27 - Respiratory symptoms
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 > 25 - Depression, anxiety, anger and delirium
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25
Depression, anxiety, anger and delirium
Ren e McCulloch
Jim Hammel F
Introduction
Despite numerous advances in paediatric palliative care over the past two decades, issues of a psychological, psycho-social, and psychiatric nature continue to experience a dearth of attention. Numerous reasons exist for the lack of evidence-based advances in the understanding and management of these areas. Firstly, clinicians in general might be hesitant to label children in any health context with a socially stigmatising diagnosis, such as depression or anxiety. Froese [1] commented on this hesitancy in the arena of paediatric referrals to a general psychiatry service; in a study of 205 children seen by a psychiatric service, Froese noted that depression and adjustment reactions were less likely to be reported correctly in medical discharge diagnoses than psycho-physiological disorders and psychoses. Secondly, clinicians might shy away from viewing a child's psychological symptomatology as inappropriate in the setting of the extraordinary life stresses inherent in life-limiting illness. Thirdly, the management of non-psychological symptoms may be the predominant concern of the clinician. Fourthly, although Paediatrics as a field is psychologically and holistically oriented, the specific issues in palliative care may be viewed as beyond the realm of expertise of the care-giver.
The timing as to when psychological symptoms may occur in the disease process is unclear, and subject to contradictory evidence in the literature. For example, a four-year prospective study of 39 children with cancer [2] found psychological problems most evident immediately after the diagnosis of cancer, only to have the symptoms gradually decline such that no difference existed between the study group and healthy controls at subsequent assessments. On the other hand, a study of 51 Swedish children with cancer showed the opposite pattern: 16 patients on treatment showed no difference in anxiety and depression compared with the healthy controls, while 35 off-treatment patients showed higher depression and anxiety than the control population [3]. With little firm data to establish the temporal pattern of psychological disturbance in paediatric palliative care, health care professionals must be aware that these symptoms may develop throughout the disease course.
Given these obstacles, it is perhaps not surprising that so little documented research exists on the subject of the identification, and particularly, the management of psychological symptoms in paediatric palliative care. Most of the studies that have been described have occurred in the paediatric oncology setting, with little work in other chronic, life-limiting, or terminal illnesses. Clearly, paediatric palliative care extends beyond the borders of oncology, yet, this is not reflected in the literature.
Extrapolating the available literature to include all paediatric palliative care patients is obviously unsound. Most oncology patients in these studies are receiving active treatment in pursuit of cure and of course, living with a life threatening or life limiting illness (HIV, chronic disease) has different connotations to being in the palliative phase. However, tentative comparison might be drawn between these groups in that they share the burden of undergoing intensive treatments and a significant number ultimately become palliative. Despite (indeed, because of) the notable absence of knowledge in this field, the clinician must be especially vigilant in identifying and treating these symptoms.
Depression
Features and diagnosis
Features and challenges
The clinical features of depression in the general paediatric population have been described as remarkably similar to those of adult depression [4]; see also Kovacs [5]. Indeed, both populations depend upon essentially the same Diagnostic and Statistical Manual of mental disorder version IV (DSM-IV) criteria for diagnostic purposes.
Despite obvious differences between healthy and ill paediatric patients, DSM-IV criteria frame the diagnosis of depression
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more than any other source. For diagnostic purposes, five or more of the following symptoms must have been present over a two-week period and represent a change from previous functioning (i.e. cause clinically significant distress or impairment in functioning ), with at least one of the symptoms being either (1) depressed mood, or (2) loss of interest or pleasure:
depressed mood;
markedly diminished pleasure in all, or almost all, activities;
significant weight loss when not dieting, or weight gain, or decrease or increase in appetite nearly every day;
insomnia or hypersomnia nearly every day;
psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed-down);
fatigue, or loss of energy, nearly every day;
feelings of worthlessness, or excessive or inappropriate guilt (which may be delusional);
diminished ability to think or concentrate, or indecisiveness (either by subjective account or as observed by others);
current thoughts of death (not just fear of dying), recurrent suicidal ideation without specific plan, or a suicide attempt, or a specific plan for committing suicide (American Psychiatric Association [6].
In the World Health Organization's ICD-10 classification (World Health Organization, The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research, World Health Organization, Geneva, 1993), the criteria for depressive episode are also defined as having a two-week duration, without any manic or hypomanic symptoms, and without a psychoactive substance or organic mental disorder etiology. The ICD-10 breaks-down depressive symptoms into two sets of criteria, from which classification can be made for mild depressive episode (at least two symptoms from Criterion B and one from Criterion C), moderate depressive episode' (at least two symptoms from Criterion B and four from Criterion C), or severe depressive episode, with or without psychotic features (all three symptoms from Criterion B and at least five symptoms from Criterion C.) Importantly, the ICD-10 criteria for severe depressive episode note, If important symptoms, such as agitation or retardation, are marked, the patient may be unwilling or unable to describe many symptoms in detail. An overall grading of severe episode may still be justified in such a case.'
The DSM-IV and ICD-10 diagnostic criteria are compared in Table 25.1. Again, all of these depressive symptoms refer to adult patients, and are problematic, given the commonly encountered constellation of symptoms in the paediatric palliative care patient. One of the primary differences between the two systems is that mood disorders assessed as secondary to a general medical condition (e.g. hypothyroidism) are categorized under Organic mental disorders in ICD-10, while in the DSM-IV they are listed as a sub-category of mood disorders. In neither case, though, are they considered in the specific context of either paediatric or palliative care patients.
While both DSM-IV and ICD-10 criteria have useful classification functions in the research setting, the clinician is best served by considering each paediatric palliative care patient on an individual basis, with the priority of evaluating the depressive severity and symptomatology within that patient's particular clinical milieu.
Attempts have been made to modify these criteria for children, so that they are more developmentally appropriate. For example, Luby et al. (2002)[7] have described modifications to the DSM-IV criteria specifically for the pre-school child, such as appending criteria 1 to include for a portion of the day for several days, as observed (or reported) in behaviour'. In a further study of 145 pre-schoolers, Luby et al. (2003)[8] have also shown that their modified depressive criteria identified a substantial proportion of children with clinically significant, but less severe, depressive symptoms missed by the standard DSM-IV criteria; however, their modified criteria themselves failed to capture the most severely affected pre-schoolers.
In general, children often have difficulty recognizing, understanding, and then reporting depressive symptomatology. It is particularly challenging to accurately assess depression in the pre-school child, given the limitations in the child's understanding of affective state, time concepts, symptom course, and questions which require some form of judgment [4, 9]. Birmaher et al. (1996)[10] found that depressed children and adolescents in the general paediatric population have fewer melancholic symptoms than adults, and children have more somatic complaints than adolescents. Furthermore, it was only with the use of developmentally adjusted DSM-IV criteria that the symptom of anhedonia was found to distinguish between depressed and non-depressed pre-school children [7].
The diagnosis of depression in children with life-limiting illness is especially challenging for several reasons. The DSM-IV does not contain criteria for depression (or anxiety) in children and adolescents with comorbid medical illnesses, life-limiting conditions, or palliative care needs. For many paediatric palliative care patients, the use of DSM-IV criteria is made particularly difficult, given the presence of disease symptoms that overlap with those of the depressive criteria. Specifically, neuro-vegetative symptoms (e.g., sleeplessness, anorexia, fatigue, and psychomotor slowing) may reflect
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disease or treatment effects, rather than depressive symptoms. This particular diagnostic challenge has been noted in the literature since 1955. In discussing the atmosphere of melancholia , often associated with the paediatric oncology patient, Richmond and Waisman commented:
Table 25.1 Depressive symptoms criteria. Comparison of DSM-IV and ICD 10 | ||||||
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Since the child's physical energy diminishes so significantly, it may be that most of the child's lack of emotional as well as physical response is due more to this factor, than to psychological awareness of the diagnosis[11].
Worchel et al. (1988)[12] have shown that somatic items are not good discriminators between depressed and non-depressed medically ill children; moreover, low self-concept (i.e. feeling that one is inferior to others, a bad person , feelings of self-blame) was present in paediatric oncology patients, regardless of their level of depression. In an attempt to address this issue, Phipps and Srivastava [13] recently devised an anhedonia scale for use in children with cancer, but found no difference on this scale between children with cancer and healthy controls. In medically ill adults, Cavenaugh et al. [14] provided evidence that cognitive symptoms better discriminate depression. Indeed, the DSM-IV criteria do caution Note: Do not include symptoms that are clearly due to a general medical condition ' They also provide the caveat that The symptoms are not better accounted for by bereavement, that is after the loss of a loved one.' Although written with the adult patient in mind, the issue of anticipatory grieving also occurs in the paediatric palliative care population. Thus, for both of these reasons, the DSM-IV criteria might be especially inappropriate for evaluating the paediatric palliative care patient.
The appearance of depression in youth with chronic and life-limiting illness may, therefore, be less clear, due to the overlap of somatic and psychological symptoms, and may thus result in depression at the sub-clinical level. Of relevance to this point, Kovacs and colleagues [15, 16] have shown that recurrent illness is seen in the majority of those with paediatric depression. In a meta-analysis of 60 studies on children and adolescents with chronic medical problems, Bennett [17] has concluded that while children with a chronic medical problem have a slightly greater risk of depressive symptoms, most are not clinically depressed.
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Adjustment disorder
Many paediatric palliative care clinicians may consider whether their patients' symptoms most accurately reflect an adjustment disorder . This diagnosis is considered when a patient develops emotional or behavioural symptoms within 3 months of a significant life change, or as a result of a stressful life event, which can include the presence of serious physical illness. In the paediatric patient, adjustment disorder is often seen in the context of hospitalization. Children with adjustment disorder often display regressive symptoms, such as enuresis and thumb-sucking. Perhaps most importantly, the emotional or behavioural distress markedly exceeds what you would normally expect from such a stressor , and does not fulfil criteria for an Axis I disorder, or worsening of a pre-existing Axis I or II disorder. For DSM-IV coding purposes (which, again, are generally more applicable in the research, rather than the clinical, setting), adjustment disorders can be specified as with depressed mood' ( The patient is tearful, sad, hopeless ), with anxiety' ( the patient is nervous, fearful, worried ), or a combination of the two ( with mixed anxiety and depressed mood'). The distinction between adjustment disorder and depression can be also aided by the timing of the symptoms. As defined by both the DSM-IV and ICD-10, the symptoms of adjustment disorder occur within 3 months of a stressor, and do not last longer than six months after the end of the stressor, In the case of the paediatric palliative care patient, though, the life stressor does not end as such. Moreover, the DSM-IV specifies that the symptoms are not caused by bereavement, which can be problematic in the palliative care setting, given the prevalence of anticipatory grieving.
Risk factors
As with assessment of depression in the general paediatric population, it is important to identify factors that may place paediatric palliative care patients at risk of depression.
In paediatric palliative care, and especially in the case of the dying child, the potential for isolation and social neglect places the child at substantial risk of depression. Almost 25 years ago, Chapman and Goodall [18] commented on this, reporting, We have heard this referred to as the dying child syndrome and such neglect is conducive to depression.
In considering depression in the paediatric palliative care patient, it is crucial to consider the possible role of co morbid pain. This relationship has been discussed in the chronic paediatric pain literature [19, 20], where depression has been found to be strongly associated with chronic pain. The depression- pain linkage is particularly relevant in the paediatric palliative care setting. For example, a French study of 80 children with cancer, aged 2 6 years, found an association between disease-related pain and a depression-like reaction, which correlated with the pain's intensity. [21]. In a study of 43 in-patient paediatric oncology patients referred for psychiatric evaluation, Steif and Heiligenstein [22] found that 20% of the psychiatric consultations resulted in a primary recommendation for improved pain control. When assessing both depression and pain, it is imperative to bear in mind the symbiotic nature of these two common issues.
Depression is also more likely in the paediatric patient to whom diagnosis and health status are not disclosed. Last and van Veldhuizen [23] studied a sample of 56 children with cancer, aged 8 16 years, and showed significantly less depression if parents told them about their diagnosis and prognosis at the initial stage of the disease. In an Italian study of 30 leukaemic children in the first year of remission [23], children who received poor communication regarding their illness experienced more affective disturbances (including insecurity, irritability, poor self-perception, instability, and depression). A Finnish study of 53 patients who had electively discontinued treatment for leukaemia and lymphoma (mean age 12.8 at completion of study surveys) found that patients more
Table 25.2 Depressed mood compared with adjustment disorder | ||||||||||||
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informed of their disease process were less depressed than poorly-informed children. [25].
