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.

Integrative and supportive therapies

Management of anorexia-cachexia syndrome includes, preferably pre-emptive, acknowledgment that this is not unexpected. The provision of information and education to the child and his or her family is extremely important and should not be underestimated. Allowing for anticipatory exploration of emotional and spiritual subjects offers a forum to air out and deal with the commonly held beliefs that may be destructive to the therapeutic relationship if left unaddressed.

Beliefs include feeling it is necessary to feed the child in the face of reduced food intake. These feelings are very powerful and innate while others, such as their child receiving inadequate care when the wasting process relentlessly progresses, can be borne of feelings of frustration and helplessness.

The profit from such deliberations may be the ability to arrange, in advance, strategies to help empower the child and family and by this means improve appetite and food intake. This will not necessarily improve survival, but has the opportunity to enhance the quality of life and feelings of comfort for the child and their family. Strategies that may increase food intake are:

• Offering the child favorite foods and nutritional supplements he or she enjoys,

• Eliminating dietary restrictions,

• Reducing portion sizes and increasing the number of meals,

• Making food look more enticing,

• Avoiding disliked food odors.

This approach can be supported by sufficient evidence ¹⁰² that hypercaloric feeding does not increase lean tissue mass and there is no significant improvement in survival. Hypercaloric feeding particularly does not increase skeletal muscle mass, the loss of which is a defining⁹⁶ event in cachexia.

There has been significant interest in the influence that more specific nutritional factors can have on cachexia with much of the focus on omega-3 fatty acids such as eicosapentaenoic acid (EPA). There has been a general trend in favor of EPA use from studies with a 2009 prospective, randomized; open-label study ¹⁰³ finding a decrease of cancer-induced weight loss in 33 children with cancer. The patients were fed a protein- and energy-dense nutrition supplement containing EPA when compared with 19 children who did not receive the supplements. However, a 2007 Cochrane review¹⁰⁴ had concluded there was insufficient data to establish whether EPA was better than placebo in adults. This finding has been further supported by the publication of preliminary results of a randomized phase III clinical trial¹⁰⁵ of 475 adult patients with cancer-related anorexia-cachexia syndrome who received one of five treatment arms (95 patients per arm) including pharmaco-nutritional support containing EPA. This arm of the study was withdrawn after analysis of 125 patients (25 each arm) indicated a worsening of lean body mass, resting energy expenditure, and fatigue compared with the other groups.

Psychological approaches should be seen as an extension of the exploration of emotional and spiritual issues and could include:¹⁰⁰

• Encouraging child and family interaction to reduce psychological distress,

• Supporting the family to distinguish between things they can and cannot control, such as normal disease progression vs. helping their child find comfort,

• Exploring the emotional components and the meaning of their child not eating and losing weight,

• Assessing the impact of symptoms on the child and his or her family,

• Assessing the quality of life of the child and his or her family.

Pharmacology

Pharmacologic management of anorexia-cachexia syndrome is adjunctive to the integrative and supportive measures highlighted previously. This statement is supported by the finding that both anorexia and weight loss occur in high frequency and respond poorly to treatment in children and/or young people with progressive malignant disease.⁹⁷ This suggests that available pharmacologic agents are not successful in alleviating these symptoms and this is further reflected in the large number of existing and experimental agents reported to be helpful (Tables 33-3 and 33-4). The data supporting the majority of medications are limited in adults and nonexistent in children. Arguably, the most studied medications are those of the progestational group of which Megestrol acetate has received the most scrutiny. This has culminated in a Cochrane review in 2005¹⁰⁶ and an update in 2007. Megestrol acetate was demonstrated to improve appetite and weight gain in adult patients with cancer although this is largely due to fat rather than muscle mass, the tissue lost in cachexia. No overall conclusion could be drawn on quality of life because of statistical and clinical heterogeneity. Similarly, patient numbers and methodological shortcomings allowed no recommendations to be made about megestrol acetate use in patients with AIDS or other underlying pathologies.

TABLE 33-4 Existing and Experimental Pharmacologic Agents for Anorexia and Cachexia

Megestrol acetate has been trialed in a small number of children with cachexia, not necessarily at a time of palliation, due to cancer,¹⁰⁷^–¹⁰⁹ cystic fibrosis,^110,¹¹¹ and HIV disease¹¹² and reported to improve nutritional status by increasing appetite and weight. Adverse effects were significant, with most children studied reported to have adrenal suppression, with one child manifesting clinical hypoadrenalism with hemodynamic collapse requiring ionotropic support.¹⁰⁸ This effect was shown to be transient¹⁰⁹ as a normal adrenocorticotropic hormone (ACTH) stimulation test was returned once megestrol acetate was discontinued. However, replacement glucocorticoid therapy was advised during times of severe stress.

