31 - Complementary and alternative medicine
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 > 29 - Haematological symptoms
29
Haematological symptoms
Erica Mackie
Marie-Louise Millard
Introduction
One of the principles that should underpin good palliative medicine in children, is that investigations and treatment should be used discriminatingly. In deciding what medications to prescribe, or investigations to order, we need to consider whether the net effect will be to the child's benefit.
The decision is often clear-cut. In prescribing morphine, the burden to most patients is small and the potential benefit, very significant. In managing haematological symptoms, however, things are not always as straightforward. For example, anaemia can have a profound impact on the quality of some children's lives, preventing them from socialising through its effect on fatigue, and even contributing to other symptoms such as shortness of breath. On the other hand, embarking on blood transfusion will often mean additional trips to the hospital, and blood tests that would, otherwise, be unnecessary.
The cellular components of blood are synthesized in the bone marrow. Bone marrow failure is a common, late complication of many life-limiting conditions, particularly malignancies. This chapter considers how the symptoms caused by bone marrow failure can be identified, investigated, and treated. The chapter also considers the balance of burden and benefit to patients and how this should influence our approach to such symptoms.
Anaemia
Anaemia is a challenging and not infrequent problem in children with life-limiting conditions and is the most common haematological abnormality identified in those with a malignant disorder. However, the underlying mechanism in the terminal period is usually multifactorial for each child [1]. Equally, with the wide-ranging disorders that are managed in the palliative setting, from a child with a neuro-degenerative disease to one with underlying bone marrow dysfunction, decisions about how to manage anaemia become particularly complex.
Many children who are life-limited, have potentially long periods of good quality living and this may affect decision making for this group, compared to children who are reaching the end-stages of their lives. Indeed, there is a significant number of studies that demonstrate lower survival, and poorer growth and development in children with iron deficiency anaemia, sickle cell disease, and thalassaemia [2, 3, 4, 5]. Relating the contribution of the underlying disease process from the anaemia to poor outcome, however, is not always possible.
Definition
It is generally agreed that in the palliative setting, the absolute haemoglobin concentration is less critical than the symptoms that are experienced by the child or the young person [6, 7]. Normal ranges for haemoglobin levels are documented for reference, however, in Table 29.1.
Symptoms of anaemia
Clearly, many of the symptoms secondary to anaemia are nonspecific and often impossible to separate from other difficulties experienced by the terminally ill young person. Fatigue and dyspnoea, classically associated with anaemia, have rarely been studied in relation to the anaemia of the terminally ill, with little evidence-based guidelines in the literature, to inform management [8]. Many children with long standing
Table 29.1 Normal haematological values | ||||||||||||||||||||||||||||||||||||
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anaemia adapt physiologically to low haemoglobin levels, experiencing few symptoms. Equally, as the child becomes more unwell, adjustment is made to daily activities and consequently, the child may not necessarily complain of new problems. Symptoms that are commonly identified in a child with anaemia include weakness, dyspnoea, and dizziness [6, 9] (Box 29.1).
Causes of anaemia in paediatric palliative care
The underlying mechanisms resulting in anaemia in a life-limited child or young person, depend on the underlying disease process. The common causes during the palliative period are given below (Box 29.2).
Anaemia of chronic disorder
Characteristic features are a relatively mild, and non-progressive anaemia, which is unresponsive to iron therapy. Morphologically, there is a normochromic, normocytic picture or a mild hypochromia. This anaemia presents in response to an underlying chronic inflammatory or malignant process. Typically, a low haemoglobin count will be identified alongside a low reticulocyte count and low circulating levels of iron. Conversely, however, tissue-storage forms of iron, such as ferritin, are high [10]. The pathophysiology of anaemia of chronic disorder can be explained by the inability of the bone marrow to respond adequately to a relative decrease in red cell survival. This occurs because of both impaired iron utilisation, resulting in diminished red cell production, and also a blunted erythropoietin (EPO) response to the developing anaemia. Inadequate response of EPO has been identified in cohorts of adults with anaemia, secondary to both malignancy [11] and acquired immunodeficiency syndrome [12].
