Intestine Transplantation



Intestine Transplantation


Beverly Kosmach-Park, RN, DNP, FAAN

Maria DeAngelis, MScN, NP



I. INTRODUCTION

A. Intestine transplantation was recognized in 2000 as the standard of care for adults and children with life-threatening intestinal failure in the United States. This was followed by an increased number of international cases being performed with the development of intestine transplantation becoming a successful procedure for patients with intestinal failure who could not be treated with long-term parenteral nutrition.1

B. History



  • First performed over 50 years ago, but clinical success has been challenging with improvements in survival and outcomes occurring only recently


  • First cohort: 1964-1972:



    • Eight intestine transplants were performed internationally.


    • Longest survival of this cohort was 6 months.


    • Poor survival was attributed to technical complications, infection, and inability of available immunosuppressive protocols to control and treat rejection.2


  • Cyclosporine era: 1984-1989:



    • Renewed attempts in intestine transplantation were based on the success of cyclosporine as the primary immunosuppressant for kidney, liver, and heart transplantation.


    • Mean survival (n = 6) improved to 25.7 months.3


    • Cyclosporine did not have a similar impact on survival in intestine transplantation as compared to other solid organs.


    • There is one surviving recipient from this cohort who received an isolated intestine transplant in 1989; however, immunosuppression is now maintained with tacrolimus (Francis Lacaille, personal communication, March 31, 2015).4


  • Significantly improved patient and graft survival has been achieved since the early eras of intestine transplantation due to



    • Improved immunosuppressive strategies




      • Tacrolimus was first used in 1990 as the primary immunosuppressant in intestine transplantation with significantly improved survival.


      • Induction therapy: The use of preconditioning protocols with antilymphoid medications such as alemtuzumab and antithymocyte globulin has been shown to decrease the incidence of early rejection and improve survival.5


    • Innovative surgical techniques


    • Improved infection surveillance and treatment

C. Current Data



  • Intestine Transplant Registry (ITR):



    • Registry of worldwide data from intestine transplant centers since 1985.


    • Data reflects global trends because case volumes are low within each transplant center.


  • 2013 ITR Registry Report5:



    • The 2013 Registry Report contains data from 82 contributing centers.


    • As of February 2, 2013: 2,887 transplants have been performed in 2,699 patients. The majority of these transplants (76%) have been performed in North America.


    • Although the number of cases had increased annually since 1985, there has been a steady decline in intestinal transplantation since 2009. This can be partially attributed to improvements in the multidisciplinary care and treatment of patients with intestinal failure-associated liver disease (IFALD), thus decreasing the need for concomitant liver transplant and/or intestine transplant.


    • Isolated intestine transplantation, without the liver component, is now the most common type of intestine transplant.



      • Inclusion of the liver with the intestine graft is associated with significantly better graft survival (p = 0.017).


    • Transplantation of the colon is performed more frequently.


    • Length of stay has been reduced to a median of 44 days.


    • Induction therapy is used in a majority of patients (72%).


    • Tacrolimus is the primary immunosuppressant medication used for maintenance immunosuppression (92%).


    • Actuarial patient/graft survival for transplants performed since 2000:



      • 77/71% at 1 year


      • 58/50% at 5 years


      • 47/41% at 10 years


    • Retransplantation:



      • 8% of patients have received a second or third transplant.


      • Survival of the second or third graft is 56% at 1 year and 35% at 5 years.


    • Leading causes of graft loss:



      • Sepsis (>50%)


      • Rejection (13%)


      • Cardiovascular events (8%)


    • Improved graft survival related to



      • Waiting at home at time of transplant


      • Younger recipient age


      • Maintenance therapy with rapamycin


      • Presence of a liver component



    • Outcome:



      • At >6 months posttransplant, most recipients (63%) are well or have only minor issues and have returned to normal activities.


      • TPN has been discontinued in 67% of recipients.


II. INTESTINAL FAILURE

A. Intestinal Failure (IF): Defined as “the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth.”6



  • Classifications of IF based on gastrointestinal or systemic diseases6:



    • Short bowel: due to extensive surgical resection or congenital disease including mesenteric infarction, Crohn’s disease, intestinal volvulus, or necrotizing enterocolitis.


    • Intestinal fistula: abnormal communication between two parts of the gastrointestinal tract, between the GI tract and other organs, or the GI tract and the skin. Etiology may be inflammatory, neoplastic, iatrogenic, infectious, or due to trauma.


    • Intestinal dysmotility: motility disorder leading to poor propulsion through the intestine in the absence of any occlusions (chronic intestinal pseudo-obstruction).


    • Mechanical obstruction: due to a physical abnormality that affects the intestine (tumors, bowel lesions).


    • Extensive small-bowel mucosal disease (microvillus inclusion disease, tufting enteropathy, radiation enteritis).


  • Intestinal failure results in alterations in absorption so that the patient is unable to gain or sustain weight and/or maintain fluid balance. Growth and development are affected in the pediatric population.


  • Prognosis depends on residual bowel length, anatomy, and residual bowel function.



    • Indications for poor prognosis7:



      • Length <10% of normal age-expected bowel length


      • Absence of the ileocecal valve or colon


      • Prematurity


      • Presence of bacterial overgrowth


      • Presence of persistent liver disease


  • Common causes of intestinal failure (Table 13-1)








TABLE 13-1 Common Causes of Intestinal Failure









Adult


Pediatric




  • Ischemia



  • Crohn’s disease



  • Desmoid tumor



  • Trauma



  • Volvulus



  • Pseudo-obstruction



  • Gardner’s disease




  • Midgut volvulus



  • Necrotizing enterocolitis



  • Gastroschisis



  • Congenital atresias



  • Hirschsprung’s disease



  • Chronic intestinal pseudo-obstruction



  • Microvillus inclusion disease




III. INTESTINAL REHABILITATION

A. Goals of Intestinal Rehabilitation and Treatment8



  • Maximize the absorptive capacity of the intestine remnant.


  • Minimize symptoms of malabsorption.


  • Eliminate the need for parenteral nutrition.

B. Rehabilitation Strategies



  • Intravenous nutrition:



    • Nutritional requirements are maintained through total parental nutrition (TPN) via central venous lines (CVLs).



      • Macronutrients, micronutrients, and/or fluid requirements are provided through daily infusions.


      • Patients with intestinal failure require 30% to 70% more calories to compensate for malabsorption.9


      • Patients require long-term venous access.