Cyproheptadine hydrochloride has been used in children with cancer and/or cancer treatment-related cachexia and shown ¹¹³ to improve average weight gain by 2.6 kg and significantly enhance mean weight-for-age z-scores in 50 of 66 children. The main side effect was drowsiness. Seven of the nonresponding children then received megestrol acetate with five demonstrating an average weight gain of 2.5 kg with one child developing low cortisol levels and hyperlipidemia.

A preliminary report ¹¹⁴ on the use of recombinant human growth hormone in four HIV infected children with failure to thrive suggested mean fat-free mass and weight gain were increased with no deleterious effect on disease control.

Summary

Anorexia and cachexia are common symptoms that increase near the end of life. Both symptoms and the anorexia-cachexia syndrome respond poorly to treatment, although there is some evidence for improved appetite and weight with the progestational agent, megestrol acetate. However, this comes at the expense of potentially significant adrenal suppression and no data to support improvement in quality of life.

In view of this, management should embrace an integration of information, education and psychological support to the child and his or her family with medication being considered but not being unduly favored.

Distressing Symptoms of Mouth and Throat

Mouth care

The care of a child’s mouth during palliative care is an essential element of his or her overall care and one in which an informed child and family can take a lead role. This can be associated with an improved quality of life, create a sense of control and prevents mouth care from being overlooked. This aspect of palliative care for children has been well documented ¹¹⁵ with respect to children with cancer, with many of the recommendations applicable to children with life-limiting illnesses of non-malignant origin.

Evaluation and Assessment

The majority of problems will be readily diagnosed with nothing more than a good history and a look inside the mouth. A number of oral assessment tools have been reviewed ¹¹⁵ with only one tool, Eiler’s Oral Assessment Guide,¹¹⁶ being identified as user-friendly and appropriate for everyday clinical use in children and adults. This guide covers the assessment of voice, ability to swallow, lips, tongue, saliva, mucous membrane, gingival, and teeth and/or dentures.

Integrative and Supportive Therapies

The mainstay of preventing the development of mouth problems is maintaining the twice-daily routine of careful and gentle cleaning of the teeth and gums with a fluoride toothpaste.¹¹⁵ This should also apply to cooperative severely disabled children. Mouth-care sponges dipped in mouthwash can be applied to the gums and teeth in the unconscious or less-cooperative child. This has the added advantage of keeping the mouth moist. Cream or soft white paraffin can be applied to the lips to prevent dryness and cracking.

Where children have much longer palliative needs, regular dental review and oral assessment by a dentist or dental unit with specific training should be a standard part of their pediatric care. There are no recommended preventative therapies in the palliative care setting for the highlighted conditions.

Pharmacology

Pharmacological management is detailed in Table 33-5. Management of xerostomia is dealt with in Table 33-6.

TABLE 33-5 Pharmacologic Measures for Common Mouth Problems

Condition	Pharmacologic management
Candidiasis	Use absorbed or partially absorbed anti-fungal agent such as fluconazole for visible thrush^117,¹¹⁸
Ulceration	For aphthous ulcers, use local orobase agents For traumatic ulcers, consider dental review if recurrent If severe mucositis, use appropriate pain control There is only weak, unreliable evidence for specific therapies to improve or eradicate cancer-related mucositis ¹¹⁹
Bleeding gums¹²⁰	Use tranexamic acid mouthwashes Use hemostatic agents, including Gelfoam and Gelfilm Platelet transfusions may be required, depending on stage of palliation

TABLE 33-6 Management of Non-Specific Xerostomia

Supportive measures	Pharmacologic measures
Regular oral hygiene Avoid oral drying agents Food and fluids with high sugar content Rinses with an alcohol content Offer crushed ice, unsweetened pineapple chunks/juice, and sugarless chewing gum Use a moisturizing lip balm regularly

KY Jelly can be very effective and well tolerated ¹²⁰

Artificial saliva

*Pilocarpine¹²¹

* Pilocarpine use in children is limited to a case study of one child receiving this drug to prevent xerostomia.

Xerostomia

Xerostomia, or dry mouth, has a reported prevalence ³ of about 40% during the last week of life and causes quite a bit to very much distress at a similar level as pain. It results from a reduction in saliva secretion, particularly the serous component. This can lead to difficulties with eating and speaking and contribute to anorexia, changes in taste, and increase the risk of oral infections.

Evaluation requires a thorough review of the possible causes (see previous) with a review of medication essential. The list of medications implicated with xerostomia is large, but anticholinergics, tricyclic antidepressants, antipsychotics, anticonvulsants, antihistamines, and diuretics are more commonly involved. Alternative therapies should be asked about.

Identified specific causes should be managed as is appropriate for the stage of the child’s palliation. For instance, depending on the level of distress caused, connected medications may be reduced in dose or changed. In the case of dehydration, the underlying reason could be corrected and the oral fluid intake of the child increased, if appropriate. Equally, the use of subcutaneous and intravenous fluid administration could be considered a legitimate intervention.

