25 - Depression, anxiety, anger and delirium
Editors: Goldman, Ann; Hain, Richard; Liben, Stephen
Title: Oxford Textbook of Palliative Care for Children, 1st Edition
Copyright 2006 Oxford University Press, 2006 (Chapter 34: Danai Papadatou)
> Table of Contents > Section 3 - Symptom care > 23 - Gastrointestinal symptoms
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23
Gastrointestinal symptoms
Marek W Karwacki
Introduction
Providing the best possible care for the child and the family is the first consideration for professionals working in paediatric palliative care. Dying children and their families generally prefer home care and even intense symptoms can usually be managed in this environment with appropriate planning, expertise and support [1, 2, 3, 4, 5, 6, 7, 8, 9]. Currently toddlers and adolescents with neurodegenerative life-threatening illnesses (NLTIs) account for a significant proportion of children requiring palliative care [1, 7, 8, 9. The high prevalence of neurological syndromes and genetic disorders in population of dying children is reflected in a spectrum of symptoms in which gastrointestinal (GI) problems are of great significance. Our experience at the Warsaw Hospice for Children (WHC1), is similar to that of other hospices worldwide in this respect. The most frequently documented GI symptoms are: Nausea and vomiting, constipation, sialorrhoea, hiccup, anorexia (Table 23.1), swallowing difficulties, precutaneous endoscopic gastrostomy, diarrhoea. This chapter will consider each of these common GI symptoms in turn.
The gastrointestinal tract is a sensitive and highly reactive system that not only monitors the material flowing through it, but also provides information about dysfunction and dis-integration of the entire body. Symptoms arising from this system are among the most frequent complaints in childhood. Constipation is a particular problem, but nausea and vomiting as well as diarrhoea are common symptoms even among healthy children. In the population of children suffering from chronic, intractable disorders, GI symptoms are common [10]. Specific medical conditions and developmental disabilities are often associated with certain feeding complications, among which gastro-oesophageal reflux is the most prevalent condition [11]. Feeding problems in children with neurological impairment are common and severe [12]. These issues may be of major concern to parents, and careful appraisal of the suffering child and of the parent-child interaction is always indicated. The occurrence (Table 23.1) and escalation of particular GI problems depend on the specific cause and rapidity of disease progression, any coexisting conditions and of course the child's general health.
This chapter covers the most common gastrointestinal problems encountered in a palliative practice setting. It is organised by symptoms and offers practical guidelines on pathogenesis and treatment. Aetiology and criteria for diagnosis are also highlighted. Emphasis is on the approach to the patient and palliative care practices. A rational strategy for symptom control, depending on the predicted survival of the child and the rate of disease progression, is the aim of the chapter.
Nausea and vomiting
Nausea and vomiting (N&V) are often considered as a single phenomenon when, in fact, they are distinct physiologic conditions and may occur independently.
Nausea ( sickness of the stomach; feeling sick ) is defined as an unpleasant sensation, usually vaguely located in the epigastrium and abdomen and often accompanied by a tendency to vomit. The term comes via Latin (meaning: seasickness) from the Greek word naus (ship) and has been used in English since 16th Century. This highly subjective symptom is objectively described by science as a conscious recognition of the need to vomit .
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Table 23.1 Prevalence of GI symptoms among 235 children treated in Warsaw hospice for children (9 years experience:September 1994 September 2003) | ||||||||||||||||||||||||||||||||||||||||||||
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Vomit (emesis) or the act of vomiting means a spasmodic, forceful ejection of gastric contents through the mouth as the result of involuntary muscular spasms of the stomach and oesophagus. The word comes from Latin vomere . It starts with a sensation of nausea, then closing of the glottis, strong contraction of the abdominal muscles which forces the stomach contents to be ejected as the gastro-oesophageal sphincter relaxes. Repeated regurgitation of stomach contents is elicited by a variety of stimuli, including touching the region of the fauces of the tonsils. Nausea may occur independently of vomiting.
Regurgitation is distinct from vomiting. It is not preceded or accompanied by nausea. It seems to occur whenever the barriers that should prevent it, the oesophageal sphincters, do not hold against elevated pressures in the fluid-filled stomach or oesophagus.
Causes may not be physical. Emotionally children very often respond to stress with nausea or vomiting. Anticipatory nausea and vomiting is a classic conditioned response that can be activated by a number of triggers (such as memory of the hospital, sight of syringe or the presence of a nurse). The process is exaggerated by anxiety. Anticipatory nausea or vomiting significantly impacts on the quality of life of children undergoing treatment for malignancy. It may start well before they reach the oncology ward for chemotherapy. The sensation may be so deeply rooted that even at home, long after treatment has finished, memories of the ward can provoke nausea.
Pathophysiology of nausea and vomiting
Nausea and vomiting are different entities but may represent extremes of a continuum [13]. Emesis is a highly conserved evolutional mechanism designed to protect the organism from ingested substances that are interpreted as being poisonous or toxic.
Nausea, which is mediated by the autonomic nervous system, is usually accompanied by symptoms such as pallor, tachycardia, increased salivation and cold sweat. The vagal nerve and its neurotransmitter, acetylcholine, mediates this mechanism. Nausea corresponds to the first phase of emesis, called pre-ejection. The stomach relaxes and gastric acid secretion is inhibited. The next step of the vomiting reflex, the ejection phase, comprises a single retrograde giant contraction (RGC) of the small intestine. This alkalinises and confines ingested toxins to the stomach. Retching and vomiting do not occur until RGC reaches the stomach. During retching, intra-thoracic pressure decreases while intra-abdominal pressure increases. Contractions of the abdominal muscles and the diaphragm become coordinated and increasing pressures in thorax and abdomen compress the stomach, forcing its contents upward through the mouth and nose.
The period following a vomiting episode (post-ejection phase) is often characterized by relief of nausea. Retching may occur long after gastric contents have been expelled and has become an important indicator of effectiveness in the evaluation of new antiemetics. The number of retching episodes, as well as the number of emetic episodes and self-report of the severity of nausea, are currently considered the most appropriate outcome measures in antiemetic clinical trials.
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Both nausea and vomiting are controlled by the central nervous system, but through different mechanisms [14, 15, 16]. Nausea is mainly mediated through the autonomic nervous system. Rapid enlargement of an encapsulated organ, or dis-tension of a hollow viscus are important factors provoking nausea in many abdominal diseases. It accompanies, for example, sudden distension of the stomach, billiary tract, or intestine and rapid enlargement of the liver or pancreas, but not distension of oesophagus, and only weakly of the colon. Gastric mechanoreceptors are the main initiators. Lessfrequently, nausea may arise from direct excitation of receptors in the medulla by systemic toxins. This explains the sensation of nausea that accompanies many systemic infections and elevated intracranial pressure associated with brain tumours. It can also be elicited by vestibular stimulation.
Vomiting centre
Emesis, in contrast, requires stimulation of a complex reflex, coordinated by a putative true vomiting centre (VC). Rather than a discrete anatomical entity, the VC is better considered as a central integrating complex within the reticular formation of the brain stem. It comprises a network of neuroanatomical connections of several brain-stem nuclei, including the parvicellular reticular formation (PCRF), the nucleus tractus solitarus (NTS), and the somatic motor nuclei involved with the act of emesis. These include dorsal motor vagal nucleus innervating the abdominal viscera and the dorsal and ventral respiratory groups. The VC receives convergent afferent stimulation from several central neurologic pathways:
a chemoreceptor trigger zone (CTZ);
the cerebral cortex and the limbic system;
the vestibular-labyrinthine apparatus of the inner ear;
(4) peripheral stimuli (Figure 23.1).
It is anatomically less well defined than the CTZ, and is separated from the blood by the blood-brain barrier.
The vomiting centre of the third ventricle is the central emetic generator. Interestingly, the opioid 2 receptors of the third ventricle are antiemetic (not emetogenic, as might be expected from the clinical side effect profile of opioids). Acetylcholine (ACh), dopamine (D2), gamma amino butyric acid (GABA), histaminic (H1), and serotonin (5HT2) receptors are emetogenic.
Chemoreceptor trigger zone
The CTZ is located in the area postrema, one of the circumventricular regions of the brain, on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle, in close proximity to the nucleus tractus solitarus. Unlike vasculature within the blood-brain barrier, the area postrema is highly vascularised with fenestrated blood vessels that lack tight junctions (zonae occludentes) between capillary endothelial cells. There is therefore free passage of solute between blood and CTZ. The CTZ is anatomically specialised to detect elements present in the circulating blood and cerebrospinal fluid, such as drugs, biochemical products and other toxins. The CTZ plays a general role as a chemoreceptor, and is also implicated in controlling food intake, conditioned taste aversion, and modulating GI tract motility. The CTZ contains emetogenic receptors for acetylcholine (muscarinic receptors MACh), dopamine (D2), opioids ( 2) and serotonin (5HT3). There are many other neurotransmitters in or around the CTZ, including noradrenaline, somatostatin, substance P(SP), histamine, enkephalins, and corresponding receptors.
Other regions of CNS
The cerebral cortex and the limbic system respond to sensory stimulation, particularly smell and taste, psychological distress, and pain. The vestibular-labyrinthine apparatus of the inner ear is sensitive to body motion. Motion sickness, labyrinthitis and ototoxic drugs are the most common stimuli. Tumour is a rare cause. Higher cortical centres can modulate vomiting and nausea reflexes and taste aversions, but the connections involved have not yet been clarified.
Peripheral stimuli
Input seems to come from several sources. Peripheral stimuli come from visceral organs and vasculature via vagal and spinal sympathetic nerves, as a result of excitation by exogenous chemicals and by endogenous substances that accumulate during inflammation, ischaemia, and irritation. The vagus nerve plays a key role in acute emesis associated with chemotherapy, radiation therapy to the epigastrium, and abdominal dis-tension or obstruction. Different receptors are found in the stomach wall: D2 receptors, which mediate gastroparesis; vagal 5HT3 emetogenic receptors; and enteric 5HT4 prokinetic receptors. The 5HT4 receptors require ACh as a mediator within the myenteric plexus. Prokinesis is therefore antagonised by anticholinergics, and the two should never be co-prescribed.
The gastrointestinal wall contains 5HT3 receptors for SP a neuropeptide also found in the central nervous system in the area postrema. SP induces nausea by binding neurokinin-1 receptors (NK1). NK1 receptor antagonists have broad-spectrum emetogenic activity and have shown promise in clinical trials.
Other neurochemicals found in the upper GI tract, including dopamine, neurotensin, vasoactive intestinal peptide (VIP) and polypeptide (PYY), may also play a role in emesis.
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Fig.23.1 Main receptors and pathways involved in emesis. |
Mechanoreceptors within the gut wall respond to contraction and overdistension, and stimulate the vagal and splanchnic nerves.