Non-illness related psycho-social life events can also act as risk factors for depression. In a one-year longitudinal study of 38 children and adolescents with cancer, Kaplan et al. [26] found that depressive scores were highly related to psychosocial life events, but not related to the course of the oncologic illness (e.g. relapse or remission status, number of relapses, length of time since diagnosis, and number of weeks of treatment until remission).
The presence of maternal depression can also serve as a risk factor for depression in the child. Mulhern and colleagues [27] studied a sample of 99 children with cancer, and their mothers. They found that the severity of the mothers' self-reported depressive symptoms, assessed with the Beck Depression Inventory, was associated with higher levels of child depression by both child- and parent-reported measures. Similarly, maternal depression has been associated with poorer quality of life in children with cancer. In a study of 32 leukaemic children [28], children who self-reported poorer quality of life had mothers who were more depressed.
Diagnostic tools
All diagnostic tools for assessing paediatric depression have been developed for children and adolescents without the comorbidity of medical illness. Due to their low sensitivity, several screening tools (e.g. the Child Depression Inventory, the Pediatric Symptom Checklist, the Child Behaviour Checklist) may not be appropriate for use with chronically medically ill children and adolescents [29]. While highly specific (i.e. they may confirm the clinician's concerns), these tools are poorly sensitive (i.e. they may miss many disorders in chronically ill youth), and may thus undermine clinical judgment. The absence of assessment tools designed specifically for the paediatric palliative care patient further hampers the clinician's ease of diagnosis, as has already been noted in paediatric oncology [30].
One of the commonly cited deficiencies in screening tools for paediatric depression is the poor concordance on patient symptomatology. Many authors have reported low level, of agreement when comparing children's self-report scores and measures from parents [32, 33], teachers, and peers. Andrews and colleagues [32] reported that a sample of general paediatric patients reported more depressive symptoms about themselves than their parents. Furthermore, Braaten et al. [31] have shown in a sample of 186 youth-mother pairs that youths reported a milder form of depression compared with that identified by parental reports.
In contrast to the general paediatric population, Challinor et al. [34] studied 43 paediatric oncology patients and found high positive correlations between scores from patients and their parents for depression, and high positive correlations between teachers and patients for depression; they also found that parents over-report depressive symptoms in their children. On the other hand, a study of 107 children with cancer and 442 healthy controls [13] found that both, a self-report depression inventory and a measure for anhedonia, were not significantly related to parental and physician ratings of depression. The contradictory findings between these studies are possibly due to the different measures used in each study, or to the health status of their respective patient samples. Thus, conclusions as to the concordance between parent-, child-, and teacher-symptom assessment are difficult to make.
The most commonly used diagnostic tool is the Children's Depression Inventory [CDI] [35]. This child self-report questionnaire utilises 27 items, each rated on a scale of 0 2, with more severe symptoms receiving higher ratings. In a direct comparison of the CDI and DSM-III in 231 child psychiatric patients [36], depressed and non-depressed children were shown to differ across all domains (including depressed-related symptoms, cognitive processes, and social activity). Nevertheless, many have questioned the validity of the CDI, given the poor correlations between CDI and non-self-report ratings from peers, parents, or teachers [37, 38]. Kronenberg et al. [39] have found that non-interview techniques, such as the CDI and the Child Behaviour Check List, were less reliable in diagnosing affective disorders in general paediatrics, compared to a non-directive interview with psychological projective testing and a semi-structured psychiatric interview. The apparent superiority of diagnostic interviews over traditional survey evaluations has found additional support. In a study of 102 youth (ages 7 17), Carlson et al. [40] identified more children with sub-clinical and masked depression using a systematic interview, than, with standard evaluative procedures. Similarly, comparison of the validity and reliability of the CDI and Depression Self-Rating Scale found both to have only moderate discrimination between depressed and non-depressed patients, with no significant relationship between teachers' assessments of classroom behaviour and the two scales; as an additional potential barrier to these tools, better agreement was seen in more verbally intelligent children, irrespective of age [41]. Finally, it must be emphasised that even if the CDI is used, a clinical or structured interview is necessary to determine diagnostic status [42].
As acknowledged previously, the presence of somatic items in paediatric depressive scales clouds the issue, and raises the question of whether it is truly depression, or rather, disease course being measured. Thus, the clinician may
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over-estimate the presence and severity of depression in using scales that incorporate somatic symptoms into the assessment. In a sample of 24 paediatric oncology patients referred for psychiatric assessment, Heiligenstein and Jacobsen [43] modified a common screening tool for depression (the Children's Depression Rating Scale Revised or CDRS-R; [44] to eliminate items assessing somatic complaints. They found that this modified scale did not correlate with functional impairment, and also maintained the same level of diagnostic sensitivity in the clinicians' identification of depression severity.
Prevalence/incidence
The prevalence and incidence of depression in the general paediatric population vary by age, assessment duration, and population. As thoroughly reviewed by Axelson and Birmaher [45], the prevalence of depression in children and adolescents from a 3-month assessment period is approximately 2.0%, while that from a 6 12 month period varied substantially between 1.6 18.0%. (Of note: all of these studies relied on DSM-III/III-R or IV criteria, included parent and/or child interviews, and had sample sizes between 222 and 3733). As reviewed by Son and Kirchner [46], depression affects 2% of pre-pubertal children, and 5 8% of adolescents in the general population.
Depression incidence has also been reported in children and adolescents with chronic illness. In a study of 44 epilepsy patients between the ages of 7 18 years, 26% exhibited significantly increased depression scores on the Child Depression Inventory [47]. The lifetime prevalence of depression in cystic fibrosis has been shown to be 11.5%, a marginally higher figure than that quoted previously in the general population; interestingly, though, the same study [48] also showed a significantly higher lifetime depression prevalence in Crohn's disease (29%) and ulcerative colitis (21). Thus, it appears that the prevalence of depression in youth with chronic illness is higher than in the general paediatric population, but cystic fibrosis a chronic illnesses that is also life-limiting does not appear to follow this pattern. Similarly, in a meta-analysis of 60 studies on paediatric chronic illness, Bennett [17] has reviewed the finding that depression is more likely in children with asthma and sickle cell anaemia than those with cystic fibrosis and cancer. In contrast, though, an Indian study [49] found depression (and anxiety) to be more common in 35 leukaemic children, compared with 35 children with chronic illness.
Other life-limiting illnesses that have a chronic deterioration in adolescence, such as Duchenne muscular dystrophy, may be unique in their manifestation of depression. These boys appear to develop depression over time. In a study of 23 Duchenne boys in Dublin, Fitzpatrick et al (1985)[50] found depression to be more common in Duchenne patients than in matched healthy controls, and observed that this only occurred in boys older than nine years of age. This finding could be due to the previously discussed difficulty in diagnosing depression in younger children. It is also possible that depression in life-limiting illness may only become manifest as the illness progresses in severity, or as the child develops a greater understanding of the disease process and increasing limitations. Again, diagnosing depression in this particular group can be extremely challenging, due to the obvious overlap of symptoms that exist between depression and disease progression. Adolescents and young men with Duchenne muscular dystrophy frequently suffer from poor appetite, weight loss, weakness, headaches, and sleep disturbance, symptoms that occur within the spectrum of a depressive disorder. It is very likely that depression is under-diagnosed in this group. It should be considered and evaluated at appropriate intervals, in order to maximise well-being.
In children with cancer, the incidence of depression shows wide variability, with rates reported as high as 17% (using the DSM-III criteria; [51]) and as low as 7 8% [27]. Similarly, Dunitz et al. [52] studied depression prevalence in 34 children with newly-diagnosed paediatric oncology disease over a 14-month period, and found a clearcut depression in six of the children. Although not specifically diagnosing depression, Collins et al. [30] found 36% of a sample of 159 children with cancer feeling sad, (with 60% of those reporting the symptom severity between moderate' and very severe. ) Worchel et al. (1992)[53] have discussed this wide variability in depression prevalence, and have shown that this might be explained by both the various measures used and patients' selective reporting of symptoms.
However, children with life-limiting illness and palliative care needs do not demonstrate depression as frequently as might be assumed. In a recent Taiwanese study, Chao and colleagues [54] found no difference on CDI scores between 24 paediatric cancer patients and a normative sample. Phipps and Srivastava [13] compared 107 children with cancer and 442 healthy controls, and found significantly fewer depressive symptoms in the children with cancer, and no difference between the two groups on the measure of anhedonia they designed. Bose et al. [55] found that children with HIV did not score as high on anxiety and depression scales when compared with the parental reports, and in fact, described low levels of depressive and anxious affect and generally positive self-regard. Worchel et al. [12] compared a paediatric sample of 72 oncology patients, 42 in-patient psychiatry patients, and 304 control schoolchildren. They found that the oncology group reported less depression than the psychiatric and control samples. Within the context of repressive adaptation (discussed further in this chapter), Canning et al. [56] also reported
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significantly lower levels of depression in 31 cancer patients, compared to 83 healthy controls. This contrary finding of lesser-than-expected depression in paediatric oncology could be explained by the issue of repression.
The lower prevalence of depression might also simply be a reflection of the timing of depression assessment in the disease course. For example, in a study of 42 British adolescents with cancer compared with 174 healthy controls, Allen and colleagues [57] found that, contrary to the study's hypotheses, the adolescents with cancer were no more depressed than the controls, when assessed at the time of diagnosis.
Distinguishing from the normal range
As discussed, disease symptoms in the paediatric palliative care patient may result in a different clinical presentation from that seen in the general paediatric population. At the same time, though, the prevalence of depression may not necessarily be greater in palliative care than the norm. Indeed, few studies report greater depression in paediatric oncology than the healthy population (for an example, see [58]. Thus, studies showing greater depression in paediatric oncology patients, compared to the healthy paediatric population, are actually the exception rather than the rule.
In a study of 12 adolescents with end-stage renal failure, the incidence of depression, as well as anxiety and hostility, was described as no different from a healthy adolescent sample [59]. Noll and colleagues [60] compared 76 paediatric oncology patients with 76 case control classroom peers, and found no significant differences on measures of depression and loneliness. In a Brazilian study of 75 children (leukaemia = 21, blood dyscrasia 21, controls 33), no significant differences in depressive symptoms were found between the leukaemics and the two other groups of children[61].
Repression
Children with cancer and other life-limiting illnesses may report less depression than expected, due to the use of coping mechanism such as repression, denial, and defensiveness. As early as 1976, Kagan[62] described the use of denial as an appropriate coping mechanism in adolescents with bone cancer, resulting in a fluctuation between levels of denial and acceptance. Over the past decade, work has highlighted the attention being paid to repressive adaptation and defensiveness in children with cancer and other illnesses. Canning et al. [56] compared 31 adolescent cancer patients with 83 healthy high school students, and identified the feature of repressive adaptation' in those reporting low anxiety and high defensiveness; a significantly higher proportion of the cancer patients were identified as repressors, and, correspondingly, the cancer patients reported significantly less depression than the healthy controls. Phipps and colleagues [63] conducted a study of 107 oncology patients aged 7 16 years, and compared measures of depressive symptoms, trait anxiety, defensiveness, and coping styles. They found a significant excess of children using a repressive coping style in the oncology group, and those who used this repressive coping style self-reported the lowest levels of depression. Moreover, repressive adaptation in the cancer patients was unrelated to duration of time since their diagnosis. In a subsequent study [64], a longitudinal assessment of children with cancer showed repressive adaptation to start at the time of diagnosis, and be maintained until 6-month and 1-year follow-ups post-diagnosis. Thus, repression seems to be a long-term phenomenon in children with cancer, and may explain why depressive symptoms may appear less commonly than expected [65]. Finally, Worchel et al. [12] have noted that the use of self-report measures is particularly problematic in paediatric oncology patients using denial or repressive adaptation as coping skills.
