In establishing that a given intervention is in the child’s best interest, it is clearly necessary to be aware of the existing evidence. In an age where evidence-based medicine is a professional requirement,² it is important that practice is not just based on anecdotes and experience, but also is justified with research. Critical appraisal and clinical reasoning must underpin practice. Systematic reviews or meta-analyses, where they exist, are authoritative sources of such evidence. Individual carefully designed double-blind trials are also powerful evidence. Anecdote and case history, however, are not indicators of effectiveness. They are important signposts to studies that should take place, but should not result in an uncritical change of practice by themselves.

The literature pertaining to non-pharmacological approaches to the management of neurological symptoms is particularly sparse. A rational and logical approach does not, however, mean that practice should be limited only to that rather narrow range of therapeutic options that have been subjected to study in children. It is often necessary to extrapolate from evidence in the adult specialty, or from related disciplines such as acute pain management. Sometimes, professionals working in pediatric palliative care need to be therapeutically creative, using a sound knowledge of pharmacology and therapeutics to develop an approach that, while it may not be fully supported by evidence, is nevertheless rational.

Complementary and alternative medicine (CAM) ap- proaches should be used in conjunction with conventional medicine to aim to provide better symptom control and meet the cultural, spiritual, and psychosocial needs of the child and family.³ Many neurological symptoms are exacerbated by depression, anxiety, and/or fatigue. There is evidence to suggest these are ameliorated by some CAM approaches, including massage,⁴^–¹² acupuncture,^8,^10,¹³^–¹⁶ and transcutaneous electrical stimulation (TENS)^8,¹⁷ can offer some assistance with this. The effectiveness of TENS is unclear^18,¹⁹ but it is well tolerated by most patients. Music therapy and hydrotherapy are naturally enjoyable interventions for children (Fig. 27-1).

Fig. 27-1 Child’s depiction of successful family-centered interdisciplinary care of child with neurological symptoms.

Symptoms

For a summary of doses and indications of medications in this chapter, see Table 27-1.

TABLE 27-1 Doses and Indications for Medications Mentioned in This Chapter

Medication	Indication	Dosage
Midazolam	Status epilepticus and terminal seizure control. Breakthrough anxiety, such as panic attacks. Adjuvant for pain of cerebral irritation. Dyspnea	For status epilepticus: By buccal administration, Neonate 300 micrograms/kg as a single dose Child 1-6 mo, 300 micrograms/kg (max. 2.5 mg), repeated once if necessary Child 6 mo-1 yr, 2.5 mg, repeated once if necessary Child 1-5 yrs, 5 mg, repeated once if necessary Child 5-10 yrs, 7.5 mg, repeated once if necessary Child 10-18 yrs, 10 mg, repeated once if necessary For terminal seizure control: By subcutaneous or intravenous infusion over 24 hrs, 50-300 mcg/kg/hour up to maxi. 160 mg For anxiety or dyspnea: Approximately 50% above doses

Diamorphine As for morphine. Useful where large doses need to be dissolved in small volume Relative potency parenteral preparations 3x that of oral morphine. Phenobarbital Adjuvant in pain of cerebral irritation. Control of terminal seizures. Sedation

By mouth:

Neonates, loading dose by slow intravenous injection, then 2.5-5 mg/kg by mouth once a day

Child 1 mo-12 yrs, 1-1.5 mg/kg twice a day, increased by 2 mg/kg daily as required (usual maintenance dose 2.5-4 mg/kg once or twice a day)

Child 12-18 yrs, 60-180 mg once a day.

Diazepam Short-term anxiety relief. Relief of muscle spasm. Treatment of status epilepticus

Short-term anxiety relief:

By mouth:

Child 2-12 yrs, 2-3 mg three times a day

Child 12-18 yrs, 2-10 mg three times a day

Relief of muscle spasm:

By mouth:

Child 1-12 mo, initially 250 mcg/kg twice a day

Child 1-5 yrs, initially 2.5 mg twice a day

Child 5-12 yrs, initially 5 mg twice a day

Child 12-18 yrs, initially 10 mg twice a day, maxi.

