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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e3182187bab
Short Communication

Neostigmine in the Treatment of Refractory Constipation in Critically Ill Children

González, Rafael; López-Herce, Jesús; García, Ana; Botrán, Marta; Solana, Maria Jose; Urbano, Javier

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Author Information

Pediatric Intensive Care Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Address correspondence and reprint requests to Dr J. López-Herce Cid, Pediatric Critical Care Department, Hospital General Universitario Gregorio Marañón, Dr Castelo, 47, 28009 Madrid, Spain (e-mail: pielvi@hotmail.com).

Received 17 November, 2010

Accepted 3 March, 2011

The authors report no conflicts of interest.

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Abstract

ABSTRACT: Constipation is a common complication in critically ill children and it is occasionally resistant to the drugs typically used in treatment. Neostigmine has been used in some cases of refractory constipation in critically ill adults. There is no reference to its use in critically ill children. We describe 3 cases of refractory constipation in critically ill children treated with intravenous neostigmine by continuous infusion. Two patients responded well. There were no adverse effects. We conclude that continuous intravenous neostigmine can be effective in critically ill children with refractory constipation. Further studies are necessary to determine the dose and safety of the treatment.

Constipation is one of the most common complications in critically ill children, although its incidence and clinical repercussions have not been studied in detail (1). In critically ill patients, constipation can cause abdominal distension and decreased tolerance to enteral feeding (2,3).

The severity of the patient's condition, the lack of movement, the change in diet, and the administration of drugs that reduce gastrointestinal motility are the factors that are most frequently implicated in the onset of constipation in critically ill patients (4,5).

Lactulose, stimulants such as bisacodyl or sennoside, polyethylene glycol, and rectal enemas are the treatments most frequently used in constipation in critically ill children and adults (6). Occasionally, however, the condition does not respond to these drugs, and this can give rise to cases of therapy-resistant constipation (7) for which other therapeutic measures are needed.

Neostigmine is an anticholinesterase drug that has been used in some cases of refractory constipation in critically ill adults (8–11). There is no reference to its use in critically ill children. The study was approved by the local institutional review board.

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CASE 1

A 4-year-old boy was admitted to the pediatric intensive care unit (PICU) after Fontan surgery for hypoplastic left heart syndrome. In the postoperative period, he presented significant hemodynamic disturbances and supraventricular tachycardia, requiring treatment with dopamine, milrinone, epinephrine, levosimendam, amiodarone, esmolol, and cardiac pacing. In addition, he developed a chylothorax, which was treated using a medium-chain triglyceride-based diet and intravenous octreotide infusion. Prolonged mechanical ventilation was therefore necessary, and the patient was administered sedation-analgesia with midazolam (maximum dose 5 μg · kg−1 · min−1), fentanyl (up to 3 μg · kg−1 · h−1), propofol (up to 4 mg · kg−1 · h−1), and dipyrone (by continuous infusion at 6.6 mg · kg−1 · h−1). He presented with constipation (defined to be an absence of elimination of fecal material) from the time of admission, with no feces in the rectum. Starting on the second day of admission, he received transpyloric enteral nutrition with a lactose-free formula, which was well tolerated. There were no bowel movements despite dietary (high-fiber diet), pharmacological (polyethylene glycol at a maximum dose of 1.6 g · kg−1 · day−1), and mechanical (normal saline, liquid petrolatum, and sodium picosulfate enemas, in addition to several attempts at manual disimpaction) measures. After 11 days, the patient presented significant abdominal distension with the appearance of feculent residues via the nasogastric tube. Abdominal radiography showed signs of ileus. Abdominal ultrasound excluded mechanical obstruction, and a diagnosis of refractory constipation secondary to paralytic ileus was made. The administration of opiates was interrupted and the enteral nutrition was changed to total parenteral nutrition. In view of the failure of the usual laxatives and the attempts at manual disimpaction, and after obtaining informed consent from the parents, intravenous neostigmine was started at a dose of 11 μg · kg−1 · h−1. The administration of neostigmine was started 48 hours after discontinuation of the opioids. Ten hours after starting the infusion, intestinal peristalsis was found to have increased, evidenced by an increase in bowel sounds, the passage of gas, and an abundant bowel movement; we were thus able to withdraw the neostigmine after 12 hours. No treatment-related adverse effects were observed. Oral feeding was then recommenced with a high-fiber diet and polyethylene glycol was administered enterally with a good subsequent clinical course.

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CASE 2

A 7-year-old boy was admitted to the PICU after Fontan surgery for hypoplastic left heart syndrome. After surgery, he presented with multiorgan failure with a low cardiac output that required a continuous infusion of dopamine, milrinone, epinephrine, and norepinephrine. Mechanical ventilation was needed for 15 days and continuous venovenous hemodiafiltration for 21 days because of renal insufficiency. Sedation and analgesia were provided to the patient initially with continuous infusion of fentanyl (maximum dose 2 μg · kg−1 · h−1) and midazolam (maximum dose 2 μg · kg−1 · min−1) and later with propofol (maximum dose 3 mg · kg−1 · h−1).