Non-pharmacological support
Open communication, informed choice on therapeutic options, and the provision of clear support to the patient and family are the non-pharmacological foundation to decreasing the presence of depression in paediatric palliative care patients. As early as 1980, Chapman and Goodall[18] emphasised the necessity of open communication with the child or adolescent as the initial management strategy in addressing depression in paediatric palliative care.
In the general child and adolescent population, depression has been treated non-pharmacologically, with diverse modalities. As reviewed by Findling et al. [66], these non-pharmacological approaches have even included light therapy and electro-convulsive therapy modalities which would be of highly questionable use in the paediatric palliative care population. Of the psychotherapeutic approaches to depression in the general paediatric population, cognitive-behavioural therapy (CBT) has been shown to be the most useful. As might be expected, comorbidity with an anxiety disorder has been shown to be a predictor of poor response to CBT therapy for children with depression [67, 68]
For children with chronic illness, some studies have hinted at the benefit of community-based support groups. Chernoff et al. [69] have described a randomised controlled trial of 136 children, aged seven to eleven years, with sickle cell anaemia, cystic fibrosis, diabetes mellitus, or moderate to severe asthma. After participation in a 15-month community support program, fewer children in the experimental group (19% at baseline, 10% post-intervention) scored in the maladjustment range (as measured by the Children's Depression Inventory, the Revised Children's Manifest Anxiety Scale, and the Self-Perception
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Profile for Children); in the control population of children, there was an increase in these number, (15% vs. 21%).
Unfortunately, very few studies have examined the role of non-pharmacological support in the paediatric palliative care setting. In 1982, Nitschke and colleagues [70] described their unique hospital-based approach to decrease depression and psychological disorders in end-stage paediatric oncology patients. They organized a conference which emphasised patients acknowledgement of the progression of the disease and the imminence of death' and patient-guided informed decision-making; subsequently, the majority of the 43 children who took part chose supportive care without chemotherapy, and severe depression and severe behavioural problems were rarely seen to occur.
Pharmacological management
To date, there have been no reported studies on the specific use of any anti-depressants in paediatric patients with life-limiting illness or in the palliative care setting. Nevertheless, insight from adult palliative care practitioners is helpful in planning a therapeutic strategy in paediatric palliative care patients. For example, Block [71] has suggested that sometimes a short therapeutic trial can help clarify whether or not a patient suffers from depression.'
It is standard practice that prior to commencing several of these psychotropic medications (amitriptyline and some antipsychotics) an electrocardiogram (ECG) is performed. Despite the fact that these medications may be prescribed for palliative symptom control, it would be appropriate to exclude any underlying cardiac rhythm abnormality.
At present, the mainstay of treatment for paediatric depression involves the use of selective serotonin reuptake inhibitors (SSRI's). Many authors have studied the extensive prescribing of SSRI's for paediatric patients even prior to any evidence-based research to support their use [72]. Rushton et al. [73, 74] surveyed 453 general paediatricians and 306 family physicians, and found that 72% had prescribed an SSRI for a child or adolescent (with depression as the most common indication) despite the lack of published randomised controlled trials on safety, efficacy, or guidelines in the paediatric population during the study period. As might be expected given the overlap with the adult population, more family physicians reported prescribing SSRIs for paediatric patients, compared to paediatricians (91% vs. 58%). In a finding related to the challenges inherent in the present discussion, more family physicians than paediatricians (22% vs. 11%) agreed that they were comfortable with the management of childhood depression.
Two large randomized controlled trials have now shown the efficacy of SSRI's specifically, fluoxetine 20 mg daily and paroxetine 20 40 mg daily as superior to placebo in the general paediatric population [75, 76]. As of January 2003, the United States Food and Drug Administration approved the use of the fluoxetine for the treatment of obsessive-compulsive disorder and depression in paediatric patients of ages 7 to 17. While these results look promising, it should be added that at least a few clinicians have questioned the level of efficacy found. Improvement with SSRIs may take 4 6 weeks, and the dose should be maintained for at least 6 weeks, if the child shows a clinical response by 4 weeks [78]. As seen in adults , the adverse effects of SSRIs in children and adolescents include nausea, tiredness , nervousness, dizziness, and difficulty concentrating [77, 79]. All of these side effects are dose-dependent, and generally subside with time. After 19 weeks of treatment with fluoxetine in one clinical trial, children and adolescents weighed two pounds less, compared to those treated with a placebo[77]. Effects of fluoxetine on sleep parameters include disturbed subjective sleep, increased Stage 1 sleep, increased number of arousals, and increased rapid eye movement density [80].
Little research has been conducted on SSRI's in the management of dysthymic disorder, the second form of depression with which paediatric patients can be diagnosed. A small open trial of fluoxetine in 11 of 15 paediatric patients showed a reduction in symptoms, such that they no longer met criteria for dysthymic disorder or major depression [81]. Randomised controlled trials are clearly needed to further elucidate the efficacy of SSRIs in dysthymic children and adolescents.
SSRIs in children and adolescents: Emerging concerns and controversy
SSRIs have radically changed the treatment of depression and anxiety across the developmental spectrum. As early as 1991, however, concerns began to emerge regarding an association between SSRIs and self-harm [82]. In 2003, the Food and Drug Administration (FDA) in the United States received unpublished data from placebo-controlled trials which suggested that paroxetine, taken by paediatric patients with major depressive disorders, might be associated with a potentially elevated risk of suicide attempts'and possibly suicide-related events. In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) then issued a warning against prescribing paroxetine for depressed patients under 18 years of age. In December 2003, the MHRA in the United Kingdom issued similar contra-indications to the use of venlafaxine, sertraline, citalopram, and escitalopram, with the recommendation that fluoxetine was the only SSRI with a sufficiently favourable profile for use in the paediatric population [83].
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In January 2004, the American College of Neuropsychopharmacology issued a report from its Task Force on SSRI's and Suicidal Behaviour in Youth. This task force studied the use of SSRIs (specifically, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine) in more than 2000 children and adolescents, and concluded, After reviewing the evidence as a whole taking SSRI's or other new generation antidepressant drugs do not increase the risk of suicidal thinking or suicide attempts and that the benefits of SSRIs for treatment of depression in youth outweigh the risks. There were no completed suicides in any of the trials. [84]. The task force also emphasized that there were no completed suicides in any of the trials, and, using data from toxicology studies in autopsies, raised the suggestion that suicide is more likely when depressed individuals do not take their medications, rather than when they take it.
On October 15, 2004, the United States FDA [85] Public Health Advisory issued a black box warning in the United States for anti-depressants and youths:
Today the Food and Drug Administration (FDA) directed manufacturers of all anti-depressant drugs to revise the labeling for their products to include a boxed warning and expanded warning statements that alert health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies.
The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine anti-depressant drugs, including inhibitor SSRIs and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients, were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving anti-depressants. The average risk of such events on drug was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. Based on this data, FDA has determined that the following points are appropriate for inclusion in the boxed warning:
Antidepressants increase the risk of suicidal thinking and behaviour (suicidality) in children and adolescents with MDD and other psychiatric disorders.
Anyone considering the use of an anti-depressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.
Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behaviour.
Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.
A statement on whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).
Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Importantly, the following day the American Psychiatric Association (APA) released an APA Statement on the FDA's Hearing on Antidepressant Use in Pediatric Patients. [86] The statement concludes: It is key to note that the advisory committee's recommendation for black box warnings was adopted by a split vote, with 15 committee members in favour, and eight opposed. The APA believes that several dissenters' concerns that such warnings, which limit access to care, are valid, and should be taken into account by the FDA as it proceeds In addition, we will work with physicians including pediatricians and general practitioners to help them better understand their patients' needs, and properly monitor patients.'
In the past year, a multitude of studies have examined whether SSRIs are associated with an increased risk of suicidal behaviour in children and adolescents. Valuck et al. [87] studied more than 20,000 United States adolescents with major depressive disorder, and concluded, anti-depressant medication use had no statistically significant effect on the likelihood of suicide attempt in a large cohort of adolescents across the US after propensity adjustment for treatment allocation and controlling for other factors. Jick et al. [88] studied 159,810 users of four antidepressant medications (fluoxetine, paroxetine, amitriptyline, and dothiepin (dosulepin), and concluded, there were no significant associations between the use of a particular study anti-depressant and the risk of suicide. They also concluded, however, that the risk of suicidal behaviour is increased in the first month after starting antidepressants, especially during the first 1 to 9 days. A recent study by Grunebaum et al. [89] found that the suicide rate among United States adults fell 13.5% from 1985 1999, with a fourfold anti-depressant prescription rate (mostly due to SSRI's) during the same period. A similar study by Olfson et al. [90] found an association between a 1% increase in use of anti-depressants by adolescents in the United States, and a decrease of 0.23 suicides per 100,000 adolescents per year. The authors found this inverse relationship particularly significant for male adolescents of age 15 19 years, and adolescents residing in lower socio-economic regions (all P .001). In an August 2004 study from the Journal of the American Medical Association, March et al. [91] studied 439 depressed patients, between ages 12 and 17 years, and treated with fluoxetine alone, CBT, both fluoxetine and CBT, or placebo. They found that clinically significant suicidal thinking, which was present
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in 29% of the sample at baseline, improved significantly in all four treatment groups, and that fluoxetine alone was superior to CBT alone in decreasing depressive scores; even further clinical efficacy was seen when fluoxetine was combined with CBT.
One of the primary difficulties inherent in this discussion comprises the distinctions between suicidal ideation, self-harm, attempted suicides, and completed suicides. Although such distinctions are beyond the scope of the present chapter, the reader should be aware that this is one of the most problematic methodological aspects of research in this area of risk assessment. As noted in the ACNP task force report, Actual suicidal events in the studies reviewed here are poorly defined. Attempts were defined by the treating clinician at the site, and therefore, varied not only across studies, but across sites within the study. Further confusing the picture, many of the studies evaluating the efficacy of SSRIs have not included unpublished data, or data from unpublished trials. For example, as reviewed by Whittington et al. [92], unpublished data on paroxetine and sertraline indicated that risks outweigh benefits in the use of these medications, while data from unpublished trials of citalopram and venlafaxine revealed unfavourable risk-benefit profiles. Thus, one of the primary means of clarifying the issue of SSRI safety is more widespread and translucent availability of data.
Further work is sorely needed on the use of antidepressants in the paediatric patient, and in the paediatric palliative care patient in particular. As in the field of general paediatrics, or child and adolescent psychiatry, the importance of close monitoring, frequent clinical contact, and multi-modal and multidisciplinary treatment cannot be emphasized enough. There is no doubting the understandable and inherent risk of depression, anxiety, and related psychiatric issues in paediatric palliative care; similarly, though, there is no excuse for not actively addressing, diagnosing, treating, and researching these same issues.
Tricyclic antidepressants and stimulant medication
Tricyclic antidepressants (TCAs) have been commonly used in adult palliative care (given their proven efficacy for treatment of both neuropathic pain and depression), but in the paediatric population this is not the case. TCAs have not been shown to be any more efficacious than placebo in the treatment of depression in children [76, 93]. When used to treat paediatric neuropathic pain, the dose is far less than that prescribed for psychological disturbances. Moreover, the high side-effect profile of TCAs includes bothersome anti-muscarinic effects, such as dry mouth, insomnia, night terrors, epigastric discomfort, constipation, tachycardia and palpitations, blurred vision, and urinary retention. The most concerning side effects with TCAs of course, involve cardiac conduction disorders [76, 94], with cardiovascular side effects manifesting as tachycardia, hypertension, and postural hypotension [95]. It is worth noting that cardiotoxic effects have occurred in depressed children receiving doses within the therapeutic range [96]. Thus, TCAs are not of proven therapeutic benefit for depression in the paediatric population [97, 87]; given their side effect profile and need for close serum monitoring [99, 100], they are especially inappropriate in treating depression in the paediatric palliative care patient.