Total daily dose 40 mg

Status epilepticus:

By intravenous injection over 3-5 min:

Neonate, 300-400 mcg/kg repeated after 10 min if necessary

Child 1 mo-12 yrs, 300-400 mcg/kg repeated after 10 min if necessary

Child 12-18 yrs, 10-20 mg repeated after 10 min if necessary

By rectum:

Neonate, 1.25-2.5 mg repeated after 10 min if necessary

Child 1 mo-2 yrs, 5 mg repeated after 10 min if necessary

Child 2-12 yrs, 5-10 mg repeated after 10 min if necessary

Child 12-18 yrs, 10 mg repeated after 10 min if necessary

Levomepromazine Antiemetic where cause is unclear, or where probably multifactorial. Secondary effects include sedation and analgesia

Antiemetic:

By mouth:

Child 2-12 yrs, starting dose 0.1-1 mg/kg, max 25 mg

Child greater than 12 yrs, 6.25-25 mg by mouth once or twice daily

By continuous intravenous or subcutaneous infusion over 24 hrs:

Child 1 mo-12 yrs, 100-400 mcg/kg over 24 hrsChild greater than 12-18 yrs, 5-25 mg over 24 hrs

For sedation:

By subcutaneous infusion over 24 hrs:

Child 1 yr-12 yrs, 0.35-3 mg/kg over 24 hrs

Child over 12-18 yrs, 12.5-200 mg over 24 hrs

Analgesic: May be of benefit in a very distressed patient with severe pain unresponsive to other measures

Stat dose 0.5 mg/kg by mouth or subcutaneously. Titrate dose according to response; usual maximum daily dose in adult 100 mg subcutaneous or 200 mg by mouth

Fentanyl Severe pain (synthetic opioid analgesic), particularly as rotation from morphine or if patch formulation desirable

By transmucosal application (lozenge with oromucosal applicator):

Child 2-18 yrs, 15-20 mcg/kg as a single dose, max. dose 400 mcg

By transdermal patch:

Based on oral morphine dose-equivalent Product monogram,

Oral morphine 60-134 mg = 25 mcg/h patch of fentanyl

Oral morphine 180-224 mg = 50 mcg/h patch of fentanyl

Oral morphine 27-314 mg = 75 mcg/h patch of fentanyl

Hydromorphone Severe pain (opioid analgesic) especially if diamorphine unavailable and solubility is an issue

By mouth:

Child 12-18 yrs, initially 1.3 mg every 4 hrs, increasing as required

Tizanidine Muscle spasm

By mouth:

Adult dose, initially 2 mg increasing in increments of 2 mg at intervals of 3 to 4 days. Give total daily dose in divided doses up to 3-4 times daily. Usual total daily dose 24 mg. Maximum total daily dose 36 mg

Baclofen Chronic severe spasticity of voluntary muscle

By mouth:

Initially, Child 1-10 yrs 0.75-2 mg/kg daily or 2.5 mg 4 times daily.

Increased gradually to maintenance:

Child 1-2 yrs, 10-20 mg daily in divided doses

Child 2-6 yrs, 20-30 mg daily in divided doses

Child 6-10 yrs, 30-60 mg in divided doses

Melatonin Sleep disturbance caused by disruption of circadian rhythm (not anxiolytic)

By mouth:

Dose unknown, initially 2-3 mg, increasing every 1-2 wk dependent on effectiveness up to maximum 10 mg (higher doses have been used)

Seizures

Management of seizures outside the terminal phase is beyond the scope of this chapter. The palliative care professional should continue to liaise carefully with colleagues in neurology, even as death approaches. Potentially, this can achieve several important objectives:

• Rationalization of anticonvulsant medications

Children with life-limiting conditions in ACT categories III and IV (Table 27-2), which are often chronic neurological conditions, are likely to have seizures that have been difficult to control for some time. The result is typically that, at the time it is clear a palliative phase has been entered, children are on a large number of different anticonvulsants.

TABLE 27-2 Life-Limiting Conditions

The long-term management of seizures requires a neurologist to balance carefully immediate benefit with long-term side effects. In the palliative phase, such a balance may no longer be necessary. Discussion with neurology colleagues may allow:

• Discontinuation of some anticonvulsants,

• Reduction in the number of anticonvulsants,

• Substitution of specific anticonvulsants with broader range ones with additional desirable benefits such as anxiolysis or activity against neuropathic pain.

Management of breakthrough seizures usually requires a parenteral approach. This presents a conflict with one of the aims of palliative care, which is to offer the family the choice of locations, typically home, hospital, or hospice, for death to occur. The intravenous and subcutaneous routes may not be appropriate, because they are not usually available except to professionals who may not be immediately on hand.

The solution to this is to use the buccal route. Small volumes of water soluble drugs such as midazolam and diamorphine can be administered between the cheek and the gum. They are absorbed rapidly through the oral mucosa, effectively providing an alternative parenteral route without needles. This is increasingly used for management of breakthrough seizures in neurology ²⁰ and is ideally suited to their management in the terminal phase.

• Management of terminal seizures

The two mainstays of seizure management in the terminal stages are phenobarbital and midazolam. Both may be given as continuous subcutaneous infusion, though phenobarbital must be given separately from other medications. The decision as to which of these should be first-line use is largely up to the clinician; there is little evidence to suggest which is likely to be more effective, and it may depend on the individual circumstances and patient.