Box 29.1 Common symptoms of anaemia in palliative care
Weakness
Fatigue
Dizziness secondary to postural hypotension
Dyspnoea
Anorexia
Tachycardia
Headache
Box 29.2 Common causes of anaemia in palliative care
Anaemia of chronic disease
Inadequate nutrition
Haemorrhage
Bone marrow dysfunction
Chronic renal failure
Inadequate nutrition
Maintaining appropriate nutrition in children with a life-limiting condition, can pose an enormous challenge for both the parents and health professionals. The contributors to malnutrition are many and include poor food intake as well as cancer-cachexia syndrome (Chapter 23, Gastrointestinal symptoms). Normal red cell production can be impaired as a consequence of the deficiencies secondary to malnutrition (Box 29.3).
Bone marrow dysfunction
Bone marrow failure, resulting in pancytopenia, is a common end-stage of both haematological malignancy and solid tumours such as neuroblastoma and rhabdomyosarcoma. Most commonly, this is secondary to marrow infiltration with malignant cells, although bone marrow suppression following palliative chemotherapy must also be considered. A primary bone-marrow disorder, such as aplastic anaemia, can also
Box 29.3 Required for red cell production
Metals
Iron
Manganese
Cobalt
Vitamins
Vitamin B12
Folate
Vitamin C
Vitamin E
Pyridoxine
Thiamine
Riboflavin
Aminoacids
Hormones
Erythropoietin
Androgens
Thyroxine
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cause a pancytopenia. The use of blood products for these children is controversial and is discussed later.
Haemorrhage
Chronic haemorrhage can occur due to bleeding, often occult, from a neoplastic lesion. This is usually characterized by a microcytic, hypochromic blood picture, and associated iron deficiency. It is essential to identify the underlying source, which can include lesions in the gastrointestinal tract, liver, brain, and pathological fractures. Surgery, radiotherapy, or topical adrenaline may be required to achieve local control. Blood loss secondary to gastric irritation or peptic ulceration can be managed with an H2 antagonist, such as ranitidine or other alternatives, including sucralfate, and omeprazole.
Chronic renal failure
There is evidence that correction of anaemia in chronic renal failure enhances both quality of life and functional status [2, 13]. Improved school attendance, physical wellbeing and growth have been reported in children with partially treated anaemia [4, 5]. Improved cardiovascular status has also been documented in children with end-stage renal failure, who have been treated successfully with recombinant human erythropoietin (rHuEPO) [14]. Unfortunately, a prospective, multi-centre, crossover trial comparing outcome data, such as exercise capacity, and cognitive function with partial haematocrit correction is still necessary [2]. However, rHuEPO has been shown to be effective in children with chronic renal failure and dialysis and also in those with failing transplants [5]. Dosage of rHuEPO is comparable to adult requirements [15], with optimal bio-vailability via the subcutaneous route. The Renal Association and the Royal College of Physicians of London published a standards and audit document in August 2002, part of which outlines the standards and recommendations for anaemia in children with chronic renal failure [16] (Box 29.4).
When a child ceases active therapy for end-stage renal failure, the approach towards the management of anaemia also becomes less aggressive. However, it is generally thought that rHuEPO still has a role to play in improving the quality of life for some children during this period.
Management of anaemia in palliative care
In considering the management of any child in the palliative phase, it is essential to consider the overall objectives of interventional therapy. The physical wellbeing of the child must be reviewed alongside the emotional and social needs at any individual point in time. The role of different factors in decision making will vary from one family to another and may include the stage of the child's illness, whereby active interventions become less appropriate as the child reaches the terminal phase. Equally, the proximity to a healthcare facility, such as the hospital or a local hospice, and the skill mix of the community team can potentially influence decisions regarding the type of treatment offered. The family and the child may have lifestyle or cultural commitments that effect the management options. For instance, a Jehovah's Witness would not consider the administration of blood products for religious reasons, or a family may simply live at a distance too great to consider travelling for interventional or time consuming therapy, as their child reaches the end stages of life.
