Oxford Handbook of Palliative Care (2 edn)
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Anaemia in chronic disorders
Anaemia is defined as a haemoglobin concentration in adults of less than 13.0g/dL in men and 11.5g/dL in women. Anaemia occurs commonly in chronic renal disease, endocrine diseases and connective tissue disorders.In the latter, various factors may contribute and commonly more than one is present. It is also a common problem, occurring in over 50% of patients with solid tumours and in most patients with haematological malignancies such as multiple myeloma and lymphoma.
Symptoms caused by anaemia include:
Fatigue
Weakness
Breathlessness on exertion
Impaired concentration
Chest pain
Exacerbation of congestive cardiac failure
Low mood
Loss of libido
Anorexia
There are no specific criteria for the functional assessment of anaemia. However, randomized controlled trials of the management of anaemia in malignancy have used validated tools in assessing its effect on quality of life (QOL), e.g.:
Cancer Linear Analogue Scale (CLAS)
Functional Assessment of Cancer Therapy—Anaemia (FACT—An)
Causes of anaemia
Reduced red cell production due to bone marrow infiltration:
multiple myeloma
prostate cancer
breast cancer
leukaemia
Chemotherapy-induced bone marrow suppression
Anaemia of chronic disease related to malignancy
Malnutrition/malabsorption, e.g. post-gastrectomy:
vitamin B12 deficiency
folate deficiency
iron deficiency
Blood loss:
gastrointestinal
haematuria
Chronic renal failure
Reduced red cell survival/haemolysis:
autoimmune haemolysis—lymphoproliferative disorders
physical haemolysis—microangiopathic haemolytic anaemia (MAHA) in some adenocarcinomas
Anaemia of chronic disorder related to malignancy—a combination of effects:
suppressed erythropoietin production
impaired transferrin production
shortened red cell survival
Management of anaemia (
see Table 6l.1)
Investigate cause of anaemia where appropriate
Diagnostic indicators
Reduced marrow production/bone marrow failure:
full blood count—pancytopenia and reduced reticulocytes
bone marrow examination—may show infiltration by non-haematological cells, e.g. prostatic or breast carcinoma, or hypocellular marrow post-chemotherapy
Bleeding:
clinical—haematuria, melaena
acute—blood count and film: normochromic, normocytic anaemia, reticulocytosis and polychromasia
chronic—iron deficiency anaemia
Malabsorption/malnutrition:
low serum vitamin B12
reduced serum or red cell folate
reduced ferritin
Haemolysis:
blood film: polychromasia; autoimmune—spherocytes; MAHA—red cell fragments (schistocytes); reticulocytosis
autoimmune—positive direct Coombs test
bilirubin—raised
| Iron deficiency anaemia | Anaemia of chronic disease | |
|---|---|---|
Blood film | Hypochromic microcytic | Normochromic or hypochromic |
Red cell distribution width (RDW) | Increased | Microcytic ± Normal |
Total iron-binding capacity (TIBC) | High | Normal/low |
Plasma iron | Low | Low |
Serum ferritin | Low | Normal/raised |
| Iron deficiency anaemia | Anaemia of chronic disease | |
|---|---|---|
Blood film | Hypochromic microcytic | Normochromic or hypochromic |
Red cell distribution width (RDW) | Increased | Microcytic ± Normal |
Total iron-binding capacity (TIBC) | High | Normal/low |
Plasma iron | Low | Low |
Serum ferritin | Low | Normal/raised |
N.B. The two causes can coexist.
Decrease bleeding risk
Consider discontinuation of drugs that may increase risk of bleeding, e.g.:
aspirin
NSAIDs
anticoagulants
steroids
Consider gastroprotection using:
proton pump inhibitors
H2-receptor antagonists
prostaglandin analogues, e.g. misoprostol
Give vitamin K in liver disease-related coagulopathies as evidenced by prolonged prothrombin time (PT). Vitamin K tablets (menadiol phosphate) 10mg p.o. daily for 1 week, then recheck PT
Give tranexamic acid (antifibrinolytic agent) 1g p.o. t.d.s. or q.d.s. for mucosal bleeding. Tranexamic acid can also be given topically and as a mouthwash. (Use with care in bleeding from the bladder or prostate as clot formation is enhanced and subsequent urinary retention may become a problem.) Etamsylate may also be useful
Replace haematinic deficiencies
Iron deficiency:
ferrous sulphate 200mg b.d. or t.d.s. (or Ferrograd 325mg p.o. daily) before food for 3 months
Folate deficiency:
folic acid 5mg o.d.
