This chapter aims to provide treatment algorithms for individual gastrointestinal symptoms as originally proposed in 2000.⁸ The evidence for any recommendations made is often poor due to the lack of randomized controlled trials (RCTs) in pediatric palliative care and, unfortunately, pediatrics continues to be hampered by the common, unacceptable problem of many medications not being approved for use in children or for the specified indication resulting in off-label use.

Nausea and Vomiting

Nausea and vomiting is one of the most distressing symptoms for ill children and their caregivers. Gastrointestinal, central nervous system (CNS), metabolic, pharmacologic, and psychological factors may all contribute, and prolonged episodes of nausea and vomiting may themselves contribute to the development of anticipatory nausea and conditioned vomiting. Treatment approaches are best based on the presumed, following careful assessment, underlying pathophysiology and management should include integrative therapies, such as cognitive behavioral therapies, aromatherapy, and acupressure, where appropriate.

Pathophysiology

Vomiting is controlled by two distinct brain centers, the vomiting center and the chemoreceptor trigger zone (CTZ). Both are located in the medulla oblongata with the CTZ lying outside the blood-brain barrier in the area postrema at the floor of the fourth ventricle, while the vomiting center is located inside the blood-brain barrier.

Excitation of the vomiting center results in nausea and vomiting and the reflex may result from the following input:

• Direct activation of the CTZ. Responds to metabolic products or medications in the blood or cerebrospinal fluid.

• Dopamine type 2 (D₂)-receptors in the area postrema are stimulated by emetogenic substances such as calcium, uremia products, opioids, and digoxin.⁹

• 5-Hydroxytryptamine (5HT)₃-receptors, also located at the area postrema, respond to many cancer-directed chemotherapy drugs and uremia.

• Stimulation via the vestibular apparatus.

• Muscarinic acetylcholine (ACh_m).

• Histamine (H₁) excitatory receptors.

• Gut wall and vagal and/or splanchnic afferents. Both carry 5HT₃-receptors, the former also has 5HT₄ and D₂-receptors.

• All play an important emetic role and are activated by distention in the gut lumen, abdominal radiotherapy, and chemotherapy when serotonin (5HT) is produced by the enterochromaffin cells lining the lumen epithelium.

• Peripheral or central afferents. Emetogenic stimuli reaches the central nervous system via afferent pathways with the nucleus tractus solitarii probably playing a coordinating role.

• Sensory stimuli such as smells that have previously been associated with episodes of vomiting can become triggers for anticipatory nausea and so-called conditioned vomiting.

Toxins commonly associated with nausea and vomiting during the pediatric end-of-life period include medications such as chemotherapeutic agents, antibiotics, and opioids, and metabolic byproducts of uremia or hepatic failure.¹⁰

The majority of receptors in the vomiting center and CTZ are excitatory, that is, they induce nausea and vomiting with stimulation. An important exception is the presence of the μ-opioid receptor in the vomiting center. Opioids seem to have a dose-dependent interaction on emesis. At standard doses, opioids may cause nausea by stimulating D₂-receptors in the area postrema but at high doses opioids are often not emetic. This is postulated to be due to an antiemetic or inhibitory effect at the μ-opioid receptor in the vomiting center.^9,¹¹

Opioid-Induced Nausea

Although individual patients may tolerate one opioid better than another, data suggest that prevalence of these side effects differ greatly among the commonly used opioids. Children usually develop tolerance to nausea, however this may take days to occur. From experience the single most helpful approach to opioid-induced nausea in the Minneapolis pediatric pain and palliative care patients represents a rotation or a switch to another opioid at an equianalgesic dose.¹²

Alternatively, low-dose naloxone infusions, at 0.25–1 mcg/kg/h, can reduce the frequency and severity of nausea without antagonizing analgesia in children who receive opioids.¹³ Infusion rates used are several-fold lower than infusion rates typically used to produce measurable reversal of analgesia or respiratory depression.