Continuous enteral feeding with a complete polymeric diet via a transpyloric tube was started 48 hours after admission to the PICU. Six days after surgery he developed abdominal sepsis with suspected necrotizing enterocolitis. Feeding was therefore changed to parenteral nutrition and intravenous antibiotics were started. Exploratory surgery was performed, but intestinal resection was not required. Enteral nutrition was reintroduced 6 days later. Bowel sounds had not returned 10 days after the exploratory laparotomy; there had been no elimination of fecal material since admission, and abdominal distension was seen to be increasing. Mechanical obstruction was not observed after abdominal radiography, ultrasound, and barium enema, and a diagnosis of refractory constipation was made. Opioid drugs were discontinued on suspicion of paralytic ileus. One dose of macrogol (6.5 g) was provided.

A continuous intravenous infusion of neostigmine was started on day 16 after admission (10 days after withdrawal of intravenous opioids and 3 days after withdrawal of enteral opioids). Elimination of fecal material was observed within 2 hours after initiation of the neostigmine infusion. The maximum dose of neostigmine used was 5 μg · kg−1 · h−1 and there were no adverse effects. The infusion of neostigmine was discontinued after 18 hours. After resolution of the refractory constipation, continued laxative treatment was provided with polyethylene glycol.

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CASE 3

A 17-year-old boy was admitted to the PICU after a heart transplant. In the postoperative period, he developed cardiogenic shock requiring treatment with dopamine, dobutamine, milrinone, epinephrine, norepinephrine, isoproterenol, and amiodarone. Prolonged mechanical ventilation was required and the patient received sedation-analgesia with midazolam (up to 6 μg · kg−1 · min−1), dipyrone (continuous infusion at 4 mg · kg−1 · h−1), propofol (maximum dose 4 mg · kg−1 · h−1), remifentanil (up to 0.16 μg · kg−1 · min−1), and fentanyl (up to 2 μg · kg−1 · h−1). Enteral nutrition was started 3 days after admission in a complete polymeric diet, which was well tolerated, although the patient had no bowel movement. Seven days after admission, significant abdominal distension developed and a high-fiber enteral feed was started. Enemas and oral polyethylene glycol were administered, and several attempts were made to achieve manual disimpaction. After 6 days there was no response to these measures and the patient presented increasing abdominal distension; the enteral nutrition and administration of opiates were therefore interrupted, and, after obtaining informed consent from the patient's father, an intravenous infusion of neostigmine was started the same day. A maximum dose of 11 μg · kg−1 · h−1 of neostigmine was used, but there was no response and the infusion was therefore discontinued after 30 hours of treatment. No treatment-related adverse effects were observed. The situation resolved 2 days later, after increasing the dose of polyethylene glycol to a maximum dose of 2 g · kg−1 · day−1.

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DISCUSSION

Several factors, including dietary changes, electrolyte disturbances, and drugs (particularly opioids), may be implicated in constipation in critically ill patients. Despite correction of these factors and other therapeutic measures, refractory constipation can develop in critically ill children, and alternative therapeutic approaches are needed.

Neostigmine acts by inhibiting acetylcholinesterase, thus increasing the concentration of acetylcholine in the synaptic space. Its effect is to increase parasympathetic activity, which enhances motor activity of the digestive and urinary tracts and increases the secretions of the exocrine glands (sweat, lacrimal, bronchial, gastric, intestinal, and pancreatic acinar), and there is an increase in respiratory secretions and bronchoconstriction. In the cardiovascular system, it provokes a decrease in heart rate, in atrial contractility, and to a lesser degree, in ventricular contractility, causing hypotension at high doses.

Neostigmine is used to reverse neuromuscular blockade provoked by nondepolarizing agents, to treat myasthenia gravis, and to prevent postoperative bladder distension and urinary retention.

A number of authors have reported using neostigmine in adults with intestinal pseudo-obstruction (8–12). The doses used have been variable, from bolus injections of 0.1 to 2.5 mg for 3 to 5 minutes to continuous infusions for several hours. Only 2 prospective, randomized studies have demonstrated the efficacy of neostigmine compared with placebo in acute colonic pseudo-obstruction (10) and in constipation in critically ill patients (11).

No studies have prospectively investigated the treatment of constipation in critically ill children. We found only 2 case reports on the use of neostigmine for the treatment of pseudo-obstruction in children. Kim et al (13) administered 3 doses of 0.01 mg/kg of neostigmine subcutaneously at intervals of 12 hours to a 9-year-old child with intestinal pseudo-obstruction during chemotherapeutic treatment for cerebellar medulloblastoma. Khosla and Ponsky (14) administered 0.01 mg/kg intravenously every 24 hours for 2 days to a 3-year-old child with sickle cell anemia who developed intestinal pseudo-obstruction. The treatment was effective in both cases. We have not found any study regarding neostigmine use in functional constipation in children.