Incidental causes of nausea and vomiting
Vomiting and nausea are often multifactorial in origin [14]. Even in children with life-limiting conditions, incidental age-related causes have to be considered. The most common is gastroenteritis. Congenital abnormalities and anatomic obstruction (e.g. pyloric stenosis), gastric chalasia, gastrooesophageal reflux, overfeeding, and systemic as well local (e.g. otitis media) infection represent the most common cause for N&V in infants. Posseting ( innocent vomiting and spitting-up ), are terms used to describe the repeated, effortless regurgitation of small quantities of milk into the mouth after feeding. It occurs almost universally in the early months of life and, by definition, the child is well and thriving. Gastro-oesophageal reflux disease (GORD) may co-exist with posseting and in contrast can impact on growth. Both usually resolve over the first year of life. The underlying mechanism in the young infant is immaturity of the gastro-oesophageal sphincter mechanism.
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Emotional causes
When N&V occur with no associated symptoms, an emotional origin should be considered. Emotional emeses are often seen in healthy children in stressful situations. Some may successfully conceal other symptoms of emotional illness, but it is hard to hide vomiting. Nausea is a common presenting complaint in depression and anxiety in children. The term nervous vomiting has been used to describe a syndrome of infant stress [17]. Infant rumination syndrome, another functional vomiting disorder, has been associated with emotional distance of the main caregiver [17]. The baby learns to bring up gastric contents into the mouth for the purpose of self-stimulation. These illustrate that recurrent vomiting may indicate psychological issues, rather than organic disease.
Opioid-induced nausea and vomiting
Opioid-induced nausea frequently resolves spontaneously a few days after initiation of treatment [16]. It may persist in some patients, from the accumulation of toxic opioid metabolites. Combined with anaesthetics, opioids can trigger Ach-mediated nausea in the vestibular apparatus. Furthermore, opioids invariably produce constipation if prophylactic measures are not taken and constipation itself is a cause of nausea. Stimulation of visceral mechanoreceptors and chemoreceptors by distension of the gut, and retention of toxins from the bowel are the probable mechanism. Autonomic dysfunction often accompanies neurodegenerative conditions, and can result in decreased gastrointestinal motility, early satiety, and chronic nausea.
Patients who associate nausea with opioid analgesia may be reluctant to take more, creating a potential barrier to effective pain management. It has recently been proposed that and k opioid receptors are emetogenic, while receptors are antiemetic, but it is unclear how important this distinction is in clinical practice [16].
Assessment of nausea and vomiting
A thorough knowledge of the aetiology and pathophysiology of N&V is crucial as different causes will require distinct interventions (Tables 23.2 and 23.3). The optimal management of N&V is based on ongoing assessment and historical documentation of the patient. Work in adult patients showed a significant mismatch between physicians', nurses' and patients' ratings of the severity of nausea and vomiting, and underline the need for simple symptom score scale [17].
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Table 23.3 Antiemetic drugs: indications and dosage | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Management of nausea and vomiting
The basis for pharmacological antiemetic therapy is neuro-chemical control of vomiting [14, 15]. Peripheral neuroreceptors and the CTZ as well as VC express receptors for serotonin (5-HT3 or 5-HT4), histamine (H1 and H2), dopamine (D2), acetylcholine (AchM), opioids and numerous other endogenous neurotransmitters (Figure 1). D2-mediated nausea is probably the most frequently targeted for initial symptom management, even when the precise mechanism of nausea is not known. Refractory cases of N&V often require combinations of medications from different classes (Table 23.3).
Phenothiazines
Phenothiazines and butyrophenones are divided into three categories according to their receptor profiles: narrow (e.g. haloperidol); medium (e.g. prochlorperazine, promethazine, and chlorpromazine); and wide spectrum (e.g. levomepromazine and olanzapine). Chlorpromazine, thiethylperazine and perphenazine act both peripherally and centrally on dopaminergic receptors, but are also cholinergic and hista-mine receptor antagonists. Wide-spectrum phenothiazines are in effect broad spectrum antiemetics which block D2, ACh, 5HT2, and 5HT4 receptors. Hypotension may result if intravenous phenothiazines are administered rapidly at high doses.
This broad spectrum of action means that aliphatic phenothiazines can cause sedation and anticholinergic effects. Piperazines (e.g. prochlorperazine, thiethylperazine, perphenazine, and fluphenazine) are associated with less sedation but greater incidence of extrapyramidal reactions. These may include acute dystonias, akathisias, and rarely akinesias and dyskinesias, as well as neuroleptic malignant syndrome. Levomepromazine, though an aliphatic phenothiazine, is minimally sedating at low, but usually still powerfully antiemetic, doses.
Some reports on olanzapine, a new atypical antipsychotic wide-spectrum phenothiazine, have suggested a role as an adjuvant in opioid and chemotherapy induced N&V [18].
Butyrophenones
Another class of D2 subtype receptor antagonist, structurally and pharmacologically similar to the phenothiazines, butrophenones, is represented by droperidol and haloperidol. Both have potent antiemetic activity. Both induce extrapyramidal reactions. Although these are usually self limiting and harmless, they can be frightening for patient and family.
Haloperidol is an ideal agent when delirium accompanies nausea, though this is rare in children. Its anticholinergic activity is negligible. It produces little drowsiness but has greater risk of extrapyramidal side effects than other phenothiazines.
D2 antagonists
Metoclopramide is an antagonist at dopaminergic receptors and, at higher doses, 5HT3+4 agonist. Beside its central (CTZ) and the peripheral activities, metoclopramide also increases lower oesophageal sphincter pressure and enhances the rate of gastric emptying. Prokinesis is mediated by the myenteric plexus system which relies on acetyl choline and is therefore antagonised by co-prescription of anticholinergic drugs. Dexamethasone adds to its antiemetic potential. Metoclopramide is associated with akathisia, particularly in patients over 30 years of age, and dystonic extrapyramidal effects, more commonly observed in persons under the age of 30. Diphenhydramine, benztropine (benzatropine) mesylate, and trihexyphenidyl can be used to counter the risk.
Anticholinergics
The vagus has a crucial role to play in mediating vomiting of all causes, and anticholinergics may be effective in most clinical situations. They include cyclizine and hyoscine. Cyclizine is also antihistamine and is often used in N&V associated with raised intracranial pressure, though its usefulness can be compromised by drowsiness and practical difficulties with administering it subcutaneously.
5 HT3 antagonists
This group of very potent antiemetics, is particularly effective in N&V associated with chemotherapy and have also been used for treatment and prevention of perioperative N&V. Currently, this class includes ondansetron, granisetron, tropisetron, and dolasetron. They prevent serotonin, which is released from enterochromaffin cells in the gastrointestinal mucosa, from initiating afferent transmission to the CNS via vagal and spinal sympathetic nerves. 5 HT3 antagonists may also block serotonin stimulation at the CTZ and other CNS structures. The advantage of 5 HT3 antagonists over other entiemetics is a superior toxicity profile with equal or superior to high doses of metoclopramide antiemetic response. The major adverse effects include constipation, headache (which can be treated with mild analgesics), diarrhoea, fatigue and dry mouth. Recent data suggests no major differences in efficacy or toxicity between 5HT3 receptor antagonists in the treatment of chemotherapy-induced acute N&V [19]. Dolasetron differs from the others in its long half-life. These agents
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demonstrate greater antiemetic efficacy in combination with corticosteroids [18].
Other agents
Agents used as prophylaxis and treatment for chemotherapy-induced N&V, alone or in combination antiemetic regimens, include corticosteroids dexamethasone, and methylprednisolone, and a cannabinoid, dronabinol.
Corticosteroids possess intrinsic antiemetic properties and enhance the effect of some other antiemetics. The mechanism may involve changed permeability of blood-brain barrier to chemicals, reduced release of neurochemicals from damaged cells, changed GABA concentration in medullary antiemetic neurones and decreased release of leu-enkephalins in the brainstem.
Cannabinoids have been used in N&V associated with chemotherapy, human immunodeficiency virus therapy, and gastrointestinal malignant metastases [20]. They can be potent antiemetics in anticipatory N&V. Dronabinol (9 tetrahydrocannabinol, one of the main ingredients in cannabis) and the synthetic cannabinoid compound nabilone are currently available by prescription in some countries. The mechanism is not clear. It is possible that cannabinoids act at specific cannabinoid receptors (e.g. CB 1) in the cortex, hippocampus, and hypothalamus to inhibit cyclic adenosine monophosphate (cAMP). They may even act at opioid receptors [21]. It has recently been suggested that endocannabinoids constitute a novel neuroregulatory system involved in the control of emesis [22]. The class has yielded many potential areas of clinical application, including pain relief, antiemesis, appetite stimulation, relief of muscle spasticity, movement disorders, epilepsy, and glaucoma. The most promising clinical applications for cannabinoids are in stimulation of appetite, relief of nausea and vomiting, and analgesia [22, 23].
Recently published studies concerning substance P antagonists and neurokinin 1 receptor antagonists have demonstrated an improvement of the control of chemotherapy induced acute N&V. NK1 receptor antagonists have antiemetic activity against emetogenic chemotherapy, opioids, and radiation. One important advantage was control of delayed N&V compared with placebo [14].
Octreotide, synthetic analogue of somatostatin, reduces intestinal secretions. It can moderate nausea, vomiting, and abdominal cramps, particularly malignant bowel obstruction [24]. This is partly due to inhibition of motilin and vasoactive intestinal peptide hormone release [19]. Its main indication is N&V where the volume is high, where over-distension of the gastrointestinal tract is a probable factor.
Benzodiazepines are valuable adjuncts in combination with acute as well as chronic antiemetic regimens, especially in depressed or anxious children. They bind to type 2 GABA2 receptors that are widely distributed throughout the CNS (cortex, reticular formation, and limbic region) [25].
Multiple antiemetic regimens have been proposed for the management of chronic nausea [1, 26, 14, 15, 16]. Metoclopramide or domperidone are generally recommended as first-line agents because they improve gastrointestinal motility and are anti-D2 at the chemoreceptor trigger zone. A continuous parenteral infusion of metoclopramide may relieve intractable chronic nausea in children. Judicious use of corticosteroids such as dexamethasone, in selected patients, can also be useful in conjunction with other antiemetics. In complete bowel obstruction prokinetics are contraindicated as they simply induce painful colic.
Nausea and vomiting can be treated orally but this route may be ineffective. When vomiting persists, parenteral routes are preferable. Some antiemetics can be given rectally (in suppository or soluble tablet form).
Non-drug methods are important. These can include avoidance of food smells or unpleasant odours, diversion, and relaxation. Relaxation with guided imagery includes hypnosis, passive relaxation, active relaxation, and EMG biofeedback. Other relaxation techniques include systematic desensitization, and attentional distraction, and require a therapist with specific training, usually a psychologist. These techniques may well be useful adjuncts, but they have not been systematically tested [27].
Some patients report benefit from acupuncture or acu-pressure bands. A small but growing body of research suggests that acupressure (transcutaneous electrical and manual) is effective alone, or can enhance the antiemetic effects of ondansetron, metoclopramide, and phenothiazines following surgery or chemotherapy [27, 28].