      • Patients are at great risk for developing life-threatening complications:



        • Hepatotoxicity


        • Sepsis


        • Loss of venous access


    • Interventions to improve or preserve liver function in patients who are TPN dependent10:



      • Decrease the dextrose and lipid load of the TPN solution when possible.


      • TPN cycling with enteral feedings may be helpful to preserve liver function in patients who will tolerate at least minimal enteral feedings.


      • Patients with normal intestinal motility of their existing gut should receive enteral nutrition to avoid intestinal stasis. Enteral nutrition is the most important intervention for preventing and treating TPN-induced cholestasis.10


      • Omega-3 lipid formulation (Omegaven):



        • Short-chain fish oil-based lipid emulsion may be helpful in preserving liver function.


        • Although sample sizes are small, some studies report cholestasis to be reversed and that progressive liver disease is halted, while others suggest that although serum bilirubin levels are significantly reduced, the degree of hepatic fibrosis is not affected.11,12,13,14


      • Ursodiol may be helpful in facilitating bile secretion in patients with cholestasis.


  • Enterocyte growth factors used with nutritional support to promote intestinal adaptation:



    • Recombinant growth hormone (rGH):



      • The use of rGH with glutamine and an optimal diet has been shown to significantly reduce the volume, calories, and frequency of parenteral nutrition in adults.15


      • Reported to increase absorption with improved uptake of carbohydrates, protein, sodium, and water; decreases stool output.


      • The experience of rGH use in pediatrics is limited.


    • Teduglutide:



      • Approved in the United States and Europe as a treatment for adults with short-bowel syndrome-associated intestinal failure.16



      • May promote mucosal growth, reduce gastric emptying and secretion, decrease fecal losses, and increase absorption.


      • Has been shown to increase citrulline levels, a biomarker for mucosal mass.


      • Reduces the number of days and volume of parenteral nutrition required in adult patients with intestinal failure.


      • Optimal results depend on the length of remaining intestine, the presence of the colon, and less volume of TPN.8


      • Approval for use in pediatrics is pending.


  • Surgical interventions:



    • Autologous reconstruction:



      • Potential intervention for patients with a disconnected GI tract and multiple enterocutaneous fistulae.17


      • Intestinal segments exhibiting normal motility should be reconnected, closing all stomas, whenever possible.


      • When reanastomosed, dysmotile segments increase the risk of bacterial translocation due to intestinal stasis.10


    • Bowel lengthening techniques:



      • Bianchi procedure: Longitudinal Intestinal Lengthening and Tailoring (LILT)18:



        • A type of longitudinal lengthening procedure that has been most successful in patients who have had a period of normal adaptation following intestinal resection.


        • The bowel is divided along the longitudinal axis into two tubes with independent blood supply. Bowel division is possible because the mesenteric vasculature bifurcates to provide the blood supply for half of the bowel circumference. The two tubes are then connected to form a segment that is nearly double the length and half the circumference of the preoperative intestine.


        • Good outcomes and survival are associated with bowel length, liver function, and the ability to wean from parenteral nutrition.19


      • Serial transverse enteroplasty procedure (STEP):



        • Performed in patients with dilated bowel loops.


        • Near-doubles the length of the intestine through serial transverse stapling from opposite directions that creates a zigzag appearance.


        • The International STEP Data Registry reports that 47% of patients attained full enteral nutritional support. Results were less favorable for patients with a higher direct bilirubin and shorter bowel length.20


  • Medical issues and interventions:



    • Bacterial overgrowth:



      • Characterized by an increased number and/or abnormal type of bacteria in the small intestine.


      • Intestinal stasis provides the opportunity for bacteria to proliferate.


      • Value suggested is a finding of ≥1 × 103 colony-forming units (cfu) per milliliter of proximal jejunal aspiration.21


      • Most common causes: gastric achlorhydria due to long-term use of proton pump inhibitors, anatomic abnormalities of the small intestine with intestinal stasis, motility disorders, and gastrocolic or coloenteric fistula.21


      • Symptoms: bloating, flatulence, abdominal pain, diarrhea, weight loss, and steatorrhea. May lead to systemic infection and sepsis syndrome.22



      • Diagnosis21:



        • Quantitative culture of jejunal aspirate (suggested ≥1 × 103 cfu/mL).


        • Hydrogen breath test (older children and adults).


        • Stool studies to confirm steatorrhea.


        • Lab tests: B12 deficiency, anemia, low serum prealbumin, elevated serum folate, and vitamin K levels.


        • Barium studies and CT enterography are used to identify mechanical causes.


      • Treatment:



        • Goals: treat the underlying condition, eliminate bacterial overgrowth, and address nutritional deficiencies.


        • No consensus in regard to antibiotic regimen. Options include trimethoprim/sulfamethoxazole, rifaximin, ciprofloxacin, metronidazole, gentamicin, neomycin, and/or colistimethate.21,22


        • Antibiotics are given continuously or for a short intermittent course, such as every other week or 2 weeks on/2 weeks off.22


    • Central venous line (CVL) infections23:



      • Patients are at risk for developing systemic infections leading to hemodynamic instability and death.


      • Goals: eradicate the organism(s) and preserve the CVL.


      • Symptoms: fever, reduced enteral tolerance, and irritability (infants).


      • Diagnosis: blood cultures.


      • Treatment:



        • Based on patient’s history


        • Start with broad-spectrum coverage until organisms with sensitivities are confirmed, and then modify antimicrobial therapy.


        • Remove the CVL if



          • The organism continues to be cultured positive despite antimicrobial therapy.


          • The CVL is cultured with S. aureus or yeast.


          • The patient becomes hemodynamically unstable.


    • Lock therapy:



      • Antimicrobial lock therapy (ALT):



        • Strategy to preserve catheters and decrease the incidence of infection


        • Used when there are >2 days of persistently positive cultures in the setting of appropriate antimicrobial therapy22


        • Catheter salvage reported to be increased with the use of antimicrobial lock therapy24


        • Procedure25:



          • An antibiotic solution is instilled into the hub of the CVL when it is not in use to achieve a concentration of antibiotic that is greater than the minimal inhibitory concentration (MIC) for the cultured organism.


          • The antibiotic dwells in the catheter for a minimum of 8 to 12 hours and then is removed.


          • The lock is instilled daily for a minimum of 1 to 4 weeks based on the organism and antimicrobial agent.