The role of stimulants (e.g., dexamphetamine, methylphenidate) in the management of depressive symptoms in paediatric palliative care is unclear. This is despite their therapeutic history with attention deficit-hyperactivity disorder, and their use in adult palliative care, especially as an adjunctive treatment for depression and pain in cancer and HIV-positive patients [101, 103]. As noted by House and Hughes (1996) [104], stimulants in these patients should not be first-line therapy, should be used in short courses, and only be prescribed after specialist psychiatric and medical assessment. Findling (1996) [105] has studied the co-administration of SSRIs and methylphenidate in 7 paediatric patients (ages 10 16) and 4 adults (ages 38 44) with comorbid depression and attention deficit-hyperactivity disorder. None of the patients developed suicidality, increased heart rate, increased aggressiveness, or mania, and only one patient developed a signifi-cant change in blood pressure (20 mm Hg increase in diastolic pressure). Findling reports that this combination therapy appeared efficacious in decreasing depressive symptoms. Further work is clearly needed on the use of SSRIs and psycho-stimulants in paediatric palliative care. Nevertheless, these studies illuminate a possible area of significant pharmacologic efficacy and benefit in depression management.
Anxiety
Features and diagnosis
Features and challenges
Anxiety in the paediatric palliative care patient usually takes the form of separation anxiety, loneliness, procedure-related anxiety, fear of abandonment and death anxiety. It is important to recognise the difference between anxiety as a transitory state' dependent on the situation, and as a personality trait less influenced by the situational milieu. For example, Kellerman et al. (1980)[106] noted that adolescents may understandably develop state anxiety related to painful procedures; nevertheless, their study of 168 adolescents with chronic medical illnesses (including cystic fibrosis, leukaemia, solid
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tumours, nephrotic syndrome, diabetes mellitus, systemic lupus, and congenital cardiac conditions) found no evidence of trait anxiety, compared with 349 healthy adolescent controls. Interestingly, prognosis did appear to influence the presence of trait anxiety, in the ill adolescents: those patients whose physicians rated their prognosis as improved,' uncertain,' or deteriorating were all more likely to exhibit trait anxiety than those whose physicians rated their prognosis as stable.
Using the Child Medical Fear Scale and the State-Trait Anxiety Inventory for Children (STAIC), Hart and Bossert (1994)[107] evaluated the fears of 82 hospitalised children (ages 8 11) from the general paediatric population. They found the fears with the highest mean scores to be: separation from the family, procedural-related anxieties ( having shots and finger sticks'), prolonged in-patient admission, and receiving bad news regarding their health.
The assessment of anxiety symptoms in the general paediatric population may be challenging, due to the lack of consensus regarding definitions, thresholds, and thus, what symptoms would qualify as disorders [108]. In the paediatric palliative care setting, clinicians may be especially hesitant to label anxious symptoms as a disorder, as they may appear entirely appropriate, given the stresses on the child.
Risk factors
As occurs in depression, anxiety has also been associated with paediatric chronic pain [20]. In a sample of 56 paediatric oncology patients, Last and van Veldhuizen (1996)[23] have shown that anxiety is reduced when parents provide their child with information regarding their diagnosis and prognosis. Frank et al. (1997)[109] reported on the psychosocial adjustment of 86 paediatric oncology patients, and found that children diagnosed at younger ages reported greater levels of anxiety. On the other hand, Grootenhuis and Last (2001)[65] found no association between anxiety and time since diagnosis, in a sample of 43 children with cancer in remission, and 41 children not in remission.
The ICU setting has been indicated as a risk factor for the development of anxiety and apprehension in the hospitalized paediatric patient. In a study of 43 hospitalized children (ages 6 17), Jones and colleagues (1992)[110] have concluded that anxiety and psychological trauma are more common in critically ill children in the intensive care unit, as well as in children with prolonged and repeated hospitalizations. These findings, of course, further support the traditional goals in paediatric palliative care of maximizing comfort and limiting traumatic experiences.
As in depression, the presence of maternal psychiatric disorder can serve as a risk factor for the same disorder in children. In a study of 61 leukaemic children and their mothers, Brown et al. (1993)[111] have documented increased self-reporting of anxiety in the children of mothers meeting DSM-III-R criteria for any psychiatric disorder. Similarly, a study using the Children's State-Trait Anxiety Inventory and adult State-Trait Anxiety Inventory in 74 paediatric oncology patients (ages 9 18) found a positive association between the adjustment responses of children and those of their mothers [112].
This chapter has not addressed symptoms that may manifest themselves in siblings or even parents, although clearly, all family members have the potential to be vulnerable to the same symptoms presented here. Nevertheless, it is worth noting a specific population of family members who can, in a sense, come under the care of the clinician in the oncology setting: donor siblings. In a comparison of 23 donor- and 21 non-donor siblings (ages 6 18) of surviving paediatric bone marrow transplant patients, donors self-reported more anxiety than non-donors [114]. In addressing this unique population, programs have been described which provide support to donor siblings [114].
Diagnostic tools
Anxiety scales, while useful in providing an overall estimate of anxiety levels, are not sufficient to establish a concrete diagnosis of an anxiety disorder [108]. Greenhill et al. (1998)[115] have reviewed the many diagnostic tools and self-report instruments designed to identify anxiety symptoms and disorders in general paediatrics, and have discussed the problems of discriminant validity and reliability which they uncovered. Challinor et al. (1999)[34] studied 43 paediatric oncology patients, and found high positive correlations between scores from patients and their parents for anxiety, using the Behavioural Assessment System for Children. Ireland and Malgady (1999)[116] have created a unique scale, the Thematic Instrument for Measuring Death Anxiety in Children. They describe a culturally sensitive tool, specifically designed to assess death anxiety in children with AIDS. Recent work on the assessment of children's anxieties and fears has also included human figure drawings [117].
Prevalence/incidence
In the general paediatric population, anxiety disorders have a point prevalence estimated to range from 3 13% [118], making them the most common psychiatric disorders in children and adolescents [119].
In their study of 168 adolescents with chronic medical illnesses, Kellerman et al. (1980)[106] found no difference between the prevalence of anxiety in patients with cystic fibrosis, leukaemia, solid tumours, and congenital heart
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disease and those with diabetes mellitus, recurrent urinary tract infections, and rheumatic heart disease; moreover, these chronically ill adolescents, as a group, did not show higher anxiety than the 349 healthy controls. In 44 patients with epilepsy, 16% met the criteria for significant anxiety symptomatology, according to the Revised Child Manifest Anxiety Scale [47]. The prevalence of separation anxiety disorder in a sample of 26 dialysis-dependent children with end-stage renal failure has been reported as over 50% [120].
In a study of 35 children and adolescents with cancer, Kashani and Hakami (1982)[51] found separation anxiety in 12 (34%) of the children, while 13 children (37%) reported a related symptom of being frightened, scared, or fearful. Although not specifically diagnosing anxiety, Collins et al. (2000) [30] assessed symptoms in 159 children between the ages of 10 18 years. Thirty-six percent reported feeling nervous', and 35% reported worrying (with 56% and 66%, respectively, rating the severity of the symptoms between moderate' and very severe ).
Death anxiety
The presence of death anxiety in children with palliative care needs is neither surprising nor new. Over three decades ago, Schowalter (1970)[122] observed that death anxiety may be greatest at the age of 6 10 years, when the concept of terminal illness has first entered the child's awareness, but death is still poorly understood. Of importance, most studies concur that dying children over the age of 10 years have an awareness of their poor prognosis, whether or not this is disclosed to them [123]. Death anxiety in the child younger than five years commonly manifests as separation anxiety, loneliness, and fear of abandonment. As early as 1955 [11], authors were discussing death anxiety and recognizing the role of repression:
Even among adolescents, who intellectually may know much about cancer, the question concerning diagnosis and the possibility of death usually was not raised, as it often is by the adult patient. Our suspicion is that this does not reflect an awareness, but rather represents an attempt at repression psychologically of the anxiety concerning death.
Regarding the efforts to keep the child with leukaemia from becoming aware of his prognosis,' Spinetta (1973)[123] concludes that the child somehow picks up a sense that his illness is very serious and very threatening. The fatally ill child is aware that his is no ordinary illness.' It is therefore not surprising that the paediatric palliative care patient may experience profound and appropriate anxiety which may, ironically, be aggravated by the family's and caregiver's desire to protect the child.
Non-pharmacological support
In the founding years of the field of paediatric palliative care, clinicians were already addressing the need for nonpharmacological support in decreasing anxiety symptoms. In their 1980 article, Symptom control in ill and dying children, Chapman and Goodall[18] suggested that the first approach to treating anxiety centres on communication and allowing the paediatric palliative care patients to express their fears, anxieties, and concerns:
If personal discussion does not bring relief to the patient and family, anxiolytic drugs may be needed, but the second should not be prescribed without the first We must provide opportunities for such anxieties to be spelled out if we are to hope to relieve them.
The importance of patient expression in reducing anxiety has continued in current non-pharmacological approaches to anxiolysis. Barrera et al. (2002)[124] have recently described the use of interactive music therapy as an efficacious means of reducing anxiety in 65 hospitalized children with cancer. Robb and Ebberts (2003)[125] have, similarly, shown anxiety reduction in a small study of bone marrow transplant patients, who participated in a song writing and digital video production intervention.
The non-pharmacological approach to anxiety disorders is largely dictated by whether the patient is experiencing separation anxiety, generalised anxiety, procedure-related anxiety, death anxiety, or another form of the disorder.
In the case of separation anxiety, the initial approach should involve maximizing parent-child interaction. Such an approach is especially relevant in the pre-school population with life-limiting illness, where separation is a risk factor for the aetiology of both anxiety and depression (Hollenbeck et al., 1980)[126].
Non-pharmacological support of the anxious toddler or pre-schooler in even the general paediatric setting can be especially challenging, and thus requires equally unique therapeutic approaches. For example, Olness and Gardner (1978)[127] posited that children are more receptive to using hypnosis than adults, since they engage in fantasy and imagination without the cognitive inhibitions of adults. Discussing the role of hypnotherapy, they note:
In addition to reduction of specific symptoms through hypnotherapy, children benefit by the sense of mastery which they acquire, a sense which is surely needed to overcome the feelings of hopelessness, loss of control, and depression induced by many diagnostic and therapeutic procedures in medicine.
Kohen et al. (1984)[128] subsequently described the use of relaxation mental imagery' ( self-hypnosis ) in 505 children and adolescents including children as young as three years old with 51% reporting complete resolution of their
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presenting problems (including acute pain, chronic pain, and anxiety). Similarly, Ott (1996) [129] has described the use of guided imagery as an adjunct modality in the care of toddlers and pre-schoolers who are experiencing anxiety.
For the patient with procedure-related anxiety, amelioration of anxiety symptoms can occur through several means. An intervention that combined hypnosis with acupuncture in six weekly sessions has been shown to significantly decrease anticipatory anxiety in 33 chronic-pain youth (ages 6 18) [130].
As reviewed by Labellarte et al. (1999)[119] and Manassis (2000)[131], numerous controlled studies have shown CBT to be efficacious in treating anxiety disorders in the general paediatric population. In the specific area of procedure related anxiety, the efficacy of CBT has become increasingly evident. Cognitive-behavioural approaches have been used to decrease the anxiety associated with lumbar punctures and bone marrow aspirations [132]. In a study of 30 paediatric oncology patients (ages 5 15) undergoing bone marrow aspiration, Liossi and Hatira (1999)[133] have shown that CBT training and hypnosis result in decreased pain-related anxiety, when compared to both controls and the patients' own baselines. In a recent follow-up study [134], the authors have studied lumbar-puncture-associated anxiety in 80 paediatric oncology patients (ages 6 16 years), and found that patients in hypnosis intervention groups reported less anxiety and pain than controls. However, when patients where switched to self-hypnosis, the therapeutic benefit was observed to degrade. This finding thus suggests that the presence of the therapist trained in hypnosis may be necessary for the desired anxiolytic effect.
Pharmacological management
Despite being among the most common psychiatric disorders in children and adolescents, anxiety disorders have lacked substantial data on the efficacy of pharmacological options [135, 72]. With the recent exception of SSRIs, the efficacy of anxiolytics has received only minimal support in the evidence-based literature. This dearth of research has been quickly changing in the past two years, though, with several well-designed studies in the general paediatric population [135].
Benzodiazapines are commonly used in the treatment of procedure-related anxiety, despite minimal research supporting their use as paediatric anxiolytics. The published studies of paediatric benzodiazepine use primarily address status epilepticus, rather than anxiety disorders. In critically ill infants and children, differences in plasma clearance and potential anxiolytic side effects must be taken into account. Finally, concern for both benziodiazepine dependence and withdrawal [136, 137] has reduced its use in clinical practice as a paediatric anxiolytic [131]. It is thus not surprising that benziodiazepine usage recommendations are limited to adjunctive medications in severe anxiety [138], short-term anxiolytics for specific anxiety-provoking situations, or as temporary anxiolytics when an SSRI has been started, but is not yet efficacious [131].