If neither an opioid rotation nor low-dose naloxone infusion are effective or feasible in the disease trajectory, then the addition of a dopamine (D₂)-receptor antagonists such as metoclopramide and antiemetics of other classes should be considered, see later in this chapter.

Treatment algorithm

They may, however, be underused due to an overemphasis on possible extrapyramidal reactions. Metoclopramide has been associated with a dyskinetic syndrome and reported to occur with an incidence of 1:5000 in teenagers.³¹ Any such reaction can be treated with either a centrally acting antihistamine, such as diphenhydramine (Benadryl), or central anticholinergic, such as benztropine. This concern extends to a lesser extent to phenothiazine derivates (psychotropics) such as haloperidol (Haldol), prochlorperazine (Compazine), and chlorpromazine (Thorazine). Chlorpromazine and prochlorperazine are also H₁– and ACh_m– receptor antagonists.

Domperidone does not cross the blood-brain barrier and therefore does not cause extrapyramidal side effects. The intravenous form of domperidone was discontinued following reports of cardiovascular adverse effects.

Prokinetics should not be administered concurrently with antimuscarinic agents, such as diphenhydramine or scopolamine, as these block the final common pathway for prokinetic agents. The concurrent administration of diphenhydramine and metoclopramide to prevent a dyskinetic syndrome, as practiced in some centers, will therefore result in the loss of metoclopramide’s prokinetic effect, however not of its antiemetic effect. The concurrent intravenous administration with 5-HT₃-receptor antagonists increases the risk of cardiac arrhythmia. Droperidol (Inapsine), a butyrophenone neuroleptic similar to haloperidol, can no longer be recommended because of the risk of QT prolongation.

H₁– and ACh_m– Receptor Antagonists

Histamine-1 and muscarinic acetylcholin receptor antagonists are effective antiemetics in daily clinical practice though there are no pediatric RCTs. These medications have an astounding regional preference without any head-to-head comparison. The first-generation antihistamine diphenhydramine (Benadryl) has a significant anticholinergic, especially sedating, side effect and is hardly used as a first-line medication outside North America. Promethazine (Phenergan), commonly used in Australia, is similarly sedating. In central Europe the preferred pediatric antiemetic is dimenhydrinate (Dramamine), which in clinical practice rarely causes over-sedation. The most commonly used antinausea drug in the UK on the other hand is cyclizine.

Scopolamine, an ACh_m, but not H₁, receptor antagonist with stronger anticholinergic side effects than dimenhydrinate or cyclizine, can also be administered as a transdermal patch.

Medications that also have D₂-receptor antagonistic properties include chlorpromazine, prochlorperazine, and levome-promazine. The latter, in our experience, is particularly helpful in refractorary nausea in pediatric palliative care and is not available in the United States.

NK₁-Receptor Antagonists

Aprepitant (Emend), a neurokinin-1 receptor antagonist, possesses antidepressant, anxiolytic, and antiemetic properties. NK₁ receptors can be found in the central and peripheral nervous system, as well as the gastrointestinal tract. RCTs indicated it to be superior to ondansetron 24 to 48 hours post-surgery when given as a single pre-operative dose ^32,³³ but, in general, pediatric data is scarce.³⁴ One RCT (n = 46) in adolescents with chemotherapy-induced nausea and vomiting showed the combination of aprepitant (125 mg IV TID), dexamethasone, and ondansetron to be superior to dexamethasone and ondansetron alone.³⁵

Cannabinoids

The activation of the endocannabinoid system suppresses behavioral responses to acute and persistant noxious stimulation, and d-9-tetrahydrocannabinol (THC) has been shown to have an antiemetic effect.³⁶ THC can also stimulate appetite in addition to minimizing nausea.

Two types of cannabinoid receptors have been identified, CB₁ and CB₂. CB₁ receptors are found in the central nervous system, including periaqueductal gray, rostral ventro-medial medulla and in peripheral neurons, where activation produces a suppression in intestinal neurotransmitter release.³⁷ Dronabinol and nabilone do not fully replicate the effect of total cannabis preparations³⁸ but a meta-analysis of 30 RCTs (n = 1366 patients)³⁹ showed cannabinoids to be effective for controlling chemotherapy-related sickness in adults. Adverse effects included dizziness, dysphoria, depression, hallucinations, paranoia, and arterial hypotension.