• Phenobarbital

Phenobarbital is rarely used in seizure disorders because of the risk of adverse effect in long-term use. In the palliative phase, however, where these are unlikely to be a significant consideration, it has a number of potential advantages over many other anticonvulsants, though not all are proved. It is anxiolytic, rather than simply sedative,²¹ effective against cerebral irritation; is sedating it may have some activity against neuropathic pain.²² It can also be given orally or through a gastrostomy tube.

It does, however, also have some disadvantages:

It induces its own metabolism, so the dose may need to be kept under review; and its long half-life means it cannot easily be titrated against its effect, particularly if given orally.

• Midazolam

Midazolam is a short-acting benzodiazepine. It is often used by neurologists for breakthrough seizures, but rarely for background control because of its short half-life. In the palliative phase, Midazolam is usually given by continuous subcutaneous infusion although there is no reason in principle why it should not also be given intravenously. It can be mixed with other medications in the same syringe driver, including diamorphine, morphine, levomepromazine, and other medications commonly used in the final days of life. It is easy to titrate against symptoms due to its short half-life; ²³ powerfully anxiolytic, amnestic and sedating; and has a broad range of anticonvulsant activity. Midazolam is widely used in pediatric palliative care, so it has reasonable clinical experience and evidence base. Also, it is highly soluble so can be given by buccal route.

Midazolam’s disadvantages are that paradoxical agitation can occur in some children ²⁴ and its short half-life makes it inappropriate for background control of seizures except by parenteral infusion. The drug can cause confusion; and in cognitively aware children, loss of memory may be a disadvantage, particularly if it impairs family relationships.

The decision as to which is the better first-line approach will depend largely on individual circumstances. For a child who has otherwise no need for parenteral access, phenobarbital given orally may be preferable. For a child needing benzodiazepines for other reasons, midazolam may be the logical choice. For many children, adequate control of seizures in the terminal phase will in practice require both drugs to be given parenterally as the swallowing reflex becomes lost.

Breakthrough seizures

Before embarking on management of breakthrough seizures, it is important to discuss with the child’s family what their expectations are. Most families have lived with a child with complex seizure disorder for many years and will be able to fully engage in a discussion about what can and cannot be achieved in the way of control in the final days and weeks of life.

It is important to acknowledge that seizures are more unpleasant and frightening for those observing them than they are for the child who experiences them. If seizures do not appear to distress the child, then vigorous attempts to abolish them may result in replacing acceptable seizures with unacceptable adverse effects. For families used to a child who has many seizures a day, reducing them to only one or two seizures a day may be an acceptable outcome.

It is also important to acknowledge that complete control of seizures may simply not be possible. If complete absence of seizures can only be achieved by means of anesthesia and ventilation, from which there is no realistic prospect of the child’s recovering, it is a price too high for the child to pay. This needs to be explored with the family at the time management of terminal seizures is initiated.

It is usual for children with complex seizure disorders to have a detailed seizure protocol that has been agreed between neurologist and family. It is important that the palliative care pediatrician be aware of this protocol, and that he or she work carefully with the neurology team and the family themselves before suggesting any modification. This protocol should be accessible to all those involved with the child and identify what is normal for that child, when a seizure has become prolonged and requires medication, and at what stage and to what level further help should be sought if seizure activity continues.

One common medication used for treatment of breakthrough seizures, when indicated, is diazepam, which may be given by the rectal route. The metabolites of diazepam are active and long-lasting, but this is rarely a problem in children. Children prefer to avoid the rectal route where possible, as it is uncomfortable and undignified. Nevertheless, it is certainly preferred to a needle by most and may be the most accessible in the midst of a seizure. The rectal route is contraindicated in neutropenia or marked thrombocytopenia.

Non-pharmacological management

Even in the terminal phase, immediate nursing interventions aimed at making the child comfortable are important. These would include correct positioning of the child, and oxygen if indicated. The timing of anti-seizure medications should be carefully defined ahead of time in a clear seizure protocol, that takes account of the needs and priorities of the individual child and family. Short, self-limiting seizures will commonly need no such intervention.

The mainstay of non-pharmacological management of seizures is to avoid over-handling. Intractable seizures are likely to be exacerbated by stimulation and, as most therapeutic interventions entail touch and some stimulation of the senses, involvement of therapists is likely to be in managing co-existing symptoms such as pain and muscle spasms. If triggering seizures is perceived by the child, family, and care team to be a small burden whilst the benefit gained from a pleasurable intervention such as music therapy or massage is more significant, then such therapies should be offered. The therapist should, however, be cautiously aware and constantly re-evaluate.