Constipation
Dietary modifications are useful adjuncts to antiemetics and must be individualised for each patient.
There is no single definition of constipation. It is often described as the slow movement of faeces through the large intestine that results in the passage of dry, hard stool. The longer the transit time of stool in the large intestine, the greater the fluid absorption and the drier and harder the stool becomes. For some children it may be normal to pass stools only every few days, but hard stools that are difficult to pass accompanied by pain or a sense of incomplete bowel evacuation should be considered constipation.
Prolonged constipation may be mistaken for diarrhoea by parents, as liquid faeces can leak around hard stool in the rectum and escape voluntary control.
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Normal bowel habit
This changes markedly between birth and adolescence. Breast fed babies pass stool more frequently than those fed formula milk, up to ten daily. At 2 3 years of age, the mean is two bowel motions per day. From age three years to adulthood, normal variation is huge; between three times per day and three times per week. Concern for bowel habit should be reserved for recent change, or where there are symptoms.
Scope of the problem
Constipation occurs in up to 10% of a healthy paediatric population [30, 31, 32]. Chronic constipation with or without soiling is reported to make up 3% of referrals to out-patient general paediatric clinics, occurs in 1 3% of primary school children and is more prevalent in males than females.
The population of children needing palliative care is significantly at risk of constipation. Children with profound neurological deficit are particularly prone, such as cerebral palsy, neuromuscular and neurodegenerative disorders or spinal cord injury [33]. The major causes are:
altered muscle tone
prolonged time in one position
reduced physical activity
abnormal colon movement
lack of muscle coordination
reduced intake of fluid and dietary fibre [34].
In other groups, causes can include depression, coercive toilet training, attention deficit disorders, and sexual abuse. Over-the-counter cold medications and antacids as well as antidepressants, anticonvulsants or opioids can contribute to the problem (Table 23.4).
Table 23.4 Commonly used drugs exacerbating constipation | ||||||||||||||||||||
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Constipation is a common problem in people with intellectual disability (ID). Laxatives are frequently prescribed with disappointing results. In a population of 215 patients with severe intellectual disability [35], 69.3% suffered symptomatic constipation. It was significantly correlated with being nonambulant, cerebral palsy, the use of anticonvulsive medication or benzodiazepines, H2-receptor antagonists or proton pump inhibitors, food refusal, and IQ lower than 35. Faecal soiling was found in 15% of subjects, while manual evacuation of faeces was performed in nearly 7% of cases.
Physiology of normal defaecation reflex
Normal defaecation is a combination of autonomic and voluntary functions. It is voluntarily controlled in healthy people. It requires a concerted complex action, coordination and sequential activation of a large number of muscles in the anal canal and pelvic floor. Distension of the rectum is the stimulus that initiates reflex defaecation. There is voluntary contraction of the abdominal wall muscles and diaphragm, raising intra-abdominal pressure to force the rectal contents toward and into the anal canal. This intensifies the sensation of defaecation and marks the end of the voluntary phase. When the faecal bolus distends the rectum, sensory receptors in the rectal wall are stimulated, leading to conscious perception of rectal distension and involuntary relaxation of the internal anal sphincter. In the absence of voluntary contraction of the puborectalis muscle and the external anal sphincter, the faecal bolus is expelled.
The defaecation response is probably mediated in the distal spinal cord. The neural pathways involve parasympathetic, sympathetic, and somatic innervation to the colon, rectum, and anus. The intrinsic enteric nervous system, comprising submucosal Meissner and myenteric Auerbach plexuses, regulates segment-to-segment movement of the gastrointestinal tract. The vagus supplies the upper segments of the gastrointestinal tract up to the splenic flexure. The pelvic splanchnic nerves (nervi erigentes) carry parasympathetic fibres from the S2 S4 spinal cord levels to the descending colon and rectum. The hypogastric nerve sends out sympathetic innervation from the L1, L2, L3 spinal segments to the lower colon, rectum, and sphincters. The pudendal nerve (S2 S4) provides somatic innervation to the external anal sphincter and pelvic floor.
Spinal cord lesions above the conus medullaris are upper motor neuron lesions. They result in underactive propulsive peristalsis, overactive segmental peristalsis, and rectal distension. A lesion at the level of the conus medullaris, cauda equina, or inferior splanchnic nerve is a lower motor neuron lesion and leads to colonic slowing, resulting in constipation, faecal incontinence, and difficulty with emptying.
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Intestinal transit time is closely related to defaecation frequency and decreases as childhood progresses. In the first month of life transit of stool takes 8 hours, whereas at age 2 16 h and between 3 and 13 years 26 h. Normal transit time in adults can be 48 hours or more; in all ages it is largely influenced by the amount of fibre in the diet. Fibre-rich diets favour the retention of water and result in increased stool weight and volume, shorter transit time and more frequent defaecation. The water content of normal stools is 60 85%. The desiccation of colonic contents in constipation is due to increased duration of mucosal contact rather than an alteration of mucosal absorptive function.
Pathophysiology of constipation
Constipation is frequently multifactorial in origin and can result from systemic or neurologic disorders as well as from medications. Causes of the symptom are usually classified into three broad categories:
normal-transit constipation,
slow-transit (functional) constipation, and
disorders of defaecatory or rectal evacuation [36].
Normal-transit constipation Stool traverses at a normal rate through the colon and the stool frequency is normal. Patients believe they are constipated, as they perceive difficulty with evacuation or the presence of hard stools. Factors responsible for the sense of constipation include bloating and abdominal pain or discomfort, increased psychosocial distress, increased rectal compliance and reduced rectal sensation.
Slow-transit defaecation Infrequent urge to defaecate, bloating, and abdominal pain or discomfort are often symptoms associated with slow-transit constipation. Hirschsprung's disease represents an extreme form. Histopathological studies have shown alterations in the number of myenteric plexus neurons expressing the excitatory neurotransmitter SP, abnormalities in the inhibitory transmitters vasoactive intestinal peptide and nitric oxide, and a reduction in the number of interstitial cells of Cajal, which are thought to regulate GI motility [37, 38, 39]. In patients with a minimal delay in colonic transit, a high-fibre diet may increase stool weight, decrease colon-transit time, and relieve constipation. Patients with more severe problems, who have infrequent bowel movements (once a week or fewer), have a poor response to dietary fibre and laxatives. In such patients, there is often delayed emptying of the proximal colon and relatively few high-amplitude peristaltic contractions after meals that normally induce movement of content through the colon. Colonic inertia, a related condition, is characterised by slow colonic transit and the lack of an increase in motor activity after meals, and after the administration of bisacodyl, cholinergic agents, or anticholinesterases [40].
Defaecation disorder Anismus, pelvic-floor dyssynergia, paradoxical pelvic-floor contraction, obstructed constipation, functional rectosigmoid obstruction, the spastic pelvic-floor syndrome, and functional faecal retention in childhood are frequently used terms to describe defaecatory disorders. It results from dysfunction of the pelvic floor or anal sphincter. Failure of the rectum to empty effectively may be due to an inability to coordinate the abdominal, rectoanal, and pelvic-floor muscles during defaecation [41] and can be functional or organic. Functional defaecatory dysfunction can be provoked by prolonged avoidance of the pain, for example in association with anal fissure. There may be a history of sexual or physical abuse, or an eating disorder. Ignoring or suppressing the urge to defaecate is a widespread cause of chronic constipation in general population in both adults and children. Secondary encopresis often accompanies functional faecal retention in children. Extensive leakage of liquid stool around impacted stool may lead to an initial misdiagnosis of diarrhoea [42].
Signs, symptoms, and complications of chronic constipation
Symptoms and signs can include [32, 33, 34,]:
vague abdominal pain around the navel or even severe attacks of abdominal pain
decreased appetite, nausea, or vomiting
urinary incontinence, frequent urination, or bed-wetting
recurrent urinary tract infections
Faecal impaction occurs in up to 80% of adult patients with chronic constipation. [27, 43]. Impaction refers to the accumulation of dry, hardened faeces in the rectum or colon. Left untreated, impaction can result in bowel distension and megacolon. This in turn can be further complicated by chronic inflammation, infection, intestinal perforation and even death.
Management of constipation
The principle of treating constipation is to use the minimum intervention that will relieve the symptoms. Management plan includes attention to comfort and privacy, possible elimination of medical factors that may contribute to constipation, as well as therapeutic interventions. The type of medical procedure used depends on the child's age and exact problem [45, 46].
Classes of laxative drugs
There are numerous types of laxatives, including bulk-forming agents and surfactants, lubricants, osmotic agents, contact cathartics, prokinetic drugs, and agents for colonic lavage.
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Bulk laxatives
Fibre supplementation should be started at a low subtherapeutic dose and titrated upwards on a weekly basis until the desired effect is achieved. Combined with diet and liquids, bulk laxatives institute a natural , but also hardly effective long-term treatment for constipation. Their slow onset of action (between 12 and 72 h) limits their usefulness in acute management of constipation. Providing there is enough fluid intake and adequate gut motility, added fibre can helpful. However, many dying patients have neither of these, and additional fibre can worsen the situation, causing a soft impaction and abdominal discomfort. Wheat bran is one of the best and least expensive of the bulk laxatives. Methylcellulose, psyllium (e.g. Metamucil), and polycarbophil are bulk laxatives that are safe, more refined, and more concentrated than wheat bran.
Osmotic laxatives
The osmotic agents cause retention of fluid, which distends the colon and increases peristaltic activity. Reduced absorption of water from stool and increased secretion into the gut lumen may be achieved by adding osmotically active particles such as magnesium and phosphorus salts, or non-absorbable sugars, such as lactulose or polyethylene glycol.
Magnesium citrate and magnesium hydroxide (Milk of Magnesia) decrease colonic transit time by stimulating cholecystokinin and drawing fluid into the colon by their osmotic effect. Their rapid onset of action (between 30 min and 3 h) makes them an excellent choice for acute management of constipation. These laxatives commonly cause abdominal cramping and, in patients with renal failure, may cause magnesium toxicity.
Polyethylene glycol is often considered the laxative of choice. The onset of action is between 24 and 48 h. It is equally effective, but better tolerated than the older osmotics, lactu-lose and sorbitol [47]. Because it is not fermented, gas and cramps are minimal. Sickly-sweet sorbitol and lactulose may not be palatable and may have the side effect of cramps, abdominal distension, and flatulence. Both are poorly absorbed sugars, likewise have rapid onset of action (8 12 h), but flatulence and abdominal distension may limit tolerance. Lactulose, whose breakdown products are mainly stimulant, is a particular culprit and is not usually recommended in paediatric palliative care.
Hyperosmolar solutions may worsen dehydration by drawing body water into the gut lumen and some are contraindicated in renal failure.
