25 Gastrointestinal Symptoms

Kevin Madden and Margaret M. Mahon

Introduction

Symptoms involving the gastrointestinal (GI) tract, including nausea, vomiting, diarrhea, and constipation are common throughout childhood and occur for a wide range of reasons in healthy children as well as in those with underlying diseases. When caring for a child in the context of serious illness, these symptoms may be of important clinical significance; thus, diagnosing their source and identifying a treatment strategy are critical. Approximately 1 in 10 children receiving specialty palliative care have a primary GI condition¹ while children with other primary life-limiting or life-threatening illnesses suffer from bothersome GI symptoms that are severe enough to warrant visits to the emergency department.² Anticipating such eventualities with the family can make even emergencies less stressful.

Parents or other caregivers are often the first to become aware of a child’s symptoms, either through observation or through the child’s disclosure. Parents and often the children themselves are the experts in how this disease, treatment, and side effect affect this child. Symptom burden is not just determined by the severity of a symptom, but also by the extent to which it interferes with a child’s quality of life.^3,4 One of the hallmarks of pediatric palliative care is collaboration with families to anticipate and recognize the needs of the child and then help the family provide effective symptom relief. In this chapter, we describe the assessment and management of pediatric GI conditions that are likely to be seen by palliative care providers. The crux of this care is interdisciplinary, and different interventions may be initiated, either individually or in combination, along the trajectory of a child’s illness.

Symptoms of the Mouth and Throat

The care of a child’s mouth is an essential element of a child’s 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 prevent mouth care from being overlooked. This aspect of palliative care for children has been well-documented⁵ for children with cancer, with many of these recommendations also applicable to children with a life-limiting illness or life-threatening illness of nonmalignant origins.

Most problems are diagnosed with a good history and an examination of the mouth. Many oral assessment tools have been reviewed,⁵ but only Eiler’s Oral Assessment Guide⁶ is 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 or dentures.

Several possible conditions or symptoms may require management, including

• Poor oral hygiene

• Oral candidiasis

• Mouth ulceration, including mucositis

• Xerostomia, or dry mouth

The mainstay of preventing the development of mouth problems is the twice-daily routine of careful and gentle cleaning of the teeth and gums with a fluoride toothpaste.⁵ This should apply to all cooperative children, including those with severe disabilities. In the unconscious or less cooperative child, mouth-care sponges dipped in mouthwash can be applied to the gums and teeth to keep the mouth moist. Cocoa butter, cream, or soft white paraffin can be applied to the lips to prevent dryness and cracking.

For children with a life-limiting illness or a life-threatening illness, a regular dental review and oral assessment by a dentist with specific experience and training in pediatrics, and often specializing in conditions such as cerebral palsy, autism, or cancer, should be a standard of care. Ongoing evaluation and management by a dental specialist is likely to vary across the trajectory of the child’s condition. For children in the advanced stages of illness, routine dental appointments may not be as crucial.

Xerostomia

Xerostomia, or dry mouth, is very common across the course of many serious illnesses. This symptom can cause significant distress at a level similar to pain. Dry mouth results from a reduction in saliva secretion, especially the serous component. This can lead to difficulties with eating and speaking, contribute to anorexia, cause an altered sense of taste (dysgeusia), and can increase the risk of oral infections.

Specific etiologies should be managed in the context of the child’s current health status and goals of care. For example, if xerostomia is due to a medication, everything from dose reduction to rotating to a similar medication in the same class without the particular side effect to discontinuing the offending class of medications altogether should be considered. In the case of dehydration, the underlying reason could be corrected and the oral fluid intake of the child increased, if consistent with the goals of care. Similarly, the use of subcutaneous and intravenous fluid administration could be considered if aligned with the overall goals of care of the child and the family. The prevalence of xerostomia in the last week of life is about 40%⁷; it can be managed with artificial saliva, although anecdotally many children find the taste and consistency of artificial saliva to be more bothersome than the sensation that accompanies xerostomia.

Dysphagia

Dysphagia is difficulty swallowing, in contrast to odynophagia, which is painful swallowing. These conditions might occur independently or together and can occur in children who are relatively well. While seemingly simple, swallowing is a complex, highly coordinated process that begins in the cerebrum and ends with the coordination of the oral, pharyngeal, and esophageal musculature. Dysphagia can occur when the nerves along the pathway do not function properly. This may be caused by a variety of conditions: hypoxic-ischemic encephalopathy, metabolic disorders, medications, pain, and deconditioning of the musculature from lack of use over a sustained period are all common etiologies. Many parents of children who suffer from dysphagia benefit from education about how deceptively complicated this process is, as, for most of us, swallowing is a subconscious process.

Dysphagia can occur due to progression of underlying disease process, treatment of the underlying disease, surgical interventions, radiotherapy, chemotherapy, and medications. For example, damage to the brain and central nervous system (CNS) from cerebral palsy, neurodegenerative disorders, metabolic disorders, brain tumors, or congenital and genetic disorders can impair the ability to swallow normally and safely. Structural problems secondary to obstruction or infiltration or compression from solid tumors of the head and neck can disrupt the normal swallowing process. The progressive weakening and deconditioning of skeletal muscle from muscular dystrophy (MD) can make it challenging for these children to swallow. And perhaps the overall most common cause of dysphagia in children is actually a secondary dysphagia that stems from significant pain due to the treatment of cancer from radiation or chemotherapy.