      • Ethanol lock therapy:



        • Used in combination with antimicrobial lock therapy and after antimicrobial treatment to reduce the incidence of line infections



        • Ethanol26:



          • Antimicrobial and fibrinolytic agent


          • Reported to be effective in preventing and treating CVL infections


          • Also an anticoagulant and can maintain line patency


        • Procedure24:



          • Hospital guidelines vary, but usually, 0.8 to 3 mL (based on catheter size) of 74% ethanol is instilled for a minimum of 2 hours from three times weekly to daily.


          • Following the required dwell time, the ethanol is withdrawn and discarded and the line is flushed with saline.


          • Compromised line integrity in polyurethane catheters from exposure to ethanol has been reported.


  • Outcomes of intestinal failure patients:



    • Rehabilitation through medical and surgical interventions based on the patient’s age, bowel length, absorptive capacity, and transit time.


    • If nutritional autonomy cannot be achieved, intestinal transplantation should be considered as a treatment for intestinal failure.


IV. PRETRANSPLANT CARE AND ASSESSMENT

A. Objective Measures of Intestinal Failure



  • Vital signs: temperature:



    • Monitor routinely as indicated and more frequently with complaints of illness and malaise.


    • Fever is usually a symptom of infection, which requires immediate attention.


    • Increased risk for sepsis:



      • Central venous lines


      • Intestinal stasis due to impaired motility of the residual intestine, which contributes to bacterial overgrowth and translocation


  • Vital signs: blood pressure/heart rate:



    • Hypotension and tachycardia may indicate



      • Dehydration


      • Sepsis


      • Bleeding in patients with impaired synthetic function from hepatic dysfunction


    • Hypertension may occur with impaired renal function secondary to prolonged and frequent administration of aminoglycosides and antifungals in patients with recurrent sepsis.


  • Laboratory tests (Table 13-2):



    • Assessment through laboratory tests varies in patients with intestinal failure based on



      • Disease etiology


      • Effect on other organ systems


      • Organ deterioration


      • Infection history


      • Amount, type, and macro-/micronutrient content of parenteral nutrition


    • Lab tests are obtained weekly or every other week to monitor abnormalities and to make appropriate adjustments in contents of TPN solution and volume.











      TABLE 13-2 Electrolyte Imbalances in Intestinal Failure and Postintestinal Transplantation

















































































      Electrolyte


      Alteration


      Cause


      Symptoms


      Treatment


      Sodium


      Hypernatremia Na >150 mEq/L




      • Water loss secondary to diarrhea and vomiting



      • Increased evaporative water loss: fever



      • Excess sodium intake: increased oral or IV source


      Nonspecific: thirst, irritability, lethargy, increased deep tendon reflexes, seizures




      • Reduce serum sodium slowly through administration of appropriate IV fluids and volumes.



      Hyponatremia Na <130 mEq/L




      • Edema-associated states: hepatic failure leading to third spacing of fluid



      • Hyperglycemia



      • GI losses: vomiting, ostomy losses, tube drainage, diarrhea



      • Diuresis; thiazides and loop diuretics


      Nonspecific: headache, lethargy, nausea weakness, encephalopathy, seizures


      Dependent on cause




      • Restore intravascular volume.



      • Edematous state (low albumin)—do not restrict water intake but restrict NA intake.



      • Hyperglycemia: resolve hyperglycemia.


      Potassium


      Hyperkalemia K+ >5.5 mEq/L




      • Metabolic acidosis



      • Increased K+ intake: supplements, blood transfusions



      • Decreased renal excretion: K+ sparing diuretics, calcineurin immunosuppression



      • Increased tacrolimus levels post transplant


      Cardiac arrhythmias (V fib and asystole)
      Muscle weakness, decreased tendon reflexes, ileus, anorexia, tingling of mouth and extremities, malaise, tetany


      Dependant on cause and severity. May include administration of:




      • Kayexalate



      • Lasix



      • Sodium Bicarbonate



      • Insulin



      • Salbutamol



      • Dialysis



      • Calcium gluconate



      • Administer K+ supplementation (oral/IV).



      Hypokalemia K+ <3.5 mEq/L




      • Increased GI losses: vomiting, diarrhea, ostomies, tube drainage



      • Increased renal losses: drug-related aminoglycoside toxicity


      Cardiac arrhythmias (bradycardia, V tac, AV block, premature atrial and ventricular beats), fibrillation, muscle paralysis, ileus, tetany, confusion, hypotension, polyuria, polydipsia



      Magnesium


      Hypermagnesemia Mg >2.5 mEq/L




      • Excess magnesium intake (i.e., oral prep, via TPN)



      • Decreased renal excretion; assess GFR


      Decreased deep tendon reflexes; weakness, confusion, lethargy, and hypotension with levels >7 mEq/L, bradycardia




      • Remove excess source.



      • Administer calcium.



      • Dialysis.



      Hypomagnesemia Mg <1.5 mEq/L




      • GI losses: diarrhea, prolonged NG drainage



      • Malnutrition: ↓ calories, ↓ protein



      • Fat malabsorption



      • Increased renal losses: renal tubular acidosis, diuretic therapy, drugs (aminoglycosides, amphotericin, calcineurin inhibitors)



      • Pancreatitis



      • Refeeding


      Weakness, tremors, anorexia, seizures, cardiovascular manifestations (widening QRS complex, prolonged PR interval, ventricular arrhythmias), increased susceptibility to digitalis toxicity




      • Administer magnesium supplement (IV/PO).


      Phosphate


      Hypophosphatemia (varies by age)




      • Decreased intestinal absorption (diarrhea, vitamin D deficiency, antacid abuse, fat malabsorption)



      • Internal redistribution (recovery from malnutrition, sepsis, rickets)



      • Decreased phosphate intake



      • Hyperventilation


      Muscle weakness, bone pain, arthralgias, hemolytic anemia, anorexia, nausea, vomiting, confusion, rhabdomyolysis




      • Low phosphate associated with hypercalcemia; treating high calcium often resolves low phosphate



      • Administer phosphate once calcium and renal function assessed.



      Hyperphosphatemia (varies by age)




      • Increased external load (IV/oral)



      • Increased endogenous load (bowel infarction)



      • Reduced renal excretion (Mg deficiency, bisphosphonate therapy)



      • Hypocalcemia


      With associated hypocalcemia, tetany can occur. Ectopic calcification in vessels and wall tissues




      • Restrict phosphate intake.