For procedure-related anxiety, Ljungman and colleagues (2000)[139] have studied the efficacy of intranasal midazolam in a randomised, double-blind, placebo-controlled trial of 43 children with cancer. Parents, nurses, and children reported significantly reduced anxiety and procedure problems, with no serious or unexpected side effects. The most common side effect was nasal discomfort, the primary reason for dropouts (8/43 patients), thus suggesting that its use may be limited without optional administration routes. Midazolam is now used buccally, and is available in some countries in a flavoured preparation. In order to elucidate potential hypersensitivity to midazolam, a small test dose (0.2 mg/kg) is recommended if the child is benzodiazepine na ve.
Intranasal, oral and buccal midazolam have also been used to decrease anxiety in dying children. Bentley and colleagues (2002)[140] have described the use of intranasal and oral midazolam in a sample of 4 dying patients of ages 8 months to 24 years. Symptoms treated were agitation, death anxiety, and extreme anxiety related to increasing pain. In the dying child, the ease of administration and rapid onset of intranasal or buccal midazolam can greatly assist parents in the home setting.
Given the overlap between paediatric depression and anxiety, it should not be surprising that the pharmacological treatment of anxiety bears many similarities to that of depression. Nevertheless, as with depression, there have been no reported studies on anxiolytic pharmacotherapy in paediatric palliative care patients.
Following successful results from several open studies [141, 142, 143], SSRIs have recently been proven efficacious in two large randomised controlled trials of paediatric anxiety disorders. Walkup et al. (2001)[144] conducted a randomized controlled trial in 128 paediatric patients (ages 6 17), with diagnoses of social phobia, separation anxiety, or generalized anxiety disorder. After an eight-week course, the patients who received fluvoxamine were more likely to show a clinical response (as measured on the Pediatric Anxiety Rating Scale) than the placebo group (76% vs. 29%). Similarly, Birmaher et al. (2003)[145] recently reported on a randomized controlled trial on 74 anxious youth (ages 7 17), and found much' to very much improvement in 61% of the fluoxetine group (vs. 35% in those taking placebo). The only side effects they reported were mild and transient headaches, and
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gastrointestinal disturbance. These trials are occurring in the general paediatric population, and not in the palliative care setting.
Depression-anxiety co-morbidity
Paediatric diagnosis and treatment of depression and anxiety are especially problematic, given the co-morbidity between the two conditions [146]. In an excellent review of the subject, Axelson and Birmaher (2001) [45] have noted that 10 15% of anxious youth have depression, and 25 50% of depressed youth also possess anxiety disorders. Furthermore, younger depressed children display higher rates of comorbid separation anxiety and phobias [147]. Moreover, Gurley et al. (1996)[138] showed that in children and adolescents with sub-clinical symptomatology, anxiety and depression were particularly difficult to identify as separate entities. Finally, it is important to note that a child experiencing a dysthymic disorder, rather than major depressive disorder, may display persistent irritability as the predominant mood, instead of depression. In order to meet the DSM-IV criteria for dysthymic disorder, this mood disturbance must last for one year (American Psychiatric Association, 1994)[6]. In a study of 159 children with cancer conducted by Collins and colleagues (2000)[30], 35% reported feeling irritable, with 64% rating the symptom severity between moderate' and very severe. Moreover, Hollenbeck et al. (1980)[126] have discussed a pattern of agitation preceding depression in pre-school children being treated for cancer.
Therapeutically, it is thus helpful that both sets of symptoms have been demonstrated as being responsive to SSRI's and CBT. In fact, randomised controlled trials of psychosocial therapies have only shown CBT to be efficacious in treating both paediatric depression [149, 150] and anxiety [151, 152, 153]. In a review of depression in the general adolescent population, Parker and Roy (2001) [154] have observed that SSRI efficacy appears most clear in cases of anxious or irritable depression. This combination of depression, anxiety, fear, and even irritability is relevant to the paediatric palliative care patient, and would support the potential use of SSRIs in these patients.
Anger
The symptom of anger can be seen to accompany both depression and anxiety, and can be recognised as a manifestation of these disorders, or as a symptom in its own right. In the general paediatric population, Sherry and Jellinek [155] have described the manifestation of depression in preschoolers as aggressive or destructive behaviour. In chronic illness, patients may display a paradoxical pattern, with decreased expression of anger. For example, Meijer et al. (2000) [156] found that 107 chronically ill children were less likely to report aggressive behaviour than healthy children.
The appearance of anger as a psychological symptom has been examined in different paediatric oncology populations. Kashani and Hakami (1982)[51] noted that 17 of 35 of their patients demonstrated anger and irritability, based on self-and parental report. Kvist and colleagues (1991)[24] have described aggression as the dominant psychological response in children with malignant disease.' A study of 53 oncology patients who had electively discontinued treatment for leukaemia or lymphoma (mean age 12.8 years at completion of questionnaires) reported aggression in the form of irritation and anger, more common in girls than in boys. These dying patients also reported the co-morbidity of depression, hypersensitivity, phobic anxiety, death anxiety, and night terror. The child with cancer may not manifest aggression in all settings. Noll et al. (1999)[60] showed that peers and teachers reported less aggression in 76 children with cancer, compared with 76 classroom peers.
Agitation and delirium
Features and diagnosis
Agitation is a physical and psychological phenomenon that can exist in many forms. The causes of agitation are numerous, and in the paediatric population, are especially varied, and sometimes difficult to define. As referred to earlier in this chapter, agitation can be a feature of both depression and anxiety. It may also be a prominent characteristic of some neurodegenerative syndromes, such as Batten's and juvenile onset of Huntingdon's disease. In these conditions, changes in behaviour, movement patterns, or even sleep disturbance may be described as agitation. Occasionally, these changes can be more acute in nature, and agitation has been associated with the onset of visual and auditory hallucinations. Agitation manifests itself in many situations. In the young baby or toddler, it may purely be a reflection of a tired state of mind. When assessing agitation, the clinical context as a whole must be examined.
In more extreme forms, agitation may be associated with the dying process. Several terms have been used to describe this agitated state of mind at the end of life, including terminal agitation, terminal restlessness, or terminal delirium. Burke (1997) [157]defines terminal restlessness as agitated delirium in a dying patient, frequently associated with impaired consciousness and multi-focal myoclonus. In
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contrast, the term terminal anguish has been used to refer to the extreme emotional or spiritual turmoil that people may exhibit at the end of life [158]. The multiple synonyms used to describe this neuro-psychiatric state reflect the ubiquitous nature of the condition, rather than any diagnostic quandary.
In the adult literature, the term delirium is frequently used to describe a form of agitation at the end of life, often in patients with advanced cancer. This neuro-psychiatric syndrome is described as a disturbance of consciousness, cognition and perception, with a course that may wax and wane over a period of hours' [6]. As an alteration in psychomotor activity, it has been specifically classified as hyper-manic, hypomanic and mixed [159]. Classical features of delirium include an acute onset and fluctuating nature, and although it is described as being a transient and potentially reversible disorder, it frequently occurs as an irreversible event in the terminal phase of life [160]. Delirium causes extreme distress not only to the patient, but also to the family and carers. At a time when communication and clarity of thought are important, delirium hinders decision-making, and contributes added burden to suffering.
Causes of agitation and delirium
There has been much debate in the adult literature as to the possible causes of delirium in the terminally ill, and the potential for reversibility of these distressing symptoms. The causes of delirium are often multi-factorial [161, 162], and include the presence of primary cerebral disease (cancer, cerebrovascular accidents) and other factors that may indirectly affect cerebral metabolism (sepsis, organ failure, electrolyte disturbance, psycho-active medication, nutritional deficiencies, drug withdrawal).
A leading study in 1992 by Bruera and colleagues [163] found a biological cause for cognitive failure in 44% of adult cancer patients at the end of life. Subsequent studies went on to identify opioid toxicity as a reversible cause of delirium, and recommended that opioid rotation could improve symptoms of delirium, whilst maintaining pain control [164, 165]. Neuroexitatory features such as agitation, myoclonus, tactile hallucinations and hyperalgesia are symptoms suggestive of opioid toxicity. In some palliative care centers, opioid rotation and rehydration have become standard practice upon detection of cognitive failure; Bruera and colleagues have produced data to support this practice (1995)[166]. A small prospective study by Morita et al. (2002)[167] showed an increase in plasma morphine metabolites in eight patients, after the development of terminal delirium. Of note, all patients had clinical multi-organ failure.
Two recent well-designed prospective adult patient studies have identified precipitating factors of delirium, and the incidence of reversibility of symptoms in adult cancer patients receiving palliative care (Lawlor et al. 2000, Morita et al. 2001)[160, 168]. Lawlor found that 49% of delirium episodes in 71 patients were reversible, and that psycho-active medications (predominantly opioids) and dehydration were precipitating factors associated with reversibility. Lawlor specifies, however, that dehydration tends to act in association with other reversible factors such as opioid toxicity,' and in isolation, is not a primary cause of delirium. Hypoxic encephalopathy and metabolic factors were associated with non-reversibility.
Morita identified precipitating factors in 93% of the 153 cases of delirium studied, and specified the main pathologies as hepatic failure, medications, pre-renal azotaemia, hyper-osmolality, hypoxia, disseminated intravascular coagulation (DIC), organic central nervous system damage, infection and hypercalcaemia. Interestingly, medication-induced delirium often showed a hyperactive clinical picture. Complete recovery of symptoms occurred in 20% of patients, and was most commonly achieved in cases with medication- and hypercalcaemia-induced delirium. In contrast, a low remission rate was achieved when hepatic failure, dehydration, hypoxia and DIC were present. The author states that the relatively low reversibility rate in this study might well be due to variability in patient selection, as most patients in this Japanese study were referred for terminal care, rather than symptom control.
Distinguishing delirium from other conditions
The diagnosis of delirium can be difficult. In adults, delirium is frequently misdiagnosed as depression or dementia. Several instruments are available to assess delirium and distinguish it from other psychiatric disorders, namely, the Confusion Assessment Method (CAM) [169], Delirium Rating Scale [170], and the Memorial Delirium Assessment Scale [171]. The CAM, devised by Inoue, has been validated as a diagnostic tool for the medically ill population, and is easy to use even for non-psychiatrists. The Memorial Delirium Assessment Scale, by Breitbart, is a ten-item scale specifically designed to measure the severity of delirium, and can, therefore, measure change, which the CAM does not. The Memorial Delirium Assessment Scale [171], the Communication Capacity Scale, and the Agitation Distress Scale [172] have been particularly validated to measure delirium in adult cancer patients. Unfortunately, there is no tool available to assess delirium in the paediatric population.
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Prevalence/incidence
As with many symptoms in paediatric palliative care, the incidence of delirium (or terminal agitation) has not been evaluated. Anecdotally, it is not an uncommon feature of the dying process in children. Recent studies of adults dying, mostly of cancer, have revealed that 68 90% are delirious prior to death [160, 163, 168, 173, 174].
Non-pharmacological support
Management of agitation, delirium and restlessness in patients at the end of life involves a thorough clinical assessment and an individual treatment plan. The goals of treatment should be discussed with the family, and should be appropriate to the situation. Any potentially reversible cause, of which there may be more than one, should be corrected, if possible. In clinical practice, however, priorities such as patient comfort, setting (home or hospice), and appropriateness of diagnostic procedures will limit the degree of investigation. The ability to rectify a problem with minimal burden to the patient and his or her family must also be considered. Relatively low-burden interventions, such as altering drug doses, discontinuing or changing psychoactive medication, and a trial of hypodermoclysis, might be considered.
All those nearing the end of life must be considered at risk of developing symptoms of agitation or delirium. Preventative measures, such as encouraging regular sleep through breathing and relaxation exercises, and quiet music or familiar stories to facilitate rest, may help the child feel calm. Treatment should be arranged to allow maximum periods of uninterrupted rest. Avoidance of sedative medications, such as antihistamines and choral hydrate, are advisable, as they do not relieve anxiety or fear, but paradoxically, may result in an agitated, confused and very tired child.