The overall prevalence of dysphagia in children receiving specialty palliative care is unknown, likely reflective of the diverse patient population served. For children with MD, the prevalence approaches 100%; for others it varies widely depending on the underlying etiology. The prevalence of dysphagia during the last month of life, however, affects about one-quarter to one-third of dying children,^7,8 and in the advanced cancer population the prevalence increases over time.⁸

Physical Exam and Diagnostic Tests

Evaluation of dysphagia and other throat symptoms requires a holistic approach that goes beyond the observation of feeding.⁹ The symptoms most likely to be associated with dysphagia are a wet voice, wet breathing, and cough.¹⁰ Age and neurological status influence the significance of these clinical markers. Despite the association between clinical symptoms such as coughing during feeds, changes in voice, and color changes while feeding, the ability to clinically detect dysphagia is low and studies comparing a therapist’s judgment to a videofluoroscopic swallowing study (VFSS) had both low sensitivity and specificity.¹¹

As with any intervention in children with serious illness receiving specialty palliative care, however, one must carefully balance the benefits of eating and drinking with the risk of aspiration. In the case in which a child and family do not want to assume the risk of aspiration, the pleasure of taste is often overlooked. Oral foam care brushes can be dipped in any beverage and many foods. When gently placed in the mouth, it can bring great pleasure and improve the quality of life of a child who may not have tasted anything for days to weeks to months. There is also an appreciable benefit for the parent, who can feel reassured that they are continuing to provide loving attention and enhancing their child’s quality of life.

Symptoms that may indicate the presence of dysphagia include

Several investigations can be undertaken to provide more information to guide diagnosis and management of the child’s condition. These include

• Videofluoroscopic swallowing studies

• Barium swallow/upper GI series

• Endoscopy

• Esophageal manometry

• Laryngoscopy

The extent to which dysphagia is managed depends on the stage of the child’s illness and the goals of the child and the family. Speech therapists bring a level of knowledge and experience that is invaluable in the assessment and treatment of dysphagia. (In some institutions, this role may be assumed by occupational therapists, or sometimes a collaborating dietician.) They can 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.¹²

Some therapists who are not typically a part of the palliative care team and are not used to working in the context of changing goals of care may be uncomfortable with modifying recommendations. Explaining the necessity for changing goals of care when a child is at end of life may allow the therapist to become more engaged in the child’s care.

Treatment: Pharmacologic Therapies

Underlying causes of dysphagia that may be amenable to treatment include xerostomia, concomitant infection of the oropharyngeal cavity, pain, gastroesophageal reflux disease (GERD), and, in rare circumstances, anxiety, fear, and depression. Dysphagia from oropharyngeal neutropenic mucositis and thrush due to Candida albicans usually require additional medications to effectively treat. Treatment of the underlying odynophagia—opioids for mucositis and antifungal medications for thrush—usually result in less pain and improved swallowing.

Children at end of life with dysphagia that is unaccompanied by odynophagia (such as seen with or thrush) may not benefit from treatment. The exception would be a procedure that could reverse a process or improve quality of life, such as radiotherapy to shrink a tumor mass or widen a stricture. Treatment-related dysphagia may be caused by a medication or other treatment. If medication-related, the medication should be rotated or discontinued. In other conditions, dysphagia may be irreversible, in which case the focus should be on alleviation of the symptom. If death is close, interventions that promote comfort, including opioids, orally or intravenously, perhaps with patient-controlled analgesia (PCA) should be considered.

At its simplest, anorexia is a loss of appetite. It is a common clinical symptom in children with life-limiting and life-threatening illnesss.^1,7,13,14 The rituals around the provision of food are deeply embedded in religious, familial, and sociocultural belief systems, allowing anorexia to permeate almost all aspects of a child’s life. Children may feel excluded and isolated from social activities that involve food, such as family gatherings, birthday parties, and events at school. Despite their intentions and often astonishing efforts, caregivers can feel powerless in their ability to enhance their child’s appetite.

Most research on anorexia is in children with cancer, where it is consistently one of the top five most prevalent symptoms.^15,16,17 Anorexia is present in one-quarter of these patients, usually as a consequence of chemotherapy or radiation therapy but can also arise from pain, dysphagia, depression, or severe constipation. Almost all children with anorexia^15,18 and their caregivers¹⁹ experience high levels of distress caused by their change in appetite. Yet for children with cancer referred to a specialized palliative care team, anorexia was the most common symptom identified by patient-reported outcome tools that was not previously diagnosed or treated by the referring oncology service.¹⁷ This finding serves to underscore the importance of systematic symptom assessment of children receiving specialized palliative care. If a child’s cancer is advanced, the frequency of anorexia increases to almost one-third of children in the last 12 weeks of life.¹⁵

Cachexia comes from the Greek words kakós and hexis, which translates to “bad condition.” It is a condition of involuntary weight loss and is defined medically as “a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass.”²⁰ Cachexia is usually associated with anorexia in a complex state of advanced protein-calorie malnutrition recognized as anorexia-cachexia syndrome. Growth failure may be the initial manifestation of anorexia-cachexia syndrome in children rather than weight loss. For many parents, the sight of their child visibly losing weight may intensify feelings of helplessness and failure as parents and lead to misunderstanding and blame within the extended family.

The process of anorexia-cachexia syndrome is complicated, but it is clear that 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, repress energy expenditure, and decrease anorexigenic signals, corticotrophin-releasing factor, and melanocortin to achieve the same effect.²¹

There is increasing evidence that the cachectic process is established by an acute phase response mediated by several cytokines of which tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interferon-gamma have been implicated. The evidence suggests that these cytokines stimulate the expression and release of leptin and mimic the hypothalamic negative feedback signaling from leptin, which in turn prevents the standard compensatory mechanisms that are typically initiated in the face of reduced food intake and decreasing weight.