Because many children who experience seizures near the end of life have chronic neurological conditions, it is likely that they will also have other symptoms that may benefit from therapeutic involvement. Although not directly treating the seizures, effective tone-reducing positioning may ensure that the child is more comfortable and functional between seizures. Positioning aids such as sleep systems and soft splinting should not forcibly restrain abnormal movement patterns but should encourage comfort positions and allow function by supporting where required. For example, a child with trunk and lower limb hypertonia, when positioned in supine is likely to extend. By positioning the child on his or her side in flexion or in supine but with appropriate soft positioning aids to encourage trunk, hip, and knee flexion, even if a tonic-clonic seizure occurs, the child is not going to injure himself or herself but once resolved they will recover back into a tone-minimizing and, by the same token, comfortable position.

Non-Seizure Movements

It is not always possible to distinguish definitively between seizures and non-seizure abnormal movements. The purpose of making such a distinction is to establish the most appropriate therapeutic intervention. Where there is diagnostic uncertainty, it may sometimes be necessary to institute a trial of therapy.

Again, it is important to discuss with family and the child when possible in order to establish their expectations, and to negotiate reasonable and attainable goals. It is rarely possible to abolish abnormal movements completely, and attempts to do so may risk jeopardizing a child’s quality of life through overmedication.

Many children with abnormal movement patterns due to any neurological condition, palliative or not, have developed ways in which to use the fluctuations in muscle tone to enable them to carry out functional activities, such as walking. The aim, particularly in the palliative phase when these movements are likely to be increasing in amount and severity, should be to minimize the negative effects but optimize function to enable the child to manage desired activities (Box 27-2).

BOX 27-2 Movement Disorders

Explore impact of symptoms on family, and negotiate achievable goals, particularly distinguishing between painful and painless movements.

Review existing medications, particularly identifying combinations that multiply the risk of adverse effects without significantly increasing the likelihood of effectiveness, such as anti-dopamined domperidone in a patient already receiving phenothiazine nozinan.

Remove medications that are unnecessary because of duplication or because their effect is no longer necessary in the palliative phase.

Reconsider medications in discussion with neurologist. Medications that are contraindicated because of adverse effects in long-term use, such as phenobarbital, may have valuable effects in the shorter term of palliative care.

Introduce any new interventions in proportion to the severity of the symptom, its importance to the child and family, the relative balance of good and harm that are likely, and the stage of illness.

Dystonia

Dystonia is characterized by repetitive and sustained contraction of the muscles, leading to abnormal posture. It can result from the underlying condition, or from medications used in its treatment. Prolonged dystonia is referred to as status dystonicus.²⁶

Drug-induced dystonias are associated with drugs that block dopamine receptors. These particularly include pure dopamine antagonists such as haloperidol and dopamine. The actual incidence of dystonic reactions with these medications is small, but more likely in pediatric than in adult practice.²⁷ The medications are relatively frequently used in the palliative phase, however, and are important causes. Dystonic reactions caused by medication can be reduced or even avoided by the use of anticholinergics such as procyclidine or antihistamines such as diphenhydramine.

Phenothiazines such as levomepromazine, chlorpromazine, or prochlorperazine are also dopamine antagonists, but the incidence of dystonia is rather rare. This may be because they are also anticholinergic and are antihistamines.

Drug-induced dystonias, while frightening, are not usually painful or dangerous. It is important to warn patients and families of the possibility that they may occur before prescribing haloperidol or metoclopramide. The usefulness of these medications in managing nausea and vomiting associated with metabolic causes, haloperidol, or with gastric outflow obstruction, metoclopramide, is such that they are valuable medications in palliative medicine and should not be unreasonably withheld.

Conditions causing dystonia in the absence of medication include many of the metabolic disorders, particularly meta-chromatic leukodystrophy, the gangliosidoses and mitochondrial disorders. Deep brain stimulation,²⁸ in which electrodes are placed in the globus pallidus area of the brain, is effective in such primary dystonias in children. This should be combined²⁶ with attention to hypertonia.

Myoclonus

Myoclonus describes jerking interactions of a muscle or muscle group. They are typically brief, abrupt, and involuntary.²⁹

In contrast with dystonia, myoclonus characteristically occurs in children who are cognitively aware. Although not usually painful, it can be disproportionately distressing.

The most common single cause of myoclonus in palliative care is as a consequence of opioid therapy. The risk is minimized by careful titration in strict accordance with the World Health Organization (WHO) guidelines. The appearance of myoclonus generally indicates that opioid dose is too high, either because titration has been too rapid, such as when it has been escalated with insufficient regard to pain intensity, or because the pain is partially or completely opioid unresponsive. This is usually due to significant emotional and spiritual components to the pain that are not amenable to analgesics alone. It can also result from physical pain that is inherently less opioid-responsive, such as when neuropathic in origin.