Box 29.4 Anaemia in Children with Chronic Renal Failure (The Renal Association)
Standards
Target haemoglobin is age-specific:
Children under 6 months>or = to 9.5 gms/l
Children aged 6 months to 2 years>or = to 10.0 gms/l
Children over 2 years>or = to 10.5 gms/l
Children should achieve a serum ferritin between 100 800 g/l
Recommendations
Evaluate of anaemia when the haemoglobin falls:
Children under 6 months <10.0 gms/l
Children aged 6 months to 2 years <11.0 gms/l
Children over 2 years <12.0 gms/l
Low ferritin, despite oral supplements, is an indication for intravenous iron therapy. Haemoglobin concentration should be monitored every 1 2 months. Iron status should be monitored every 3 months.
To treat or not to treat?
Whatever the factors involved, it is clear that in the terminal phase of a child's illness, active treatment of anaemia should only be considered if the child is symptomatic or if it is felt that the quality of the child's life will be enhanced. Equally, if therapy is to be considered, an understanding of the underlying cause is essential and clearly, it is inappropriate to initiate investigations, without intent to treat. A child with a life-limiting condition, but who has not yet reached the terminal phase, may for instance, require careful nutritional evaluation, with appropriate dietary supplementation recommended. With chronic blood loss, on the other hand, control of the haemorrhage remains the most important aspect of management,
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with the possibility of blood transfusions reserved for those cases where local therapy has failed.
To transfuse or not to transfuse?
As a child makes the transition from active to palliative management, the role of supportive therapy also shifts. Red cell transfusions during treatment for children receiving chemotherapy, are routinely based on a full blood count result and indeed, even parents will become experts at monitoring the haemoglobin indices, with a corresponding expectation for transfusions at a certain level. The change in emphasis during the palliative phase can, not surprisingly, be a significant challenge for families. The regular blood counts, on which so much previously depended, become a much lower priority in the child's management. Together with the often-controversial debate about the role of the blood transfusion in this new phase, families can feel vulnerable and uncertain about what is now best for their child.
So, what is the evidence that red cell transfusions benefit patients in the palliative phase? The adult literature suggests that blood transfusions can improve quality of life in certain situations [7, 17]. The UK South West Thames Palliative Medicine Collaborative Audit Group assessed 97 patients with malignant disease, over one year, in whom transfusion was felt appropriate. In the three parameters of weakness, dyspnoea and overall well being, a significant proportion demonstrated an improvement following transfusion. This was particularly documented in those presenting with weakness as a symptom [18]. However, a National Hospice Study from North America, examining the use of transfusion in terminal care patients, identified that those in conventional care settings were ten times more likely to be transfused than patients in home-care hospices. As the outcome, in terms of comfort and satisfaction, was similar for both groups, the authors suggested that red cell transfusions tend to be over-prescribed in the terminal phase [19]. Transfusions administered during the last four weeks of life are unlikely to influence the quality of life [8], but when it is felt clinically appropriate, both blood and platelet transfusions can be successfully administered in the home with no complications [20].
Is it ethical to transfuse in the terminal phase?
As with all symptom control in palliative care, an assessment of the risks, burdens and benefits should be made for each intervention. Treatment should only be offered which contributes to the child's overall good and where the clinician feels that it will be physiologically effective. Potential burdens must be identified and discussed with the child and the family and it is the professional's duty to explain the situation, where the burdens and the risks may outweigh the benefit [21].
In the case of a blood transfusion, it may be that life is temporarily prolonged, but at the expense of different and more challenging symptoms emerging. As always, a balance needs to be found where the benefits/risks calculus is in favour of enhancing the child's life. At the beginning of the terminal phase, a blood transfusion may improve symptoms of anaemia, allowing a child to participate in a special trip, or family event (Case Study 1). However, as time progresses, the symptomatic benefit from a transfusion may diminish, with an increasing risk of symptoms developing secondary to progressive disease.
Transfusing red blood cells
When a decision has been made to prescribe a blood transfusion, it is essential that all necessary precautions be taken to maximise the safety of the child. It is not acceptable to consider the transfusion of un-cross matched blood in the palliative setting. A blood sample must be taken from the patient to test red cell compatibility. It is essential that the blood sample is accurately labelled; at least 5% of samples arriving at the laboratory bear a labelling error, leading to delays, and potentially serious complications [22].
