Prokinetics

Whereas their effectiveness in terms of reducing clinical symptoms is poor, prokinetic drugs are systematically used in CIPO, probably because of their potential to improve digestive motility, as evidenced by manometric findings. Lack of effectiveness is possibly explained by the poor intestinal bioavailability of oral drugs. In some cases, combinations of prokinetics could improve digestive motility. New prokinetic drugs should be evaluated in the near future.

Treatment of Bacterial Overgrowth

Intestinal bacterial overgrowth has been well documented as a complication of intestinal motility disorders, and it has been shown that promoting digestive motility reduces bacterial overgrowth. Sequential antibiotic therapy is very effective in treating intestinal bacterial overgrowth and reducing malabsorption. Correlations between bacterial translocation and an absence of migrating motor complex activity has been demonstrated and can result in a further impairment of the digestive motility disorder. Systemic sepsis is a potentially life-threatening consequence of bacterial overgrowth.

Dietary Measures

Dietary measures are influenced by disease phenotype and aim to provide sufficient intake of micro- and macronutrients orally. Patients with gastroparesis usually feature diminished oral intake because of early satiety, whereas patients with predominantly small bowel involvement often suffer nausea, abdominal pain, and diarrhea. In individuals with delayed gastric emptying, liquid or blenderized food is better tolerated than solid food. Oral intake should also be fractionated and divided into 5 to 6 meals per day. Dietary measures should also include the use of a low-lactose, low-fiber, low-fat diet to optimize gut motility and to decrease the risk of bacterial overgrowth and gastric bezoar formation. Associated multivitamin and micronutrient supplementation is also needed (iron, folate, calcium, and vitamins D, K, and B12) to prevent the development of specific deficiency states.

Enteral Nutrition

Enteral feeding by ostomy is a potentially effective method of providing nutritional support, which could be used despite oral feeding intolerance. However, it should be commenced carefully with an iso-osmolar nutrient formulation delivered by slow continuous infusion rate to optimize tolerance and prevent enteral nutrition-related pneumonia. If this trial period is tolerated, the infusion rate and the volume of infusion can be increased progressively. An ostomy could be also helpful to provide venting.

Parenteral Nutrition

HPN is necessary in severe CIPO patients in whom there has been failure of other supportive methods. Because of higher cost, morbidity and mortality, and the low probability of being able to wean off HPN, it should not be initiated before there has been an adequate trial of oral or enteral nutrition feeding. Issues specific to the use of HPN in CIPO patients are relate to the impact of chronic bowel obstruction and poor oral intake.

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  Higher fluid volume is required to prevent dehydration, especially in cases of refractory vomiting or permanent ostomy suction/drainage. Fluid volume requirements must also be adapted in real time because of frequent and variably fluctuating digestive losses (diarrhea, vomiting). The same is true for fluid and electrolyte balance and for sodium, potassium, and magnesium, in particular.

  
  
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  More infusions occur per week (6–7 per week for CIPO patients versus 4–5 for short bowel syndrome; unpublished personal data).

  
  
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  To prevent parenteral nutrition (PN)-related liver disease, especially in those maintained exclusively on HPN (ie, patients with intractable obstruction), lipid parenteral intake should be limited (to that minimal intake necessary to prevent fatty acid deficiency).

  
  
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  Micronutrient and vitamin supplements (such as selenium, vitamins B1, B6, and E) should be provided and their intake adapted according to regular nutritional surveys.

  
  
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  There is necessity to maintain minimal oral feeding to (1) reduce parenteral caloric needs and (2) prevent complications of being maintained exclusively on HPN (bacterial translocation, liver disease, biliary complications, intestinal partial villous atrophy, especially, that induced by bacterial overgrowth …)

  
  
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  Mitochondrial cytopathies may require specific vitamin supplementation regimes: coenzyme Q10, ubiquinone or its synthetic variant, idébenone.