This abnormal response was observed in a study²² 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 versus a mean NPY and leptin level of 430.16 pmol/L and 0.192 ng/mL, respectively in those children who died of their disease during the follow-up period. Furthermore, the mean NPY level declined and the mean leptin level increased during chemotherapy in the children studied. Other hallmark features of anorexia-cachexia syndrome include hypermetabolism and changes in the metabolism of carbohydrates, proteins, and fats.

Physical Exam and Diagnostic Tests

While there are no specific diagnostic criteria for anorexia-cachexia syndrome, knowledge of the underlying disease process, clinical history, and focused physical examination allows for an accurate clinical diagnosis. Body weight, skinfold thickness, and body composition can aid in the confirmation of the diagnosis if needed, although they are often not necessary. Anorexia or cachexia may be a part of a lifelong illness. For example, children with chronic kidney disease have a risk of protein energy wasting or of cachexia.²³ If a child is at the end of life, if goals of care are focused on comfort, the child and family may decide against additional procedures, which may allow the child to remain at home.

Body weight can be useful in monitoring the rate of deterioration either by detecting a frank weight loss or failure to grow over time. A rapid decline in weight may be suggestive of a change in fluid balance. If consistent with the child’s and family’s goals, it may be reasonable to intervene and correct the problem.

Extensive laboratory tests evaluating nutritional depletion are of limited value²⁴ and can often stir a great deal of anxiety and apprehension in children and young people. They, therefore, cannot be recommended as routine. Albumin is the most common laboratory value checked because of its low cost and accuracy when liver and renal disease are absent.²⁵ However, testing for potentially reversible causes such as hypercalcemia are warranted if the child’s underlying diagnosis, history, and physical exam are suggestive of electrolyte abnormalities.

• Adverse effects of medication

• Dehydration

• Mouth problems, such as oral thrush, xerostomia

• Dysphagia, GERD, constipation, intestinal obstruction

• Infection

• Nausea and vomiting

• Pain

• Psychological factors, such as anxiety, fear, depression

• Offering the child favorite foods based on pleasure, not on “should” and “ought”

• Eliminating dietary restrictions

• Reducing portion sizes and increasing the number of meals

• Making food look more enticing

• Avoiding disliked foods

It is crucial to counsel parents that there is evidence²⁶ that hypercaloric feeding does not increase lean tissue or skeletal muscle²⁰ mass, and there is no significant improvement in survival.

Psychological, emotional, and spiritual issues include²⁴

• Encouraging child and family interaction to reduce psychological distress

• Helping the family to distinguish between things they can and cannot control (e.g., helping their child find comfort vs. halting disease progression)

• Exploring what the child’s not eating and losing weight means to the family. This discussion may provide better understanding of their distress, as well as added opportunity to clarify misconceptions.

• Assessing the impact of symptoms on the child and family

• Assessing the quality of life of the child and family

Pharmacologic management of anorexia-cachexia syndrome is adjunctive to the integrative and supportive measures highlighted previously. Data suggest that both anorexia and weight loss occur in high frequency and respond poorly to treatment in children and young people with progressive malignant disease.⁸ Many extant pharmacologic agents are not successful in alleviating the symptoms, though a large number of existing and experimental agents have been reported to be helpful. Data supporting the use of medications to manage anorexia and cachexia are limited in adults and nonexistent in children. Arguably, the most studied drugs are those of the progestational group, most prominently megestrol acetate. A Cochrane review²⁷ found that megestrol acetate improved appetite and weight gain in adult patients with cancer. It did not, however, improve muscle mass or the tissue lost in cachexia, and the weight gain was mainly due to increases in body fat. 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.

Cyproheptadine hydrochloride has been used in children with cancer and cancer treatment–related cachexia and was shown²⁸ to improve average weight gain. The main side effect was drowsiness. In a systematic review, cyproheptadine has been helpful in achieving weight gain for some children of all ages and across a range of conditions.²⁹ These findings did not, however, apply to children with HIV, cancer, or other progressive diseases and so while it is recommended and used in children receiving specialty palliative care, the child’s and parental expectations must be tempered with accurate anticipatory guidance that it may not be as helpful as they hope for.

Megestrol acetate has been trialed in a small number of children with cachexia due to cancer,^30,31,32 CF,^33,34 and HIV disease³⁵ and has been reported to improve nutritional status by increasing appetite and weight. Additionally, adverse effects were significant, including most children developing adrenal suppression and one child manifesting clinical hypoadrenalism with hemodynamic collapse requiring ionotropic support.³¹ This effect was shown to be transient³² as a normal adrenocorticotropic hormone (ACTH) stimulation test was returned once megestrol acetate was discontinued.

Other Interventions: Feeding Devices and Total Parenteral Nutrition

If integrative and pharmacotherapy are not effective and the goal of care is to optimize the child’s function and nutritional status, the child may benefit from nutrition supplied through an alternative route. Nutrition may be administered through an enteral feeding device such as a nasogastric (NG), nasoduodenal (ND), nasojejunal (NJ) gastric (GT), gastrojejunal (GJ), or jejunal (J) tubes. Gastric feeding devices can further be characterized by whether they were placed endoscopically or surgically, and this will be discussed later. Multiple professional organizations^33,36 support nutritional support for neurologically impaired children via enteral tube feedings and recommend that they 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. These devices are very common, as a survey study of six large pediatric palliative care programs in the United States and Canada revealed that almost half of all children receiving specialty palliative care had a GT.¹

There are distinctions to each route of feeding. Both NG and GT are commonly used to feed or administer medication in children with complex chronic conditions when there are risks with oral intake. While NG or NJ tube feedings have historically been reserved for short-term nutritional intervention and GT or GJ tube feedings for circumstances where long-term nutritional rehabilitation is required,³³ each child’s situation is unique. Providers should be flexible, mindful, and fluid in making recommendations that would help children and their families achieve their goals in the context of their illness.