Throat problems

Dysfunction of the throat, esophagus, and upper stomach in the form of dysphagia and gastroesophageal disease (GERD) are not uncommon in the palliative care of children, with the most affected group being those with neurological impairment. This group has been reported ¹²² to have an aspiration prevalence of 68% to 70% and a silent aspiration rate of 94%.¹²³ They generally enter services with these conditions identified and managed but these symptoms can develop or, in the case of GERD, be unrecognized.¹²⁰

Troublesome hiccups are a less common problem but can be a source of considerable challenge.

Dysphagia

Swallowing is a complex process in which a bolus of food or fluid is prepared in the mouth and propelled to the stomach without entering the trachea, which would cause aspiration. This requires the coordination of oral musculature for the preparatory and transport phase, pharyngeal musculature, and esophageal musculature. Swallowing difficulties or dysphagia results when there is interference to the nerves involved in the process or there is damage along the pathway.

The prevalence of dysphagia has been reported ^3,⁹⁷ to be a significant problem in 23% to 30% of dying children during the last month of life, and in the palliative cancer population the prevalence increases with time.⁹⁷

Dysphagia can be the result of disease process, previous treatment, or symptoms associated with progressive disease. Treatment-related swallowing difficulties can result from surgery, radiotherapy, chemotherapy, and other drugs. Diseases progression results in dysphagia through:

• Damage to brain and/or nervous system from cerebral palsy, neurodegenerative disorders, metabolic disorders, brain tumors or congenital and genetic disorders,

• Structural problems of the swallowing pathway that are secondary to obstruction, infiltration or compression from solid tumors of the head and neck,

• Muscular damage such as that from muscular dystrophy.

Evaluation and Assessment

Evaluation of dysphagia and other throat symptoms to be discussed requires a holistic approach that goes beyond observation of feeding ¹²³ and, in children at the end of life, may not require action once the wishes of the child and/or his or her family are considered.

The diagnosis can be made clinically and improves with experience.¹²² However, comparison of a therapist’s judgment to a videofluoroscopic swallowing study (VFSS) only indicated a sensitivity of 80%, specificity of 42% and positive and negative predictive values of 65% and 60%, respectively, for clinical evaluation to detect penetration of liquids. Disturbingly, the sensitivity, 70%, specificity, 55%, and positive, 41%, and negative, 80%, predictive values were inferior when detection of penetration of solids by clinical evaluation were analyzed.

Suggestive Symptoms

Symptoms associated with eating and/or drinking that may herald the presence of dysphagia include:

• Infants with poor coordination of their suck and swallow

• Back arching

• Children taking a long time to eat

• Difficulty in chewing food

• Trying to swallow a single mouthful of food several times

• Gagging

• Food or liquids coming out of the nose during or after feeding

• The presence of drooling, vomiting, and/or coughing

• Frequent sneezing after feeding

• Inability to coordinate breathing

• A feeling that food or liquids are sticking in the throat or esophagus, or that there is a lump in these areas

• Discomfort in the throat or chest

• Chest congestion

• Wet or raspy sounding voice during or after feeding

• Tiredness or shortness of breath during feeding

• Color change during feeding, such as becoming blue or pale

• Change in voice before or after eating

• Recurrent pneumonia

• Weight loss

A retrospective analysis ¹²⁴ of various signs and symptoms of aspiration and dysphagia revealed wet voice, OR 8.9, wet breathing, OR 3.35, and cough, OR 3.3, to be good clinical markers for children aspirating on thin fluid, but not on purée. Age and neurological status influenced the significance of these clinical markers. The significant predictive qualities of cough for fluid aspiration and penetration had previously been determined.¹²² This same study also indicated the aspiration risk factor increased when other features such as voice changes, color changes, and/or delayed swallow were also present.

Further evaluation should be considered necessary only if the investigation is likely to change the diagnosis or management for the child. Investigations to be considered are:

• Videofluoroscopic swallowing studies

• Barium swallow/upper GI series

• Endoscopy

• Esophageal manometry

• Laryngoscopy

The appropriateness of these assessments depends on what course of action is being contemplated and must be individualized to the child and his or her situation. Debatably, if a single study were used to determine the presence of dysphagia and aspiration, then VFSS, where the child’s swallow is examined by a series of x-rays after they take a small amount of liquid and/or solid containing barium, would be that study.

Treatable Conditions

Dysphagia in children under palliative care, by definition, suggests a disease process that is not curative and unlikely to be treatable. The exception would be where a palliative procedure was able to reverse a process to improve quality of life, such as radiotherapy to a tumor mass or widening a stricture under anesthetic. Likewise, treatment-related dysphagia is liable to be irreversible unless the cause was an adverse drug effect that could be resolved by discontinuing the medication.

More potential exists for dysphagia caused by symptoms associated with disease progression, such as:

• Xerostomia

• Infection of the mouth, throat, or esophagus

• GERD

• Pain

• Psychological factors including anxiety, fear, and depression

Integrative and Supportive Therapies

The extent to which dysphagia is managed is dependent on the stage of the child’s palliation and the goals of the child and/or the family. A speech therapist’s involvement is advisable from the time of evaluation through to the child’s management. They are able to provide specific exercises to improve coordination and muscle strength or suggest individualized strategies to compensate for impaired swallowing function and enhance the ease and safety of oral intake ¹²⁵ (Table 33-7).