Surgical Procedures

Surgical procedures often take place before or during CIPO management. Surgery cannot be curative in this context, so its use should be limited to refractory form of CIPO and in very selected indications. The most common and effective surgical procedure is the creation of a venting or feeding ostomy. Venting ostomies decrease the frequency of vomiting and of admission for acute obstructive symptoms and also prevent abdominal pain and retching in patients who have undergone antireflux surgery. Besides, gastrointestinal motility may improve as the bowel becomes less dilated. Furthermore, a combined nasogastric-nasojejunal tube is available that allows simultaneous gastric suction and jejunal infusion. Exploratory laparotomy could be done to lyse adhesions where there is a suspicion of mechanical bowel obstruction caused by a previous laparotomy. In those cases, full-thickness biopsy or limited small bowel resection can be performed to facilitate a detailed histopathologic study. Bowel resection or surgical bypass should be resisted at all cost. Only a very few patients with disease that is well documented to be isolated to a given segment can benefit from resection or bypass procedures. On the contrary, those with extensive disease will not benefit and are likely to experience perioperative complications. In those rare cases in which patients with CIPO are nonresponsive to maximal medical and surgical therapy and have developed complications, such as dehydration or severe intestinal translocation, they may benefit from subtotal bowel resection or intestinal transplantation. Intestinal transplantation has become a life-saving procedure for patients with irreversible intestinal failure. The indications were defined as life-threatening complications of HPN, lack of venous access for HPN, chronic intestinal failure with a high risk of mortality, and primary disease-related poor quality of life despite optimal HPN. To date, approximately 1300 intestinal transplantations have been performed (40% in adult patients); approximately 8% of adults underwent transplantation for intestinal failure caused by CIPO. Multivisceral transplantations were often performed for this indication with a 1-year patient and graft survival rates (approximately 80% and 65%, respectively) that were relatively similar to those for other etiologies of intestinal failure. Intestinal transplantation should be considered in adult patients suffering from CIPO who have life-threatening complications related to PN.

Natural History

Pediatric forms of CIPO usually present at birth or in early infancy. Adult forms occur in young people (20–40 years), with more women than men (sex ratio of 2:3) affected. Symptoms of CIPO are directly related to ineffective propulsion and include the classic features of bowel obstruction, including nausea, vomiting, abdominal pain or distension, anorexia, and weight loss. Symptoms often are chronic and continuous and progressively increase in frequency and severity with time. There seems to be no difference in the nature of symptoms at the time of onset and at follow-up. Sometimes CIPO is revealed only at the time of surgery for an acute obstructive episode mimicking mechanical bowel obstruction. In its more severe clinical form, CIPO manifests as total oral intolerance, permanent obstruction, intractable pain, and rapid loss of weight with protein energy malnutrition and life-threatening deficiencies, requiring HPN.

Long-term outcome is generally poor, despite surgical and medical therapy. Three types of complications are frequently reported in CIPO: (1) HPN-related complications (catheter related sepsis, thrombosis, PN-related liver disease) ; (2) complications related to associated diseases, such as renal and urinary, cardiac, and central and peripheral nervous system diseases; and (3) specific complications of CIPO (dehydration, metabolic disturbances, bacterial translocation, peritonitis, gastroesophageal reflux disease with or without Barrett’s mucosa, aspiration pneumonia). In the literature, the incidence of PN-related complications does not seem to differ between CIPO-related and other causes of intestinal failure. However, one would predict that PN-related liver disease may develop more rapidly in patients with CIPO because of the presence of bacterial overgrowth and the occurrence of bacterial translocation.