Corticosteroids

Nausea caused by raised intracranial pressure secondary to a brain tumor may show dramatic short- to medium-term improvement with corticosteroid administration. Agents such as dexamethasone are thought to act by reducing the peri-tumor edema. In addition, corticosteroids inhibit prostaglandin synthesis, which may also play an antiemetic role. Because of the significant side effect profile, including mood swings and excessive weight gain, associated with this class of drugs use in palliative care is controversial.⁴⁰

Benzodiazepines

Low-dose benzodiazepines, such as midazolam, lorazepam, or diazepam, can be a part of an effective antiemetic drug treatment in pediatric palliative care. However, there is only limited pediatric data with RCTs showing effectiveness for postoperative nausea ^41,⁴² and chemotherapy-induced nausea.^43,⁴⁴

Propofol

Propofol possesses antiemetic properties at subhypnotic doses.^45,⁴⁶ The mechanism of action of this short-acting hypnotic and general anesthetic is not well defined and possibly includes potentiation of GABA-A receptor activity,⁴⁷ sodium channel blocking activity,⁴⁸ and activation of the endocannabinoid system.⁴⁹ One adult case study reports successful nausea management in palliative cancer care at 0.6–1 mg/kg/h intravenously.⁵⁰ Little pediatric data is published⁵¹ but the experience of the program in Minnesota with low-dose propofol in 12 children and teenagers⁵² points to it having an important role in managing refractory pain and nausea at the end-of-life when other agents fail (Table 33–1).

TABLE 33-1 Medications in the Treatment of Nausea and Vomiting

Summary

A multimodal approach to controlling nausea and/or vomiting should be directed toward the most likely assessed pathophysiology. Uni-modal approaches including pharma-cology alone have a high risk of treatment failure in pediatric palliative care. The evidence does not allow for a step-by-step approach when the underlying mechanism remains unclear but clinical experience would suggest the following pharmacologic approach can work well. The palliative care teams in Minneapolis as well as in Auckland usually schedule a single medication and add another scheduled agent acting on a different receptor group if ineffective, not infrequently requiring two, three, or even four scheduled around-the-clock antiemetics.

First Line

1. 5-HT₃-receptor antagonist, such as ondansetron; and/or

2. D₂-receptor antagonist, such as metoclopramide; and/or

3. H₁ & ACh_m-receptor antagonist, such as dimenhydrinate

Second Line

1. Consider adding corticosteroid, such as dexamethasone as a short-term pulse.

2. Add a low-dose benzodiazepine such as midazolam.

3. Substitute first-line drugs of same class, such as rotation to granisetron, haloperidol, diphenhydramine.

4. Consider substituting phenothiazine, such as chlorpromazine, for both antihistamine and dopamine receptor antagonist.

Third Line

1. Consider aprepitant.

2. Add cannabis, such as dronabinol.

3. Consider low-dose propofol.

Considerations in the setting of bowel obstruction include octreotrid (see following text).

Constipation

Hardly any other topic in palliative care provokes more discussion than the treatment of constipation. This could be in part due to it being such a common symptom, at 27% to 59% in children at the end of life, that healthcare workers feel sufficiently knowledgeable about its treatment to have an opinion. Yet, constipation can be quite difficult to manage, resulting in a significant impact on the child and their family. This makes prevention of constipation of utmost importance in pediatric palliative care.

Normal stool frequency varies in children from three times per day to once every 3 days, and in the case of a breast-fed infant, up to once every 2 weeks. Common reasons for constipation in pediatric palliative care include dietary changes, a decrease in fluid and/or food intake, and a decrease in mobility and activity as colon peristalsis is, in part, stimulated by activity.

