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