In CIPO, HPN is required from 60% to 80% of infants and 20% to 50% of adults. In infants, long-term outcome is characterized by a 10% to 25% likelihood of mortality before reaching adulthood. Although part of the morbidity and mortality is attributable to complications of treatment, including surgery and parenteral nutrition, studies have identified some factors predictive of a poor outcome in children: short small bowel, exclusively parenteral nutrition with enteral feeding not possible, urinary tract involvement, neonatal forms of CIPO, absence of migrating motor complex activity on manometry, and the presence of a visceral myopathy. Congenital CIPO has also been associated with increased morbidity and mortality compared with acquired forms. While initial reports revealed a 25% to 30% mortality rate at early follow-up, recently, 2 studies reported a 10% mortality rate after a mean follow-up of, respectively, 17.5 and 4.6 years.

In Our Practice

In adults, the clinical course, long-term outcome, and prognostic factors are less well known because available data are limited to clinical series reporting on small numbers of patients of heterogeneous etiology and variable disease severity. From January 1980 to April 2006, we reviewed the medical records of all consecutive adult patients with a diagnosis of CIPO followed up at our institution for HPN. In this population (51 CIPO patients), from the first symptom occurrence to the time of diagnosis, a body mass index (BMI) decrease from 20 ± 3.4 kg/m ² to 17 ± 3.2 kg/m ² was observed. Delay between first symptom occurrence and HPN initiation was 3.2 (range, 0–23) years. HPN duration was 2.5 (range, 0–21) years. The number of infusions per week was 5.9 ± 1.4, with a volume per infusion of 2354 ± 793 mL and a total energy input of 1444 ± 349 kcal per infusion. The degree of HPN dependence was 64% ± 25%. A clinically important improvement in BMI from 16.8 ± 3.2 kg/m ² to 18.5 ± 2.5 kg/m ² was observed with dietary and HPN management, although reversal to premorbid BMI was not achieved. Considering the oral intake, 33% had adaptive hyperphagia, whereas 30% had a total oral intolerance to oral intake. At the end of follow-up, the Buzby index was 82% ± 10% and, of the 51 patients, 33% and 55% still featured moderate and severe malnutrition, respectively.

Surgery was required in 84% of cases with 3.0 ± 3.3 procedures per patient. Nineteen patients (37%) had undergone surgery at the time of their first presentation and before the diagnosis of CIPO. After the diagnosis of CIPO, a clinically significant reduction in the mean (per patient per year) number of surgical procedures was observed, decreasing from 2.2 ± 5.3 to 0.3 ± 0.5, and, specifically, the number of exploratory laparotomies decreased from 0.57 ± 1.4 to 0.008 ± 0.02. Surgical procedures were explorative laparotomy in 43% of cases, intestinal resection in 67%, and venting or end ostomy in 69%. Intestinal resections included subtotal colectomy (n = 14), small bowel resection (n = 19), ileocolonic resection (n = 13), and subtotal small bowel resection (n = 8). Twenty-eight venting (or feeding) gastrostomies were performed during follow-up.

Survival of CIPO patients was not significantly different than that in our population of short bowel patients (n = 309; 78% vs 72% at 5 years, P = .07) . In multivariate analysis, mortality was significantly decreased when there was an ability to restore oral feeding at baseline (hazard ratio [HR], 0.2 [0.06–0.65]; P = .008) and where symptoms occurred before the age of 20 (HR, 0.18 [0.04–0.88]; P = .03). In contrast, mortality was significantly increased in systemic sclerosis (HR, 10.4 [1.6–67.9]; P = .01).

Thirty-nine (76.5%) patients were permanently dependent on HPN. Six patients had experienced intermittent periods of weaning off HPN. Three of these 6 patients were definitively weaned off after a mean HPN period of 7 (range, 3–16) months. The other 3 patients restarted HPN after a mean delay of 70 (range, 31–130) months. Actuarial HPN dependence probabilities were 94%, 75%, and 72% at 1, 2, and 5 years, respectively . The likelihood of weaning off HPN was significantly lower in the idiopathic form of CIPO (HR, 30.4, confidence interval (CI) [2–489]; P = .02) and where the postabsorptive plasma citrulline level was lower than 20 μmol/L (HR, 17.3, CI [1–292]; P = .05).