In the presence of opioid induced myoclonus, two approaches should be considered simultaneously. The first is the immediate prescription of a benzodiazepine. The first-line choice, if it is available, would be midazolam by continuous infusion. If this is not available, or it is important to avoid parenteral medications, long- or medium-acting benzodiazepines such as lorazepam or diazepam can be considered instead. In either event, a breakthrough dose of midazolam buccally should be made available should the problem recur.

At the same time, an opioid substitution should be carried out. As always, the effectiveness of this relies on incomplete cross-tolerance; that is, the fact that tolerance to adverse effects may occur later than tolerance to analgesia. In this instance, the hope is that it is possible to obtain at least the same analgesia with a lower dose of opioid by substituting an opioid of a different class, to which tolerance has not yet occurred.

To be effective, substitution should be to an opioid of a structure as different as possible from the original. There would, for example, be little point in substituting diamorphine for morphine, because the two medications are almost identical. If myoclonus occurs on morphine, substitution should be to a synthetic opioid such as fentanyl. If this is not available, a semi-synthetic opioid such as hydromorphone may be sufficiently different.

It should be noted that myoclonus can also be associated with normal phenomena such as anxiety, exercise or as one falls asleep.

Chorea

Chorea can be seen as intermediate in duration between myoclonus and dystonia.²⁹ Like them, it is brief and purposeless and can seem to flow from limb to limb, called choreoathetosis.

Again, it is associated with neurodegenerative diseases in children’s palliative care, as well as with cerebral palsy. The choreoathetotic type of cerebral palsy is thought to be due to anoxic damage at the basal ganglia.

Again, chorea can be associated with complications of some of the important medications used in pediatric palliative care such as haloperidol, metoclopramide, or phenothiazines. Withdrawal of these medications, if responsible, is clearly a first important step.

Non-Pharmacological Treatment

Dystonic and choreoathetotic movements are usually not painful but can cause distress, discomfort, and frustration. Positioning, soft splinting, and proprioceptive feedback may help to reduce and control the movements and enable a child to function or rest. For example, a therapist may improve the repetitive, writhing choreoathetotic movements of an upper limb by placing a firm, but not restrictive, hand cupping the shoulder of the child and applying firm but gentle pressure diagonally over the child’s chest toward the opposite hip with the therapist’s forearm. The movement is not restricted but the proprioceptive feedback provided around the key point of the shoulder and across the core of the trunk may normalize the fluctuating tone and reduce more distal involuntary movement. If effective, this technique should be taught to the family and caretakers to enable them to assist the child. Often, the ability to soothe through touch benefits not only the child but the family as well by enabling physical contact and the feeling of doing something practical to help settle the child, a nurturing instinct frequently limited in palliative care. This dynamic form of splinting can be replicated by applying stocking bandage to the key points to provide similar feedback. It is important that movement is not restricted, preventing any potential injury to the child.

Hyper- and hypotonia

Alongside dystonia, chorea, athetosis and spasms, abnormalities in the underlying tone in children with chronic neurological conditions often changes toward the end of life. Hypertonia is almost universal among children with conditions in ACT/RCPCH groups III and IV, particularly those with cerebral palsy.

Pharmacological Interventions

A number of interventions can reduce muscle tone.³⁰

Benzodiazepines and baclofen are enhancers of activity of the neurotransmitter GABA, while tizanidine is a centrally acting α₂-adrenergic agonist.

Midazolam infusion can relieve hypertonia in the short term, but is not suitable for long-term management. Longer-acting benzodiazepines such as diazepam or clobazam are more appropriate. Tizanidine has to be titrated carefully against its adverse effects, which include hypotension. It is a relatively novel drug, and should probably be used only in discussion with neurologists.

Baclofen can be given orally, but in some children its effect on truncal muscle tone is more marked than in the limbs, impairing posture so that the net impact can be adverse. The effectiveness of intrathecal baclofen in generalized hypertonia of cerebral palsy,³¹ particularly using a surgically implanted pump, is such that it is a useful modality despite its complications.³² A risk of accelerating the progression of scoliosis has been suggested,^33,³⁴ but remains unproved.³⁵ Baclofen may have an additional effect as an adjuvant in neuropathic pain.^36,³⁷

Botulinum toxin ³⁸ binds irreversibly to the motor endplate, causing paralysis of a muscle unit until the endplate is re-synthesised. The safety profile is good.³⁹

Non-Pharmacological Approaches

The same principles apply as in treating movement disorders. Normalizing tone through proprioceptive feedback and appropriate positioning to promote comfort and function is key. Encouraging weight-bearing exercise may also help with control. For example, supported sitting may enable a child to participate more in activities than being positioned in bed. Side-lying may encourage an increase in tone around the shoulder enabling better hand function in a child who previously has had little control. In addition, hypertonic postural patterns can be released with passive range of movement and stretching exercises and then positioning with the tight muscle group at its longest to maintain a more comfortable position. In addition, minimizing stimulation to overactive muscle groups will help to prevent hypertonic postural patterns that are difficult to release.