TABLE 33-7 Strategies for Impaired Swallowing

General strategies	During feeding
Postural changes	Taking smaller mouthfuls
Changes in rate of food presentation	Chewing on the stronger side
Use of modified feeding tools	Double-swallowing
Modifications to amount and texture of food-softer consistencies, thickened fluids	Suctioning, when necessary

However, there will be situations where it will be appropriate for children to have nutrition administered through an enteral feeding device such as a nasogastric (NG) tube or gastrostomy (GT).

Feeding Devices

A 2006 clinical report ¹²⁶ on the nutrition support for neurologically impaired children recommended, among other things, that enteral tube feedings be initiated early in children who are unable to feed orally or who cannot achieve sufficient oral intake to maintain adequate nutritional or hydration status. It also recognized that parental concerns and family issues have a role in the decision to provide aggressive nutritional support. The latter reflection, questionably, becomes even more valid when considering an interventional approach in the palliative care setting.

Both NG and GT are common pieces of equipment used to feed and/or administer medication in medically fragile children when there are undue risks with oral intake. However, NG or nasojejunal (NJ) tube feedings should be reserved for short-term nutritional intervention and GT or gastrojejunostomy (GJ) tube feedings may be used when long-term nutritional rehabilitation is required.¹²⁶

NG requires the placement of, usually, a silicone-based tube, down the nasopharyngeal airway into the stomach and in the case of NJ tubes into the jejunum. Success of placement can be measured by the drawing back of acidic stomach contents in the case of NG insertion or, as with NJ tubes, radiological visualization. Removal is a reversal of the process.

GT requires a surgical procedure where an opening through the abdomen into the stomach is made through which a feeding device is inserted. This bypasses the mouth and throat of the child and allows for feeds directly into the stomach. There are a variety of devices on the market, with three main types: percutaneous endoscopic gastrostomy (PEG), Malecot tube, and a tube or button balloon device.

The pros and cons for each device are relative to the situation and include the child’s medical condition, age, previous and future operations, and preference of the surgeon. The Malecot device is typically considered temporary, being replaced by a balloon device after 1 to 2 months, and removal does not require surgery. Removal of a balloon device requires only deflation of the balloon, but a PEG removal requires endoscopic extraction. Care of all feeding devices is important and has been well detailed in a 2003 best practice guideline from Scotland.¹²⁷

In a study ¹²⁸ on the effects of tube feeding on 26 children, with 13 NG, 10 NG changing to GT, and 3 GT, for a mean of 23 months indicated a significant improvement from 73% to 94% in mean percent ideal body weight for height-age for the whole group. Seventeen parents perceived an enhanced mood in their child and they spent less time in caring for their child after NG or GT feedings began. No hospitalizations due to tube-feeding complications were reported.

A 2004 Cochrane review ¹²⁹ that highlighted the considerable uncertainty about the effects of gastrostomy for children with cerebral palsy remains because of the lack of well designed and conducted randomized controlled trials. Despite the lack of these trials an improvement in body weight was confirmed in a review¹³⁰ of the benefits and risks for GT or GJ feeding in comparison to oral feeding for children with cerebral palsy. On the downside, there was an approximately fourfold increase in risk of death reported in one cohort of GT-fed children and many complications were reported, including potential for increased gastroesophageal reflux and fluid aspiration into the lungs. In 2006,¹³¹ published evidence refuted an increased respiratory risk to children with cerebral palsy following GT insertion.

Similarly, a prospective cohort study ¹³² of 57 caregivers of Caucasian children with cerebral palsy detailed a significant, measurable (short-form 36 version II) quality of life at 6 months and 12 months after GT insertion. Improvements were noted in social functioning, mental health, energy and/or vitality, and general health perception. When compared to baseline data and values at 12 months, results were not significantly different from the normal reference data. The value of gastrostomy placement has conceivably been enhanced further by a prospective controlled study of children¹³³ that found significant clinical benefit at no significant extra cost. The cost of food did increase post surgery from $65 to $78 per week with the mean net cost difference being $41 per week per child inclusive of food and surgery. Community service costs were significantly lower post surgery and few parents reported personal costs at either time point, although many had reduced or stopped paid work to care for the child.

Unfortunately, enhancements in the quality of life of neurological impaired children through use of feeding devices have not been so evident. A recent prospective report ¹³⁴ of 50 neurologically impaired children receiving either GT or GJ feeding noted the mean weight-for-age z-score and ease of medication administration increased significantly over time but there was no improvement in either their quality of life or health related quality of life over a 12-month period. Also, the eight children with a progressive neurological disorder had a significantly lower quality of life over time. Nonetheless, caregivers were of the opinion that GT and GJ tube feeding had a positive impact on their child’s health at 6 months (86%), and 12 months (84%).