Vitamin B12 deficiency:
hydroxycobalamin 1000mcg IM every three months
Blood transfusion
Patients who are becoming terminally ill may receive blood transfusions inappropriately. The decision to transfuse should not be made on the basis of one haemoglobin result alone, but in the context of symptoms attributable to anaemia which are adversely affecting quality of life. It is important to document the clinical effect of the transfusion which will help in discussing the merits or otherwise of further transfusions. Blood transfusion helps about 75% of patients in terms of well-being, strength and breathlessness.
Since 1998, all red cells have been leuco-depleted, therefore an in-line blood filter is not now required. One unit of leuco-depleted packed red cells (approximately 300mL) results in a rise in haemoglobin of 1g/dL
The aim should be to transfuse up to 11–12g/dL but this will vary according to the individual clinical situation
Patients at risk of pulmonary oedema should have furosemide cover (20mg p.o. with alternate units)
Patients should be told that the beneficial effects may not be apparent for a day or two post-transfusion
Indications for blood transfusion in patients with palliative care needs
Haemoglobin of less than 9g/dL (patients may benefit from transfusion at higher levels)
Prognosis longer than two weeks
Reasonable performance status (i.e. not predominantly bedbound) (ECOG >2)
Presence of at least two of the following symptoms in association with Hb < 9g/dL:
breathlessness on exertion
weakness
angina
postural hypotension
worsening cardiac failure
worsening fatigue
Blood transfusion reactions
Acute life-threatening transfusion reactions are very rare; however, new symptoms or signs that occur during a transfusion must be taken seriously as they may herald a serious reaction. As it may not be possible to identify the cause of a severe reaction immediately, initial supportive management should generally cover all possible causes. These include:
Acute haemolytic transfusion reaction
Infusion of a bacterially contaminated unit
Severe allergic reaction or anaphylaxis
Fluid overload
Transfusion-related acute lung injury (TRALI)
Febrile non-haemolytic transfusion reaction
Acute haemolytic transfusion reaction
Incompatible Group A or B transfused red cells react with the patient’s own anti-A or B antibodies. This results in acute renal failure, and can cause disseminated intravascular coagulation (DIC) The reaction can occur after only a few ml of blood have been transfused.
Symptoms: acute onset of pain at venepuncture site, loins, chest
Signs: fever, hypotension, tachycardia, oozing from venepuncture sites
A similar picture is seen with the transfusion of bacterially contaminated red cells
Action: If a severe acute reaction is suspected:
stop the transfusion, keep the IV line open with sodium chloride 0.9% infusion
monitor temperature, heart rate, BP, respiratory rate, urine output
recheck the patient’s identification, the blood unit and documentation
inform the blood bank
further management will depend on the patient’s developing clinical picture
Infusion of bacterially contaminated unit
This may cause haemolysis or clots within the blood bag. For this reason, visual inspection of every unit is part of the pre-transfusion check. Symptoms and signs are identical to acute haemolytic transfusion reaction. Treat as for acute haemolytic transfusion reaction in addition to:
taking blood cultures
sending the blood unit to microbiology
Major allergic reactions
Rare but life-threatening complications usually occur in the early part of a transfusion. These complications are more common with plasma-containing blood components, e.g. fresh-frozen plasma (FFP) or platelets.
Symptoms: chest pain, breathlessness, nausea and abdominal pain
Signs: hypotension, bronchospasm, periorbital and laryngeal oedema, vomiting, urticaria
Action:
stop transfusion
high concentration O2
chlorphenamine 10–20mg IV over 1–2 minutes
Hydrocortisone 100–200mg IV
Adrenaline 0.5–1mg (0.5–1mL of 1 in 1000) IM
Salbutamol 2.5–5mg by nebulizer
Maintain IV access
Fluid overload
More common in patients with a history of heart or renal disease, but any patient with advanced malignancy is susceptible. In these patients, each red cell unit should be given over 3–4h and a maximum of two units given per day. Clinical signs to be aware of:
Symptoms: Breathlessness with basal crepitations
Signs: BP may be raised initially, tachycardia, raised jugular venous pressure (JVP) may be present
Action:
stop transfusion
high concentration O2
furosemide 40mg IV
Transfusion-related acute lung injury (TRALI)
Usually caused by antibodies in donor’s plasma that react strongly with the patient’s leucocytes.