      • Administer phosphate binding salts (aluminum, calcium, magnesium).



      • Saline diuresis if normal renal function


      Calcium


      Hypocalcemia (varies by age)




      • Low albumin



      • High phosphate



      • Low magnesium



      • Vitamin D-deficient rickets



      • Pancreatitis


      Muscle weakness, numbness, and tingling in extremities, cramps, hyperreflexes, tetany, seizures, prolonged QT interval




      • Correct other electrolyte imbalances.



      • Administer calcium (IV/oral).



      • Vitamin D therapy



      Hypercalcemia




      • Excess vitamin D administration



      • Thiazide drug therapy


      Renal etiology: polyuria, polydipsia, nephrocalcinosis, renal insufficiency
      Nonrenal etiology: fatigue, weakness, nausea, vomiting, constipation, symptoms of pancreatitis, headache, pruritus, bone pain, hypotonia, hypertension, arrhythmias, short QT interval, heart block




      • Correct dehydration.



      • Saline diuresis



      • Loop diuretics



      • Steroids



      • Calcitonin



      • Bisphosphonates


      Metabolic Acidosis


      Assessed on blood gas




      • Low pH



      • Reduced HCO3




      • GI losses: diarrhea, intestinal fluid loss from ileostomy, NG drainage



      • Excess acid via TPN



      • Renal losses: drugs (spironolactone, amphotericin)


      Vomiting, nausea, diarrhea, hyperventilation, headache, lethargy




      • Treat underlying cause.



      • Bicarbonate



      • Correct fluid balance.


      Metabolic alkalosis


      Assessed on blood gas




      • High pH



      • Elevated HCO3




      • GI losses: vomiting, NG drainage, chloride losing diarrhea



      • Renal losses: diuretics, penicillins



      • Low chloride intake



      • Refeeding syndrome



      • Hypocalcemia



      • Hypokalemia



      • Massive blood transfusions (excessive citrate)


      Related to underlying cause. Refer to hypokalemia.
      Refer to hypocalcemia. If volume depleted: thirst, lethargy, muscle cramps, irritability




      • Treat underlying cause.



      • Correct K+ deficit.



      • Correct calcium deficit.



      • Correct chloride deficit.



      • Correct fluid imbalances.




    • Lab tests commonly obtained include



      • Electrolyte panel (calcium, magnesium, phosphorus, sodium, potassium, carbon dioxide, chloride)


      • Renal function tests (blood urea nitrogen, creatinine)


      • Cholesterol and triglycerides


      • Nutritional status: micronutrient deficiencies are common in intestinal failure. Albumin, protein, trace elements, zinc, copper, selenium, iron, and vitamins A, D, E, K, and B12 are monitored routinely.27


      • Absorption: D-xylose testing and fecal fat testing


    • Assess electrolyte imbalances:



      • Patients are at risk for increased fluid losses with electrolyte imbalances due to



        • Development of a hypersecretory state, bacterial overgrowth, infection, and/or intrinsic deficits


        • Interruptions in ability to provide optimal TPN because of venous access problems


    • Monitor liver function:



      • Monitored by liver function tests (ALT, AST, GGTP, and bilirubin)


      • Markers for synthetic function (PT/PTT and INR), platelets, and hemoglobin


      • Ammonia level (NH3)


    • Monitor for infection:



      • Infection should be considered with an increase in the white blood cell count, sedimentation rate (ESR), and platelet count.


      • If infection is suspected, blood cultures should be obtained to identify the specific organism causing infection.


      • Stool, sputum, and/or urine cultures are obtained as indicated.


  • Radiology tests:



    • Completed during the evaluation for intestine transplantation or as complications arise related to disease etiology


    • Upper GI with small-bowel follow-through28:



      • Used to assess the residual native bowel and any abnormalities:



        • Test completed with water-soluble contrast or barium


        • Observe for dilated loops of bowel, strictures, or narrowing of the bowel


        • Provides an estimate of bowel length and transit time


      • Structural etiologies28:



        • Assess for short-bowel length:



          • Adults: <200 cm10


          • Pediatrics: <25% of the predicted length for age at primary surgery29


      • Functional etiologies28:



        • Normal or near-normal length


        • Distended bowel loops may be present


        • Hyper- or hypomotility of native intestine:



          • Motility testing performed in patients with Hirschsprung’s disease or chronic intestinal pseudo-obstruction to assess transit time


        • Gastric emptying scan to assess gastric function


    • Barium enema:



      • Used to assess anatomy and function of the remaining colon



    • Vascular patency28,30:



      • Ultrasound of great vessels to assess patency of internal jugular, subclavian, and iliac veins.


      • Important to identify any occlusions of common central venous access sites because access may be required for prolonged parenteral nutrition in intestinal failure or for up to a year or more posttransplant.


      • Angiography may be indicated in some cases.


      • An MRI is used to confirm any reported occlusions of the primary vasculature.


    • Abdominal ultrasound28,30:



      • Used to visualize and identify vascular anatomy, preexisting conditions, and any variants that may affect the surgical approach.


      • Is not specific or exact enough to replace cross-sectional imaging in intestinal failure patients, but may provide additional information for a patient in no immediate danger.


      • Minimizes radiation exposure from CT angiography.


      • The aorta, bilateral common iliac arteries and veins, and IVC are assessed:



        • IVC thrombosis or stenosis may preclude intestine transplant depending on the location of the variant.


        • The portal venous system, IVC, and liver inflow and outflow are assessed in liver/intestine transplant candidates.


      • CT angiography is completed if the ultrasound cannot adequately visualize vessels.


      • CT also used to assess for hepatomegaly, splenomegaly, and/or ascites.


    • Liver biopsy:



      • Performed in patients with deteriorating liver function to determine the extent and severity of liver disease.


      • Evidence of bridging fibrosis or cirrhosis is an indication for concomitant liver transplantation.


      • The extent of liver disease, rate of progression, and estimated waiting time to transplant are also considered in listing for liver transplant.


    • Cardiac assessment:



      • Completed to rule out cardiac anomalies and contraindications for surgery.