Gastroesophageal Reflux Disease (GERD)

In GERD, food or liquid travels backward from the stomach to the esophagus, resulting in symptoms from irritation of the esophagus. It is a common diagnosis in neurologically impaired children and infants, ranging from 15% to 75% of children,¹²⁰ and children with cystic fibrosis and children nearing the end of life, especially when cachexia, general debility and restriction to the supine position are evident.

Suggestive Symptoms ¹²⁰

The clinician should have a high index of suspicion for the possibility of GERD, particularly in the previously mentioned group of children. A thoughtful history and focused examination can go a long way toward determining the diagnosis with suggestive symptoms being:

• Gastrointestinal

• Food refusal vomiting, especially during or after feedings or when supine

• Dysphagia

• Weight loss or failure to thrive

• Hematemesis or melena secondary to esophagitis

• Respiratory

• Excessive secretions

• Aspiration pneumonia

• Recurrent respiratory tract infections

• Bronchitis

• Cough

• Wheeze

• Choking and/or gagging

• Other symptoms, often having a temporal relationship to feeding

• Irritability, more so when supine

• Pain

• Hyperextended posturing

• Sandifer’s syndrome: neck extension and head rotation during or after meals in infant or young child often associated with iron deficiency anemia and severe esophagitis

As with other issues in pediatric palliative care, further investigation warrants careful consideration of the risks and benefits of the procedure on the child’s management, and these deliberations will have a different outcome depending on where the child is in their palliative journey. It would not be too controversial to suggest that investigations for GERD could be relegated to a time when a trial of therapy had failed or when symptoms were out of keeping with the expected progression of the child’s condition. The common investigations to be considered are:

• 24-hour esophageal pH study

This study measures the pH in the esophagus over a 24-hour period thereby providing a direct measurement of how much acid from the stomach reaches the esophagus while symptoms are recorded on a time chart. The data can then be analyzed to determine reflux frequency and any relationship with symptoms over time. However, the study can fail to diagnose GERD or associated problems.

• Barium swallow

This study overlaps with the analysis of dysphagia and gives a more direct assessment of the anatomy and, to a degree, the function of the upper GI tract. Reflux can be visualized but this, while suggestive, is not sufficient to provide a diagnosis of GERD as there is no information about frequency and relationship to symptoms.

• Upper GI endoscopy

Direct visualization of the upper GI tract allows for the visualization of the upper GI tract and the diagnosis of inflammation, bleeding and altered anatomy. A study can be conducted in situations where there is concern about the presence of esophagitis and/or gastritis, other symptoms such as pain, dysphagia and/or persistent vomiting, or an unexpected development in the case of a child with cancer.

Integrative and Supportive Therapies

The presence of GERD in children and infants regularly leads to a number of lifestyle and nutritional change recommendations (Table 33-8). These have, most commonly, been considered in the context of relatively healthy children or infants with mild symptoms. They are unlikely to be successful as the sole modality of management for children with life-threatening conditions and/or moderate to severe symptoms.

TABLE 33-8 Common Recommendations to Reduce GERD

Recommended lifestyle and nutritional changes
Adjust posture • Elevate the head of the bed/cot by using blocks of wood under the legs of the bed or a foam wedge under the mattress • Avoid lying down after eating or lie left side down

Uses gravity to prevent reflux by having the head and shoulders higher than the stomach

Extra pillows are not helpful, can worsen reflux

• Children/infants can slip off

• Can cause a bend in the body increasing pressure on the stomach

Minimize exposure to tobacco smoke

• Including second hand smoke

Smoke promotes GERD by:

• Reducing saliva (acid neutralizing qualities) in the mouth and throat

• Lowering the pressure in the lower esophageal sphincter

• Provoking cough

Avoid reflux inducing foods

• Caffeine, chocolate, alcohol, peppermint and acidic beverages including cola and orange juice

These foods can cause relaxation of the lower esophageal sphincter

Alter feeds and feeding regimen

• Thicken feeds

• Check for overfeeding

• Decrease feed/meal frequency and volume of feed/meal

• Allow for longer time before going to bed

In NG/GT feeding

• Consider overnight/continuous feeds

• Give more slowly, even to point of allowing gravity feed

There have been a limited number of studies even in the healthy pediatric population and two Cochrane reviews ^135,¹³⁶ could find no evidence to support or refute the efficacy of feed thickeners in newborn infants with GERD. However, between the ages of 1 month and 2 years this strategy was deemed helpful in reducing GERD symptoms,¹³⁵ but elevation of the head of the cot was not supported as a helpful strategy.

The adult literature has been reviewed in 2006 ¹³⁷ with the evidence for the effect lifestyle measures had on GERD in adults pointed toward an improvement in the overall time esophageal pH was less than 4.0 through bed head elevation and left lateral decubitus position, while weight loss improved pH profiles and symptoms. Furthermore, there was physiologic evidence that exposure to tobacco smoke, alcohol, chocolate, and high-fat meals decreased lower esophageal sphincter pressure but cessation of tobacco smoking and alcohol, and other dietary measures did not directly support betterment in GERD.