Red cell compatibility
The ABO type must be determined and compatibility tested as illustrated in Table 29.2. Ensuring Rhesus compatibility is not mandatory in palliative care, although the child's serum should be tested by the local transfusion department against the red cells to be transfused.
If red cells with the incorrect group are transfused, the child's antibodies will bind to these cells, leading to complement activation and consequent damage to the red cells. Released haemoglobin may lead directly to acute renal failure, whilst cell membrane fragments may activate the coagulation pathway, causing disseminated intra-vascular coagulation. An error such as this, could be disastrous and is clearly avoidable.
Table 29.2 To demonstrate the ABO blood groups and compatible donor blood groups | |||||||||||||||
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Box 29.5 Signs and symptoms of an acute haemolytic transfusion reaction
Feeling uncomfortable' or agitated
Flushed
Pain in abdomen, flank, chest or infusion site
Fever
Hypotension
Generalized oozing from wounds
[23] If incorrect red cells are administered by mistake, there is an approximately 1 in 3 chance of ABO incompatibility. The reaction is most severe if Group A cells are received by a Group O child [22].
Management of transfusion reactions
Prevention, with close attention to all safety measures must be the most important aspect in the management of any potential transfusion reaction. The child should, if possible in the palliative setting, be observed for at least the first fifteen minutes of a blood transfusion. Both allergic and acute haemolytic reactions can occur within minutes of initiating the transfusion. Whereas an allergic reaction is usually characterised by pruritis and urticaria, the symptoms of an acute haemolytic reaction are more diverse (Box 29.5). If the latter is suspected, the blood transfusion must be stopped immediately, the blood returned to the blood bank, along with appropriate blood samples from the child. If this diagnosis or possible bacterial contamination is confirmed, treatment must be considered that is relevant and ethical for the child's situation.
In the case of an allergic reaction, it is usually sufficient to slow the transfusion and administer an antihistamine. When a child has previously experienced an allergic reaction, an anti-histamine such as oral chlorpheniramine (chlorphenamine) should be given thirty minutes prior to the transfusion (Box 29.6).
Anaphylaxis is extraordinarily rare, but should be managed in the usual way with fluid boluses, oxygen, and appropriate medication, dependant on where the transfusion is being delivered. Adrenaline, hydrocortisone, and chlorpheniramine (chlorphenamine) should however, be available even in the home or hospice setting (Box 29.7).
Safety measures
Labelling
Along with the accurate labelling of the initial blood sample, the UK Blood Transfusion and Tissue Transplantation Guidelines outline the labelling required for each unit of red blood cells. This includes the ABO group, the date of collection and expiry date, the unique donation number, and the details of the type of blood product. In addition to the careful scrutiny of this documentation, the compatibility label must be checked, together with a general inspection of the blood pack for signs of any damage [23].
Box 29.6 Dosage of drugs commonly used in the management of transfusion reactions
Chlorpheniramine
|
Given 30 min prior to transfusion
|
Must be given slowly over at least 1 min
Hydrocortisone
4 mg/kg intravenously
Adrenaline
| |||||||||
Medicines for Children 2003 Royal College of Paediatrics and Child Health
Box 29.7 Doses of tranexamic acid [35]
|
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Infusion procedure
Due to the risk of bacterial proliferation, the red cells should only be removed from the refrigerator when the unit is ready to be checked and transfused. The whole procedure, from start to completion of the transfusion, should take no longer than four hours. If for some reason the transfusion is delayed by more than 30 min, the unit of blood must be returned to the blood bank, and labelled with this detail.
Case
Dan was a 6-year old boy who relapsed 16 months after completing treatment for a Stage IV neuroblastoma. Apart from a short history of leg pain and a recent nosebleed, he had been exceptionally well and leading a normal life. Investigation revealed distant relapse, with widespread bone metastases and neuroblastoma infiltration of the bone marrow. A full blood count confirmed bone marrow involvement, with a Hb of 8.1 gm/dl, WCC of 3.2 109/l, with neutrophils of 1.1 109/l, and a platelet count of 45 109 /l. After discussions with Dan and his parents, it was accepted that no further curative therapy was available. A decision was, therefore, made to proceed to symptom control alone, enabling Dan to return to school and enjoy some time at home.