General environmental measures, aimed at reducing anxiety and disorientation, should be employed [175] at the first sign of symptoms. These include strategies such as familiarizing a room (i.e., using a child's own bedclothes and belongings), consistency in staff, reducing the level of noise stimulation, having adequate lighting with a clock visible, and, of course, the near presence of family members. It is extremely important to educate parents and family as to the nature of delirium and agitation, as the situation can be frightening and upsetting, and their reactions may exacerbate the patient's distress.
Pharmacological management
The pharmacological treatment of delirium and agitation should aim to alleviate symptoms, and bring the patient closer to his or her normal mental state. It is important to distinguish between medication that aims to clear the mind and medication that aims to sedate the patient. Careful consideration as to the balance between sedation, suppression of symptoms, and the potential adverse side effects of medication must be made. For example, sedative medication may improve symptoms, but increase cognitive impairment, hindering communication and interaction.
Several agents are commonly used in the terminal phase in children, but as with most drugs in paediatric practice, they are off-licence, and little or no data exists to support their use. In adult palliative care, there is a similar lack of evidence-based protocols, however, the mainstay of treatment depends upon antipsychotic (neuroleptic) drugs, such as haloperidol and the benzodiazepines.
Haloperidol is a potent neuroleptic with antidopamine activity, but relatively few anti-cholinergic effects (potentially, it may cause extra-pyramidal side effects, but usually at higher doses). It improves cognition (onset of action is rapid; hours to days), and is sedative at high doses. Haloperidol can be administered through many routes (oral, subcutaneous, intravenous and intramuscular) [176]. It is the drug of choice in the treatment of delirium in adult patients [177], and is effective in relieving agitation, paranoia and fear.
Olanzapine and risperidone are new antipsychotic drugs that are less sedating than traditional neuroleptics, and are reported to have fewer extra-pyramidal side effects [178, 179, 180, 181, 182, 183]. Of note: evaluation of the pharmacological treatment of delirium has been mostly in the elderly population, and these drugs are not currently available in the parental formulations for rapid onset. Olanzapine is available in a rapid orally disintegrating tablet, marketed in the USA as Zyprexa Zydis. Risperidone has recently been released as a two-week depot injection (marketed in the USA as Risperdal Consta). Nevertheless, neither of these formulations has been designed for, or tested in, the paediatric population.
Benzodiazepines are frequently used in paediatric practice for their anxiolytic effects, and ease of administration. Lorazapam, midazolam and clonazepam can all be administered via the sublingual or buccal routes, and are therefore valuable in the home setting. The therapeutic aim of benzodiazepine treatment must be explicit, as, in higher doses, sedative and hypnotic effects occur. Paradoxically, at higher doses, benzodiazepines can also cause agitation and delirium in some patients. However, many paediatric patients who have been taking regular benzodiazepines for the treatment of neurological disorders, such as seizures and spasm, can tolerate high doses of these agents, with perceived benefit, and little or no adverse effects. Lorazepam or midazolam are frequently used in combination with haloperidol for symptoms of
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agitated delirium. Benzodiazepines alone do not improve delirious symptoms, and actually worsen cognition, as shown by Breitbart in a double-blind randomized trail of haloperidol, chlorpromazine, and lorazepam in hospitalised AIDS patients [184]. As noted by Galloway and Yaster [185], some children remain agitated despite benzodiazepines and opioids, and it is preferable to switch to a different class of drugs, rather than continue with higher doses.
An alternative medication is the barbiturate phenobarbi-tone (Phenobarbital), used as a second line treatment in children and young people when symptoms remain uncontrolled, or drug side effects are intolerable. It has been shown to be a useful agent in controlling symptoms of agitation [186]. Phenobarbitone (Phenobarbital) is particularly beneficial when anti-convulsant action is also required. It should be considered in patients who are known to be suffering from CNS irritability, as it elevates seizure threshold [187], whereas phenothiazines lower seizure threshold. Phenobarbitone (Phenobarbital) should be administered by subcutaneous infusion (occasionally with an intramuscular or subcutaneous loading dose) as a single agent. It can cause skin irritation in some patients.
Induction of deeper levels of sedation is sometimes necessary in the management of agitated delirium or severe agitation. This may be a temporary treatment whilst a cause for the agitation is elicited, or may be on-going to control refractory symptoms, or where definite treatment is not possible [188]. When sedation is required, midazolam and levomepromazine are the agents most commonly used [189, 190, 191, 192, 193, 194]. Levomepromazine (methotrimeprazine) is a phenothiazine with anti-dopaminergic properties that has been frequently used in children as an anti-emetic; at higher doses, it can be rapidly titrated to induce sedation. (See also Chapter 32, symptom control at the end of life.)
Conclusion
There is much we do not know about the assessment and management of psychological symptoms such as depression, anxiety, agitation, and delirium in paediatric palliative care, due to the lack of research into these issues. What we do know has been extrapolated from adult palliative care studies, as well as from the pediatric psychological and psychiatric literature. Symptoms of depression, anxiety, and anger are often present together in different degrees at different times in the course of illness of the child. The complexity of these difficult-to-quantify symptoms cannot be understated. At the same time, much can be done to help, if not eliminate, then at least reduce, the severity that these symptoms may have on the quality of life of the child and family. First principles in the management of these symptoms are to get the best assessment possible by active listening and direct observation. In some cases the intervention that is most needed and useful is the caring, active-listening professional. This approach, coupled with the judicious use of pharmacological and non-pharmacological management techniques, can serve to reduce the burden of suffering that these symptoms represent. The assessment and management of agitation and delirium has been well studied in adults at the end of life, and offers an initial approach that can be used in approaching these issues in children. By first reviewing possible iatrogenic causes (e.g., opioid toxicity), and investigating easy-to-treat and common physiological causes (e.g, hypercalcemia), the clinician may be able to alleviate symptoms with minimal interventions. Thus, although there is much that is still not known about the management of distressing psychological symptoms in palliative care for children, there is also much that is already known, that can effectively reduce the burden of suffering and improve quality of life. (See also Chapter 8, Psychological impact of life-limiting illness on the child.)
References
1. Froese, A.P. Pediatric referrals to psychiatry: III. Is the psychiatrist's opinion heard? Int J Psychiatry Med 1977;8(3):295 301.
2. Sawyer, M. et al. Childhood cancer: A 4-year prospective study of the psychological adjustment of children and parents. J Pediatr Hematol Oncol 2000;22(3):214 20.
3. von Essen, L. et al. Self-esteem, depression and anxiety among Swedish children and adolescents on and off cancer treatment. Acta Paediatr 2000;89(2):229 36.
4. Ryan, N.D. Diagnosing pediatric depression. Biol Psychiatry 2001; 49(12):1050 4.
5. Kovacs, M., Presentation and cause of major depressive disorder during childhood and later years of the lifespan. J Am Acad Child Adolesc Psychiatr 1996;35:705 715.
6. Association, A.P., Diagnostic and Statistical Manual of Mental Disorders (4th edition). Washington, D.C.: American Psychiatric Association 1994.
7. Luby, J.L. et al. Preschool major depressive disorder: Preliminary validation for developmentally modified DSM-IV criteria. J Am Acad Child Adolesc Psychiatr 2002;41(8):928 37.
8. Luby, J.L. et al. Modification of DSM-IV criteria for depressed preschool children. Am J Psychiatr 2003;160(6):1169 72.
9. Perez, R., Ascaso, L., Domenech Massons, J., and de la Osa Chaparro, N. Characteristics of the subjects and interview influencing the test-retest reliability of the Diagnostic Interview for Children and Adolescents-Revised. J Child Psychol Psychiatry 1998;39: 963 72.
10. Birmaher, B. et al. Childhood and adolescent depression: A review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatr 1996; 35(11):1427 39.
P.404
11. Richmond, J. and Waisman, H.A., Psychologic aspects of management of children with malignant diseases. A.M.A. Am J Dis Child 1955; 292: 42 47.
12. Worchel, F.F. et al. Assessment of depression in children with cancer. J Pediatr Psychol 1988;13(1):101 12.
13. Phipps, S. and Srivastava, D.K. Approaches to the measurement of depressive symptomatology in children with cancer: attempting to circumvent the effects of defensiveness. J Dev Behav Pediatr 1999; 20(3):150 6.
14. Cavanaugh, S., Clark, D., and Gibbons, R., Diagnosing depression in the hospitalized medically ill. Psychosomatics 1983;24:809 15.
15. Kovacs, M. et al. Depressive disorders in childhood. II. A longitudinal study of the risk for a subsequent major depression. Arch Gen Psychiatr 1984;41(7):643 9.
16. Kovacs, M. et al. Depressive disorders in childhood. I. A longitudinal prospective study of characteristics and recovery. Arch Gen Psychiatry 1984;41(3):229 37.
17. Bennett, D.S. Depression among children with chronic medical problems: a meta-analysis. J Pediatr Psychol 1994;19(2):149 69.
18. Chapman, J.A. and Goodall, J. Helping a child to live whilst dying. Lancet 1980;1(8171):753 6.
19. Kashikar-Zuck, S. et al. Depression and functional disability in chronic pediatric pain. Clin J Pain 2001;17(4):341 9.
20. Varni, J.W. et al. Chronic pain and emotional distress in children and adolescents. J Dev Behav Pediatr 1996;17(3):154 61.
21. Steif, B.L. and Heiligenstein, E.L. Psychiatric symptoms of pediatric cancer pain. J Pain Symptom Manage 1989;4(4):191 6.
22. Last, B.F. and van Veldhuizen, A.M. Information about diagnosis and prognosis related to anxiety and depression in children with cancer aged 8 16 years. Eur J Cancer 1996;32A(2):290 4.
23. Verri, A.P. et al. [The leukemic child after therapy. Psychological aspects]. Pediatr Med Chir 1985;7(4):545 8.
24. Kvist, S.B. et al. Aggression: The dominant psychological response in children with malignant disease. Psychol Rep 1991;68(3 Pt 2): 1139 50.
25. Kaplan, S.L. et al. Depressive symptoms in children and adolescents with cancer: A longitudinal study. J Am Acad Child Adolesc Psychiatr 1987;26(5):782 7.
26. Berard. Psychiatric symptomatology in adolescents with cancer. Paediatr Heamatol and Oncol 1998;15:211 21.
27. Mulhern, R.K. et al. Maternal depression, assessment methods, and physical symptoms affect estimates of depressive symptomatology among children with cancer. J Pediatr Psychol 1992;17(3):313 26.
28. Vance, Y.H. et al. Issues in measuring quality of life in childhood cancer: measures, proxies, and parental mental health. J Child Psychol Psychiatry 2001;42(5):661 7.
29. Canning, E.H. and Kelleher, K. Performance of screening tools for mental health problems in chronically ill children. Arch Pediatr Adolesc Med 1994;148(3):272 8.
30. Collins, J.J. et al. The measurement of symptoms in children with cancer. J Pain Symptom Manage 2000;19(5):363 77.
31. Andrews, V.C. et al. Mother-adolescent agreement on the symptoms and diagnoses of adolescent depression and conduct disorders. J Am Acad Child Adolesc Psychiatr 1993;32(4):731 8.
32. Angold, A. et al. Parent and child reports of depressive symptoms in children at low and high risk of depression. J Child Psychol Psychiatr 1987;28(6):901 15.
33. Braaten, E.B. et al. Methodological complexities in the diagnosis of major depression in youth: An analysis of mother and youth self-reports. J Child Adolesc Psychopharmacol 2001;11(4):395 407.
34. Challinor, J.M. et al. Somatization, anxiety and depression as measures of health-related quality of life of children/adolescents with cancer. Int J Cancer Suppl 1999;12:52 7.
35. Kovacs, M. Rating scales used to assess depression in school-aged children. Acta Paedopsychiatrica 1981;46:305 15.
36. Kazdin, A. Identifying depression in children: A comparison of alternative selection criteria. J Abnorm Child Psychol 1989;17(4): 437 54.
37. Asarnow, J.R. and Carlson, G.A. Depression Self-Rating Scale: Utility with child psychiatric inpatients. J Consult Clin Psychol 1985; 53(4):491 9.
38. Eason, L.J. et al. The assessment of depression and anxiety in hospitalized pediatric patients. Child Psychiatry Hum Dev 1985; 16(1): 57 64.