NG tubes require the insertion of a silicone-based tube into the nasopharyngeal airway with an end in the stomach. In the case of NJ tubes, they end in the jejunum. The success of placement can be evaluated by the drawing back of acidic stomach contents in the case of an NG or by radiological visualization with NJ tubes. The long-term use of the nasopharyngeal route is associated with the development of ulceration and possible perforation of the nasal septum. It is prudent to closely monitor the duration of use, and, with consideration given to the context of the child and their illness, review whether a more permanent device should be placed in the stomach.

Tubes that enter the stomach can be placed either via a percutaneous endoscopic route by a pediatric gastroenterologist or surgically by a pediatric general surgeon. After its introduction in the 1980s, the percutaneous endoscopic gastrostomy (PEG) tube quickly became one of the most preferred methods due to its minimally invasive nature, speed, and low cost when compared to a surgical gastrostomy tube. Furthermore, there were fewer complications and a shorter duration of post-placement antibiotics in the PEG group compared to the surgically placed group.³⁷ In patients with complex anatomy (scoliosis, malrotation, situs inversus) it may be advisable to proceed with a surgically placed GT to ensure proper placement.

Where a GT terminates—in the stomach, duodenum, or jejunum—largely depends on the precise reason a tube is being placed in the first place. For children who need the administration of medications and delivery of sufficient nutrition and hydration but lack significant GERD or delayed gastric emptying, a true gastrostomy that ends in the stomach should suffice. For children with significant GERD, more complex gastrointestinal pathology, or other gastrointestinal comorbidities, a duodenal or jejunal tube is likely to be more beneficial.

The location of the distal end of a duodenal or jejunal tube allows for the post-pyloric delivery of enteral nutrition, thereby minimizing the risk that contents could propel backward into the esophagus. Medications cannot be given through the jejunal part of the feeding tube, but rather go through the gastric port. Duodenal and jejunal tubes, however, are rife with potential limitations and complications, and so the decision of where a GT should terminate is a nuanced one. Enteral nutrition cannot be given via bolus feeds into the duodenum or jejunum as the intestines do not have the same capacity as the stomach to handle larger volumes of food. Food must be delivered as a continuous infusion, which increases the amount of medical technology and equipment to maintain, travel with, and troubleshoot. Additionally, given the tube’s location in the intestine, it must be placed—and replaced when dislodged or accidentally removed—at a medical facility with proper placement confirmed by direct visualization.

The delivery of nutrition and hydration by a feeding tube has been consistently associated with an improvement in mean percent ideal body weight for height-age,^38,39 a parental perception of improved mood of the child,³⁹ and a significant improvement in caregiver quality of life at 6 months and 12 months after GT insertion⁴⁰ with no significant increased financial burden.⁴¹ The lack of well-designed randomized controlled trials⁴² in children with cerebral palsy who have feeding devices—and who represent a large proportion of patients receiving specialty palliative care—highlights the uncertainty involved in the decision-making process. Unfortunately, improvements in the child’s health-related quality of life decline after 12 months.⁴³ Some studies have demonstrated an association between feeding tubes and an increased risk of death, with many complications reported, including potential for increased gastroesophageal reflux and aspiration into the lungs.³⁹ Children with jejunostomy tubes are at an increased risk for GERD and intestinal perforation, as well as frequent dislodging that requires anywhere from one to three tube replacements per year, depending on age.⁴⁴ Older children are more likely to need more frequent replacements than younger children, while younger children are more likely to suffer an intestinal perforation.⁴⁵

The phrase that many parents of children with a life-limiting or life-threatening illness use to succinctly capture their goals is for their child to “live as long as possible, as well as possible.” This accounts for both extending life and maintaining or enhancing the quality of life—the two are not mutually exclusive and can be interdependent. When the use of feeding devices does not meet the goal of providing sufficient nutrition to sustain growth, families will often inquire about total parenteral nutrition (TPN). The request stems from a desire to extend their child’s life without sacrificing their child’s quality of life. Yet the traditional view is that, in most cases, long-term provision of TPN does not extend nor improve the quality of life, with the exception of children who have intestinal failure. Compounding this sentiment is that there are no clear consensus guidelines from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition or the European Society for Paediatric Gastroenterology Hepatology and Nutrition that address the unique needs of these patients. While some data in adult cancer patients demonstrate no improvement in quality of life⁴⁶ with the use of TPN, other studies suggest that the use of TPN is associated with both an improved quality of life^47,48,49,50 and an extension of life.^51,52 Evidence is emerging that the use of home TPN in children does not adversely affect the quality of life when compared to children with enteral feeding devices,⁵³ and the long-term health-related quality of life of pediatric intestinal failure patients receiving home TPN is similar to that of healthy peers.⁵⁴ As children with complex chronic conditions live increasingly longer lives and medical technology becomes progressively available, transportable, and efficient, the question of home TPN will likely become increasingly relevant to palliative care providers, the subspecialists who manage TPN, and the children and families who may benefit from this therapeutic intervention.

The decision to initiate artificial nutrition and hydration is not an easy one and should be viewed as we view other technological interventions that sustain life, such as mechanical ventilators or dialysis. For those deciding to pursue a feeding device for their child, proper care of all feeding devices is essential and is well-described in the literature,⁵⁵ along with best practice guidelines.⁵⁶ The issue of forgoing artificial nutrition and hydration is more comprehensively addressed in Chapter 14 “Advanced Care Planning Along the Continuum” and Chapter 27 “Easing Distress When Death Is Near.”