Symptoms: Rapid onset of breathlessness and dry cough
Signs: Chest X-ray shows bilateral infiltrates—‘white-out’
Action:
stop transfusion
give 100% O2
seek expert advice and treat as adult respiratory distress syndrome (ARDS)
Febrile non-haemolytic transfusion reaction
Affects 1–2% of patients.
Symptoms and signs: A rise in temperature <1.5°C from the baseline or an urticarial rash +/- rigors usually occurs towards the end of a transfusion or up to two hours after it is finished; BP and heart rate remain stable
Action:
treat with paracetamol
give chlorphenamine 10mg p.o. or IV for rash
continue transfusion at a slower rate
observe for any deterioration
Iron overload is not often a concern in palliative care but if 50–75 units of red cells have been given, haemosiderosis may develop causing heart and liver dysfunction or failure of pancreatic endocrine function.
Contraindications to blood transfusion
Patient refusal
No symptomatic benefit from previous transfusion
Patient moribund with life expectancy of days
Erythropoietin
This is a hormone made by the kidney. It stimulates the production of red blood cells and is licensed for anaemia of chronic renal failure and for patients undergoing chemotherapy who are receiving platinum-containing chemotherapy (NICE guidance)
It may also be effective in improving the chronic anaemia of cancer
An injection of 150–300 units/kg SC three times a week for 4–6 weeks increases the Hb significantly in 50–60% of patients with cancer. The patients most likely to benefit include those with a low erythropoietin concentration, adequate bone marrow reserve and those who have an initial good response (i.e. an increase in Hb of >1g/dL within four weeks of starting treatment)
The maximum benefit is achieved after about two months, whichmay be a factor limiting its usefulness in palliative care patients where prognosis is short
Patients should be given iron supplements during erythropoietin therapy to maximize the response
The haemoglobin level must be monitored weekly to ensure this does not increase above 12.0g/dL, because of the thrombotic risk
Complications
Hypertension
Thrombosis
Iron deficiency, if not on iron supplements
Screening of donated blood products is inevitably becoming ever more stringent and blood transfusion may become justified only for the most needy. Erythropoietin may therefore become more commonly used. It is already used where appropriate for Jehovah’s Witnesses.
Bleeding and haemorrhage
Bleeding occurs in about 20% of patients with advanced cancer and may contribute to death in 5%. Bleeding may be directly related to the cancer itself, e.g. local bleeding from fungating tumours, or indirectly related, e.g. peptic ulceration or nose bleeds secondary to treatment with NSAIDs or thrombocytopenia, respectively.
A systemic deterioration in a patient’s condition may be mirrored by a decline in the haematological profile.
Obvious bleeding
Oral mucosa or nose
Gums
Nasopharynx
Haemoptysis
Haematemesis
Skin/muscle
Hidden bleeding
Gastrointestinal—melaena, anaemia, (raised urea may be noted)
Pulmonary—worsening breathlessness, pleural effusion
Urogenital—macroscopic or microscopic haematuria
Cerebral—headache, visual disturbance, change in neurology
Gynaecological—vaginal bleeding
General management of bleeding
Where possible and when appropriate, attempt to correct haemostatic factors that contribute to a bleeding tendency.
The sight of blood can have a profound effect on patients and their carers. Relatives and patients who have coped calmly with a full range of demanding symptoms may become very distressed in the event of a bleed. If that bleed is significant there are few who are stoic enough not to be frightened. Explanation of what is happening, or what happened and the opportunity for fears to be expressed and listened tocan be a very important part of professional supportive care in such circumstances.
Factors that contribute to bleeding
Platelets
Thrombocytopenia due to:
Reduced marrow production:
marrow infiltration
myelosuppression following chemotherapy
Increased consumption/utilization:
disseminated intravascular coagulation (DIC)
autoimmune
Splenic pooling:
hypersplenism
Abnormal function
As seen in:
Acute myeloid leukaemia
Myelodysplasia
Myeloproliferative disorders
Paraproteinaemias, e.g. multiple myeloma
Treatment with NSAIDs, aspirin
Renal failure
Coagulation factors
High-level expression of tissue factor leading to:
Extrinsic pathway activation
Thrombin generation
Consumption of clotting factors
DIC
Metastatic liver disease
Results in:
Reduced synthesis of vitamin K-dependent factors
DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
Acute DIC is uncommon and presents as a mixture of thrombosis and bleeding. The skin may develop petechiae and purpura, and gangrene may occur in areas of end circulation such as the digits, nose and ear lobes. Bleeding may occur in areas of trauma such as at venepuncture sites or as haematuria in the presence of a catheter. Treatment includes platelet infusions, FFP and cryoprecipitate.