Again, anxiety, pain, and distress compound non-seizure movements and tonal abnormalities and ensuring that these are minimized will help with control. CAM therapies can play a valuable part.

Cerebral irritation

One of the basic principles of palliative care in children is that it should flow from the child’s own subjective experience of their symptoms. This is difficult when the child is pre- or non-verbal. Children in ACT/RCPCH group IV includes those with cerebral palsy as a result of perinatal events. Typically, a long period of chronic disability is preceded by many weeks or months of acute symptoms arising out of the brain injury itself. This is the most common form of cerebral irritation.

It is likely that the neonate with acute brain injury experiences at least three elements of total pain:

1. Acute pain arising from physical injury.

2. Fear and anxiety as a result of trauma and changed environment.

3. Amplification of both fear and pain as a result of failure of processing by damaged neurones and psyche.

The neonate is, in effect, experiencing at the same time severe acute pain and an inability to begin to make sense of it.

The clinical causes and features of cerebral irritation should be distinguished from those of central thalamic pain (Table 27-3), a specific example of neuropathic pain (see Chapter 31) caused by damage to the pain-perceiving part of the brain. However, in practice the two may co-exist in a child unable to communicate his or her experience. It is often necessary to treat both simultaneously.

TABLE 27-3 Distinction Between Central, or Thalamic, Pain and Cerebral Irritation

The distinction may not always be possible in clinical practice, and both may need to be treated in a single patient.

	Central Pain	Cerebral Irritation
Pathophysiology	Thalamic damage	Meningeal inflammation/infiltration/stretch
Causes	Cerebral vascular accident, tumor, probably metabolic conditions	Hypoxic ischemic encephalopathy, post-infection, post-trauma, leptomeningeal spread of malignancy
Type of pain	Neuropathic	Nociceptive
Chronicity	Often chronic, may be permanent	Follow acute injury, usually self-limiting over months
Characteristics	Difficult to pinpoint, all over body, often dysaesthesia	Abnormal processing, exaggerated startle, amplification of pain by unfocused anxiety, difficult to pinpoint
Pharmacological treatments	Antineuropathic agents (amitriptyline, anticonvulsants)	Aimed at reducing neuronal firing, anxiety and pain (phenobarbitone, benzos and opioids)

Pharmacological Management

Management of cerebral irritation in the neonate requires a three-pronged attack:

1. Phenobarbital. The evidence base for phenobarbital in cerebral irritation is largely from metastatic disease in adults.⁴⁰ It is a powerful anxiolytic sedative with probable anti-neuropathic properties.²² It has the additional benefit in neonates of a long track record as an effective anticonvulsant for seizures occurring in the early neonatal period.

2. Benzodiazepines. Prompt intervention with effective doses of benzodiazepines can be dramatically effective. Midazolam by subcutaneous or intravenous continuous infusion is rapidly effective and easily titrated against the child’s symptoms. Once an infusion is no longer appropriate, this should be converted to a longer-acting benzodiazepine such as lorazepam or diazepam. Breakthrough episodes of anxiety can be treated with midazolam buccally ²² because midazolam’s short half-life²³ makes it ideal for this purpose. Frequent requirements for breakthrough midazolam are an indication that the background benzodiazepine dose should be reviewed.

3. Major opioids. Major opioids should always be commenced if there is significant hypoxic brain injury. The dose and interval are not always straightforward. The painful stimulus is potentially intense, but it is hard to quantify in the absence of subjective reporting. There is animal evidence to suggest ⁴¹ that the blood-brain barrier of the neonate, particularly in the presence of inflammation, may be more permeable to opioids than in older children. Furthermore, elimination of opioids is influenced strongly by renal function.⁴² A reasonable starting dose in the absence of hypoxic renal damage would be 0.5 mg/kg oral morphine equivalent given 8 hourly regularly, with the same dose for breakthrough as needed. Titration should then progress in the usual way, that is, by reviewing every 48 hours and increasing the average 24 hourly breakthrough requirements, being careful to ensure that regular and breakthrough doses remain in proportion.

These medications should be reviewed after six months. At that time, most neonatologists would wish to substitute an alternative anticonvulsant for phenobarbital. It is usually clear at that time whether a child has required escalation of benzodiazepine and opioid doses to account for growth, or whether these are in effect sub-therapeutic and can and should be actively weaned and discontinued.

Although cerebral irritation is most commonly associated with hypoxic ischemic encephalopathy in the neonatal period, it can of course complicate brain injury at any age and a similar approach should be considered.