There is minimal pediatric data in the management of visceral hyperalgesia.⁵⁷ A trial of changing the formula type or route of administration should be considered. If these are not effective, decreasing the volume of feeds may be helpful. Such a suggestion may elicit parental anxiety, and potentially resistance, governed by a fear of “starving” the child. Reassurance that the goal is to improve distressing symptoms by decreasing the feeding volume may mitigate some of the distress, as well as the proposal of a “time-limited trial,” such as reducing daily feeding volume by 25–50% for 3 days to establish treatment effectiveness and foster parental rapport.

When these strategies are not as effective as hoped for, the addition of a gabapentinoid (gabapentin, pregabalin) or a tricyclic antidepressant can be helpful. Due to their efficacy in refractory neuropathic pain, one may consider duloxetine or methadone⁵⁸ in particularly challenging cases. The use of other opioids is reserved for children approaching the end of life. For further discussion of management of visceral hyperalgesia, see Chapter 19, “Neurological Symptoms.”

Nausea and Vomiting

Nausea is best thought of as the feeling or sensation of impending emesis, often accompanied by sialorrhea, eructation, and dizziness.⁵⁹ The word itself derives from the Greek nausia, meaning “seasickness” (naus, ship). Nausea is to be distinguished from emesis (vomiting) itself, which is a coordinated series of sensory-motor reflexes that can occur because of or in the absence of nausea.

Nausea is incredibly burdensome and disruptive to children. In a study of adolescents and young adults (AYAs) with cancer, nausea was extremely intrusive, with a severity of moderate or greater more than 80% of the time it was experienced.³ These AYAs described nausea as a priority symptom based on the degree to which it affected physical and emotional functioning and how much it impeded independence.³ The authors also found the AYA might not report the symptom, emphasizing the need for a structured approach to history and physical.³ Furthermore, nausea is a unique predictor of a child’s social disability and correlates with lower academic and social functioning.⁶⁰ Children with nausea have significantly more school absences than other children, and nausea leads to decreased overall quality of life and functional disability.⁶⁰

Vomiting, as distinguished from nausea, involves the “forceful retrograde expulsion of stomach contents through the oral cavity.”⁶¹ Vomiting is also differentiated from regurgitation, a related phenomenon that consists of the expulsion of esophageal contents but without the coordinated airway closure of the vomiting reflex.

Vomiting is not always preceded by nausea. Furthermore, the central pathways of nausea and vomiting differ.⁶² Causes of vomiting may be from within or outside of the GI tract. Factors of the GI tract leading to vomiting include GI infections (e.g., gastroenteritis, hepatitis), anatomic insults (e.g., intussusception, surgical adhesions), mucosal injuries (e.g., chronic granulomatous disease, inflammatory bowel disease), GI motility disorders (e.g., paralytic ileus, gastroparesis), visceral GI disorders (e.g., pancreatitis, cholecystitis), and other factors.⁶³ External factors include infection or inflammation, disease (e.g., chronic granulomatous disease, otitis media, pyelonephritis), endocrine derangements (e.g., carcinoid syndrome, diabetic ketoacidosis), metabolic derangements (e.g., urea cycle defects, storage disease), genitourinary disorders (e.g., uremia, hydronephrosis secondary to ureteropelvic obstruction), or neurologic disorders (e.g., hydrocephalus, concussion).⁶³

It is essential to distinguish between chronic and acute nausea. Chronic nausea may not be constant, but it is recurrent and frequent, lasting for more than 1 month. Common causes include pancreatitis, GERD, or gastroparesis. Chronic nausea might also be due to pregnancy, sometimes lower on the differential list of a young woman with a serious illness than it would be for a healthier female. The neurologic pathways of acute and chronic nausea are different; the central pathway of chronic nausea is similar to the pathway for chronic pain, which expands the repertoire of treatments for nausea to include those used for neuropathic pain, such as gabapentinoids.⁶²

Multiple afferent and efferent pathways lead to the symptom of nausea and the effect of emesis (see Figure 25.1). There are four primary pathways: the cerebral cortex, the area postrema (that contains the chemoreceptor trigger zone [CTZ]), neuronal pathways within the vestibular nuclei, and vagal afferents from the upper gut.^64,65 Stimulation of chemoreceptors and stretch receptors in the GI tract stimulate vagal afferents of the sympathetic nervous system.

All of these pathways are coordinated through the vomiting center (VC), which is located in the medulla oblongata. The VC is a convergence area formed by several anatomically distinct structures. The medulla contains muscarinic and histamine receptors.⁶⁶ The VC is mostly inside the blood–brain barrier. It receives stimulation from the CNS, including the cerebral cortex (psychological factors, including anticipation) and sensory organs, vestibular components, and the GI tract, including chemicals that affect the CTZ.⁶⁷ The CTZ contains dopamine and serotonin receptors.⁶⁶ Impulses from the VC stimulate the smooth muscles of the GI system, thereby initiating and controlling the act of emesis.

The CTZ is a part of the VC, however, the CTZ is outside the blood–brain barrier in the area postrema. Therefore, the CTZ can detect the chemical substances that can induce nausea and vomiting.⁶⁸

An Approach to the Child with Nausea

Identifying the underlying cause(s) of nausea and vomiting typically is useful for selecting the therapeutic option. Although the causes of nausea and vomiting are often multifactorial, an etiology-based approach allows identification of a primary neurotransmitter pathway, which, in turn, facilitates informed decision-making about the most useful neurotransmitter antagonist with which to initiate treatment. The most robust supportive data for the etiology-based approach are found in the treatment of chemotherapy- or radiation-related nausea and vomiting and the treatment for malignant bowel obstruction.