Our study is the first to describe the use of neostigmine in constipation refractory to other drugs in critically ill children, demonstrating that it can be effective in some cases. We decided to administer the drug by continuous infusion to achieve greater control of the possible adverse effects. The dose used was similar to that employed by Van der Spoell et al adjusted for weight (0.4–0.8 mg/h in an adult, corresponding to 6–12 μg · kg−1 · h−1) (11).

Positive effects (described as bowel movements and fecal elimination) seen after neostigmine use in our patients could be caused by other measures taken, for example, the interruption of opioid administration. The effects appeared shortly after starting the administration of neostigmine rather than following the earlier interruption of opioids.

The adverse effects most frequently reported with the use of neostigmine are the onset of muscle fasciculations, sialorrhea, nausea, vomiting, abdominal pain, and diarrhea (15). Bronchospasm, arrhythmias, coronary artery spasm, and perforation of the colon have also been reported (16–20), although rarely. No adverse effects were observed in any of our patients.

We conclude that neostigmine administered by continuous intravenous infusion can be an effective treatment in critically ill children with constipation refractory to other drugs. Further studies are necessary to determine the most appropriate dose and the efficacy and safety of this treatment.

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REFERENCES

1. Nassar AP, da Silva FMQ, de Cleva R. Constipation in intensive care unit: incidence and risk factors. J Crit Care 2009; 24:630e9–630e12.

2. Mostafa SM, Bhandari S, Ritchie G, et al. Constipation and its implications in the critically ill patient. Br J Anaesth 2003; 91:815–819.

3. López-Herce J. Gastrointestinal complications in critically ill patients: what differs between adults and children? Curr Opin Clin Nutr Metab Care 2009; 12:180–185.

4. Triantafyllou K, Vlachogiannakos J, Ladas SD. Gastrointestinal and liver side effects of drugs in elderly patients. Best Pract Res Clin Gastroenterol 2010; 24:203–215.

5. Zeino Z, Sisson G, Bjarnason I. Adverse effects of drugs on small intestine and colon. Best Pract Res Clin Gastroenterol 2010; 24:133–141.

6. Herbert MK, Holzer P. Standardized concept for the treatment of gastrointestinal dysmotility in critically ill patients—current status and future options. Clin Nutr 2008; 27:25–41.

7. Saunders M. Acute colonic pseudo-obstruction. Best Pract Res Clin Gastroenterol 2007; 21:671–687.

8. Turégano-Fuentes F, Muñoz-Jiménez F, Del Valle-Hernández E, et al. Early resolution of Ogilvie's syndrome with intravenous neostigmine: a simple, effective treatment. Dis Colon Rectum 1997; 40:1353–1357.

9. Paran H, Silverberg D, Mayo A, et al. Treatment of acute colonic pseudo-obstruction with neostigmine. J Am Coll Surg 2000; 190:315–318.

10. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med 1999; 341:137–141.

11. van der Spoel JI, Oudemans-van Straaten HM, Stoutenbeek CP, et al. Neostigmine resolves critical illness-related colonic ileus in intensive care patients with multiple organ failure—a prospective, double-blind, placebo-controlled trial. Intensive Care Med 2001; 27:822–827.

12. Trevisani GT, Hyman NH, Church JM. Neostigmine: safe and effective treatment for acute colonic pseudo-obstruction. Dis Colon Rectum 2000; 43:599–603.

13. Kim T, Lee J, Kim M, et al. Acute colonic pseudo-obstruction in postchemotherapy complication of brain tumor treated with neostigmine. J Pediatr Hematol Oncol 2007; 29:420–422.

14. Khosla A, Ponsky TA. Acute colonic pseudoobstruction in a child with sickle cell disease treated with neostigmine. J Pediatr Surg 2008; 43:2281–2284.

15. Cheng C, Sessler DI, Apfel CC. Does neostigmine administration produce a clinically important increase in postoperative nausea and vomiting? Anesth Analg 2005; 101:1349–1355.

16. Hazizaj A, Hatija A. Bronchospasm caused by neostigmine. Eur J Anaesthesiol 2006; 23:85–86.

17. Zeidan A, Baraka A. Ventricular fibrillation following atropine-neostigmine mixture in a patient with undiagnosed mitral valve prolapse. Anaesthesia 2005; 60:724–725.

18. Bjerke RJ, Mangione MP. Asystole after intravenous neostigmine in a heart transplant recipient. Can J Anaesth 2001; 48:305–307.

19. Kido K, Mizuta K, Mizuta F, et al. Coronary vasospasm during the reversal of neuromuscular block using neostigmine. Acta Anaesthesiol Scand 2005; 49:1395–1396.

20. Mollema R, Spijkstra JJ, Polderman KH, et al. Perforation of the colon after administration of neostigmine. Intensive Care Med 2004; 30:730.

Keywords:

constipation; critically ill children; neostigmine

Copyright 2011 by ESPGHAN and NASPGHAN

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