine C/S Blood C/S Endotracheal secretion/sputum C/S C-reactive protein and procalcitonin Rejection monitoring Tacrolimus level CD3 count Ileoscopy and biopsy
POD 1–5
POD 6–14
POD 15–21
POD 22–24
POD 25–29
POD 30–discharge
ICU PN
Ward PN/NJ feeds
PN/NJ/oral
NJ feeds/oral diet
Oral diet
BD BD BD BD BD
OD OD OD OD As required
OD Twice a week OD Twice a week As required
OD Twice a week OD Once a week As required
Twice a week Once a week Twice a week As required As required
Twice a week Once a week Twice a week As required As required
BD OD OD OD OD
OD Twice a week Twice a week Twice a week Twice a week
Twice a week Once a week Once a week Once a week Once a week
Twice a week Once a week Once a week Once a week Once a week
Once a week Once a week Once a week Once a week Once a week
As required As required As required As required As required
OD OD
OD OD
Twice a week Twice a week
Twice a week Once a week
Twice a week Once a week
Once a week Once a week
Thrice a week
Twice a week
Once a week
Once a week
Once a week
OD once a day, BD twice a day, POD postoperative day, ICU intensive care unit, PN parenteral nutrition, NJ nasojejunal, LFT liver function test, RFT renal function test, ABG arterial blood gases
and transported in cold UW solution at 4 deg C (Fig. 1a). Meanwhile, upon inspection and approval of the graft quality by the donor surgeon, recipient surgery was begun. Dense adhesions in the abdominal cavity were lysed. The remnant small bowel and proximal half of colon were mobilized off the retroperitoneum, inferior vena cava (IVC) and aorta, and resected to make space for the intestinal graft. The infra-renal aorta was exposed 5 cm below the origin of the right renal artery and a 5-cm long and 8-mm wide donor iliac artery conduit was anastomosed end-to-side to it (Fig. 1b). Since the SMV was thrombosed, portal vein (PV) was exposed in the hepato-duodenal ligament and a 6-cm long and 1.5 cm wide venous conduit (cryopreserved external iliac vein) was anastomosed end-to-side to it. Immunosuppression induction was done with anti-thymocyte globulin (ATG) 5 mg/kg and methylprednisolone (MP) 15 mg/kg intravenously. The intestinal graft was orientated appropriately, and implanted by anastomosing the graft SMA to the aortic conduit and the graft portal vein to the recipient PV conduit (Fig. 1c). The cold and warm ischemia times were 256 and 28 minutes, respectively. On reperfusion, the graft ‘pinked up’ immediately (Fig. 1d). Both ends of graft bowel were oversewn using interrupted silk sutures. Proximal bowel continuity was established by a graft-recipient side-to-side, double-layered jejunojejunostomy (inner continuous PDS and outer interrupted silk sutures). Distally, a side-to-side, double-layered ileo-
transverse colic anastomosis (inner continuous PDS and outer interrupted silk sutures) was done leaving 20 cm of the graft distal ileum, which was fashioned into a ‘chimney ileostomy’ (Fig. 1e). A nasojejunal (NJ) tube (Freka® Trelumina, Fresenius Kabi AG, Hamburg, Germany) was kept beyond the proximal bowel anastomosis.
Postoperative course Postoperatively, the patient was managed in an isolation room in the intensive care unit (ICU) for 6 days following which he was shifted to the ward. Both the ICU and ward rooms were positive pressure isolation rooms equipped with high efficiency particulate air filter and UV radiation. His monitoring protocol is outlined in Table 2. He was extubated 14 hours after the surgery and administered IV antibacterials, antifungals, antivirals and NJ gut decontamination. He was ambulated on postoperative day (POD) 4. PN (Kabiven) was given at 85 mL/hours in addition to calcium, magnesium, phosphate and trace element supplementation. NJ feeding was started on POD 15 and slowly increased over 10 days. PN was commensurately reduced from POD 15 and was stopped by POD 25. Oral feeding was started with liquids, followed by semi-solids and then normal diet from POD 22 onwards. By POD 30, he was completely on oral diet, with occasional need to supplement fluid intake of 500–1,000 mL every day.
Indian J Gastroenterol
Fig. 2 Histological findings: a POD 14 graft biopsy (10×10 magnification) showing moderate acute cellular rejection. Goblet cell apoptosis (black arrow) 8–10/10 crypts. Lamina propria infiltrated by mixed inflammatory infiltrate is composed of lymphocytes, plasma cells, and eosinophils (white arrow). b Pattern of CD3 counts over postoperative
course. c POD 24 graft biopsy (40×10 magnification) showing mild acute cellular rejection with goblet cell apoptosis (black arrows) 6/10 crypts. d Normal ileal mucosa after intestinal transplant—(10×10 magnification) normal crypt villous ratio, no denudation or ulceration. Apoptotic bodies,