History

While history typically focuses on proximal causes (i.e., identifying contemporaneous factors that occurred around the time of nausea), the context of the child’s underlying disease allows examination of interactive factors. Therefore, the history of nausea and vomiting focuses on potential causes.

Nausea and vomiting are common in many chronic and severe illnesses resulting from disease and treatment; however, more is known about how to treat these symptoms arising from treatment than from disease.⁶⁹ Nausea and vomiting occur not just from the GI tract, but also the CNS, and include vestibular, otic, and metabolic factors.⁶⁵ Furthermore, the anticipation of nausea and vomiting can itself cause nausea and vomiting. Understanding these factors can guide history and assessment.

Symptoms are subjective experiences. Therefore, a child’s characterization is essential. One tool commonly used is aptly called the Baxter Retching Faces Scale (BARF) scale (Figure 25.2).⁷⁰ The scale is sometimes called the Baxter Animated Retching Faces scale. The BARF scale is a 0–10 scale with six faces; the child is asked to identify which face best represents the current experience of nausea. The scale has been validated with emergency department and postoperative samples of children. In assessing the utility of the scale in children with postoperative nausea and vomiting and postdischarge nausea and vomiting, Watcha and colleagues found the tool useful for children in these groups, with a clinically relevant score difference of 1.47/10.⁷¹ The authors also found that clinically relevant nausea was common; however, the presence of nausea did not predict whether the child would be treated with an antiemetic. Only the presence of emesis predicted the administration of antiemetics.⁷¹

Physical Exam and Diagnostic Tests

The physical and laboratory examination, like the history, should consider the multifactorial causes of nausea and vomiting. This should include a physical exam and lab findings that are affected by the underlying disease or injury and those that are separate.

Treatment: Integrative and Supportive Therapies

Nonpharmacologic interventions are crucial in the management of nausea and vomiting. Children are often aware of which foods or beverages they will be more likely to tolerate. This is a critical opportunity for children to learn to “listen to their bodies.” Though not uniformly effective, a small amount (one bite, one sip) of what the child “feels like” having is a good test. If the child can tolerate oral intake, small meals taken more frequently are more likely to stay where they are intended. Avoid strong odors and flavors, which also includes food and drink that visitors might bring in. For example, the smell of a parent’s coffee or grilled vegetables might trigger nausea and vomiting. Some children do better if someone is there with them, either for company or distraction. Triggers for nausea and vomiting vary widely between children.

Therapies including behavioral techniques, hypnosis, acupuncture, acupressure, and aromatherapy (anecdotally) have been shown to be efficacious in managing nausea and vomiting in children.^4,72,73,74 Professionals from dietetics, social work, psychology, child life, rehabilitation, and education provide different perspectives to shaping the child’s care.^73,75 Behavioral therapies may also help.^4,72,73 Hypnosis and guided imagery may be particularly helpful with anticipatory nausea and vomiting.^73,76 Acupuncture may also be beneficial for this symptom; however, may not be permitted if a child is neutropenic or thrombocytopenic. Choksi and colleagues studied the integration of acupuncture into the care of children with cancer: 52% of the children chose to accept acupuncture, and 51% of participants sought treatment for nausea.⁷⁷ The authors found “no increased incidence of adverse events in children with thrombocytopenia . . . or neutropenia.” Still, institutions and treatment teams may have preferences for levels below which they do not want a child to receive acupuncture, for example, no acupuncture for a child with fewer than 50,000 platelets.⁷⁷

Sea-bands (acupressure wrist bands) use traditional Chinese medicine techniques to provide pressure to the P6 acupoint on the ventral surface of the wrist to alleviate nausea and vomiting.⁷⁸ Children can be taught to apply their own bands. While Sea-bands are helpful in some instances of nausea and vomiting, they are not beneficial for children with chemotherapy-induced nausea and vomiting (CINV) receiving highly emetogenic chemotherapy.⁷⁸

Although aromatherapy is sometimes recommended for nausea and vomiting, the evidence to support its efficacy is limited. In a Cochrane review specific to postoperative nausea and vomiting, aromatherapy was found to be no more effective than placebo.⁷⁹

Treatment: Pharmacologic Therapies

Five neurotransmitter receptors account for the majority of activity that mediates nausea and vomiting. The most important receptors include serotonin (5HT₃), dopamine (D₂), acetylcholine muscarinic (M_1, or M₃, M₄, or M₅), histamine (H₁), or neurokinin (NK₁).^64,72,80 The goal of treatment of nausea and vomiting is to antagonize the predominant neurotransmitter of the most likely pathway leading to nausea and vomiting. Most of what is known about the efficacy of neurotransmitter antagonism in children is based on research with chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting.

Understanding vomiting pathways is clinically useful for choosing antagonists in symptom management, or at least the initial antiemetic that which is most likely to be effective. Not uncommonly, more than one antiemetic is necessary to quell the child’s symptoms. If another antiemetic is required, choose one from a different receptor antagonist class. This is often empiric. Even in the management of CINV, there is a lack of consensus about optimal management.⁸¹ Please see Table 25.1 for medications for the treatment of nausea and vomiting.