Stimulant laxatives
The stimulant laxatives include diphenylmethanes, the antraquinones, and castor oil. They are more potent than bulk or osmotic laxatives. Bisacodyl, a diphenylmethane, alters electrolyte transportation within intestinal mucosa and stimulates peristalsis. These actions may cause abdominal cramping and hypokalemia. Cascara, senna, and aloe (the strongest) are all anthraquinones. Colonic bacteria hydrolyse casanthranol and senna alkaloids into its active compounds. These stimulate peristalsis by excitement of the colonic myenteric plexuses and alter water and electrolyte secretion by the gut lining, resulting in net intestinal fluid accumulation. Aloe and Cascara sagrada directly irritate the intestinal mucosa, alter fluid and electrolyte secretion and increase colonic motility. All are available for both oral and rectal administration. Castor oil is reduced to ricinoleic acid that acts on the small intestine to decrease net absorption of fluid and electrolytes and stimulate peristalsis. As a general rule, the more potent the laxative substance, the more it is likely to cause unacceptable abdominal cramping. Spreading the dose out over the day, perhaps giving small doses with each meal and a slightly larger dose at bedtime, may diminish this effect. Constipated or impacted stool should be removed before introduction of drugs increasing gut motility to avoid exacerbating cramps.
Lubricants
Adequate lubrication of stool simply eases colonic passage and minimises pain that can interfere with excretion. Mineral oils lubricate by decreasing water absorption from intestine. Mineral oils can be used as an enema as well. Its long-term use is accompanied by concerns of lipid pneumonia, lymphoid hyperplasia, and foreign body reactions. Prolonged administration may also produce deficiency of fat-soluble vitamins. Docusate sodium causes increased systemic absorption of mineral oils, so the concomitant usage of both substances should be avoided. Glycerine suppositories can provide lubrication and draw-in water due to osmotically active particles. Instead of oils the most commonly used lubricants are dioctyl sodium sulfosuccinate (DSS), which decreases stool surface tension much like soap. DSS liquid is unpleasant to taste, so it may be given to tube-fed patients or use orally in other pharmaceutical formulation. DSS is commonly used in combination with senna in opioid-induced constipation, but is generally inadequate as a sole agent.
A selection of important medications and their modes of action is summarised in Table 23.5. In summary, stimulant laxatives combined with softeners should be considered first-line therapy for children undergoing palliative care. The effects of stimulants alone can attenuate over time [35, 38]. In our practice, polyethylene glycol (PeGl) without electrolytes has become the first option for many patients and is well-tolerated [48]. Lubricant mineral oil and softening magnesium hydroxide can be used over long periods [27, 49, 50].
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Table 23.5 Pharmacological treatment of constipation in children | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Experimental therapies
In recent years some specific and experimental therapies have been tried. It is believed that the laxative effect of prostaglandins may be due to changes in water and electrolyte absorption in the intestines and the motor effect. Researchers found that misoprostol increased the weight and frequency of stools and shortened colonic transit time in patients with severe chronic constipation[51]. Cisapride is an agent currently available in some countries that stimulates the upper GI tract and is useful in patients with spinal cord injury or Parkinson's disease as well as in chronic constipation with encopresis in children [36, 52]. Colchicine, used to treat gouty arthritis, is useful in treatment of chronic constipation [53]. Erythromycin exerts its prokinetic effect by acting as a motilin agonist and has long been used in gastrointestinal motility disorders [54]. It under investigation in idiopathic and chronic constipation in children. One double-blind, placebo-controlled, crossover study [55] showed the efficacy of erythromycin in the treatment of refractory chronic constipation presenting with megarectum and faecal impaction. Another colonic prokinetic drug, tegaserod that is a selective 5 HT4 partial agonist improves stool consistency and frequency in children with chronic constipation [56].
Among recently introduced pharmaceuticals tested in multiple clinical trials, the selective antagonists of the muscarinic type 3 receptor (zamifenacin and darifenacin) and selective antagonists for neurokinin receptors type 1 and type 2 (ezlopitant and nepadudant) seem to be effective in reducing the symptoms of abdominal pain, bloating, and constipation [57]. Neurotrophin 3 (NT 3) in particular increased stool frequency, enhanced colon transit, and improved symptoms of chronic constipation. It seems to be a novel, safe, and effective agent for the treatment of functional constipation [58].
Children with internal anal sphincter achalasia have clinical characteristics that distinguish them from children with functional constipation. Intra-anal injection of botulinum toxin is a safe and effective medium-term treatment for these children. Injection of botulinum type A toxin into the puborectalis muscle may also be effective in the treatment of other defaecatory disorders involving spastic pelvic-floor muscles [59].
Aternative therapies
The options to laxatives capable to relieve symptoms accompanying chronic constipation in severely neurologically impaired children include biofeedback and behavioural training and a pulse irrigation evacuation system.
Biofeedback and behavioural training are of benefit to improve sensory and motor awareness in children with incomplete neurogenic bowel lesions. They can be used to train patients to relax their pelvic-floor muscles during straining and to coordinate this relaxation with abdominal manoeuvres to enhance the entry of stool into the rectum. It is usually performed with anorectal electromyography or a manometry catheter. Biofeedback is a simple, cost-effective technique with few adverse effects. It remains an attractive option, especially considering the complexity of the functional disorders of the colon, rectum, anus, and pelvic floor. The benefits of biofeedback appear to be long-lasting. However, it does require the presence of some degree of sphincter contraction and rectal sensitivity. Biofeedback may be less effective for patients with the descending perineum syndrome than for patients with other defaecatory disorders [60].
Pulse irrigations exploit intermittent rapid pulses of warm water to break up stool impactions and stimulate peristalsis. Some clinicians advocate use of a bowel management tube with attached balloon (e.g. Foley catheter) and subsequent administration of saline, phosphates or mannitol enema for faecal evacuation in children with neurogenic bowel dysfunction. The balloon helps to provide anal occlusion to retain the enema fluid in persons with weak or absent anal sphincter function. Enemas should be used sparingly. They tend to wash out the normal mucus in the colon that provides lubrication for stools.
Opioid-induced constipation
The pathophysiology of opioid-induced constipation has now been well characterised [61, 62]. At least two types of opioid receptor, and , have been located in gut smooth muscle, with directly affecting the myenteric plexus [63]. Endogenous opioids modulate the resting tone of gut muscle [64]. Opioids delay gastric emptying by producing gastroparesis secondary to spasm in the antropyloric region. This action appears to stem from the central nervous system and is dopamine mediated [64]. Opioids also delay stool transit through the small bowel, an effect that is greatest in the jejunum and is related to an increase in nonpropulsive contractions. Colonic transit time as well as anal sphincter tone is also increased. Exogenous opioids inhibit detection of stool in the upper anal canal and therefore interfere with the defaecation reflex, and also inhibit relaxation of the internal anal sphincter. The result is impaired defaecation response, decreased peristalsis and increased stool transit time, which in turn lead to increased electrolyte and water absorption, drying of the stool and ultimately constipation. The constipating effect of opioids is immediate and dose related, and unlike most other side-effects, patients never become tolerant to it [64, 65].
Opioid-induced constipation may also contribute to abdominal pain, distension, nausea and anorexia or gastroesophageal
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reflux, and constipation may even occasionally may progress to bowel obstruction. While opioids are prescribed, bowel habit should be monitored carefully on a daily basis, beginning with a thorough history of individual habits before commencing opioids. Factors that frequently aggravate and compound opioid-induced constipation during palliative care include dehydration, confusion, other drugs and immobility.
The most important way to manage opioid-induced constipation is prophylaxis against it. Anecdotally, children receiving opioids may not develop constipation quite as universally as adults. Nevertheless, the majority of children will, and it is more difficult to treat than to avoid. Laxatives should always be considered, and usually prescribed, prior to commencing opioid therapy. It has to be remembered that usual measures of constipation prophylaxis (e.g. fibre, fluids, exercise) may not be sufficient for patients receiving palliative care. Fibre-based laxatives may even be dangerous in children with faecal impaction, resulting in obstruction if fluid intake is inadequate, as is often the case in those with non-malignant LLC. Similarly, osmotic laxatives such as lactulose are not appropriate. Instead, a combination of stimulant laxatives such as senna or dantron, combined with stool softeners such as magnesium hydroxide or docusate, are the mainstay of prophylaxis. In some countries convenient formulations are available combining laxatives of both classes, such as codantramer or codantrusate in the United Kingdom.
Despite adequate prophylaxis, some children receiving opioids will go on to develop constipation. Management of the symptom once it occurs relies on an understanding of physiologic response to opioids [16, 66, 67, 68].
Given the role of peripheral opioid receptors in developing constipation [69], blockade of receptors in the gut seems a logical therapeutic target for managing the problem. Given orally, naloxone and other opioid antagonists were the first among effective agents used to prevent opioid-induced constipation. Methylnaltrexone and alvimopan, newer opioid antagonists that are more selective for peripheral activity, have been introduced into clinical practice more recently [70]. Both have demonstrated the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs. Interestingly, oral naloxone also been effective in other causes of constipation [71, 72, 73, 74, 75, 76].
Patients who experience nausea or constipation while taking a particular opioid may benefit from opioid rotation [77] or switching to a different route. Opioids are not all equally constipating in relation to their analgesic activity; codeine, for example, is more likely to cause constipation than fentanyl or oxycodone [78]. Given the relatively weak analgesic potency of codeine, constipation may in effect impose a ceiling on the dose of codeine that can be given.
Painful defaecation
Eliminating any pain associated with the passage of bowel movements is extremely important. Painful defaecation is the primary precipitant of constipation during early childhood [78]. Using large doses of laxatives to produce very soft stools may be necessary. Continuing laxative therapy for a number of months is often necessary. Reassuring caregivers of the safety of long-term laxative usage is of utmost important. There are many popular misconceptions about their use, and even abuse [45, 46].
If the child has anal fissures, using Xylocaine ointment or hydrocortisone suppositories for a short period of time to provide symptomatic relief, may be appropriate. Rectal agents should be avoided in children who are at risk for thrombocytopenia, leukopenia, and/or mucositis from cancer and its treatment.
Excessive intestinal gas
The other, clinically important problem often complicated prolong constipation is gaseous distension. The most common symptoms associated with excessive intestinal gas are painful eructation, flatulence, and abdominal bloating and distention. Unfortunately, few therapies have been shown to be effective in treating these symptoms. Decreasing air swallowing can treat excessive eructation. Bloating and gaseous distension can improve in some patients by avoiding foods containing partially digested or absorbed polysaccharides, by taking replacement enzymes such as alpha-galactosidase or lactase, or occasionally, by taking antibiotics directed toward altering the colonic flora. For some children replacement of cow milk proteins with the substitutes (soy or peptide and amino acid formulas) may be beneficial [79].
Faecal impaction
For hard faecal impaction, a series of enemas or aggressive use of oral cathartics can avoid the need for digital disimpaction. Effective treatments include phosphates, mannitol, senna alkaloids and mineral oil or polyethylene glycol. Such interventions may need to be accompanied by a short-acting anxiolytic benzodiazepine, or an analgesic. After disimpaction, patients should be placed on a vigorous bowel regimen to avoid recurrence.