39. Kronenberg, Y., Blumensohn, R. and Apter, A. A comparison of different diagnostic tools for childhood depression. Acta Psychiatr Scand 1988;77(2):194 8.
40. Carlson, G.A. and Cantwell, D.P. Unmasking masked depression in children and adolescents. Am J Psychiatry 1980;137(4):445 9.
41. Fundudis, T. et al. Reliability and validity of two self-rating scales in the assessment of childhood depression. Br J Psychiatr Suppl 1991;11:36 40.
42. Fristad, M.A., Emery, B.L. and Beck. S.J. Use and abuse of the Children's Depression Inventory. J Consult Clin Psychol 1997;65(4): 699 702.
43. Heiligenstein, E. and Jacobsen, P.B. Differentiating depression in medically ill children and adolescents. J Am Acad Child Adolesc Psychiatry 1988;27(6):716 9.
44. Poznanski, E.O. et al. Preliminary studies of the reliability and validity of the children's depression rating scale. J Am Acad Child Psychiatr 1984;23(2):191 7.
45. Axelson, D.A. and Birmaher, B. Relation between anxiety and depressive disorders in childhood and adolescence. Depress Anxiety 2001;14(2):67 78.
46. Son, S.E. and Kirchner, J.T. Depression in children and adolescents. Am Fam Physician 2000;62(10):2297 308, 2311 2.
47. Ettinger, A.B. et al. Symptoms of depression and anxiety in pediatric epilepsy patients. Epilepsia 1998;39(6):595 9.
48. Burke, P. et al. Depression and anxiety in pediatric inflammatory bowel disease and cystic fibrosis. J Am Acad Child Adolesc Psychiatry 1989;28(6):948 51.
49. Rao, G.P., Malhotra, Malhotra, S., and Marwaha, R.K. Psychosocial study of leukemic children and their parents. Indian Pediatr 1992; 29(8):985 90.
50. Fitzpatrick, C., Barry, C., and Garvey, C. Psychiatric disorder among boys with Duchenne muscular dystrophy. Dev Med Child Neurol 1986;28(5):589 95.
51. Kashani, J. Hakami, N. Depression in children and adolescents with malignancy. Can J Psychiatr 1982;27(6):474 7.
52. Dunitz, M. et al. Depression in children with cancer. Padiatr Padol 1991;26(6):267 70.
53. Worchel, F.F. et al. Selective responsiveness of chronically ill children to assessments of depression. J Pers Assess 1992;59(3):605 15.
P.405
54. Chao C.C. et al., Psychosocial adjustment among pediatric cancer patients and their parents. Psychiatry Clin Neurosci 2003;57(1): 75 81.
55. Bose, S. et al. Psychologic adjustment of human immunodeficiency virus-infected school-age children. J Dev Behav Pediatr 1994; 15(3):S26 33.
56. Canning, E.H., Canning, R.D., and Boyce, W.T. Depressive symptoms and adaptive style in children with cancer. J Am Acad Child Adolesc Psychiatry 1992;31(6):1120 4.
57. Allen, R., Newman, S.P., and Souhami, R.L. Anxiety and depression in adolescent cancer: Findings in patients and parents at the time of diagnosis. Eur J Cancer 1997;33(8):1250 5.
58. Cavusoglu, H. Depression in children with cancer. J Pediatr Nurs 2001;16(5):380 5.
59. Brem, A.S. et al. Psychosocial characteristics and coping skills in children maintained on chronic dialysis. Pediatr Nephrol, 1988; 2(4):460 5.
60. Noll, R.B. et al. Social, emotional, and behavioral functioning of children with cancer. Pediatrics 1999;103(1):71 8.
61. Michalowski, M. et al. Emotional and behavioral symptoms in children with acute leukemia. Haematologica 2001;86(8):821 6.
62. Kagan, L. Use of denial in adolescents with bone cancer. Health Soc Work 1976;1(4):71 86.
63. Phipps, S. and Srivastava, D.K. Repressive adaptation in children with cancer. Health Psychol 1997;16(6):521 8.
64. Phipps, S. et al. Repressive adaptation in children with cancer: a replication and extension. Health Psychol 2001;20(6):445 51.
65. Grootenhuis, M.A. and Last, B.F. Children with cancer with different survival perspectives: Defensiveness, control strategies, and psychological adjustment. Psychooncology 2001;10(4):305 14.
66. Findling, R.L. et al. Somatic treatment for depressive illnesses in children and adolescents. Child Adolesc Psychiatr Clin N Am 2002; 11(3):555 78, ix.
67. Brent, D.A. et al. Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. J Am Acad Child Adolesc Psychiatry 1998;37(9):906 14.
68. Clarke G., H.H., Lewinsohn P.M., and Andrews J. et al. Cognitive-behavioral group treatments of adolescent depression: prediction of outcome. Behav Ther 1992;23:341 354.
69. Chernoff, R.G., et al. A randomized, controlled trial of a community-based support program for families of children with chronic illness: pediatric outcomes. Arch Pediatr Adolesc Med 2002;156(6):533 9.
70. Nitschke, R., et al. Therapeutic choices made by patients with end-stage cancer. J Pediatr 1982;101(3):471 6.
71. Block, S.D. Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians American Society of Internal Medicine. Ann Intern Med 2000;132(3):209 18.
72. Kastelic, E.A., Labellarte, M.J., and Riddle, M.A. Selective serotonin reuptake inhibitors for children and adolescents. Curr Psychiatry Rep 2000;2(2):117 23.
73. Rushton, J.L., Clark, S.J., and Freed, G.L. Primary care role in the management of childhood depression: A comparison of pediatricians and family physicians. Pediatrics 2000;105(4 Pt 2):957 62.
74. Rushton, J.L., Clark, S.J., and Freed, G.L. Pediatrician and family physician prescription of selective serotonin reuptake inhibitors. Pediatrics 2000;105(6):E82.
75. Emslie, G.J. et al. Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatr 2002;41(10): 1205 15.
76. Keller, M.B. et al. Efficacy of paroxetine in the treatment of adolescent major depression: A randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001;40(7):762 72.
77. Prozac for pediatric use. FDA Consumer 2003;37(2):3.
78. Birmaher, B., Brent, D.A., and Benson, R.S. Summary of the practice parameters for the assessment and treatment of children and adolescents with depressive disorders. American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatr 1998;37(11):1234 8.
79. Alderman, J. et al. Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy. J Am Acad Child Adolesc Psychiatr 1998;37(4):386 94.
80. Armitage, R., Emslie, G., and Rintelmann, J. The effect of fluoxetine on sleep EEG in childhood depression: A preliminary report. Neuropsychopharmacology 1997;17(4):241 5.
81. Waslick, B.D. et al. Open trial of fluoxetine in children and adolescents with dysthymic disorder or double depression. J Affect Disord 1999;56(2 3):227 36.
82. King, R.A. et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatr, 1991; 30(2): p. 179 86.
83. Sood, A., Weller, E., and Weller, R. SSRIs in children and adolescents: Where do we stand? Current Psychiatry 2004.3(3):83 89.
84. Neuropsychopharmacology, A.C.O., Preliminary Report of the Task Force on SSRIs and Suicidal Behavior in Youth, Psychiatry 2004; 31 4.
85. Advisory, F.P.H. Suicidality in Children and Adolescents Being Treated With Antidepressant Medications. United States Food and Drug Administration, 2004. http://www.fda.gov/cder/drug/anti-depressants/SSRIPHA200410.htm.
86. Association, A.P. APA Statement on the FDA's Hearing on Antidepressant Use in Pediatric Patients. Arlington, Virginia. American Psychiatric Association: 2004.
87. Valuck, R.J. et al. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs, 2004;18(15): 1119 32.
88. Jick, H., Kaye, J.A., and Jick, S.S. Antidepressants and the risk of suicidal behaviors. JAMA, 2004;292(3):338 43.
89. Grunebaum, M.F. et al. Antidepressants and suicide risk in the United States, 1985 1999. J Clin Psychiatry 2004;65(11): 1456 62.
90. Olfson, M. et al. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003; 60(10):978 82.
91. March, J. et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004;292(7):807 20.
92. Whittington, C.J. et al. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004; 363(9418):1341 5.
P.406
93. Kye, C.H. et al. A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression. J Am Acad Child Adolesc Psychiatry 1996;35(9):1139 44.
94. Baldessarini, R. Drugs and the treatment of psychiatric disorders. In L.L. Hardman, J.G., Goodman, and Gilman, ed. The Pharmacological Basis of Therapeutics., New York, McGraw-Hill, 1996, p. 431 59.
95. Wamboldt, M.Z., Yancey, A.G., Jr., and Roesler, T.A., Cardiovascular effects of tricyclic antidepressants in childhood asthma: A case series and review. J Child Adolesc Psychopharmacol 1997;7(1):45 64.
96. Popper C.W. E.G. Sudden death and tricyclic antidepressants: Clinical considerations for children. J Child Adolesc Psychopharmacol 1990;1:125 32.
97. Hazell, P. et al. Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev 2002;2:CD002317.
98. Kaplan, C.A. and Hussain, S. Use of drugs in child and adolescent psychiatry. Br J Psychiatr 1995;166(3):291 8.
99. Daly, J.M. and Wilens, T. The use of tricyclic antidepressants in children and adolescents. Pediatr Clin North Am 1998;45(5): 1123 35.
100. Dugas, M, et al. Preliminary observations of the significance of monitoring tricyclic antidepressant plasma levels in the pediatric patient. Ther Drug Monit 1980;2(4):307 14.
101. Challman, T.D. and Lipsky, J.J. Methylphenidate: Its pharmacology and uses. Mayo Clin Proc 2000;75(7):711 21.
102. Fernandez, F. et al. Methylphenidate for depressive disorders in cancer patients. An alternative to standard antidepressants. Psychosomatics 1987;28(9):455 61.
103. Fernandez, F. et al. Effects of methylphenidate in HIV-related depression: A comparative trial with desipramine. Int J Psychiatry Med 1995;25(1):53 67.
104. House A., H.T. Depression in physical illness. Prescribers' Journal 1996;36(4):222 27.
105. Findling, R.L. Open-label treatment of comorbid depression and attentional disorders with co-administration of serotonin reup-take inhibitors and psychostimulants in children, adolescents, and adults: a case series. J Child Adolesc Psychopharmacol, 1996; 6(3):165 75.
106. Kellerman, J. et al. Psychological effects of illness in adolescence. I. Anxiety, self-esteem, and perception of control. J Pediatr 1980; 97(1):126 31.
107. Hart, D. and Bossert, E. Self-reported fears of hospitalized school-age children. J Pediatr Nurs 1994;9(2):83 90.
108. Klein, R., Pine, D.S. Anxiety Disorders. In M. Rutter, L. Hersov, and E. Taylor, ed. Child and Adolescent Psychiatry: Modern Approaches Oxford: Blackwell Scientific Publications. 2002;486 509.
109. Frank, N.C., Blount, R.L., and Brown, R.T. Attributions, coping, and adjustment in children with cancer. J Pediatr Psychol 1997; 22(4):563 76.
110. Jones, S.M., Fiser, D.H., and Livingston, R.L. Behavioral changes in pediatric intensive care units. Am J Dis Child 1992;146(3):375 9.
111. Brown, R.T. et al. Parental psychopathology and children's adjustment to leukemia. J Am Acad Child Adolesc Psychiatr 1993; 32(3):554 61.
112. Moore, J.B. and Mosher, R.B. Adjustment responses of children and their mothers to cancer: Self-care and anxiety. Oncol Nurs Forum 1997;24(3):519 25.
113. Packman, W.L. et al. Psychosocial consequences of bone marrow transplantation in donor and non-donor siblings. J Dev Behav Pediatr 1997;18(4):244 53.
114. Shama, W.I. The experience and preparation of pediatric sibling bone marrow donors. Soc Work Health Care 1998;27(1):89 99.
115. Greenhill, L.L. et al. Assessment issues in treatment research of pediatric anxiety disorders: What is working, what is not working, what is missing, and what needs improvement. Psychopharmacol Bull 1998;34(2):155 64.
116. Ireland, M. and Malgady, R.G. Thematic instrument for measuring death anxiety in children (TIMDAC). J Pediatr Nurs 1999; 14(1):28 37.