Surgical management of GERD may be a consideration for a child with a life-limiting illnesses and troublesome GERD that has not responded to medical management, although there is no evidence to support this claim.¹³⁸ The most frequent surgery performed is the Nissen fundoplication, either as an open (ONF) or laparoscopic (LNF) procedure. It involves wrapping the upper part of the stomach around the lower end of the esophagus, allowing the lower esophageal sphincter to close more completely, reducing reflux.

This can be seen as a safe procedure with a median duration of 70 minutes and in a retrospective study ¹³⁹ comparing Nissen, Thal, and Toupet fundoplications for 238 children without neurological impairment, all three procedures were found to be equally effective with an overall 5% intra-operative and 5.4% post-operative complication rate. Only 2.5% of children required second operations, and all but 9 children were free of symptoms 5 years out from their operation.

Earlier, retrospective analysis ¹⁴⁰ of fundoplication for GERD in 52 neurologically impaired and 25 unimpaired children indicated that impaired children had significantly fewer hospital admissions and total days of hospitalization during the first 6-month post-operative period and a short-term weight gain improvement in those with failure to thrive (FTT). However, longer term (1 and 2 years post-operation) weight gain and weight gain in unimpaired children with FTT was not improved.

The advent of the laparoscopic approach made for a faster, safer procedure with a smooth postoperative recovery and similar failure rates.¹⁴¹ A retrospective review¹⁴² of 456 children with GERD who underwent ONF (n = 150) or LNF (n = 306) concluded that the majority of re-operations occurred in the first year after operation with LNF having a significantly higher rate than ONF; 10.5% vs. 4%. The probability for a further operation increased with co-morbidities, particularly prematurity and chronic respiratory conditions.

How this and other data translates to the pediatric palliative care population is not certain, although the study populations have included children with severe neurological problems. This must be tempered with a lack of good, prospective information on the long-term efficacy, risks, and benefits of this surgery. Advice for caregivers and healthcare providers to carefully weigh the potential risks and benefits for the child remains very relevant.

Pharmacology

Drug management of moderate to severe GERD should be seen as standard care, and there are three approaches:

• Altering the viscosity of the feeds with alginates,

• Altering the gastric pH with antacids, histamine H₂ receptor antagonists (H₂RA), proton pump inhibitors (PPIs),

• Altering the motility of the gut with prokinetic agents.

Antacids+/- Alginate

Antacids provide only short-term stomach acid neutralization with each dose taken making them less effective, other than for short-term relief of symptoms. They contain aluminum, calcium, or magnesium or a combination of these chemicals, and as such long-term use cannot be recommended because it introduces the risk of toxicity. Toxicity examples include diarrhea with magnesium containing antacids, or the reported case ¹⁴³ of phosphate depletion-induced osteopenia in an infant on prolonged aluminum and magnesium hydroxide gel therapy for colic.

Aluminum/magnesium trisilicate (Gaviscon) has the added effect of serving as a protective barrier for the esophagus. It produces a viscous, demulcent antacid foam that floats on the stomach contents and in addition to reducing the frequency of reflux episodes, the alkaline foam aids the neutralization of refluxed gastric acids. Aluminum/magnesium trisilicate infant sachets were recently reported ¹⁴⁴ to be safe and able to improve symptoms of reflux.

Histamine H₂ Receptor Antagonists (H₂RA)

This group of agents reduces acid production in the stomach by antagonism of the H₂ histamine receptor. A comprehensive evidence-based review ¹⁴⁵ stated ranitidine to be safe and effective in infant GERD and the early use of H₂RA’s was supported in older children. These medications are usually taken by mouth once or twice a day with intravenous, oral syrup and effervescent tablet forms available. The effervescent ranitidine tablets may be dissolved in water, fruit juice, and carbonated drinks and one tablet dissolved in 100 mL of water is stable for 24 hrs and a tablet is soluble in water volumes down to 15 mL.

Oral dosing for ranitidine:

• Neonates: 2 mg/kg/DOSE every 12 hours

• Infants and children: 2-4 mg/kg/DOSE every 8-12 hours (max 150 mg/DOSE)

Oral dosing for famotidine:

• Infants and children: 0.5 mg/kg/DOSE every 12 hours (max 20 mg/DOSE)

Proton Pump Inhibitors (PPIs)

PPIs are highly selective and effective in their action of blocking the production of acid in the stomach at the final common metabolic pathway of gastric parietal cells. In a Cochrane review ¹⁴⁵ of adults with GERD symptoms, PPIs were found to be more effective than H₂RAs (RR 0.66, 95%; CI 0.60 to 0.73) and prokinetics (RR 0.53, 95%; CI 0.32 to 0.87). In children they were found to be highly effective, have a very good tolerability profile and have few short- and long-term adverse effects.¹⁴⁶ The safety and efficacy of omeprazole and lansoprazole were confirmed in a 2009 evidence-based systematic review.¹⁴⁴ Both also promoted symptomatic relief and endoscopic and histological healing of esophagitis in infants with GERD. The evidence also supported the early use of proton pump inhibitors in older children.