      • Tests:



        • Electrocardiogram (ECG)


        • Echocardiogram (ECHO)


        • Chest radiograph (CXR):



          • Used to assess for respiratory complications, particularly in candidates with cystic fibrosis or in premature infants with history of bronchopulmonary dysplasia


  • Physical assessment:



    • Widely variable from relatively healthy to critically ill:



      • Will vary by age, indication for transplant, severity, and duration of intestinal failure and associated complications


      • Observe for the general state of health or distress, skin color, height/weight, mobility, energy, and mood


    • Skin:



      • Jaundice and bruising are present in patients with concomitant liver disease.



      • Skin irritation, lesions, and breakdown secondary to pruritus, particularly in pediatric patients.


      • Decreased skin turgor or edema due to nutritional deficits and fluid imbalances.


      • Dry, scaling skin that lacks elasticity.


      • Poor nail growth or thin nails.


      • Thinning, dull hair.


      • Potential for ulcers, rash, and skin breakdown around catheter sites, drainage or feeding tube sites, stomas, mucous fistulas, ostomies, and around the buttocks/diaper area.


      • Assess scarring from previous surgeries for any breaks in skin integrity or keloid formations.


      • Skin mottling may be a sign of sepsis.


    • HEENT:



      • Abnormalities occur based on the indication for intestinal failure and complications.


      • Icteric sclerae are usually present in concomitant liver disease.


      • Patients who have received repeated courses of parenteral aminoglycosides should be assessed for hearing deficits.31



        • Aminoglycosides are associated with ototoxicity.


        • Deficit is related to the duration of treatment and amount of drug administered.


        • Infants are particularly at risk and often have high-range hearing deficits.


      • Cervical lymphadenopathy may be associated with infection.


      • Dentition is affected by nutritional status.



        • Assess for the presence\absence of teeth, staining, obvious caries, gingivitis, and gum integrity.



          • Tooth eruption may be delayed in nutritionally impaired infants.


      • Dehydration is assessed through skin turgor, decreased or absent tearing, sunken eyes, dry oral mucosa, and cracked lips.


      • Atrophic glossitis:



        • Smooth glossy appearance of the tongue with a red or pink background


        • May indicate a nutritional deficiency (iron, folic acid, B12, riboflavin, niacin)32


    • Cardiac:



      • There are no specific cardiac abnormalities directly related to intestinal failure; however, cardiac-related symptoms can occur as a result of complications related to intestinal failure.


      • Baseline cardiac assessment is completed to determine any cardiac illness or anomaly that may be a contraindication to the surgical procedure.


      • Signs and symptoms of compromised cardiac function may include



        • Tachycardia due to blood loss and/or volume depletion.


        • Arrhythmias secondary to electrolyte imbalances.


        • Murmurs from anemia or fluid imbalance.


        • Hypotension may be associated with bleeding, volume depletion, and sepsis.



    • Respiratory:



      • Abnormalities are secondary to comorbidities or secondary diagnoses.


      • Tachypnea may be associated with metabolic acidosis, hypoglycemia, fever, and/or anxiety.


      • Rales and tachypnea may be present with fluid overload related to hypoalbuminemia.


      • Decreased breath sounds may be due to atelectasis, effusions, and/or pneumonias.


    • Gastrointestinal:



      • GI assessment determines the extent and function of the existing intestine and any associated abdominal anomalies.


      • Abdominal assessment:



        • Observation:



          • Surgical scars


          • Enteral tubes: gastrostomy tube, jejunostomy tube, and gastrojejunostomy tube


          • Fistulas


          • Ostomies


          • Abdominal protuberance suggests ascites and/or organomegaly


          • Distended abdominal veins and telangiectasis (spider angioma) are indicative of liver disease with vascular obstruction


          • Herniations


        • Auscultation:



          • Hyperactive bowel sounds may be indicative of diarrhea or an early obstruction.


          • Hypoactivity, followed by absent bowel sounds, may indicate an ileus and/or peritonitis.


        • Palpation:



          • Hepatomegaly in patients with TPN-induced liver disease can be evaluated by palpating in the right upper quadrant and assessing the size of liver below the costal margin.


          • With splenomegaly, the spleen may be palpated well below the costal margin due to portal hypertension; tenderness may be present.


          • Epigastric and rebound tenderness are associated with pancreatitis.


          • Generalized discomfort may indicate peritonitis.


    • Musculoskeletal assessment:



      • Fractures:



        • Increased risk due to malabsorption of fat-soluble vitamins (A, D, E, and K).


        • Malabsorption of vitamin D may cause rickets and lead to fractures.


      • Joint abnormalities:



        • Assess for swollen, painful, and reddened joints.


        • May indicate arthritis-associated liver disease.


      • Muscle atrophy:



        • Decreased muscle tone, decreased muscle mass, and muscle atrophy may develop due to malabsorption and poor nutrition.


        • Disuse atrophy occurs from inactivity related to chronic illness and compromised mobility.



    • Neurologic and mental status:



      • Neurologic changes are associated with hyperammonemia in patients with liver disease.


      • Symptoms may include altered sleep patterns (day-night reversal), extreme lethargy, behavioral changes, confusion, obtundation, ataxia, asterixis, and clonus.


    • Growth and development:



      • Infants and young children with intestinal failure usually display some degree of growth failure.


      • Growth failure is associated with a small-bowel length of <50 cm and is due to inadequate absorption of nutrients.33


      • Height and weight curves are often less than the 25th percentile; growth along the curve is not commonly achieved with early-onset disease.33


      • Growth and development is closer to the norm in children or adolescents with a later onset of short gut, such as a spontaneous volvulus or trauma, or with diseases having a slower, chronic impact, such as Crohn’s disease or pseudo-obstruction.


      • Developmental milestones may not be achieved due to frequent illnesses, poor nutrition, decreased muscle mass and strength, repeated hospitalizations with impaired socialization, and isolation from the family environment.


      • Oral aversion is common in children who have been limited in their oral intake or who have had frequent extended periods of nothing by mouth.


V. PRETRANSPLANT CARE

A. Subjective Complaints of Intestinal Transplant Candidates



  • Subjective complaints are variable, depending on patient age and duration of illness, the severity of intestinal failure, nutritional status and associated complications.