Over the following month, Dan became increasingly tired and the family were concerned that he would not manage the long awaited trip to see his favourite football team at their home ground. A haemoglobin count at this time was 5.8 gm/dl, and after careful discussion with the family, a single blood transfusion was arranged at Dan's local hospital.
Dan achieved a good qualitative response and the family had a memorable weekend away together. Subsequently, Dan deteriorated quickly, requiring increasing analgesia for bone pain. It was felt at this stage, that a further blood transfusion would not be helpful, as new symptoms were emerging, the procedure would be interventional and take Dan away from his home. Dan died peacefully amidst his family several weeks later.
Thrombocytopenia
For a small number of children, in particular those with malignant disease, symptoms, secondary to a low platelet count, may warrant intervention.
Thrombocytopenia is defined as a platelet count 150 109/l [24]. Symptoms are unlikely to occur until the count is 50 109/l and the risk of bruising and spontaneous bleeding increases significantly only with platelets 20 109/l. Children, most likely to develop low platelets, are those with marrow infiltration (i.e. malignancy or storage diseases). Less commonly, platelet consumption secondary to hypersplenism or disseminated intra-vascular coagulation (DIC) may occur.
Symptoms and signs of thrombocytopenia include petechiae, bruising and bleeding, principally from mucosal surfaces.
Management
In the palliative phase, thrombocytopenia requires no treatment unless symptomatic. In the event of significant bruising or bleeding, intervention may be considered, that is: platelet transfusion or medication. The threshold for intervention will vary between patients, but episodes of bleeding such as haemoptysis or epistaxis, usually warrant treatment.
If platelet transfusion is considered, the risks associated with transfusion and the need for the patient, in some cases, to attend hospital must be weighed up against the possible benefits [20]. The decision to transfuse will also depend upon the child's overall condition and degree of activity. In the event of platelets being given, standard transfusion guidelines still apply (see above). The lifespan of transfused platelets is only a few days and a commitment to maintaining platelets can mean frequent transfusions.
Oozing and minor haemorrhage
Oozing and bleeding may also occur in the presence of normal platelet numbers, as a result of dysfunctional platelets or the influence of some medications such as aspirin.
Visible bleeding can be very distressing for the patient and the family and should be vigorously treated, if possible.
Unfortunately, there are few therapeutic options available for the management of acute bleeding in a palliative care context. Essentially, there are, generally, three means by which bleeding can be controlled: by impeding vascular flow to the area, by increasing the effectiveness of platelets, or by increasing the effectiveness of the coagulation cascade. If the bleeding point is easily accessible, as in epistaxis, local vasospasm may be induced using cautery, if the patient is stable enough for an otorhinolaryngology opinion. Packing the nose with an alginate dressing such as Sorbisan, or with gauze soaked in adrenaline may achieve the same object.
Platelet function may be compromised by metabolic disturbances such as uraemia. Bleeding is particularly likely if it was a significant feature at diagnosis, for example often in M3 promyelocytic leukaemia. It is not known whether a megakaryocyte stem-cell defect may arise in children who have been heavily treated for other forms of relapsed leukaemia, either as a result of the disease or the effect of myelotoxic drugs. Certainly, distressing bleeding during the terminal phase appears to be more common in this group of patients. Functional platelets may be transfused. In the presence of normal numbers of platelets, platelet function may, in principle be improved by the use of etamsylate. In practice, however, it seems not to help [25, 26].
Tranexamic acid (TA) is an antifibrinolytic agent, which helps to stabilize clots. It can be used to stop bleeding from
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mucosal surfaces or ulcerated, oozing lesions [24, 27, 28]. TA comes in oral and i.v. forms and can also be administered topically, as a solution of the i.v. preparation. Treatment should start with the onset of bleeding and be continued for a few days after bleeding has stopped. Evidence to support its use prophylactically is lacking.