The oral dosages recommended for infants and children are:

• Omeprazole

• Under 10 kg: 5 mg once daily

• 10-20 kg: 10 mg once daily (max 20 mg/DAY)

• Over 20 kg:20 mg once daily (max 40 mg/DAY), or 0.7-1.4 mg/kg/DAY (max 60 mg/DAY)

• Lansoprazole

• 0.73-1.66 mg/kg/DAY (maximum 30 mg/DAY)

When children cannot swallow tablets or capsules, then omeprazole capsules can be opened and the granules mixed with an acidic drink and swallowed without chewing. In the case of PEG and NG tubes, the granules can be mixed with 10 mL of 8.4% sodium bicarbonate and left to stand for 10 minutes until a turbid suspension is formed. The suspension is then given immediately and flushed with water. Lansoprazole fastabs dissolve very well in water and are less likely to block tubes.¹²⁰

Prokinetic Agents

Prokinetic agents such as metoclopramide and domperidone have been used in GERD and their action discussed in the section on nausea and vomiting. Unfortunately, two reviews ^135,¹⁴⁷ could suggest only some benefit for infants under the age of 2 years with GERD from metoclopramide in comparison with placebo, but pointed out there was insufficient evidence to support or oppose use.

Hiccups

Hiccups are a physiological process involving a reflex ¹⁴⁸ consisting of the following:

• Afferent limb, the phrenic and vagus nerves and sympathetic chain arising from T6-12

• Hiccup center, a nonspecific location between C3 and C5

• Connections to the respiratory center, phrenic nerve nuclei, medullary reticular formation, and hypothalamus

• Efferents

• Phrenic nerve (C3-5)

• Anterior scalene muscles (C5-7)

• External intercostals (T1-11)

• Glottis, the recurrent laryngeal component of vagus

• Inhibitory autonomic processes

• Decreasing esophageal contraction tone

• Lower esophageal sphincter tone

The purpose of hiccups remains a mystery and the reflex results in irregular, involuntary contractions of the diaphragm and accessory respiratory muscles, with an associated noise from sudden closure of the glottis.

Treatable Conditions

The history, examination, and any investigation are directed to elucidating the cause of the hiccup as the diagnosis of the symptom is readily apparent. Gastrointestinal mechanisms are common with gastric distention and GERD often implicated. There are many other potential considerations:

• Metabolic disorders, including hypocapnia, uremia, hypocalcaemia

• Local nerve damage and central nervous system disorders

• Anxiety

• Surgical complications

• Drugs including digoxin, corticosteroids, anti-depressants

The cause in children and infants is rarely found.¹⁴⁸

Integrative and Supportive Therapies

Nonpharmacologic therapies including well-known traditional remedies, medical interventions and complementary therapies all work on sound physiological principles and can succeed by effecting components of the hiccup reflex. These have been well detailed:¹⁴⁸

• Traditional remedies

• Stimulation of nasopharynx by forcible traction on the tongue, swallowing granulated sugar, gargling with water, sipping ice water, drinking from the far side of a glass, biting on a lemon, inhaling noxious agents such as ammonia

• C3-5 dermatome stimulation, including tapping or rubbing back of the neck, coolant sprays, acupuncture

• Direct pharyngeal stimulation with a nasal or oral catheter, which is 90% effective

• Direct uvular stimulation with a spoon or cotton-tip applicator

• Removal of gastric contents by emetics, NG tube

• Vagal stimulation (only one technique at a time is recommended)

• Iced gastric lavage

• Valsalva maneuver

• Carotid sinus massage, but only by experienced personnel after exclusion of contraindications

• Digital ocular globe pressure, but only by experienced personnel after exclusion of contraindications

• Digital rectal massage

• Interference with normal respiratory function

• Breath holding

• Hyperventilation

• Gasping, such as by fright

• Breathing into a paper bag, which increases partial pressure of carbon dioxide

• Pulling knees up to chest and leaning forward

• Continuous positive airway pressure

• Rebreathing 5% carbon dioxide

• Mental distraction

• Other

• Behavioral conditioning

• Hypnosis

• Acupuncture

• Phrenic nerve or diaphragmatic pacing

• Phrenic nerve block surgery

• Microvascular decompression of the vagus nerve

• Prayer

Pharmacology

A large array of pharmacologic agents can potentially be used to treat hiccups ¹⁴⁹ promoting the adage that the larger the variety of agents available to treat a symptom, the less likely they are to be helpful. The most positive evidence has arisen for the muscle relaxant, baclofen^149,¹⁵⁰ and, more recently, the anticonvulsant, gabapentin¹⁵¹^–¹⁵³ has been receiving favorable attention.