  • Common subjective complaints related to intestinal failure include



    • Weight loss


    • Poor growth (pediatrics)


    • Intractable diarrhea


    • Dry, scaling skin


    • Skin breakdown


    • Thinning hair


    • Abdominal distention


    • Flatus


    • Malaise


    • Lethargy


    • Weakness


    • Abdominal pain


    • Complaints related to mental status and mood changes


  • Additional complaints of patients with concomitant liver disease:



    • Bruising


    • Extreme tiredness


    • Confusion and mood changes


    • Abdominal distention


    • Bleeding



    • Abdominal pain


    • Pruritus


    • Acholic stools


  • Emotional issues:



    • Time-consuming care routine


    • Limitations in activity


    • Frequent hospitalizations


    • Inability to work/attend school


    • Social isolation


    • Impaired family support


    • Financial stressors


    • Sleep disturbances


    • Fear of dying before an organ is available


    • Mental health or mood disorders, particularly anxiety and depression


VI. PREPARING THE PRETRANSPLANT PATIENT FOR SURGERY

A. Pretransplant Period



  • Transplant evaluation (Table 13-3):



    • Protocols vary by center, adult versus pediatric candidates, and etiology of intestinal failure.


    • Essential to complete a comprehensive medical and psychosocial assessment of the intestine transplant candidate with intestinal failure and associated comorbidities30:



      • The evaluation is completed through a 3 to 5 day inpatient admission or as an outpatient over several days.


      • Focus of the evaluation:



        • Anatomy of the GI tract


        • Nutritional status


        • Liver function


        • Venous access and patency


        • Infection history


        • Cardiovascular system


      • History:



        • Birth history (pediatrics or as applicable for congenital defects)


        • Etiology of intestinal failure


        • Surgical history


        • Intestinal anatomy:



          • Remaining length of small intestine and colon


          • Presence of ileocecal valve


          • Continuity status


          • Stomas and fistulas


        • Appliances: feeding tubes, ostomies, drainage tubes, and intravenous lines


        • Stool consistency and pattern, emesis, nausea, and abdominal distention


        • Central venous lines: number of lines, access, and infections


        • Infection history and response to antimicrobial treatment


        • Nutritional history and current status: enteral and parental feeding history, oral aversion, and incidence of hypoglycemia when off TPN









        TABLE 13-3 Evaluation for Intestinal Transplantation





















































        Assessment


        Testing/Procedures


        Routine assessment


        Complete history and physical


        CXR


        ABO compatibility


        Gastrointestinal assessment


        Upper and lower barium studies to assess bowel length, anatomy, and abnormalities


        Motility testing and gastric emptying as indicated for functional indications


        D-xylose testing and fecal fat testing to assess absorption


        Nutritional assessment


        Laboratory testing: electrolytes, blood urea nitrogen, creatinine, calcium, magnesium, phosphorus, zinc, trace elements, cholesterol, triglycerides, vitamin levels (A, D, E, K, B12)


        Feeding history to assess tolerance, absorption, weight gain, growth (children)


        Caloric intake: enteral and parenteral


        Growth parameters: height, weight, skin folds, head circumference (infants)


        Assess for oral aversion, abnormal eating behaviors, pica


        Hepatic function


        Liver function tests including ALT, AST, GGT, direct and indirect bilirubin, albumin, prothrombin time, partial thromboplastin time, alpha-fetoprotein, platelets, ammonia, and factors V and VII


        Physical exam to assess for hepatomegaly, splenomegaly, ascites, caput medusae


        Liver ultrasound to further assess liver size, vasculature, and any evidence of portal hypertension


        Liver biopsy if indicated to establish baseline hepatic injury


        Vascular patency


        Catheter history with number of line placements, location, duration, and reason for replacement


        Ultrasound of the great vessels to assess vascular access and to evaluate the splanchnic venous anatomy and internal jugular, subclavian, and iliac veins


        Angiography if indicated


        MRI to confirm any reported occlusions of the primary vasculature


        Infection history and immunology assessment


        History of infections to assess etiology and frequency of infection, pathogens, response to treatment, resistant organisms


        Screening cultures of blood, urine, stool, throat, or ascitic fluid for bacterial, fungal, or viral organisms as indicated


        Complete blood count and differential


        Tissue typing and crossmatch


        Screening for hepatitis B and C and HIV


        IgG and IgM titers for CMV, EBV, herpes zoster, and MMR


        Quantitative immunoglobulins in patients with intestinal atresia


        Cardiac assessment


        EKG, ECHO


        Rule out cardiac anomalies and contraindications for surgery.


        Respiratory assessment


        CXR


        Obtain pulmonology consult for patients with a history of BPD, cystic fibrosis, or other respiratory complications.


        Neurologic assessment


        Obtain neurology consult in patients with seizure disorders or neurologic impairments.


        Development and physical functioning


        Further evaluation as indicated for developmental delays, impairments in physical functioning, oral aversion, behavioral issues


        Consults may include physical therapy, speech therapy, occupational therapy, and neurodevelopment.


        Child life, child development in pediatrics


        Psychological evaluation


        To assess patient (age-appropriate) and parent/family’s psychological status and history for psychopathology, coping skills, responses to stress, family support


        Assess for alcohol or substance abuse in adults, adolescent patients, and parents.


        Adherence history


        Referrals for psychotherapy, counseling


        Social work evaluation


        Assess patient and family psychosocial functioning.


        Provide psychosocial care and support during the evaluation and in preparation for transplant.


        Guide families in referrals for financial assistance programs and supportive services.


        Assist in referrals to volunteer pilot associations if needed for transport to the transplant center when organs are available.


        Assist family in preparing for temporary relocation needs to the transplant center.


        Clinical nurse specialist


        Addresses the educational needs of the patient and family pre- and posttransplant


        Provides clinical information and psychosocial support throughout the transplant process


        Consultation to assess developmental needs, patient or family psychosocial functioning, adherence


        Transplant coordinator


        Maintains outpatient communication with candidate and referring physician following evaluation


        Lists patient according to UNOS requirements


        Provides information to the patient and family about the transplant process


        Maintains updated medical information on the candidate to the team during the waiting period


        Follows patient post transplant to facilitate medical management and follow-up; with physician, assesses for problems or complications through lab testing and procedures; communicates medication changes and assesses for medication adherence


        Financial counselor


        Works with the family and insurer to obtain insurance coverage for transplantation


        Provides guidance in fund raising for personal expenses related to relocation


        Adapted from Kosmach-Park B. Intestinal transplantation in pediatric patients. Prog in Transplant. 2002;12(2):97-113.




      • Physical examination.


      • Patient-specific consultations:



        • Based on associated medical issues and pediatric versus adult evaluation.