In extreme situations, caecostomy may permit decompression in megacolon, and antegrade enemas are of value in in colonic inertia. Antegrade enemas through a caecostomy are a safe option for children who are neurologically intact and
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who have severe constipation that does not respond to medical treatment. There seems to be no significant difference in the rate of continence or complication between caecostomy at ileal or appendiceal segment [49].
Intestinal obstruction
Intestinal obstruction is caused by an occlusion to the lumen or a lack of normal propulsion that prevents or delays intestinal contents from passing along the gastrointestinal tract. It is not restricted to children with malignant disorders, but can also occur and even cause death in children with non-malignant LLC [80, 81, 82]. Patients in the terminal phase are often unfit for surgery and require alternative management to relieve distressing symptoms [15] associated with obstruction. The distinction is often made between complete or partial, paralytic or mechanical obstructions. In patients with advanced disease the onset is usually insidious and takes even some weeks. Symptoms usually worsen gradually and intermittent obstructive episodes often resolve spontaneously, albeit sometimes only temporarily.
Difficult cases need medical, ethical and sometimes even legal considerations. The need for surgical intervention should always be decided on an individual basis. If palliative care is the only option, all symptoms should be adequately control. Appropriate conservative treatment can be effective in controlling nausea, vomiting and abdominal pain, secondary to bowel obstruction [26, 83]. Currently octreotide seems to be very effective in symptoms control combination with traditional pharmacological treatment to ameliorate the symptoms of inoperable bowel obstruction in terminal patients [84, 85].
Sialorrhoea
Sialorrhoea (drooling) is loss of control over one's own saliva [86]. Other terms, for example salivary incompetence, hyper-salivation, ptyalism, are often (not always accurately) used synonymously.
Hypersalivation refers to the excessive production of saliva. Ptyalism is a term that includes both hypersalivation and sialorrhoea. Secretions that pool in the hypopharynx and contribute to aspiration can cause choking, dysphagia, and breathing difficulties. Sialorrhoea is a serious social handicap experienced by many neurologically impaired patients [87, 88]. It carries considerable social stigma, can interfere with communication devices, and is a barrier to interpersonal relationships. Sialorrhoea may therefore have significant negative effects on the physical, social, and psychological well being of affected children as well as their families. It also impacts on other caregivers, who may have to change the child's clothing or bib 10 to 20 times each day.
It is unlikely to cause physical harm, unless the body's normal reflex coughing mechanisms are also impaired in which case persistent micro-aspirations can result. Physical problems associated with excessive sialorrhoea include facial chapping, responsible for irritation, rash or chapping arising around the mouth and chin, chilling from facial wetness in cold weather, dental caries, lip cracking and fissures, and the possibility of transmission of infectious diseases.
Sialorrhoea is therefore a serious symptom at the terminal stage of many life-limiting diseases, but particularly non-malignant ones.
Scope of the problem
It is estimated that between as many as 58% of children with cerebral palsy, and 10% of children with other neurological disorders are faced with severe sialorrhoea that requires intervention [88, 89]. Cerebral palsy (CP) alone affects approximately 1 in 200 to 300 newborns, so the absolute number of patients who should receive effective treatment is very significant.
Whilst neurological causes (Table 23.6) are the commonest in paediatric palliative care, other causes include structural abnormalities, of mouth, jaw and nasopharynx, emotional and psychological factors as well as side effects of some drugs, particularly neuroleptics and nitrazepam.
Pathophysiology of sialorrhea
Sialorrhoea may be caused by excess production of saliva, inability to retain saliva within the mouth, or problems with swallowing. Overproduction of saliva in the absence of swallowing impairment usually does not cause sialorrhoea.
Salivary flow rates in children with CP who drool are no different from normal children [89]. The predominant pathophysiologic mechanism is not overproduction of saliva, but disturbed coordination of the highly complex, sequential patterns of swallowing. It is the oral/voluntary phase of swallowing that is most severely affected. Inefficient swallow results from poor coordination of the lips, tongue, palate, jaws, pharynx, larynx, and respiratory muscles.
Table 23.6 Neurological conditions frequently associated with drooling | |||||||||
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Nevertheless, although hypersalivation is rarely the cause of severe sialorrhoea, the pathophysiology of saliva excretion and oral cavity structure's innervation holds the key to rational therapy. Ninety per cent of saliva is normally secreted by three major pairs of salivary glands and numerous minor glands located on the palate, buccal mucosa, and tongue. Depending on demand and autonomic regulation, saliva consists of two phases thin, watery secretions and thick, mucus-containing secretions. Daily production of saliva in adults usually reaches 1.5 l. The parotid glands are responsible for about 30% of the volume, producing mostly thin, serous secretions. The submandibular glands produce between 50 and 70% of the saliva. The quality of the secretions is more viscous because of a greater mucoid component. Sublingual glands account for about 5% of saliva and again produce predominantly mucoid secretions.
The secretory innervation of the salivary glands is primarily under the control of the parasympathetic nervous system. Stimulation of the parasympathetic nerves causes profuse secretion of watery saliva. Sympathetic stimulation may also occur but is thought to be a synergistic effect that results in an increase in the flow of saliva primarily through smooth muscle contraction at the duct level. Finally, some secretions come from the respiratory tree, as part of the physiological protective mechanisms.
Saliva serves many important physiological functions (Table 23.7). Any treatment plan that changes the amount, consistency, or flow of saliva in the oral cavity must consider the impact on these. The neuroanatomy is also important for both medical and surgical therapeutic considerations.
Management of sialorrhoea
Sialorrhoea becomes less of a problem once permanent dentition has appeared [90] and invasive techniques should be postponed until this time. Most treatments, which have been developed to date, are directed at reducing the volume of saliva produced. An appropriate therapeutic strategy for sialorrhoea should be based on the individual needs of the patient and family including the severity of the problem, previous interventions, and the level of neurological dysfunction. A major problem in treatment planning is that the magnitude of the problem varies considerably, so that control is a constantly changing need. Its impact may depend on factors other than simple saliva volume. A child who is less affected but more cognitively aware of the problem may suffer a greater degree of social isolation and disability than one with a greater degree of sialorrhoea, but less awareness.
Table 23.7 Physiological functions of saliva | ||||||||||||||||||||||
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Management techniques can include behavioural, pharmacological, and surgical interventions (Table 23.8). The use of non-pharmaceutical modalities is often limited by cognitive ability and is usually unhelpful. Pharmacotherapy alone may have a useful role in many patients, especially those with only mild sialorrhoea and mild to moderate intellectual delay. Aggressive surgical interventions should be considered in many children with LLC but are not always appropriate.
Published literature and clinical observations suggest that pharmacotherapy offers only short-term solutions, often at the cost of considerable side effects [89, 91, 92, 93]. Even surgical approaches seem to lose effectiveness with time [92]. Adverse side-effects are inevitable, irrespective of modality. Excessive dryness of mouth epithelium can exacerbate existing swallowing difficulties and aggravate rate of respiratory infections and breathing difficulties. Mucus producing respiratory glands are not regulated by any major nerve supply that can be blocked. The result is that saliva production is blocked, but not production of mucus. As saliva volumes diminished, mucus thickens and can accumulate in the back of the throat, with a tendency to block airways or make food stick in the throat. Coughing it up can be a tiring and arduous process, and take its toll on children and caregivers. In the presence of swallowing difficulties, especially in children with bulbar paralysis, successful treatment of sialorrhoea may therefore paradoxically worsen symptoms.
Adequate fluid intake is the first essential step in prevention of this problem. By reducing mucosal inflammation, antihista-mines and NSAID may help [94, 95]. Suction with appropriate catheters to clear phlegm and secretions from the throat and mouth is often helpful. In the experience of the Warsaw Hospital for Children, the Cough-Assist Mechanical Insufflation-Exsufflation device (MI-E) has been of value in patients whose swallowing is impaired, especially those suffering from acute respiratory infections. It safely and effectively clears retained broncho-pulmonary secretions by gradually applying a positive pressure to the airway, and then rapidly shifting to negative pressure. The rapid shift in pressure produces a high expiratory flow from the lungs, simulating a cough.
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Table 23.8 Treatment options for drooling | ||||||||||||||||||||||
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Factors that exacerbate sialorrhoea include teething as well as sensitive and painful gums, mouth ulceration, lack of sleep and crying. Over-the-counter treatments are available which provide pain relief in the form of analgesic and anaesthetic gels, some of which also possess antiseptic or anti-inflammatory properties. There is also a wide range of home remedies, such as teething rings.
Pharmacotherapy
Medications that modify sialorrhoea do so by reducing saliva production and/or by altering its consistency. Anticholinergic drugs inhibit salivary secretion by reversible blockade of the acetylcholine-mediated activation of muscarinic receptors. They include atropine sulphate, prantheline bromide, benzhexal*, benztropine (benzatropine), saltropine, glycopyrrolate, trihexyphenidyl and scopolamine. Scopolamine, glycopyrro-late, benztropine (benzatropine) and saltropine have received the most attention in children. They are not always effective; of patients treated, 45% can expect no change in their sialorrhoea, 30% minimal to modest improvement, and only 20% complete resolution. Some have maintained an excellent result for more than five years. Adverse effects of anticholinergics in children are largely attributable to other antimuscarinic effects and include:
behavioral irritability
restlessness
sedation, and
changes in cognition
Large doses may suppress intestinal motility, exacerbating constipation. Anticholinergics may also precipitate retention in children with neurogenic bladder. Reduced bronchial secretions can lead to formation of bronchial plugs. Inhibition of sweat glands can cause disturbances in temperature regulation. Other adverse effects include photophobia and facial flushing and anti-cholinergics are contraindicated for individuals with glaucoma.
Drug interactions with other medications must also be considered.
Scopolamine (hyosine)
Scopolamine can be inhaled [96] or used orally and in transdermal system as well [83, 97, 98]. The transdermal formulation has a significant advantage over enterally absorbed as it avoids the first passage hepatic deactivation and can be used effectively in lower doses. Unfortunately its effectiveness diminishes with time [99]. Dizziness, vomiting, nausea, headache, and vertigo may occur if the patch is discontinued too suddenly.
Atropine sulphate can also be used to reduce salivation and bronchial. Scopolamine and atropine, as well as glycopyrrolate (see below) have been used in nebulisers with no superior effect [100].
Glycopyrrolate
Glycopyrrolate may have fewer adverse effects [91] and better effectiveness [101, 102] than other anticholinergics. Nevertheless, side effects require glycopyrrolate to be discontinued in approximately 20% of children [102].
Botulinum Toxin A
Clinical studies suggest that botulinum toxin A (BTX) injections into salivary glands are effective in decreasing sialorrhoea. It is reliable and well-tolerated [103, 104, 105, 106]. The toxin originates
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from Clostridium botulinum and works by blocking acetylcholine release from nerve endings, at or near the place of injection. Typically BTX is injected into each parotid or submandibular gland only. The parotids are more important; as they are major glands producing the thin, watery part of the saliva. It takes a week to 10 days for the maximum effect of BTX injection to be seen. In patients who respond, blockade of salivary glands gradually diminished over 3 8 months. The injections can be repeated.