117. Carroll, M.K. and Ryan-Wenger, N.A. School-age children's fears, anxiety, and human figure drawings. J Pediatr Health Care 1999;13(1):24 31.
118. Costello, E., Angold, A. Epidemiology, in Anxiety Disorders in Children and Adolescents. J. March. Editor 1995, Guildford: New York. 109 24.
119. Labellarte, M.J. et al. The treatment of anxiety disorders in children and adolescents. Biol Psychiatry 1999;46(11):1567 78.
120. Fukunishi, I. and Kudo, H. Psychiatric problems of pediatric end-stage renal failure. Gen Hosp Psychiatr 1995;17(1):32 6.
121. Thompson, R.J., Jr., Hodges, K., and Hamlett, K.W. A matched comparison of adjustment in children with cystic fibrosis and psychiatrically referred and nonreferred children. J Pediatr Psychol 1990;15(6):745 59.
122. Schowalter, J. The child's reaction to his own terminal illness. In B. Schoenberger, A. Carr, and D. Peretz, ed. Loss and Grief: Psychological management in medical practice. New York: Columbia University Press, 1970.
123. Spinetta, J.J., Rigler, D., and Karon, M. Anxiety in the dying child, Pediatrics 1973;52(6):841 5.
124. Barrera, M.E., Rykov, M.H., and Doyle, S.L. The effects of interactive music therapy on hospitalized children with cancer: A pilot study. Psychooncology 2002;11(5):379 88.
125. Robb, S.L. and Ebberts, A.G. Songwriting and digital video production interventions for pediatric patients undergoing bone marrow transplantation, Part I: An analysis of depression and anxiety levels according to phase of treatment. J Pediatr Oncol Nurs 2003;20(1):2 15.
126. Hollenbeck, A.R. et al. Children with serious illness: Behavioral correlates of separation and isolation. Child Psychiatry Hum Dev 1980;11(1):3 11.
127. Olness, K. and Gardner, G.G. Some guidelines for uses of hypnotherapy in pediatrics. Pediatrics 1978;62(2):228 33.
128. Kohen, D.P. et al. The use of relaxation-mental imagery (self-hypnosis) in the management of 505 pediatric behavioral encounters. J Dev Behav Pediatr 1984;5(1):21 5.
129. Ott, M.J. Imagine the possibilities! Guided imagery with toddlers and pre-schoolers. Pediatr Nurs 1996;22(1):34 8.
130. Zeltzer, L.K. et al. A phase I study on the feasibility and acceptability of an acupuncture/hypnosis intervention for chronic pediatric pain. J Pain Symptom Manage 2002;24(4):437 46.
131. Manassis, K., Childhood anxiety disorders: Lessons from the literature. Can J Psychiatr 2000;45(8):724 30.
132. McCarthy, A.M. et al. Cognitive behavioral pain and anxiety interventions in pediatric oncology centers and bone marrow transplant units. J Pediatr Oncol Nurs 1996;13(1):3 12; discussion 13 4.
P.407
133. Liossi, C. and Hatira, P. Clinical hypnosis versus cognitive behavioral training for pain management with pediatric cancer patients undergoing bone marrow aspirations. Int J Clin Exp Hypn 1999;47(2):104 16.
134. Liossi, C. and Hatira, P. Clinical hypnosis in the alleviation of procedure-related pain in pediatric oncology patients. Int J Clin Exp Hypn 2003;51(1):4 28.
135. Kratochvil, C.J. et al. Pharmacotherapy of childhood anxiety disorders. Curr Psychiatr Rep 2002;4(4):264 9.
136. Yaster, M. et al. The management of opioid and benzodiazepine dependence in infants, children, and adolescents. Pediatrics, 1996; 98(1):135 40.
137. Hughes, J. et al. A prospective study of the adverse effects of midazolam on withdrawal in critically ill children Acta Paediatr 1994;83(11):1194 9.
138. Renaud, J. et al. Use of selective serotonin reuptake inhibitors for the treatment of childhood panic disorder: a pilot study. J Child Adolesc Psychopharmacol 1999;9(2):73 83.
139. Ljungman, G. et al. Midazolam nasal spray reduces procedural anxiety in children. Pediatrics 2000;105(1 Pt 1):73 8.
140. Bentley, R., Cope, J., Jenny, M., Hain, RDW. Use of intranasal/oral midazolam in paediatric palliative care. Archives of Disease in Childhood 2002;86:A76
141. Birmaher, B. et al. Fluoxetine for childhood anxiety disorders. J Am Acad Child Adolesc Psychiatr 1994;33(7):993 9.
142. Dummit, E.S., III et al. Fluoxetine treatment of children with selective mutism: an open trial. J Am Acad Child Adolesc Psychiatry 1996;35(5):615 21.
143. Fairbanks, J.M. et al. Open fluoxetine treatment of mixed anxiety disorders in children and adolescents. J Child Adolesc Psychopharmacol 1997;7(1):17 29.
144. Walkup J.T., L.M., Riddle M.A., Pin D.P., Greenhill, L. Klein, R. Davies, M. Sweeney M., Abikoff H., Hack S., Klee B., McCracken J., Bergman L., Piacentini J., March J., Compton S., Robinson J., O'Hara T., Baker S., Vitiello B., Ritz L., Roper M., Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001;344(17):1279 1285.
145. Birmaher, B. et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 2003;42(4): 415 23.
146. Seligman, L.D. and Ollendick, T.H. Comorbidity of anxiety and depression in children and adolescents: An integrative review. Clin Child Fam Psychol Rev 1998;1(2):125 44.
147. Ryan, N.D. et al. The clinical picture of major depression in children and adolescents. Arch Gen Psychiatry 1987;44(10):854 61.
148. Gurley, D. C.P., Pine D.S., and Brook J. Discriminating depression and anxiety in youth: A role for diagnostic criteria. J Affective Disorders 1996;39:191 200.
149. Wood, A. R. Harrington, and Moore, A. Controlled trial of a brief cognitive-behavioural intervention in adolescent patients with depressive disorders. J Child Psychol Psychiatry 1996;37(6):737 46.
150. Brent, D.A. et al. A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and supportive therapy. Arch Gen Psychiatr 1997;54(9):877 85.
151. Kendall, P.C. Treating anxiety disorders in children: results of a randomized clinical trial. J Consult Clin Psychol 1994;62(1): 100 10.
152. Kendall, P.C. et al. Therapy for youths with anxiety disorders: A second randomized clinical trial. J Consult Clin Psychol 1997; 65(3):366 80.
153. Barrett, P.M., Dadds, M.R., and Rapee, R.M. Family treatment of childhood anxiety: A controlled trial. J Consult Clin Psychol 1996; 64(2):333 42.
154. Parker, G. and Roy, K. Adolescent depression: a review. Aust N Z J Psychiatr 2001;35(5):572 80.
155. Sherry & Jellinece 1996.
156. Meijer et al. 2008
157. Burke, A.L. Palliative care: An update on terminal restlessness . Med J Aust 1997;166(1):39 42.
158. Twycross, R. Symptom control: the problem areas. Palliat Med 1993;7(Suppl 1):1 8.
159. Liptzin B, L.S. An empirical study of delirium subtypes. Br J Psychiatry 1992;161:843 845.
160. Lawlor P.G., Mancini G.B. et al Occurrence, causes, and outcome of delirium in patients with advanced cancer: A prospective study. Arch Intern Med 2000;160(6):786 94.
161. Breitbart, W., Psychiatric aspects of palliative care. In H.G.D. Doyle, N. MacDonald ed. Oxford Textbook of Palliative Medicine, New York: Oxford University Press 1998;p. 933 956.
162. Breitbart, W, C.K., Delirium in the terminally ill. In B.W. Chochinov ed. Handbook of psychiatry in palliative medicine, New York: Oxford University Press 2000, p. 75 90.
163. Bruera, E. et al. Cognitive failure in patients with terminal cancer: A prospective study. J Pain Symptom Manage 1992;7(4):192 5.
164. Maddocks, I. et al. Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone. J Pain Symptom Manage 1996;12(3):182 9.
165. de Stoutz, N.D., Bruera, E., and Suarez-Almazor, M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 1995;10(5):378 84.
166. Bruera, E. et al. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. J Pain Symptom Manage 1995;10(4):287 91.
167. Morita, T. et al. Increased plasma morphine metabolites in terminally ill cancer patients with delirium: an intra-individual comparison. J Pain Symptom Manage 2002;23(2):107 13.
168. Morita, T. et al. Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manage 2001;22(6):997 1006.
169. Inouye, S.K. et al. Clarifying confusion: The confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990;113(12):941 8.
170. Trzepacz, P.B.R. and Greenhouse, J. A symptom rating scale for delirium. Psychiatry Res 1988;23:89 97.
171. Breitbart, W. et al. The Memorial Delirium Assessment Scale. J Pain Symptom Manage 1997;13(3):128 37.
172. Morita, T. et al. Communication Capacity Scale and Agitation Distress Scale to measure the severity of delirium in terminally ill cancer patients: A validation study. Palliat Med 2001;15(3): 197 206.
173. Minagawa, H. et al. Psychiatric morbidity in terminally ill cancer patients. A prospective study. Cancer 1996;78(5):1131 7.
P.408
174. Pereira, J., Hanson, J., and Bruera, E. The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer 1997;79(4):835 42.
175. Meagher, D.J. et al. The use of environmental strategies and psychotropic medication in the management of delirium. Br J Psychiatry 1996;168(4):512 5.
176. Association, A.P. Practice guidelines for the treatment of patients with delirium. Am J Psychiatry 1999;156(suppl):1 20.
177. Adams, F., and Andersson, F.F., Emegency pharmacotherapy of delirium in the critically ill cancer patient. Psychosomatics 1986; 27:33 7.
178. Beuzen, J.N, Wesnes, T.N.K, and Wood A.A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderley volunteers. J psychopharmacol 1999; 13:152 9.
179. De Deyn, P.P. and Katz, I.R. Control of aggression and agitation in patients with dementia: Efficacy and safety of risperidone. Int J Geriatr Psychiatry 2000;15 Suppl 1:S14 22.
180. De Deyn, P.P. et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53(5):946 55.
181. Sipahimalani, A.M.P. Olanzapine in the treatment of delerium. Psychosomatics 1998;39:422 30.
182. Sipahimalani A.S.R. and Masand P., Treatment of delirium with resperidone. Int J Geriatr Psychopharmacol 1997;1:24 6.
183. Conley, R.R. Risperidone side effects. J Clin Psychiatry 2000; 61 (Suppl) 8:20 3.
184. Breitbart, W. et al. A double-blind trial of haloperidol, chlorpromazine and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153(2):231 237.
185. Galloway, K.S. and Yaster, M. Pain and symptom control in terminally ill children. Pediatr Clin North Am 2000;47(3):711 46.
186. Stirling, L.C., Kurowska, A., and Tookman, A. The use of phenobarbitone in the management of agitation and seizures at the end of life. J Pain Symptom Manage 1999;17(5):363 8.
187. Pritchard, J.W, R.B. Phenobarbital, mechanism of action. In M.R.a.M.B. Levy RH, ed. Antiepileptic Drugs, 1995, New York : Raven Press, p. 359 377.
188. Fainsinger, R., Treatment of delirium at the end of life: medical and ethical issues. In B.E. Portenoy R.K., ed. Topics in Palliative care, Oxford: Oxford University Press, 2000, pp.261 277.
189. Back, I. Terminal restlessness in patients with advanced malignant disease. Palliat Med 1992;6:293 298.
190. Bottomley, D.M. and Hanks, G.W. Subcutaneous midazolam infusion in palliative care. J Pain Symptom Manage 1990;5(4):259 61.
191. de Souza, E.J.B. Midazolam in terminal care. Lancet 1998; 1((letter)):67 68.
192. Oliver, D. The use of methotrimeprzine in terminal care. Br J Clin Pract 1985;39:339 340.
193. Power, D. and Kearney M. Management of the final 24 hours. Ir Med J 1992;85(3):93 5.
194. Stiefel, F., Fainsinger, R., and Bruera, E. Acute confusional states in patients with advanced cancer. J Pain Symptom Manage 1992; 7(2):94 8.
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