        • Consultations may include, but are not limited to, anesthesia, neurology, immunology, pulmonology, genetics, nephrology, endocrine, infectious disease, physical, and occupational therapy.


      • Psychosocial evaluation:



        • Completed by social work, psychology/psychiatry, and child development (pediatrics).


        • Assessment includes the patient’s psychological status, history of psychopathology and medications, coping skills, responses to stress, family support, drug and alcohol use, adherence history, and pain history and treatment.


      • Transplant education (Table 13-4):



        • Patient and family education is an essential component of the evaluation.









          TABLE 13-4 Educational Topics Pretransplant





























          Basic anatomy and physiology of the intestine




          • Indication for intestinal failure



          • Intestinal rehabilitation



          • Intestinal transplant


          Listing for intestine transplant




          • Listing status



          • United Network for Organ Sharing (US) or other organ procurement organization


          Waiting period




          • Patient responsibilities



          • Anxiety, stress, and coping mechanisms



          • Staying healthy



          • Communicating with your transplant coordinator and the transplant center


          Surgical procedure




          • Type of intestinal transplant



          • Duration of surgery


          What to expect in the intensive care unit




          • Unit routine



          • Length of stay



          • Appliances and drains



          • Procedures



          • Goals for transfer to the transplant unit


          Pain




          • Current pain status



          • Pain control



          • Postoperative pain



          • Treatment


          Surgical complications


          Immune system basics


          Rejection




          • Incidence



          • Symptoms



          • Diagnosis



          • Treatment



          • Outcome



          • Retransplantation


          Infection




          • Incidence



          • Most common infections



          • Symptoms



          • Diagnosis



          • Treatment



          • Outcomes


          Medications (most commonly prescribed)




          • Immunosuppressants



          • Anti-infective agents



          • Antimotility medications



          • Electrolyte supplements



          • Antacids


          Posttransplant Care




          • Follow-up care/appointments



          • Labs



          • Developmental issues (pediatrics): OT/PT, oral aversion, developmental delay, early intervention



          • Returning to work/school



          • Reproductive health



          • Activity and exercise



          • Nutrition



          • Family support



          • Psychosocial stressors


          Long-Term Outcomes




          • Patient and graft survival



          • Psychosocial functioning



          • Quality of life




        • Each member of the multidisciplinary team is responsible for presenting appropriate information about their respective area of focus; additionally, a comprehensive education session is usually provided by a transplant coordinator, clinical nurse specialist, or nurse practitioner during the evaluation period.


  • Nursing interventions:



    • Provide patients and families with a schedule for the evaluation with a list of appointments, tests, and consultations.


    • Provide education regarding test procedures and examinations through written and/or electronic media.


    • Support the patient and family throughout the evaluation by answering questions to clarify and reinforce information and by reviewing results presented by the transplant team and other consultants.


    • Facilitate discussions with the respective transplant team members for specific information and results.



      • A core group from the team may be responsible for providing an overview of the results, the immediate plan for listing and medical management, long-term management, and reinforcement of teaching.


      • The core group usually includes the transplant surgeon(s), GI physician, pretransplant coordinator, advanced practice nurse (CNS or CRNP), physician assistants, psychologist, and/or social worker.


  • Listing for intestine transplant:



    • Multidisciplinary meeting to review outcome of the evaluation.


    • A patient is accepted or rejected as a candidate for intestine transplantation based on the results of a comprehensive medical and psychosocial
      evaluation as well as the patient’s risk of developing life-threatening complications with a high risk for death without transplantation.


    • Current listing criteria34:



      • Advanced cirrhosis


      • Loss of ≥2 central venous catheter sites related to thrombosis


      • ≥2 episodes of sepsis annually, especially fungal sepsis


      • High risk of death secondary to the underlying disease


    • If accepted for transplantation, financial clearance must be obtained through the patient’s medical insurance plan.


    • After financial clearance is obtained, the patient is listed for intestine, intestine/liver, or multivisceral transplant through the United Network of Organ Sharing (UNOS).


    • Each organ is listed separately and by status:



      • Liver allocation: based on the candidate’s score as calculated by the Model for End-Stage Liver Disease (MELD) and the Pediatric End-Stage Liver Disease (PELD) as for isolated liver transplantation


      • Intestine candidates:



        • Status I: deteriorating liver function and decreased/limited venous access


        • Status II: normal liver function and adequate venous access


    • Waiting time may range from several months to years based on the candidate’s UNOS status/score, organ(s) required, patient weight, blood type, severity of illness, current medical status, and accrued waiting time.


    • Patients must have a plan for transportation to arrive at the transplant center within the appropriate time frame, usually within 6 hours of being contacted by the transplant coordinator.


  • The waiting period:



    • Medical management is usually maintained by the referring local physician.


    • The patient will return to the transplant center as requested for medical follow-up, consultations, and/or education or if there is deterioration in their condition.


    • This is an extremely stressful time for the patient and family as the patient’s health status deteriorates.


    • Nursing interventions:



      • Develop a supportive relationship with the patient and family during repeated hospitalizations.


      • Identify the patient’s fears and clarify misconceptions:



        • Recognize that the patient has increased fear and anxiety as the waiting period extends.


        • Acknowledge fears: death due to organs not being available, potential surgical and postoperative complications, pain, and prolonged hospitalizations.


      • Encourage patients to verbalize concerns to lessen anxiety.


      • Facilitate referrals for psychological, psychiatric, and/or spiritual counseling and support.


      • Be aware of patient and family’s cultural needs and religious practices:



        • Acknowledge and discuss cultural considerations regarding coping strategies, family, diet, blood products, and religious practices.


        • Facilitate care conferences to better understand cultural differences and to design appropriate supportive interventions.









    TABLE 13-5 Preoperative Orders





    Maintain NPO status.


    Obtain vital signs, height, weight, abdominal girth.


    Obtain labs: complete blood count and differential, liver function tests, calcium, magnesium, phosphate, urea, BUN, creatinine, glucose, electrolytes, PT/PTT, INR, protein, albumin.


    Type and cross for specified amount of packed red blood cells and fresh frozen plasma.


    Obtain viral serologies for cytomegalovirus (CMV), Epstein-Barr virus (EBV).


    Chest x-ray


    Infuse fluids and/or TPN as ordered.


    Administer preoperative broad-spectrum antibiotics.


    Administer methylprednisolone.