Of six patients treated in the Warsaw Hospice, there was no effect in two and good effect in another two. In the remaining two there was a therapeutic effect, but it was accompanied by a worsening of breathing difficulty, probably from thickening of bronchial plugs. If injected at the wrong site or if it spreads, BTX can paralyse muscles in the injection area and increase dysphagia and dysarthria, but if injections are given under ultrasound guidance, this is unlikely [107]. One study reports recurrent jaw dislocation as a side effect [108].
Others
Efficacy and side effects of trihexyphenidyl are similar to glycopyrrolate [109, 110]. An additional potential benefit for children with rigid or dystonic cerebral palsy is reduction in muscle tone [110].
Dryness of the mouth, is a side effect of tricyclic antidepressants (amitriptyline, imipramine) which can be turned to advantage in sialorrhoea. Central effects on mood and psyche are of additional value of treatment of sialorrhoea with these drugs.
Experimental therapies include metoprolol and clonidine [111]. Drugs blocking beta adrenergic receptors also inhibit mucus producing glands located in epithelial layer of mouth cavity and respiratory tract.
In some patients, activity against sialorrhoea has been found with older and some newer antihistamine medications and sympathomimetic agents such as ephedrine and pseudoephredrine. Sympathomimetic agents produce constriction of the blood vessels within the mucous membranes. Sympathomimetics are only effective for a short period and and can induce ischaemia. Treatment should be limited to 4 6 days. Some antihistamines possess additional anticholinergic activity [95, 96, 112, 113], and may be of value if secretions have an allergic component. Mucolytic agents alter not only mucus formation but also the consistency of saliva. Mucolytics are mainly used to reduce the thick, ropy secretions in throat and mouth that can interfere with swallowing and remain in respiratory tract.
Surgery
Surgery for severe sialorrhoea was first described in 1967 [114]. In general, surgery is reserved for children with non-progressive neurological disorders such as cerebral palsy, who do not respond adequately to non-surgical therapies.
Many surgical approaches have been reported. They are divided into two main categories: those that reduce the amount of saliva produced, and those that divert the saliva posteriorly so that spontaneous swallowing may occur more readily.
In patients who are at risk of aspiration, the former is preferable. There are 3 surgical approaches to decreasing salivary flow, including:
removing salivary glands
ligating salivary ducts
sectioning the nerves involved in salivary production.
Unfortunately results of all three have been disappointing [115, 116]. Nerve fibres regenerate and this limits long-term effectiveness. Children with severe impairment of volitional motor function and profuse sialorrhoea tended to have a poorer outcome compared with those with milder impairments [116, 117].
One of the newest procedures is combined ligation of the submandibular and parotid ducts. Currently four-duct ligation should be considered when surgery is indicated to treat sialorrhoea [117].
Other therapies
Saliva can be also reduced by irradiating the submandibular and sublingual salivary gland [118]. [There is a risk of xerostomia and secondary malignancy which may limit its usefulness in children whose life expectancy is long enough for them to become likely.]
Hiccup
Hiccup comprises an involuntary contraction of the diaphragm and the auxiliary respiratory muscles, occurring mostly in irregular series, followed by an abrupt closure of the glottis. It is a physiological phenomenon, which already exists even in utero, but its function is unknown. It is a gastrointestinal rather than a respiratory phenomenon. It may result in part from neuronal dysfunction, at the level of nerve roots or the reflex arc between inspiratory and glottic closure complexes [119]. The reflex is probably mediated by phrenic and vagus nerves and a central (brainstem) reflex centre. Irritation of the diaphragm [120] is often the underlying pathophysio-logical mechanism. Brief episodes of hiccup are benign and usually self-limiting. If a single episode lasts longer than 48 h it is termed persistent; if longer than one month, it becomes intractable. Prolonged attacks have been responsible for
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patient's tiredness and significantly interfered with both: quality of life and quality of care. Usually, the cause remains unknown, but persistent and intractable hiccups may indicate an organic disorder. Detailed evaluation based on history and physical examination can be helpful. Selected laboratory tests are sometimes indicated.
Causes of hiccup
The causes of hiccup are many and varied [121]. The most common are gastrointestinal in origin. GORD is perhaps the most important [121]. Hiccup may be induced by some drugs (such as digoxin); the same agents that are used to treat hiccups may also induce them. According to one source (114), 23% drug-induced hiccups were related to corticosteroids; 15% to psychiatric drugs, mainly antidepressants, and 13% to neurologic drugs, mainly dopaminergic antiparkinsonians. Other culprits include antibiotics, digoxin and analgesics, including opioids themselves, and it has been suggested that corticosteroids may lower the threshold for synaptic transmission in the midbrain, and directly stimulate the hiccup reflex arc [122].
Idiopathic hiccup often accompanies stress and hiccup may accompany organic conditions including malignancy, myocardial infarction, gastric distension and liver dysfunction. Uraemia and other metabolic abnormalities (such as disturbances of serum glucose, calcium, and potassium) may cause hiccup. Hiccups that are psychogenic in origin commonly abate with sleep and may be temporally related to stressful circumstances.
Management of hiccup
An evidence-based approach to management of hiccup is hard to define [123]. Virtually all current data is anecdotal. Treatment should be if possible directed at the underlying cause where one is identified. The patient's prognosis, current level of function and potential adverse effects from any proposed treatment should all be considered [124, 125].
Many drugs have been proposed to treat hiccup Table 23.9. Baclofen, a centrally acting muscle relaxant, is the only one studied in a double blind randomised controlled study [126, 127]. Its effectiveness may be increased by combination with gabapentin [128]. Among other well-established treatment modalities chlorpromazine is the most studied and appears to be the drug of choice. Its effectiveness reaches almost 80% [125].
Some older anticonvulsants include phenytoin, valproic acid and carbamazepine seem effective, especially in patients with hiccups of CNS origin. Metoclopramide has also been used successfully, especially if stomach distension is the aetiology. Haloperidol has also been used. Ketamine has been effective at a dose of 0.4 mg/kg, that is, one fifth of the usual anaesthetic dose.
The efficacy of combination therapy with cisapride, omeprazole, and baclofen (COB regimen) for treatment of idiopathic chronic hiccup (ICH) has been shown [129, 130]. Cisapride is no longer available for children in the United Kingdom following concerns regarding cardiac toxicity. Substituting gabapentin for baclofen in baclofen resistant ICH cases can occasionally be successful (COG regimen). COB and COG combination is considered by some to be therapy of choice for hiccups [129].
Infusion of lidocaine has been effective when other agents were unsuccessful [131]. Even in subanaesthetic doses, lidocaine possesses membrane-stabilizing properties that diminish neuronal excitability and reduce ectopic discharges. It seems logical therefore that it might prove beneficial in the treatment of certain patients with hiccup, particularly those in whom a neurogenic aetiology is postulated.
Other approaches have included the muscle relaxant, orphenadrine, sedatives such as amitriptyline and chloral hydrate, analgesics such as morphine and inhaled lidocaine, and stimulants such as ephedrine, methylphenidate, amphetamine (amfetamine) and nikethamide. Rarely used drugs, including edrophonium, dexamethasone and amantadine, have also been tried with equivocal results [125, 126]. Benzodiazepines may exacerbate or precipitate hiccups and should be avoided [132, 133], but sublingual nifedipine is safe and may be tried if other interventions have failed.
Non-pharmacological approaches
Time-honoured home remedies for hiccups include: gargling with water, biting a lemon, swallowing sugar or producing a fright response, and many others. Most of these, if they work at all, do so through vagal stimulation. More sophisticated techniques include:
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interrupting the respiratory cycle through sneezing, coughing, breath holding, hyperventilation, or breathing into a paper bag.
vagal stimulation through carotid massage or valsalva manoeuvre;
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interruption of phrenic nerve transmission via rubbing over the fifth cervical vertebrae;
In intractable hiccups, when other treatments fail, other approaches such as acupuncture, diaphragmatic pacing electrodes or surgical ablation of the reflex arc by cervical phrenic nerve block can also be considered [134].
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Table 23.9 Pharmacological interventions in the treatment of patients with hiccup | ||||||||||||||||||||||||||||||||||||||||||||||||
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Cachexia and anorexia syndrome
There has been considerable medical interest and remarkable progress in basic research in cachexia, despite there being no standard definition. Its Greek origins reveal that cachexia means simply poor condition . In adults with cancer, cachexia is considered to be present if there is involuntary weight loss within a 6-month period, representing more than 5% of premorbid weight. It is a complex syndrome that combines a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass.
Anorexia, which frequently accompanies malignant LLC, is one contributor to the syndrome of cachexia. However, the pattern of weight loss in cachexia differs from that seen with pure nutrient deprivation.
The anorexia-cachexia syndrome is a multidimensional maladaptation, encompassing a variety of alterations that range from physiological to behavioural. It can be associated with poor quality of life as well as short prognosis, and is therefore a legitimate therapeutic target for specialists in paediatric palliative medicine.
Causes of cachexia/anorexia syndrome
The characteristic feature of cachexia is accelerated loss of skeletal muscle, occurring in the context of a chronic inflammatory response [135]. An enormous variety of chronic or end-stage diseases demonstrate some nutritional changes of cachexia [136, 136]. In general, patients with solid tumours are more likely to suffer cachexia than those with haematological malignancies.
Pathophysiology of cachexia
Whilst the clinical features of cachexia are readily apparent, its pathogenesis is complex and poorly understood. In contrast with starvation, which is characterised by pure caloric deficiency, cachexia additionally evokes the body's acute phase response. Simply augmenting caloric intake does not reverse the process. Under normal circumstances, starvation leads to an increase in appetite, sparing of lean mass and a decrease in metabolic rate [137]. In cachectic malnutrition, on the other hand, appetite is diminished, lean body mass is reduced and there is an increase in metabolic rate [138]. Again, loss of skeletal muscle cannot be attributed simply to decreased food intake [139]. The damage to muscle is characteristic: pale muscle fibres are affected more than red ones, and damage predominantly involves myofibrillar proteins [140]. At the same time, there is an increase in visceral protein synthesis [141]. The adenosine triphosphate-dependent ubiquitin-proteasome pathway is probably the major mediator of protein degradation in cachexia [141]. Several proinflammatory cytokines stimulate production of ubiquitin messenger RNA.
Several factors may influence changes in body composition, including the patient's gender. Women lose more fat than lean mass (85% vs. 15%), while men lose similar amounts of both [142].
A milestone in the understanding and management of cachexia was the recognition that it represents an endogenous response to illness and injury. Rather than a simple increase in energy consumption by the tumour, and reduced caloric intake by the patient, cachexia is currently perceived as a metabolic abnormality resulting from a combination of host cytokine release and tumour products [139].