Non-Pharmacological Approaches

As with controlling seizures, minimizing stimulation is important for managing the neonate suffering with cerebral irritation. This time period is often one of trauma for a family. The birth and immediate post-natal period is likely to have involved unexpected complications and interventions, leaving a family feeling confused and distressed. After the initial acute stage, further neurological symptoms may evolve and must be managed effectively by the whole interdisciplinary team, as described in the other sections of this chapter.

The most important aspect of managing the care of a child with cerebral irritation is supportive care to the family. A new baby who cries or screams for hours on end and is unable to be settled, compounded by lack of sleep and grieving for the loss of the child that they had expected, can leave parents feeling anxious and struggling to cope. Respite care and support must be provided, especially when the child is cared for at home.

The use of craniosacral therapy for children who have experienced birth trauma has become more popular in recent years, although there is little clinical evidence for this, supportive or otherwise.¹⁶

Sleep-wake cycle

Diurnal sleep-wake cycle is coordinated centrally in the region of the hypothalamus. Even in the normally functioning brain, it can be disrupted easily by physical, emotional, and spiritual factors. Lying awake at night with worry is a common human experience.

In ACT groups III and IV particularly, disruption of normal brain function is the rule. It is perhaps unsurprising that in this group disruption of the sleep-wake cycle is common.^43,⁴⁴ Its impact on the family can be profound. Endless nights of broken sleep inevitably accumulate and contribute to the global exhaustion reported by many families.⁴⁵

One chemical mediator of the normal diurnal rhythm is melatonin, synthesized in the pineal gland and in T-lymphocytes.⁴⁶ Exogenous melatonin is now available for oral use, and this can be a helpful intervention.⁴⁴ The fact that it is not universally effective underlines the fact that disruption of the sleep-wake cycle is a complex and multidimensional phenomenon rather than simply a function of melatonin deficiency.

A therapeutic approach to disruption of the sleep-wake cycle can consist in three simultaneous and parallel approaches:

1. Prescription of melatonin at night. The usual starting dose is 3 mg. It is not clear what the maximum dose should be, but doses several times this have been used.⁴⁷ Other medications that can facilitate sleep include those that reduce anxiety, such as benzodiazepines, and those that are soporific but not anxiolytic, for example chloral hydrate. In the presence of probable or possible neuropathic pain, amitriptyline may be preferable to these. Larger doses of antidepressants may also be effective if the cause for poor sleep is depression itself.

2. Exaggeration of the distinction between day and night (see following). For example, ensure that lights are extinguished and noises kept to a minimum during the night. Conversely, it is important to avoid being over quiet during the day.

3. Review of prescriptions. Many of the medications required by children in ACT Groups III and IV can potentially cause drowsiness. It is often possible to review the timings of these, so that drugs with sedative or soporific effects are given at night.

Non-Pharmacological Management

The sleep-wake pattern of any ill child is often disturbed. For those children nearing the end of their lives, sleep can become further disturbed by troublesome symptoms and the effects of medication. Maintaining a routine may benefit the rest of the family and help in the palliative process.

In addition to pharmacological management, maintaining the pattern of night and day is of paramount importance. This should involve allowing the child to access natural light, if possible, and dark at the appropriate times and increasing stimulation during daytime hours and reducing it overnight. Ensuring the child is kept as physically active as possible, with regular rests, during the day is important even in the non-ambulant child. Continuing with previously enjoyed physical activities, such as hydrotherapy, may enable a child to relax more afterward. Position changes, to show the child a difference between day and night, may promote sleep and wakefulness at appropriate times. Even when a child is bed-bound, his or her positioning can be directed to restful or activity. Using high sitting or head-up side-lying in bed during the day can promote more interaction in a neurologically impaired child, while more reclined positions can be saved for sleep.

Sleep is often disturbed by anxiety, pain, depression, and other symptoms.⁴⁸ It is important to ensure that these have been addressed as much as possible, even in the pre- or non-verbal child. There is evidence from the adult palliative care research that aromatherapy and massage can help to promote better sleep patterns.¹¹ It is feasible that this may also be the case within the pediatric population.

Fatigue

Fatigue is one of the most common symptoms experienced by children with cancer.⁴⁹ (See Chapter 29.) Furthermore, it is an obvious complication of many of the conditions in ACT/RCPCH Group II, such as Duchenne muscular dystrophy. Despite this, the symptom of fatigue has received little attention in the pediatric literature. Even in adult palliative medicine, there is no single agreed-upon therapeutic approach. It is a multifactorial phenomenon, caused not only by the disease and the body’s defenses against it, but also therapeutic interventions themselves.

Fatigue is described as one of the symptoms that causes most distress ⁴⁹^–⁵⁴ and has received some attention in the adult cancer literature.⁵⁵ Despite its apparent high prevalence in children with life-threatening conditions,^49,^51,⁵² it is relatively under-recognized in children,⁵⁶ perhaps because it is difficult to diagnose and assess, and there are few effective interventions.