Chronic constipation is common in children with underlying neurologic impairments related to longstanding poor tone and immobility, while in children with cancer intra-abdominal tumors can cause direct compression of the gut or spinal cord compression.¹⁰

Treatment algorithm

Step 1: Evaluation and assessment

Constipation commonly results in abdominal pain, bloating, flatulence, nausea and vomiting. The presence of sloppy, foul-smelling feces and soiling should be an alert to the presence of constipation with overflow incontinence.

As with the evaluation of any symptom, a thorough history is required and focused examination must be completed. Adolescents in particular may not volunteer important information about changes in bowel habit because of embarrassment, so it is important to tactfully check for specific changes.

Examination includes a rectal examination, using the small finger for small children, to evaluate whether the rectum contains stool and what consistency it is. There are a number of circumstances where this part of the examination may not be advisable, particularly when the child is neutropenic or thrombocytopenic. The exam can be helpful in ruling out local pain from anal fissures or hemorrhoids as a cause for constipation.

Attention needs to be paid to warning signs indicating neurologic compromise, such as: lower extremity motor weakness, paresthesisias, urinary retention, and fecal incontinence.

If the diagnosis is in question, then an abdominal radiograph or an ultrasound may be helpful in the assessment of stool content and to rule out an obstruction.

Step 2: Treatment of Underlying Causes

Underlying causes of constipation should be treated, if possible. In addition to the previously mentioned common reasons for constipation, consideration should be given to management of anorexia (see following text), weakness, decreased abdominal muscle tone, inconvenient toilet access, poor posture, and psychological factors such as depression. More specific pathologies to consider are hypothyroidism, hypokalemia, hypercalcemia, bowel obstruction (see later text), and adverse effects of medication.⁵³

Step 3: Implement Integrative and Supportive Therapies

Whenever possible, integrative and supportive approaches need to be implemented to manage a child’s constipation, and include:

• The establishment of a regular bowel routine should be supported: The strongest propulsive contractions occur postprandial, especially after breakfast. Access to a toilet or potty, with privacy for older children, daily at this time may be beneficial.

• Encourage the increase of activity, which may include the help of physical therapy or child life specialist, outside of a bed if possible.

• Increase fluid intake of the child’s favorite drinks.

• Increase dietary fiber. Prune juice is often well liked.

• Consider abdominal massage in clockwise fashion.

• Carefully review medications and their constipating side effects, including opioids (see following text), tricyclic antidepressants, phenothiazines, diuretics, antihistamines and/or anticholinergics, and iron supplements. Self-hypnosis, biofeedback and cognitive-behavioral therapy may be effective in children with neurogenic bowel.

Step 4: Pharmacologic Management

A stool softener without a stimulant is mush without push.

A rational approach usually seems to include the scheduled administration of a stool softener and, if ineffective, the addition of a stimulant. However, with distressing constipation, especially when the rectal exam reveals hard stool in the ampulla in conjunction with abdominal pain, children may have to be unplugged first with the use of a rectal suppository or an enema. A manual evacuation would be usually reserved for adult-sized teenagers, if the former approaches fail.

Stool Softener

Stool softeners include liquid osmotic laxatives, such as lactulose, sorbitol, and polyethylene glycol, which draw water into the bowel by osmotic effect and surfactant laxatives including docusate sodium, which increase water penetration.

Outside the United States, the most commonly used stool softener in pediatrics appears to be the sugar lactulose, a combination of galactose and fructose (Enulose).^54,⁵⁵ Lactulose does not affect the management of diabetes mellitus. In North America, polyethylene glycol (Miralax) is frequently used instead, and has also shown to be effective and safe.^54,⁵⁶^–⁵⁸ Lactulose’s advantage over polyethylene glycol is the much smaller volume, which is beneficial in the pediatric palliative care setting, where children often have trouble taking medication orally. All laxatives, including stool softeners, may cause abdominal pain and meteorism.