The key hormone responsible for coordination of the homeostatic loop regulating body weight is leptin [143]. Secreted by adipose tissue, leptin controls food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus.
Many cytokines participate as mediators in the cachectic process [144], including tumour necrosis factor- (TNF- ) and interleukins 1 and 6 (IL-1 & IL-6). In addition to their immunologic and physiologic functions these proinflammatory cytokines exert a variety of behavioural and nutritional effects. They can also affect the bowel, causing altered gastric emptying, decreased intestinal blood flow, changes small bowel motility and cellular proliferation of the villi, and alterations in ion fluxes. All of these can in their turn affect the patient's nutritional status [144].
Cytokines may also play a pivotal role in suppressing appetite, by mimicking the hypothalamic effect of excessive negative feedback signalling from leptin [144]. This may result either from the persistent stimulation of anorexigenic neuropeptides, such as corticotropin-releasing factor (CRF), or from the inhibition of neuropeptide Y (NPY) orexigenic network [144]. Lipid and protein mobilizing factors (such as lipid mobilizing factors [LMF] and proteolysis-inducing factor [PIF]) produced by a tumour itself can also directly mobilise fatty and amino acids from adipose tissue and skeletal muscles, respectively [139]. This argues a role for brain serotoninergic system in the aetiology of cancer anorexia-cachexia syndrome.
Recent studies have revealed new biochemical pathways in regulation of body mass. Such research will hopefully identify molecular targets that can help in developing effective pharmacological interventions. Most are currently directed at obesity treatment, but therapies for anorexia-cachexia syndromes may also become possible [139, 143].
Clinical consequences of cachexia
Cachexia can significantly compromise quality of life. It may contribute both to morbidity and mortality [139, 143]. As
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patients with lose muscle mass, they become profoundly weak and tired, finding even the most basic activities difficult. It can alter social interaction; affecting self-image and the individual's role in the family and society. Patients with cardiac or pulmonary insufficiency may develop cachexia in association with severe dyspnoea, weakness and exhaustion [144]. Cachexia may even influence response to curative therapy in cancer [145, 146].
Management of cachexia
Cachexia, like all symptoms, does not occur in isolation but in a complex multi-dimensional context. Whilst there are often physical dysfunctions underpinning it, they are only part of the experience the child and family have to go through.
Ensuring that one's child is adequately fed is a primal drive. Watching a child choose not to eat, to lose weight and change in appearance is very distressing for parents. For the child, on the other hand, losing appetite may be a relatively insignificant issue but the accompanying changes in body image can be profound and disturbing. Management needs to consider not only the underlying physical basis but the response of the child and the family to it.
In managing cachexia, therapies that are effective may incidentally, and sometimes inappropriately, extend life [139, 143]. Strategies that are currently under investigation include anabolic steroid and human growth hormone therapy, some appetite stimulants, nutritional supplementation, and more recently cytokine antagonists Table 23.10. Some have shown early promise.
Hypercaloric diets
The ineffectiveness of simply increasing caloric intake partly defines cachexia (see above). Increasing calorie intake will not increase muscle mass [139, 143] because protein degradation exceeds synthesis. Poor food intake and cachexia may, however, co-exist. A first step in managing cachexia is therefore to optimise feeding. This can be done by encouraging flexibility in the type, quantity and timing of meals. Families may need encouragement and permission to offer the child favourite foods that they may have previously considered to be unhealthy, such as hamburgers, crisps, chips and other fast food .
Presentation of meals in an attractive manner can stimulate appetite. It is often easier to eat a complete meal if it is small, particularly when served on a small plate. This offers positive reinforcement to the child, who is enabled to finish the whole meal. Often a child who finds a normal sized meal intolerable can manage many small meals through the day. Again, families who have always had the traditional three meals a day may need permission to offer instead smaller meals five or six times a day.
Table 23.10 Existing and potential therapies for cachexia | ||||||||||||||||||||||||||||||||||||
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Factors that potentially suppress appetite, such as nausea, vomiting, constipation, pain, fatigue and taste changes may be modifiable and should be treated where possible [136].
Anorexia/cachexia and depression often co-exist. Each can be a cause of the other. Recognition of depression in childhood is very important and appropriate intervention (cross ref psych symptoms chapter ch 25 Hammel), including antidepressant drugs, can lead to an elevation of mood and improved appetite. Weight gain is side-effect associated with some psychoactive drugs, including antidepressants, anxiolytics and antipsychotics [137]. This is probably through a combination of actions, relieving the underlying condition, directly stimulating appetite centrally, and perhaps through the suppression of pro-inflammatory cytokine secretions [137].
Appetite stimulants
Appetite stimulants may increase caloric intake of some cachectic patients, especially in an outpatient ambulatory setting. Megestrol acetate (MA) and medroxy-progesterone acetate (MPA) have been found to improve appetite, caloric intake, and nutritional status [147, 148, 149]. The mechanism of
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action of progestational drugs is complex, and might be related to stimulation of NPY in the hypothalamus, modulation of calcium channels in the satiety centre and inhibition of the activity of proinflammatory cytokines. There are reports of adrenal insufficiency during megestrol therapy [150, 151, 152, 153].
Appetite stimulation and weight gain are well-recognised effects of the use of marijuana and its derivatives. They are often familiar to those treating chemotherapy-induced nausea and vomiting in children, and are often accompanied by improvement in mood. The mechanism by which cannabinoids exert their effect is still under debate. It is probable that they act via endorphin receptors, by inhibiting prostaglandin synthesis and by inhibiting IL-1 secretion [139]. Recent studies suggest that endogenous cannabinoids are present in the hypothalamus, and may activate CB-1 receptors to maintain food intake, forming part of the leptin regulatory system [154].
Serotonin suppresses appetite when injected into the VMH of animals [155]. Cyproheptadine, which inhibits serotonin, may stimulate appetite in patients with advanced carcinoid tumours [156] as do ondansetron and other 5HT3 antagonists [139]. Although corticosterioids can stimulate appetite, prolonged treatment may lead to weakness, delirium, osteoporosis, and immunosuppression as well as serious disruption of body image [157] and they should not usually be considered for this indication.
Anabolic drugs
Most effective treatments for cachexia either promote protein synthesis or inhibit protein breakdown. Although controversial, the use of growth hormone and its analogues have been reported in patients of cachexia [158]. Growth hormone (GH) diverts protein synthesis towards lean mass and away from acute phase response. There is evidence that mortality rates are increased by the use of GH [145, 159] perhaps as a result of its effect on the immune system [143] or on promoting tumour growth.
Testosterone and anabolic steroids can cause increases in fat-free mass in adults with non-malignant life limiting conditions [157]. The efficacy of anabolic steroids in adults with malignancy is still unclear [160] and there is no evidence in children.
Anticytokine therapies
In vitro studies have shown that inhibition of proinflammatory cytokine activity can decrease protein breakdown [139, 143, 144]. Many drugs exert anticytokine properties in vitro, including appetite stimulants megestrol acetate, medroxyprogesterone, and 9 tetrahydrocannabinols. Pentoxiphylline and thalidomide reduce TNF activity. Many of these agents have been shown to promote weight gain [161, 162] but few have been studied in children [144, 163, 164].
Fluorinated pyrimidine nucleoside (5';-deoxy 5 fluorouridine: 5' dFUrd; 5 FU precursor) attenuates progression of cachexia in mice bearing murine or human cancer cell lines. The mechanisms include inhibition of IL 6 and PIF [165]. Another potentially active substance is melatonin, a circadian neurohormone secreted by the pineal gland that decreases the level of circulating TNF- in experimental animals [139, 166].
Anti-inflammatories
Anti-inflammatory therapies may provide an alternative to anticytokines, since signal transduction may involve arachidonic acid metabolites. Addition of NSAIDs or steroids to other anti-cachectic therapies results in improvements in quality of life, inutritional status and exercise capacity in some adult cancer patients [167, 168, 169]. NSAIDs may have a particular role in non-malignant cachectic conditions, such as rheumatologic diseases.
A novel approach is based on anti-inflammatory activity of omega 3 fatty acids, which inhibit the production of IL 1 and TNF, and may improve the efficacy of nutritional support [139]. Other therapy that has been tried with some success is the administration of branched-chain amino acids (BCAA: leucine, isoleucine, and valine). They may serve as a protein-sparing metabolic fuel , providing substrate both for muscle metabolism and gluconeogenesis. Total parenteral nutrition enriched in BCAA has resulted in improved protein synthesis [170]. Anti-oxidants may limit protein losses in experimental cachexia models [143].
Emerging drugs and other therapies
As in so many areas of palliative care in children, many unproven measures have been tried. Some alternative medicine practitioners promote hydrazine sulphate. Hydrazine inhibits phosphoenol-pyruvate carboxykinase, a key enzyme in gluconeogenesis [139]. Efficacy has not been shown and neurotoxicity is a risk.
On the other hand, beta 2 adrenoceptor agonists such as salbutamol may suppress muscle breakdown through its action on the ubiquitin-dependent proteolytic system [139, 143]. Polyunsaturated omega 3 fatty acids inhibit cachexia model and counteract lipid mobilizing and proteolysis-inducing factors. Two substances have been studied to date: eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA). Inclusion of EPA in nutritional supplements may increase weight gain and lean body mass and lead to an improvement in performance status [171].
Autonomic failure with decreased gastrointestinal motility is a recognised complication of cancer cachexia, associated with anorexia, chronic nausea, early satiety, and constipation, further compromising caloric intake [172]. Prokinetic agents,
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such as metoclopramide, domperidone and erythromycin have been used in cancer patients with some success [139].
Novel approaches to cytokine inhibition are currently being evaluated [143]. They include an antisense therapy which binds to the promoter region of DNA and slows transcription of cytokine mRNA [173]; anti-interleukin 6 receptor antibodies [174]; anti-TNF antibodies [175]; and soluble TNF receptors [176]. The place of these therapies in palliative management is unclear.
Among metabolic regulators tested in preclinical studies, promising results have been obtained with antagonists of TNF [177]; the hypolipidaemic agent benzfibrate [178]; and a novel activator of tissue lipoprotein lipase [179].
Ethical issues in disturbed swallowing and food intake
Anorexia and marked weight loss are common in dying patients [180, 181]. Malignancy in children is only one cause; they are also a feature of many progressive and debilitating diseases.
Evidence suggests that artificial hydration and nutrition, whether parenteral or by tube, neither prolong life nor increase the comfort of imminently dying patients [1, 7, 182, 183, 184, 185, 186]. Assisted feeding may indeed compromise the quality of life for some, and palliative care physicians often see the complications of too aggressive interventions to maintain food intake. They include abdominal discomfort, nausea and vomiting, difficult breathing and increased pulmonary secretions. Parenteral fluids delivered either intravenously or subcutaneously may have adverse effects that are not always considered [184, 187]. Intravenous lines can be cumbersome and particularly painful; many patients are difficult to cannulate.