Fatigue, like all symptoms, is multidimensional,⁵⁶ including symptoms directly arising from the underlying condition, and those arising from its treatment. These include:

• Anemia. Although anemia seems an obvious cause for fatigue, in practice the two are not always closely associated, suggesting other factors may also contribute.

• Muscle abnormalities. Some of the more common non-malignant life-limiting conditions in childhood, such as Duchenne muscular dystrophy, are primary causes of muscle weakness. The cachexia associated with cancer is an immune-mediated inflammatory phenomenon rather than simply a nutritional one. Even where the underlying condition does not directly cause muscle weakness, it can cause immobility, which itself impairs muscle strength and stamina. Medications, particularly steroids,⁵⁷ can cause muscle weakness.

• Endocrine abnormalities, particularly involving endogenous steroids, thyroid or hypothalamo-pituitary axis, can lead to a sense of fatigue. Such abnormalities may be common where there is central neurological damage, such as children in ACT/RCPCH Groups III and IV, or those with brain tumors.

• Depression and anxiety can both manifest as a sensation of tiredness. Both are difficult to diagnose in children, particularly those who are cognitively impaired or non-verbal. A high index of suspicion, together with a willingness to collaborate with child mental health services in actively treating psychological illness in children with life-limiting conditions, will minimize this.

• Sleep disturbance. Many children with non-malignant life-limiting conditions in Groups II, III, and IV will also have disruption of their circadian rhythm.

Management of fatigue should, in the first instance, be directed at the underlying cause if possible. Correction of anemia may relieve symptoms of fatigue, though the benefit of this should be weighed against the difficulty of the child having to be admitted to the hospital and establish intravenous access. A review and rationalization of medication, particularly aiming to reduce co-prescription of duplicative and/or centrally acting medications, can often result in significant improvement.

Activity should be maintained at an appropriate level. The golden rule for the patient is to do as much as you can, but no more. This avoids the extremes complete bed rest and too vigorous physical demands on the principle of no pain, no gain. Neither extreme is helpful.

Diagnosis and appropriate treatment of depression or anxiety is important. Guidelines ⁵⁸ suggest that management of depression in children should be undertaken in collaboration with child mental health services if possible. Correction of an altered sleep pattern should be attempted as much as possible.

There is some literature in adults suggesting that pharmacological stimulants can improve fatigue.⁵⁹^–⁶¹ In young people, this evidence is limited to reduction of opioid-induced drowsiness.⁶² Although the evidence base is weak, methylphenidate is familiar to most pediatricians and its safe use in children has been established, albeit in a different therapeutic context. In the absence of approaches supported by better evidence, it seems a reasonable therapeutic trial where fatigue is identified as a significant problem.

Other pharmacological treatments such as steroids, adenosine triphosphate, megestrol acetate, and carnitine have been proposed, but though all are plausible none has shown unequivocal effectiveness.

Non-Pharmacological Management

The main approach for rehabilitating a patient suffering fatigue uses paced exercise programs.⁶³ For those children and families who are still able and wanting to participate in active rehabilitation, a graded, functional exercise program should be designed and implemented. For those unable or not wanting to take part in this, physical activity should be encouraged in a way and to a level that is appropriate and acceptable to the child and family. Again, this should be functionally aimed, enabling the child to participate in activities that he or she enjoys. A fine balance in the amount and frequency of activity should be found to ensure that the fatigue-reducing physiological benefits of physical activity are experienced without the child overdoing it and becoming exhausted. ”Little and often” is a useful adage to follow.

During the palliative phase, fatigue may become more and more a limiting factor in a child’s ability to take part in everyday activities. Some families may require guidance as to prioritizing tasks to ensure that the child is using his or her small amounts of energy on meaningful activities. Many families in this situation will be in a routine of care and treatment provided to their child. In the latter stages it may be more desirable to enable the child to take part in his or her own chosen, pleasurable activities even if that means a more mundane, non-essential task has to be sacrificed, such as a wash or stretching regime. At this point an occupational therapist may be able to offer energy preservation advice and aids to maintain as much independence as possible for the child whilst minimizing the energy expended on activities of daily living.

Studies of CAM approaches in the treatment of palliative adult cancer patients with fatigue ^4,^7,^17,^64,⁶⁵ suggest that massage, homeopathy, TENS, acupuncture, and even Reiki had a positive effect on participants’ perception of fatigue. There are far fewer studies in children, and all are in cancer.^9,⁶⁶ These suggest that massage measurably reduced anxiety, though it did not improve the patient’s perception of fatigue. The lack of evidence for these approaches in treating children with fatigue in palliative care should not prevent their use, however, as with all treatment, the clinician, child, and family must be able to balance the potential good and harmful effects to establish what is in the child’s best interest before deciding on the course of action.