Stimulant laxatives

Children with a full rectum containing soft feces, or those for whom stool softeners were ineffective as a single approach, may be treated with a stimulant laxative such as senna ⁵⁹ or bisacodyl, to stimulate bowel motility. These medications act by stimulation of the myenteric plexus. However, stimulants alone can be dangerous when there is obstruction or impaction.⁵³

Contrary to conventional wisdom, that stool softeners should be administered with stimulants, one recent RCT (n = 60 adults) treating opioid-induced constipation, showed that sennosides alone were superior than sennosides plus docusate.⁶⁰

Of note, the brand name Dulcolax in the United States refers to three medications: the stimulant bisacodyl and the stool softeners docusate sodium or polyethylene glycol, supporting the notion of avoiding brand names in medication.

Prokinetics

If gastrointestinal hypoactivity is a presumed pathophysiology, then prokinetics such as low-dose metoclopramide or low-dose erythromycin,⁶¹ 5 mg/kg QID, may be considered.

Suppositories and Enemas

As mentioned previously, in cases of severe impaction a child may need to receive a rectal suppository or enema for relief. Some young people are acutely embarrassed and resistant to even the thought of using a suppository or enema. This may be a particular issue in early adolescence when bodily concerns, increased self-consciousness, and concerns about privacy are prominent. Careful explanation of the choices and reasons for use of enemas or suppositories is needed, along with negotiation about who the young person would feel most comfortable with to assist them. In cancer patients with neutropenia and/or thrombocytopenia, the rectal administration needs to be weighed against the risk of infection and/or bleeding. Glycerine suppositories promote defecation by softening and lubricating the mass as well as stimulating defecation. The Pain & Palliative Care team in Minneapolis has gathered good experience with the polyphenolic bisacodyl suppositories, which act principally by promoting colonic peristalsis.

Enemas may be required if the constipation is unresponsive to combined scheduled stool softeners and stimulant laxatives. Adult data shows that sodium phosphate/sodium biphosphate enemas, or saline rectal laxatives, and docusate sodium/glycerin mini-enemas, or surfactant rectal laxatives, are equal in efficacy.⁶² However, the latter is usually preferred in pediatrics because of its much smaller enema volume of 2.5–5 mL compared with 130 mL.

If a manual evacuation is considered, adequate analgesia and sedation would be the expected standard of care.

Opioid-Induced Constipation

The mantra in adult medicine “the hand who writes the opioids without writing for laxatives is the hand who disimpacts the patient’s bowel” should serve at least as a warning in pediatrics. Unless diarrhea or other specific contraindication is present, laxatives should be prescribed routinely whenever more than one opioid dose per day is administered. The previous principles of a stool softener, possibly complemented with a stimulant and/or suppository, holds true as well.

Opioid-Antagonists

The administration of opioid-antagonists has shown to be rather effective in the management of opioid-induced constipation in adults. Pediatric studies have not yet been published.

Naloxone

The oral administration of naloxone anecdotally seems to have good effect in adult palliative care. Dose suggestions include 20% of oral morphine equivalent divided into one or several doses.⁶³ There is no published data about the intravenous administration of ultra-low-dose naloxone for constipation management, however the Minneapolis team has had several pediatric cases with very good results in their pediatric palliative care population with a dose of 0.25–1 mcg/kg/hr.

Alvimopan

Alvimopan (Entereg) is a peripherally acting μ-opioid antagonist, with limited ability to cross the blood-brain barrier. One adult RCT showed good effect without evidence of opioid analgesia antagonism, with an adult dose of 0.5 mg BID PO.⁶⁴

Methylnaltrexone

Methylnaltrexone (Relistor) is a quaternary amine μ-opioid-receptor antagonist, and has restricted ability to cross the blood-brain barrier. An adult RCT showed good effect and treatment did not affect central analgesia or precipitate opioid withdrawal with an adult dose of 0.15 mg/kg every other day subcutaneously.⁶⁵ It is unclear, whether or not this medication may be administered intravenously. Pediatric trials, although undertaken, have not yet been published (Table 33-2).

TABLE 33-2 Medications in the Treatment of Constipation

Diarrhea

A significant number of children (21% to 40%) experience diarrhea during their end-of-life period. Fecal incontinence is often particularly humiliating for older children and adolescents who have been previously independent in their personal cares.