Summary

Mouth and throat symptoms are often interrelated and a measured evaluation is required, which should include a critical review of the child’s current drug therapies. In the case of a symptom such as GERD, a high index of suspicion should be held for its presence, particularly in certain populations of children with life-limiting illness.

Assessment will often provide a rational management approach but for dysphagia, xerostomia, and intractable hiccups, resolution may not be possible. This should encourage the practitioner to use an encompassing approach of integrative, supportive, and pharmacologic techniques and, where appropriate, seek a considered surgical opinion for a more interventional approach.

Bowel Obstruction

The frequency, incidence or prevalence of bowel obstruction among children with life-limiting conditions has yet to be detailed. Clinical experience would indicate this to be an infrequent event that is most likely to be seen in children with incurable cancers of the abdomen or pelvis such as lymphoma, rhabdomyosarcoma, or Ewing’s sarcoma.

Pathogenesis

Obstruction in this setting occurs when the lumen of the bowel is sufficiently occluded to prevent the movement of intestinal contents along the gastrointestinal tract. In a report by the Working Group of the European Association of Palliative Care,¹⁵⁴ several pathological mechanisms were detailed for adults with end-stage cancer and are likely to be the process for children. These are:

• Mechanical obstruction

• Extrinsic occlusion of the lumen

• Intraluminal occlusion of the lumen

• Intramural occlusion of the lumen

• Adynamic ileus or functional obstruction

• Intestinal motility disorders from tumor infiltration of the mesentery or bowel muscle and nerves or malignant involvement of the celiac plexus

• Intestinal motility disorders from paraneoplastic neuropathy

It is important to note that even in the adult patient with end-stage cancer, benign causes such as adhesions, post-irradiation bowel damage, inflammatory bowel disease, and hernia can be the cause of the obstruction in around half of the cases.¹⁵⁵

Evaluation and assessment

The presentation of bowel obstruction is site-dependent, with symptoms determined by the sequence of distention- secretion-motor activity of the obstructed bowel.¹⁵⁴ The symptoms most likely to occur involve a combination of pain, both continuous and/or colicky; nausea and/or vomiting; and constipation with or without overflow diarrhea. Vomiting is more likely to be a feature of, and develop earlier in, small bowel obstruction particularly that of the stomach and duodenum. Large bowel involvement tends to involve deeper pain of less severity, occurring at longer intervals.¹⁵⁶

Good clinical acumen including a careful examination along with knowledge of the natural history of the disease can often be sufficient to make an accurate diagnosis of bowel obstruction. Examination findings that add credibility to the diagnosis include the presence of a distended bowel, palpable mass, tympanic percussion and abnormal bowel sounds such as high pitched, tinkling sounds. These do not have to be present for a diagnosis to be made.

The symptoms of obstruction can be mimicked by the absence or impairment of gastrointestinal motility, a pseudo-obstruction. Indicators for this include absent or reduced bowel sounds and other signs of constipation, peritonitis, septicemia, or spinal cord compression. These require specific treatment and management.

Investigations are not a prerequisite to confirm a diagnosis and would seem to be an unnecessary burden to the child and his or her family particularly, when the patient is very ill, desires a conservative approach to care, and there is no doubt as to the presence of a bowel obstruction.

If further investigation is warranted, then a plain abdominal x-ray could show the presence of bowel distension and more than six gas-fluid levels on supine and erect films. In suspected small bowel obstruction, plain supine and standing films are required and have been reported ¹⁵⁷ to be as sensitive as computed tomography (CT) in adults. However, plain films are less sensitive for detection of low grade or partial obstruction. CT scan adds a more global assessment of disease and can assist in the choice of intervention: surgical, endoscopic, or pharmacologic palliation.¹⁵⁴

Contrast studies provide information on the site and extent of obstruction, particularly partial obstructions, and can evaluate problems with motility. Barium, while it gives good definition, can cause problems with impaction because it is often not absorbed. Hyperosmolar water-soluble contrast mediums, such as Gastrografin, are safe and have a therapeutic role in that they are a predictive test for non-operative resolution of adhesive small-bowel obstruction with a pooled sensitivity of 97% and specificity of 96%.¹⁵⁸ This review also indicated contrast did not reduce the need for surgical intervention but it did reduce hospital stay compared with placebo.

Integrative and supportive therapies

Management of bowel obstruction is primarily aimed toward the relief of symptoms and this does vary according to the presence of a partial or complete obstruction.¹⁵⁹

Feeding and Hydration

In the majority of situations, good pharmacologic management precludes the need for intravenous hydration and total parenteral nutrition as the child can satisfy their appetite and thirst with sensible oral intake.

Oral feeding can continue in cases of partial and intermittent obstruction by using small, frequent meals of a low-residue, low-fiber diet. Complete and continuous obstructions do not exclude oral intake with a trial of occasional, small snacks and sips allowable.

Xerostomia may be especially troublesome as the medications used to manage pain, nausea and vomiting can be associated with this symptom.