Serotonin (5HT₃) receptors are located in the area postrema. Serotonin antagonists (e.g., ondansetron or granisetron) block serotonin viscerally (causes such as distention or GI irritation) with vagal transmission and centrally at the CTZ.⁸² The CTZ is stimulated by chemical causes, such as anesthesia or chemotherapy. These receptors respond to many cancer-directed chemotherapy drugs and uremia, producing nausea and vomiting. Therefore, serotonin antagonists are typically the first line for CINV, postop nausea and vomiting, or nausea and vomiting as a side effect of other potential toxins or GI stimulants. In some patients who do not have benefit from ondansetron, rotating to granisetron may be beneficial. Antiserotonergic agents are also used following bone marrow transplant, which is typically accompanied by a chemotherapeutic conditioning regimen. Serotonin antagonism has been recommended as the second line in the management of pediatric gastroenteritis after hydration.⁶⁷ Serotonin antagonism is also indicated before and after radiation therapy.⁸³

Dopamine type 2 (D₂)-receptors in the area postrema are stimulated by emetogenic substances such as calcium, uremia products, opioids, and digoxin. Dopamine receptors are also found throughout the gastrointestinal system. Dopamine antagonists (e.g., metoclopramide, haloperidol) are commonly used to treat nausea and vomiting in children, including CINV. The dopamine receptor antagonist metoclopramide is active in the area postrema. It also acts as a gastrointestinal prokinetic, prompting gastric emptying and increasing the tone of the lower esophageal sphincter by blocking GI dopamine receptors. Metoclopramide stimulates gastric cholinergic receptors.⁸⁴

Side effects, including sedation, sometime limit the use of dopamine antagonists, but extrapyramidal effects are the symptom to be most wary of.⁸¹ Extrapyramidal side effects are more likely with metoclopramide than with other antidopaminergic drugs.⁷⁵ Prokinetics (e.g., metoclopramide) should not be administered concurrently with antimuscarinic agents, such as diphenhydramine or scopolamine, as anticholinergic agents block the final common pathway of prokinetic agents. The concurrent administration of diphenhydramine and metoclopramide to prevent extrapyramidal effects, as practiced in some centers, will, therefore, result in the loss of metoclopramide’s prokinetic effect but not its antiemetic effect. The concurrent intravenous administration of dopamine antagonists with 5-HT₃-receptor antagonists increases the risk of cardiac arrhythmia.⁸² For patients with refractory nausea, especially CINV, a dopamine antagonist may be added as a second-line agent, in addition to an antiserotonergic.^76,83

As is true with all symptom medications, a lack of benefit from one class often leads to rotation to medicine from another group of antiemetics. Rather than rotation, if a child has incomplete relief of nausea and vomiting, it is better to add medication from another antiemetic class.⁸⁵

Mu-1 and mu-2-opioid receptors are found in the CTZ.⁸⁶ The emetogenic action of opioids is believed to be mediated through mu-2 receptor stimulation, which, in turn, potentiates the release of dopamine. For some children, this release of dopamine stimulates nausea and vomiting. Unexpectedly, however, a child who experiences emesis with a low or standard opioid dose may not experience nausea and vomiting with a higher opioid dose. This is due to the action of the higher opioid doses “at receptor sites deeper in the medulla.”⁸⁶

Histamine receptors are present at multiple sites. There are histamine receptors in the inner ear, in the CTZ in the area postrema, and in the VC in the vestibular nucleus. Nausea can result from disturbances to the vestibular system that comprises semicircular canals and otolith organs. The vestibular system is responsible for balance sensation and movements. Histamine mediates the transmission of nausea via the vagus nerve.

Histamine antagonists (e.g., diphenhydramine, promethazine) are often over-the-counter medications for the prevention or treatment of motion sickness, including nausea and vomiting, as well as for vertigo. Antihistamines are often sedating. Unfortunately, antihistamines are sometimes administered for sedation effect, rather than for the antihistamine effect. There are a few nonsedating antihistamines, such as loratadine or cetirizine; however, these medications are less beneficial in alleviating nausea and vomiting.

Acetylcholine works to increase gut motility and secretions, as well as stimulate nausea. Anticholinergics block muscarinic receptors and inhibit cholinergic transmission from the vestibular system to the VC.

Muscarinic acetylcholine receptors are G protein-coupled receptors that are found throughout the body, within and outside of the CNS. They are a part of most physiologic processes.⁸⁷ Motion sickness, nausea, and vomiting caused by motion is mediated in different areas of the brainstem, including the area postrema, the vagal nuclear complex, the VC, and the vestibular complex.⁸⁸ Anticholinergics/antimuscarinics are most often used to treat nausea and vomiting due to vestibular stimulation (e.g., meclizine, dimenhydrinate).

There are few pediatric studies of either antihistamines or anticholinergic/antimuscarinics in pediatric populations. As with other pediatric medications, their use is sometimes empirical.

NK1 antagonists. Substance P activates the neurokinin 1 (NK1) receptor. A newer antiemetic class is that of NK1 antagonists. Substance P is found through the central and peripheral nervous systems, though it is more concentrated in some parts than in others. It is also found in the GI tract. Substance P has a role in emesis, as well as in inflammatory and immune responses, cancer, pain, and other factors.⁸⁹ Substance P is ubiquitous in the CNS, although it is found in higher concentrations in some parts more than others. One part that that deals with pain is the Rexed lamina II of the spinal cord’s dorsal horn. The other part is the CTZ. Various toxins that float through the cerebrospinal fluid (CSF), such as chemotherapy agents, especially platinum-based chemotherapy agents, stimulate the production of substance P in the CTZ. This, in turn, stimulates the production of neurokinins. Therefore, this neuropeptide soup then potentiates the action of excitatory neurotransmitters, such as glutamate, increasing the rate of activity in the CTZ. This results in a continuous sensation of nausea and a desire to vomit.