Treatment algorithm

Step 1: Evaluation and Assessment

A child suffering from diarrhea in palliative care needs to be evaluated, which includes taking a careful history and performing a clinical exam. Common causes of diarrhea include gastroenteritis, malabsorption, laxative overuse, overflow constipation, fecal impaction, adverse effects to medication such as antibiotics or chemotherapy, radiation therapy, or concurrent illness, such as colitis. Anal leakage may occur following surgical or pathological injury to the anal sphincter.⁶⁶

Step 2: Treatment of Underlying Causes

Severe diarrhea resulting in dehydration may require oral rehydration with electrolyte/glucose solution. If possible and feasible in the individual child, underlying causes of diarrhea should be treated. Frequent treatable causes include:^67,⁶⁸

• Overflow incontinence caused by constipation or fecal impaction.

• Anxiety.

• Enteral feeding and/or feeding intolerance.

• Laxative overuse.

• Radiation-induced gastrointestinal damage.

• Irritable bowel syndrome.

• Inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease.

• Malabsorption and steatorrhea from decreased pancreatic function Bacterial infections: Antibiotic therapy, usual after stool sensitivity testing, is rarely indicated. Exceptions include presence of Shigella, Salmonella typhi/paratyphi, or Clostridium difficile toxine, the latter usually preceded be antibiotic administration. In severe clinical causes antibiotic treatment would be indicated with infections by camphylobacter, enteropathogen E. coli or Yersinia. In patients with AIDS, Mycobacterium avium-intracellulare may be causative in diarrhea.

• Viral infections: Pathogens include adenovirus, cytomegalovirus (CMV), ECHO-Virus, human immunodeficiency virus (HIV), Norwalk virus, and rotavirus. A specific therapy is available only for CMV, and rotavirus vaccination is effective.⁶⁹

• Enteric protozoal infections, prevalent in immunocompromised patients, such as those with AIDS: Possible pathogens include Cryptosporidium, Giardia lamblia, and Microsporidium.

• Carcinoid syndrome.

• Vasoactive intestinal peptide tumor (VIPoma).

• Rule out celiac disease, cystic fibrosis, and lactate intolerance.

Step 3: Implement Integrative and Supportive Therapies

Integrative and supportive therapies in the management of diarrhea in pediatric palliative care may include:⁶⁷

• Encourage oral rehydration with glucose/electrolyte solution, if possible.

• Consider decrease of milk intake: Bacterial gastroenteritis may result in transient lactase deficiency.

• Consider decrease of enteral intake, either solid dietary intake including bran and fruit or reduction of rate and/or osmolarity of nutrition formula.

• Prevention of skin breakdown with frequent skin care of perianal area, including application of barrier creams or zinc oxide paste.

• Assistance with toileting and washing and the use of continence aids, which need to be sensitively handled. Young people may worry especially about the possibility of incontinence while in the presence of friends and peers, and this may lead to them avoiding contact. Adopting an active problem solving approach may help to examine all possible ways of handling potentially embarrassing situations, including use of disposable pads and/or continence pants, timing of visits, and enlisting a close friend or family member as support.

Step 4: Pharmacologic Management

RCT in the management of diarrhea in pediatric palliative care do not exist, however some studies include children with life-limiting conditions.

Loperamide

Loperamide is a potent μ-receptor opioid agonist and, although well absorbed from the gastrointestinal tract, it is almost completely metabolized by the liver and excreted via the bile. Loperamide does not cross the blood-brain barrier. As a result this agent acts via a local effect in the GI tract. However, it may take 16 to 24 hours for loperamide to show maximum effect in diarrhea treatment.⁷⁰ As with morphine and other opioids, loperamide decreases propulsive activity, but unlike other opioids also has an antisecretory effect.⁷¹ If toxic substances are the pathophysiologic basis of diarrhea and need to be excreted, then the use of loperamide is not recommended.