    Administer induction immunosuppression per center protocol.



  • Preparation for surgery



    • Preoperative orders and protocols are center specific.



      • Orders vary according to the patient’s medical status prior to intestine transplant, organs transplanted, and concurrent complications


    • Standard preoperative orders (Table 13-5).


    • Nursing interventions.



      • Ensure that informed consent has been given and that the consent forms are signed.


      • Establish where the family will be waiting during surgery and confirm contact information so they can be available if and when needed throughout the surgical procedure.


      • Reinforce previous teaching:



        • Duration of surgery and brief overview of the procedure


        • What to expect when seeing the patient in the intensive care unit


        • Description of the early postoperative period and the most common complications


VII. INTESTINE TRANSPLANTATION

A. Intestine Transplant Variants

There are several variants of intestinal transplantation. The surgical procedure and organ(s) are based on the indication for intestinal failure, the extent of organ deterioration, anatomic anomalies, and dysfunction of other abdominal organs.



  • Isolated intestine transplant:



    • Intestinal failure without associated liver disease or other organ involvement


    • Indications: extreme short gut, motility disorders, malabsorption syndromes, and gastrointestinal neoplasms


  • Combined intestine and liver transplantation:



    • Performed for patients with irreversible intestinal and hepatic failure


    • Usually includes the donor pancreas to allow for hepatobiliary continuity


  • Multivisceral transplantation:



    • Various combinations of intestine, liver, stomach, and/or pancreas


    • Modified multivisceral without the liver is performed if minimal cholestasis with good liver function



    • Recommended based on the etiology of intestinal failure and associated organ dysfunction


    • Indications: massive gastrointestinal polyposis, mesenteric desmoid tumors, chronic intestinal pseudo-obstruction, hollow visceral myopathy, and extensive splanchnic vascular thrombosis


  • Intestinal transplantation including the colon35:



    • Included as part of the intestinal graft in those patients with loss of colonic segments or dysmotility including necrotizing enterocolitis, chronic intestinal pseudo-obstruction or megacystis microcolon syndrome, volvulus, Hirschsprung’s disease, and Gardner’s syndrome


    • May include the donor ileocecal valve

B. Surgical Procedures



  • Donor selection36:



    • Hemodynamically stable


    • ABO-compatible, brain-dead donor


    • BMI ≤25 that matches the recipient


    • ICU stay ≤5 days with minimal vasopressor requirements


    • Crossmatch negative


    • Cold ischemia time of ≤6 hours to prevent irreversible intestinal mucosal injury


  • Recipient surgery36:



    • Operative time ranges from 6 to 18 hours or more depending on



      • Type of transplant


      • Surgically related risk factors:



        • Abdominal adhesions


        • Loss of abdominal domain due to multiple previous surgeries


      • Presence of underlying diseases


      • Recipient’s current health status


    • Patients are prepared in the usual fashion, sedated and intubated.


    • Placement of lines and tubes:



      • Require several peripheral intravenous lines in addition to the existing central venous line (CVL)


      • Arterial line


      • Nasogastric drainage tube


      • Urinary catheter


    • Midline abdominal laparotomy incision with unilateral or bilateral transverse extensions as needed.


    • Isolated intestine transplantation37,38,39,40 (Figures 13-1 and 13-2):



      • Diseased intestine removed proximally from the ligament of Treitz and distally to the ileocecal valve or ileocolic anastomosis in patients with neoplasms and functional disorders.


      • Healthy residual intestine is usually preserved in patients with structural disorders.


      • Patient may present with previous enterectomy of native residual intestine related to pretransplant complications.


      • Donor intestine, including the jejunum and ileum, is implanted using the appropriate vascular anastomoses.



        • Vascular anastomoses vary based on the patient’s anatomy and usable vessels.


      • Arterial reconstruction: the donor’s superior mesenteric artery (SMA) is anastomosed to the recipient’s infrarenal aorta using a small aortic patch.







        FIGURE 13-1 Isolated intestine transplant. (Adapted from the Department of Transplant Surgery, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center.)


      • Venous reconstruction: the donor’s superior mesenteric vein (SMV) is drained into the recipient’s portal vein, recipient SMV or splenic vein, or the recipient IVC.


      • Intestinal reconstruction:



        • The proximal end of the donor jejunum is anastomosed to the most distal segment of the recipient’s residual intestine (native jejunum or duodenum).


        • The distal end is fashioned as a permanent end ileostomy or joined to the native colon with a short portion brought out as a temporary ileostomy.



          • The ileostomy is used to facilitate frequent surveillance endoscopies in the early postoperative period.


          • The distal anastomosis varies depending on the underlying disease, motility issues, length of remnant colon, and method of ileostomy creation.


      • Jejunal feeding tubes with or without gastrostomy tubes are inserted.







      FIGURE 13-2 Vascular implantation of an isolated intestine graft using vascular conduits to the mesenteric vessel or to the aorta and IVC. (Adapted from the Department of Transplant Surgery, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center.)


    • Combined liver and intestine transplant37,38,39,40 (Figure 13-3):



      • Native liver is removed preserving the native retrohepatic vena cava in the standard piggyback fashion.


      • The healthy residual intestine (duodenum with or without a portion of the jejunum), stomach, and native pancreas are usually preserved in patients with structural disorders.


      • A duodenal C-loop and pancreas are also included with the combined liver and intestine graft to maintain hepatobiliary continuity so that a Roux-en-Y jejunal allograft loop is not needed to drain the bile duct.


      • Venous outflow of the native foregut is achieved through a permanent portocaval shunt. Venous outflow from the entire graft is from the donor suprahepatic cava to the confluence of the recipient hepatic veins and cava.


      • Arterial inflow to the graft is from the recipient infrarenal aorta.


      • Intestinal reconstruction:



        • Similar to isolated intestine transplantation with the proximal anastomosis between the end of the remnant native intestine and the donor jejunum.


        • Distal end is fashioned as a permanent end ileostomy or joined to the native colon with a short portion brought out as a temporary ileostomy.







      FIGURE 13-3 Combined liver and intestine transplant. (Adapted from the Department of Transplant Surgery, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center.)


    • Multivisceral transplantation17,37,38,39,40 (Figures 13-4 and 13-5):

Oct 27, 2018 | Posted by in NURSING | Comments Off on Intestine Transplantation
Premium Wordpress Themes by UFO Themes