More occult haemorrhage, such as intracranial bleeding, should usually be managed symptomatically. Seizures (see also Chapter 26, Neurological and neuromuscular symptoms) and pain (see also Chapter 21, Pain) are the most common symptoms.
Management of terminal haemorrhage
Catastrophic haemorrhage can be a terrifying event for the child, the family and the health professionals. Uncontrollable bleeding, usually, occurs from the site of a malignancy and commonly presents as a haematemesis, haemoptysis, or erosion of the tumour into a major artery, such as the carotid. In the terminal phase, it is essential to maintain a calm and reassuring environment for the child. Death can occur within minutes and it is more important to remain with the child, than leave the patient in search of medication, or the telephone. Anticipating the possibility of a terminal bleed can enable helpful preparation. Dark sheets and towels will mask the colour and quantity of blood and should be readily accessible. Symptom management must focus on controlling the fear experienced by the child. As time is usually limited and the situation potentially dramatic, it is essential to ensure that the necessary medication, syringes and clearly written prescriptions are readily available in the home. For some families, it can be appropriate to draw up a syringe with the correct drug dosage in advance. Distress in these situations is most effectively managed with either an analgesic or sedative drug, such as diamorphine, or midazolam [24, 29, 30, 31] (Box 29.8).
Thrombosis
Deep vein thrombosis is uncommon in the paediatric palliative setting. However, it is most likely to occur secondary to tumour mass effects, particularly in the pelvis, as a paraneo-plastic phenomenon, or following prolonged immobilization or inactivity.
The symptoms associated with thrombosis can make a significant adverse impact on the quality of a child's life. Deep vein thrombosis of the calf can cause severe pain and immobility and, of course, carries the risk of pulmonary embolism. This, in turn, can cause pain, shortness of breath, and frightening haemoptysis. Heparin not only reduces the risk of pulmonary embolism, but also is, probably, analgesic because of its effect on the surface of the clot and its contact with the sensitive vascular endothelium. There is, therefore, a good case for treating thrombosis, should it occur.
Box 29.8 Management of terminal bleeding
Maintain a calm and reassuring environment
Use dark sheets and towels
Prescribe the following medication in advance, to be given subcutaneously (or, if appropriate, buccally):
Midazolam
|
Diamorphine
|
On the other hand, traditional approaches to the management of thrombosis have required numerous blood tests, which should, if possible, be avoided in the palliative phase. Although full anticoagulation with intravenous heparin and warfarin remains an option, it is likely to be undesirable in this patient group. However, the advent of low molecular weight heparin (LMWH) has removed the need for repeated monitoring of drug levels and so presents a real alternative in the management of clot related symptoms such as swelling and pain [32, 33, 34]. (Case below).
LMWH is administered subcutaneously, once a day and in older children and young adults, no drug level monitoring is required [35]. In younger, non-palliative children, some monitoring is currently undertaken.
Case
A 15-year-old boy known to have an extensive pelvic tumour, presented with swelling, tenderness and bluish discolouration of the thigh of the right leg. Imaging revealed the presence of a deep vein thrombosis. In combination with appropriate levels of analgesia, subcutaneous low-molecular weight heparin was commenced. Within 3 days, there was significant reduction in swelling and tenderness, so allowing improved mobility during the last 2 weeks of this young man's life.
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Summary
The management of symptomatic anaemia, thrombocytopenia, haemorrhage, and thrombosis in the palliative phase, illustrate very well, the challenging decisions that face professionals working with dying children. On the one hand, modern medical interventions have the capacity to relieve some of the symptoms haematological abnormalities can cause. On the other, the interventions themselves carry morbidity and can cause not only symptoms related to physical reactions, but also often emotional and psychological ones related to otherwise avoidable hospital attendance.
The best clinical decision can only be made by considering the needs of the individual child and the family, giving appropriate weight to the risks of giving, and those of withholding an intervention, both physical and otherwise. In this respect, management of haematological symptoms is typical of thoughtful and skilled childhood palliative care in general.
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