A newer class of antiemetics has been designed to block the action of substance P and neurokinins: NK1 antagonists.⁹⁰ NK1 antagonists work primarily at the nucleus tractus solitaries and areas of reticular blocking receptors.⁶⁵ In addition to antiemetic properties, NK1 antagonists have anxiolytic and antidepressant properties.⁹¹ The biochemistry and structure of NK1 remains incompletely understood.⁸⁹ NK1 antagonists are less effective at preventing nausea and more effective at preventing vomiting.⁶⁵

Aprepitant, an NK1 antagonist, works by crossing the blood–brain barrier. Its use with children is increasing, typically in combination with an antiserotonergic.⁷⁵ As mentioned previously, the CTZ is located in the area postrema, one of the few places in the CNS where there is no blood–brain barrier. This area of neurotransmitters and antagonism is relatively new. Dysgeusia has been recognized as a side effect of NK1 antagonists and may limit their use in children undergoing treatment for cancer.⁹⁰ Those who take oral feeds while on aprepitant had increased nausea and pain scores.^91,92

Cannabinoids. The cannabinoid receptor CB₁ is found in the CNS, mainly in the periaqueductal gray and the rostral ventromedial medulla, as well as in the peripheral nervous system. Stimulation of this receptor leads to suppression of the release of intestinal neurotransmitters. Cannabinoids are therefore sometimes used as a treatment for nausea and vomiting, though they are distinct from “medical marijuana.” The US Food and Drug Administration (FDA) has approved two cannabis-derived medications for the treatment of nausea and vomiting: dronabinol and nabilone. Both of these medications are synthetic delta-9-tetrahydrocannabinol (THC). The National Academies for Science, Engineering, and Medicine⁹³ (NASEM) found substantial or conclusive evidence of benefit for CINV.⁹³ The antiemetic effect likely occurs because of the impact of the medication on the cannabinoid receptor system, the CB1 receptor.^94,95 Both dronabinol and nabilone are approved for CINV,^95,96,97 though neither is recommended as a first-line antiemetic.⁹⁸ Both have been used in the care of children; however, the benefit was low and side effects frequent.^94,99 It is not uncommon for patients who are started on a THC derivative to discontinue use due to side effects, including dizziness, drowsiness, and other symptoms.¹⁰⁰ The range in effects and side effects may also result from variability in pharmacokinetics and absorption.¹⁰⁰ More research in this area is needed.^93,101

The benefits of “medical marijuana” are poorly documented for children.¹⁰² Regardless, many families pursue its use, sometimes because they believe it is a “natural” substance, so is less likely to cause harm, and sometimes because they are frustrated with the persistence of the child’s symptoms despite traditional medical interventions. Children are given cannabis with food into which cannabis has been baked (“edibles”), oil, vaporized cannabis, or by smoking it.¹⁰² A challenge of medical cannabis is that, because it does not come in standardized doses, it is unclear how much cannabis the child is getting. Many parents might also inquire about the use of the nonpsychotropic cannabinoid, cannabidiol (CBD). While seemingly benign, CBD dramatically alters the metabolism of medications, including methadone,¹⁰³ and so children are at high risk for developing clinically significant drug-drug interactions.

Steroids are beneficial for a plethora of symptoms, including nausea and vomiting. For children on a treatment protocol, steroids may be contraindicated. Children with increased intracranial pressure (ICP) due to trauma or space-occupying lesion may benefit from steroids. The specific dynamics of how increased ICP leads to vomiting, with or without nausea remain incompletely understood.¹⁰⁴ The mechanics of how ICP leads to nausea and vomiting might vary by grade and disease severity.¹⁰⁴ This means the need for a steroid is likely to vary, even as the child’s disease changes. Corticosteroids also inhibit prostaglandin synthesis, further contributing to antiemesis. Dexamethasone is commonly used for symptom management. Side effects of steroids include mood swings and weight gain, so the cost versus benefit must be continuously evaluated.

Atypical antipsychotics (e.g., olanzapine) have been recommended in adults for the prevention of CINV.¹⁰⁵ Olanzapine works on multiple neurotransmitters, including dopamine (D_1–4), serotonin (5HT_{2a, 2c}, 5HT₃, 5HT₆), histamine (H₁), “catecholamines at alpha 1 adrenergic receptors, [and] acetylcholine at muscarinic receptors.”¹⁰⁶ Olanzapine is recommended (typically with other antiemetics) for children who are receiving highly emetogenic chemotherapy; for those for whom olanzapine is contraindicated, metoclopramide should be added.¹⁰⁷

Subcutaneous infusions. If emesis limits absorption, medication should be administered parenterally.⁶⁹ If intravenous access is difficult, consider a subcutaneous infusion. This might be helpful if the child’s nausea and vomiting are persistent, or if they have difficulty swallowing, are delirious, or have a large pill burden. Subcutaneous infusions are inexpensive, typically well-tolerated, and are practical for home use. The blood levels of medications administered subcutaneously are comparable to those given intravenously. Furthermore, multiple agents of compatible fluids can be delivered in a single infusion. For example, an antiemetic, an opioid, and a steroid can be given in one infusion. Medications that should not be given in combination include chlorpromazine, diazepam, and phenytoin.

Summary

Nausea and vomiting are common, dreaded, and complex symptoms. Understanding the pathways and neurotransmitters that lead to nausea and vomiting guides the interventions. Pharmacologic and nonpharmacologic measures should be considered. Evidence for the management of nausea and vomiting not related to chemo is weak.⁷² When addressing pharmacy, start with a single agent, adding as necessary, preferably a medication that antagonizes a different neurotransmitter. Consider that several antiemetics antagonize more than one neurotransmitter. When determining whether the medication should be scheduled (e.g., before a specific medication), around the clock, or as needed, consider the cause. Also, one should consider what has worked for the child in similar circumstances in the past. The child and family are often the best guides.

Please refer to Box 25.1 for the nausea and vomiting treatment algorithm.

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