Conversely, starvation and dehydration may exert analgesic effects and reduce discomfort at death [180, 181, 186, 187, 188,] . The only common discomfort associated with dehydration near death is xerostomia, which can usually be relieved with oral swabs or ice chips [188, 187]. Many children refuse to eat just before death, and they should not be forced.
The right to forgo food and water, whether by mouth or by artificial means, derives from the fundamental right of competent patients to refuse medical treatment and to be free of unwanted bodily intrusion [188, 189]. Force-feeding a competent patient who clearly refuses food and water violates autonomy, liberty, and dignity. Many ethicists have sought to blur the ethical distinction between introducing an intervention that will kill, and refraining from starting one that may prolong life. The distinction is a fundamental one in palliative medicine. One of the logical consequences is the principle of double effect . The principle argues that an intervention (or the withholding of an intervention) may not be morally wrong, even if it results in an outcome that is not desired. This remains true, argues the principle, even if the unintended consequence is foreseen.
The principle of double effect was articulated by Roman Catholic moral theologians in the Middle Ages, but derives from the basic ethical principle of justice. The principle has an ethical validity that is independent of religious framework.
In considering the withdrawal of feeding, the issue is one of weighing up the balance of benefit and burden to the patient. To withdraw fluids or feeding simply in order to shorten life would not be ethically justifiable. However, if the intention is to reduce the severity of some symptoms such as secretions, bloating, or nausea and vomiting, it can usually be justified. It is unusual for withdrawal of hydration or feeding to be the primary cause of death. Even on those rare occasions when it occurs, however, the principle of double effect would argue that if the intention was primarily to relieve symptoms, the fact that death was a foreseen outcome does not mean it was the intended one.
Despite research, myths about eating and drinking at the end of life persist among patients, their families, and many healthcare professionals. Those working with dying children can come under considerable pressure to initiate or to continue inappropriate hydration and/or feeding. The need to nourish ones child is a very basic one. A child's refusal, or even inability, to eat and drink is often perceived by parents to be a failure on their part to fulfil this basic role [1, 27].
It can therefore be very difficult for parents to accept, but families should usually be counselled that neither food nor hydration is necessary to maintain a patient's comfort. They need to be reassured that, near the end of life, food will not increase the patient's strength nor will it substantially delay death. At the same time, families should be given concrete recommendations such as advice on positioning the patient, use of favourite foods, small portions of simple meals and foods that are easy to swallow. Children who find it difficult to swallow may, for example, prefer milk puddings, fruit yoghurts or cottage cheese preparations and similar simple meals. Pieces of fruit frozen so that they can be sucked to moisten the mouth may help. Pineapple is a traditional recommendation for this, but individual patients may prefer apples, pears, oranges and bananas.
Xerostomia is one of the few adverse effects of not providing artificial hydration. It can be relieved using artificial saliva spray, petroleum jelly on the lips and careful oral hygiene. Once again, these interventions can involve the family and enable them to feel, rightly, that they are caring for the child even without needing artificial hydration or feeding.
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For some families, the symbolic emotional meaning of artificial fluids or nutrition is so important to the family (or indeed the patient, or even health care professionals) that they become inescapable. It may then be necessary to modify the rates in order to avoid some of the adverse effects. For example, 50% or two-thirds maintenance will usually be enough hydration and may reduce the risk of excess secretions.
Inability to swallow
Inability to swallow can create a number of medical problems, among them the high risk of aspiration. Feeding may nevertheless be considered appropriate in children unable to swallow who are expected to survive more then 7 14 days, when there is a true hunger and thirst in the setting of a functional gut. Thus, nasogastric tubes or gastrostomies should be limited to patients who are able to benefit from nutrition as well as hydration. In general, enteral feeding is preferred to parenteral options [1, 27, 190, 191].
In general nasogastric tubes (NGT) are useful only in the short term. Potential complications make them inadvisable for periods longer than 2 3 weeks. The useful life of some silicone NGTs can be extended beyond this [192]. Complications of NGT include aspiration pneumonia or mechanical difficulties (occluded or clogged tube, nasal irritation or erosion, sinusitis and epistaxis, tube displacement). Any tube which traverses the gastro-oesophageal junction promotes GORD.
Direct enteral access is preferred when feeding extends beyond 30 days [192, 193]. Children may benefit from a gastrostomy for feeding or administering medications, to decompress the stomach, or both. The choice of access route gastrostomy, gastrojejunostomy, or jejunostomy and the choice of placement technique surgical, endoscopic, or radiologic depend on the needs of the individual patient [194].
Percutaneous endoscopic gastrostomy
Introduction of percutaneous endoscopic gastrostomy (PEG) into clinical practice has radically changed the approach to gastrostomy access. This minimally invasive procedure has largely replaced surgical gastrostomy [195]. Endoscopic gastrojejunostomy and direct endoscopic jejunostomy have also been used, [196]. Gastrostomy tubes may still predispose to gastro-oesophageal reflux and many patients are at risk of aspiration [196, 197, 198, 199].
Uncorrectable coagulopathy and the absence of a safe access route are considered contraindications [195]. Nissen fundoplication or a similar procedure may be helpful if reflux is shown in preoperative studies and is often performed simultaneously to minimise the number of anaesthetics. Complications of PEG Table 23.11 are infrequent [194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207] but can include wound infection, peritonitis, septicaemia, peristomal leakage, tube dislodgement, aspiration, bowel perforation, and gastrocolic fistula. Pneumoperitoneum after PEG is usually of no significance, unless of course accompanied by peritonitis. Dislodged tubes can often be replaced without imaging guidance. External rings or fasteners, and intraluminal balloons or special clips may be useful in preventing the exit of gastric contents, and development of cellulitis, erythema and tenderness around the catheter. Muscle atrophy, severe spasticity and obesity increase the risk of such problems. They often resolve rapidly with local antiseptic wound care.
Table 23.11 Complications of gastrostomy | ||||||||||||||||||||||||
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Diarrhoea
Persistent chronic diarrhoea is rare in children dying from most life-limiting diseases [27, 45, 208]. It commonly complicates immunodeficiency, particularly in HIV/AIDS (cross ref. HIV AIDs, chapter 32. Norval) [27]. Villous atrophy due to immune-mediated HIV enteropathy and necrotizing enterocolitis resulting from chronic intestinal infections is a common gastroenterological complication of late HIV infection. The treatment of HIV-related diarrhoea consists of specific antimicrobial, fungicidal and antiparasitic drug regimens. These are combined with cholestyramine (colestyramine) to absorb toxins. Antimotility agents are not indicated routinely for infectious diarrhoea, except for refractory cases of Cryptosporidium infection. Racecadotril, an oral enkephalinase inhibitor, is safe and has been successfully used in the treatment of acute diarrhoea of infectious origin, but especially in patients with HIV infection [209].
Pancreatic exocrine deficiency is another cause of chronic diarrhoea. Poor dietary control and inadequate supplementation of pancreatic enzymes during the course of cystic fibrosis and other rare hereditary disorders can result in diarrhoea in the terminal phase of disease.
In cancer patients severe polymucositis and diarrhoea often complicate high dose chemotherapy and occasionally radiotherapy.
The management of diarrhoea should usually be tailored to the underlying cause. It is often self-limiting. Opioids such as codeine and loperamide may be effective. For high output diarrhoea, octreotide may have a role. Ocreotide is a synthetic analogue of somatostatin which increases fluid resorption from the bowel. It is given subcutaneously, either as a bolus or as an infusion. The dosage range is usually between 60 and 1200 g depending on the size of the child.
Closing remarks
Children deserve the best of care at all times, but perhaps especially at the end of life. The experience of palliative team members suggests that greater attention to symptom control and the overall well being of children with advanced disease can ease their suffering. The care of children at the end of life is gradually improving. Nevertheless, more than half suffer from intractable symptoms before dying.
Gastrointestinal symptoms are among the most common problems of terminal illness. The range of problems includes dysphagia, nausea, vomiting, anorexia, cachexia, constipation, diarrhoea and bowel obstruction. GI issues are a major chronic problem in 80 to 90% of with neurodevelopmental disabilities who represent the growing population among children required palliative care [35]. Many different malignancies and other intractable and/or chronic diseases can give rise to gastrointestinal dysfunction and specific symptoms needing appropriate pharmacological, surgical or complementary management. Beside the basic principles and pathophysiology of symptoms, some new drugs and innovative endoscopic and surgical techniques in the management of gastrointestinal symptoms have also been presented in the chapter.
It should be of some concern to the paediatric palliative care specialist that many currently available therapies have been introduced into every day practice without well-documented evidence concerning their efficacy and safety in children. Many perhaps most drugs are administered according to a regimen that is simply extrapolated from practice in adults. In reality, although the principles of palliative care apply equally to children and adult patients, a number of fundamental differences influence their application in the paediatric population. Palliative medicine has developed as a specialised field of practice in recent decades, but the focus has until recently been very much on adults with incurable malignancies. The issues in children are fundamentally different; they include a heterogeneous patient population, pathophysiological factors and developmental issues. Children are not little adults; their immaturity, developing cognition and dependence on caregivers all influence the diagnosis and multidimensional management of symptoms.
The paediatric palliative care team gives professional medical care, and provides sophisticated symptom relief. When evidence is lacking, an empirical approach is often necessary and appropriate. There is still a lack of specialised knowledge concerning the population of children dying from chronic, progressive diseases. Further research is needed to increase the evidence base for practice. Recent concerns over toxic effects of drugs in newborns, infants and children have stressed the need for better knowledge of drug kinetics during development. Children with life-limiting problems need a systematic and comprehensive approach if we are to ensure that their particular needs are met.
The management of gastrointestinal symptoms in dying children illustrates very well many of the principles that should underlie good symptom management. Treatment should be evidence-based where possible and empirical where necessary. The benefit to the patient of an intervention should always be expected to outweigh the burden before it is introduced. The ethical issues around withdrawing or withholding hydration or nutrition, for example, are often finely balanced. However, a clear understanding of the ethical principles involved, and in particular of the principle of double effect, will usually enable professionals to put the individual child's needs first, without putting themselves in ethical peril.
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Notes
Warsaw Hospice for Children (a Non-Governmental Organization) is a home-based palliative care programme responsible for 24 -a-day, and 7 days-a-week care for incurable children with progressive diseases inevitably leading to death. It closely cooperates with Department of Palliative Care, National Research Institute for Mother and Child, Warsaw, Poland. The latter is an institution responsible for scientific supervision on on-going clinical trials, which are financed by WHC, and training in paediatric palliative care.
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EAN: 2147483647
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- Chapter I e-Search: A Conceptual Framework of Online Consumer Behavior
- Chapter III Two Models of Online Patronage: Why Do Consumers Shop on the Internet?
- Chapter IV How Consumers Think About Interactive Aspects of Web Advertising
- Chapter VI Web Site Quality and Usability in E-Commerce
- Chapter XVI Turning Web Surfers into Loyal Customers: Cognitive Lock-In Through Interface Design and Web Site Usability