Although three pediatric trials (n = 95) did not show a significant lorapamide effect,⁷²^–⁷⁴ four other trials were able to demonstrate a decrease in stool frequency and duration of diarrhea.⁷⁵^–⁷⁸ A case series of 15 children with chronic diarrhea following resection of advanced abdominal neuroblastoma, possibly resulting from disruption of the autonomic nerve supply to the gut during clearance of tumor from the major vessels of the retroperitoneum, demonstrated that loperamide reduces but did not abolish symptoms.⁷⁹

Adverse effects, such as constipation or bloating, were uncommon in these trials and case reports. However children, especially infants, occasionally demonstrated central nervous side effects such as opioid over-sedation. Of note, inhibitors of P-glycoprotein such as ketoconazole, omeprazole, quinidine, and verapamil allow loperamide to cross the blood-brain barrier and as a result manifest central opioid effects.⁸⁰ An overdose of loperamide in 216 cases has not resulted in life-threatening adverse effects or deaths with doses up to 0.94mg/kg.⁸¹

Bismuth subsalicylate

The mechanism of bismuth subsalicylate (Pepto-Bismol) is not well understood. A decrease in length of acute diarrhea symptoms could be shown in children with acute ^82,⁸³ and chronic^70,⁸⁴ diarrhea. To prevent Reye’s syndrome, this medication and other salicylates should not be administered in children with viral infections.⁸⁵ The administration of bismuth subsalicylate may result in black stools.

Colestyramine

Colestyramine (Questran) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. Cholestyramine is primarily administered in the management of hypercholesterolemia, but also in the treatment of pruritus induced by liver failure and chronic diarrhea. Three pediatric trials ^74,^86,⁸⁷ (n = 78) resulted in a reduction in the duration of diarrhea. Case reports in the successful management of chronic pediatric diarrhea have been published.⁸⁸^–⁹¹ One study (n = 39 infants and children) showed treatments with cholestyramine and bismuth sub-salicylate were equally effective in decreasing stool frequency in patients with green diarrhea, such as following partial illeocolectomy or Candida albicans overgrowth, however children with brown stools had an insignificant response to therapy.⁷⁰ Because cholestyramine is not absorbed systemically, there are no severe systemic side effects. Possible adverse effects, such as abdominal pain, flatulence, and constipation, were not reported in the pediatric literature.

Octreotride

In the management of secretory diarrhea, including carcinoid-associated, vasoactive intestinal peptide (VIP) tumors, or AIDS, the administration of the somatostatin analogue octreotride may represent a successful approach. The secretory effect of several gastrointestinal active hormones. such as gastrin, colecystokinine, secretine, VIP, and motiline/ may be inhibited. Four case reports (n = 6 children) showed a successful approach in the treatment of chronic diarrhea caused by intestinal graft vs. host disease, cryptosporidium enteritis, and status post ileum resection.⁹²^–⁹⁵ See Bowel Obstruction later in this chapter (Table 33-3).

TABLE 33-3 Medications for the Treatment of Diarrhea

Anorexia and Cachexia

At its simplest, anorexia is a loss of appetite, while the definition of cachexia has been disputed until recently. In 2008 a consensus definition for cachexia emerged as “a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass.”⁹⁶ Anorexia and cachexia are two interrelated symptoms that are often acknowledged together as the anorexia-cachexia syndrome.

The symptoms of anorexia and cachexia, assuming weight loss is a marker of cachexia, appear to be highly prevalent in children with life-limiting conditions of both malignant ^3,^6,⁹⁷ and non-malignant origin.³ In a study⁹⁷ of 164 children and young people who died of progressive malignant disease, 48% had anorexia and 41% had weight loss on entering the study and these symptoms increased to just more than 67% in the last month of life, indicating anorexia and weight loss were not responsive to any treatments used. They were significantly more evident in children with CNS tumors when compared with leukemia and/or lymphoma or solid tumors. Similarly, a study⁶ reported a high prevalence of anorexia in children dying from cancer. However, this did not seem to result in a high level of suffering, but neither was it successfully treated.

A lower prevalence in the last week and day of life for anorexia, 33% and 24%, respectively, and weight loss, 20% and 21%, respectively, was found in 30 children dying in the hospital environment; 12 children had non-malignant conditions.⁶ They were not believed to cause undue distress to the child, but in more than half the children with the symptom were of moderate to severe intensity.

Anorexia-cachexia syndrome characterized by anorexia, involuntary weight loss, tissue wasting, weakness and poor physical function is a condition of advanced protein calorie malnutrition that inevitably leads to death ⁹⁸ if the underlying condition cannot be treated. In contrast to adults, children may manifest this problem as growth failure rather than weight loss.

For many parents the sight of their child visibly losing weight may intensify feelings of impotence and failure as parents, and lead to misunderstanding and blame within the extended family.

The mother of a teenage girl who had severe lung and liver disease as a result of cystic fibrosis became tearful and distressed by the sight of her daughter’s “stick-like legs.” After years of intense focus on weight gain and enhanced calorie intake in the management of the cystic fibrosis, the mother believed that she was failing as a mother and allowing her daughter to “starve to death.”

Pathogenesis

The process of anorexia-cachexia syndrome is complex, but what is clear is anorexia, alone, is inadequate for the syndrome to develop. In normal circumstances the reduced caloric intake from anorexia results in a loss of fat stores, which stimulates an adaptive response to maintain the fat stores. This response is driven by declining levels of leptin, a hormone secreted by adipose tissue. The consequence of low levels of leptin in the brain is for the hypothalamus to increase orexigenic signals such as neuropeptide-Y (NPY) to stimulate appetite and repress energy expenditure and decrease anorexigenic signals, corticotrophin-releasing factor and melanocortin, to achieve the same effect.⁹⁸

There is increasing evidence that the cachectic process is established by an acute phase response mediated by several cytokines of which tumor necrosis factor-α, interleukin-1, interleukin-6 and interferon-γ have been implicated. The evidence to date would suggest these cytokines stimulate the expression and release of leptin and/or mimic the hypothalamic negative feedback signaling from leptin and, in so doing, prevent the normal compensatory mechanisms in the face of reduced food intake and decreasing weight.

This abnormal response has been suggested in a study ⁹⁹ that reported on the possible role of leptin and NPY levels as prognostic indicators in children with cancer. The study revealed a mean NPY level of 82.32 pmol/L and mean leptin level of 6.60 ng/mL at diagnosis in children who achieved complete remission, vs. a mean NPY and leptin level of 430.16 pmol/L and 0.192 ng/mL, respectively in those children who died with disease during the follow-up period. Furthermore, the mean NPY level declined and mean leptin level increased during the course of chemotherapy in the 23 children studied.

Other factors indicated in this syndrome include hypermetabolism or an elevation in resting energy expenditure and changes in carbohydrate, protein, and fat metabolism.

Evaluation and assessment

There are no specific diagnostic criteria for this syndrome, but this is not required as knowledge of the disease process, clinical history and focused physical examination makes for an uncomplicated clinical diagnosis. This basic evaluation can be augmented with measures such as body weight, skin fold thickness, and body composition. These are often not necessary in the clinical setting, especially when one keeps in mind the lack of tolerance sick, debilitated children have to even the simplest procedure and that they are likely to receive the majority of their care at home.

Body weight can be useful in establishing a broad measure of the rate of deterioration either by detecting a frank weight loss or failure to grow over time. If, for example, there was a rapid decline in weight, then changes in fluid balance are much more likely to be the cause and it may be reasonable, depending on the overall situation, to intervene and correct the problem.

Laboratory tests evaluating nutritional depletion are of limited value ¹⁰⁰ and because they often cause a great deal of apprehension in children and young people cannot be recommended as routine. Albumin is the most common to measure because of its low cost and accuracy when liver and renal disease is absent.¹⁰¹ However, judicious testing for potentially reversible causes such as hypercalcemia are warranted.