Chronic DIC (as measured by laboratory tests) is more common and may be asymptomatic but thrombotic symptoms of DVT, PE or migratory thrombophlebitis may occur. Treatment is usually with heparin (low molecular weight).
Laboratory investigations for DIC
D-dimers—are more specific than fibrin degradation products (FDPs). A significant increase in D-dimers + prolonged PT, reduced fibrinogen, and thrombocytopenia are necessary for diagnosis (D-dimers are also increased in infection, impaired renal function, post-transfusion, malignancy and with increasing age)
Prothrombin time (PT)—less sensitive, usually prolonged in acute DIC, but may be normal in chronic DIC
Activated partial thromboplastin time (APTT)—less useful, as may be normal or shortened in chronic DIC
Platelets—reduced or falling count found in acute DIC
Blood film—may show red cell fragments (schistocytes)
THROMBOCYTOPENIA
Spontaneous bleeding due to thrombocytopenia is rare if the platelet count is >20 × 109/L but traumatic bleeding is problematic if the platelet count is less than 40 × 109/L. Sepsis will increase the bleeding tendency. If platelet function is abnormal, bleeding may occur at higher counts.
A platelet transfusion may be considered if there is bleeding which is distressing. It will only raise the platelet count for a few days. This treatment should not be given routinely if there is no evidence of bleeding and the count is greater than 10 × 109/L. If the platelet count is less than 50 × 109/L and the patient is bleeding, platelets should be given
A pool of platelets is derived from four units of donated blood and is approximately 300mL
Platelets must be kept at room temperature and transfused within 30min, using a sterile administration set or a platelet infusion set. Never use an in-line filter
The donor should be ABO compatible with the patient
Occasional reactions with rigors and fever may occur. These respond to chlorphenamine 10mg IV and hydrocortisone 100mg IV
It is important to anticipate which patients are likely to require platelet transfusions and to decide the appropriateness prior to a crisis. The whole team should be involved in decisions concerning ongoing regular prophylactic transfusions and their withdrawal. With platelet counts of 10–20 × 109/L the risk of a major bleed is small, severe bleeding occurring mostly with counts less than 5 × 109/L.
Tranexamic acid (inhibits fibrinolysis) can be used to control mucosal bleeding due to thrombocytopenia:
1g orally t.d.s. or slow IV injection
Mouthwash 1g every six hours for oral bleeding
Topical tranexamic acid for superficial fungating tumours
On average, it takes two days of therapy to slow down bleeding and four days for bleeding to stop.
Blood products
These are less commonly used in the palliative care setting and close liaison with the haematology department is essential when considering administration. The list below outlines some products and their indications.
Indications for blood products
Fresh-frozen plasma (FFP)
Disseminated intravascular coagulation
Rapid correction of warfarin overdose
Liver disease
Coagulopathy due to massive blood loss
Cryoprecipitate
In DIC when fibrinogen <1.0g/L
For bleeding in cases of dysfibrinogenaemia
Bleeding directly related to cancer
Radiotherapy should be considered in patients with local bleeding caused by cancer, e.g. ulcerating skin tumours, lung cancer causing haemoptysis, gynaecological cancer causing vaginal bleeding and bladder/prostate cancer causing haematuria.
Specific situations
Nose bleeds
Most nose bleeds are venous, and when arising from the anterior septum can often be stopped by pressure
Silver nitrate caustic pencil can be applied to the bleeding point. The nose can be packed with calcium alginate rope (e.g. Kaltostat) or with ribbon gauze soaked in adrenaline (epinephrine 1:1000 1mg in 1mL).If the bleeding is more posterior, and continues into the nasopharynx, a Merocel nasal tampon may need to be inserted for 36 hours with antibiotic cover, or the nose packed with gauze impregnated with bismuth iodoform paraffin paste (BIPP) for three days. These should be performed by a clinician with previous experience, preferably by an ENT surgeon
The ENT department may need to be contacted for further management with a balloon catheter or cauterization under local anaesthetic
Surface bleeding
The bleeding from tumour masses may respond well to radiotherapy. Other measures include the following:
Physical
Gauze applied with pressure for 10 min soaked in adrenaline (epinephrine) 1:1000 1mg in 1mL or tranexamic acid 500mg in 5mL:
silver nitrate sticks applied to bleeding points
haemostatic dressings, i.e. alginate, e.g. Kaltostat, Sorbsan
Drugs
Topical:
sucralfate paste 2g (two 1g tablets crushed in 5mL KY jelly)
sucralfate suspension 2g in 10mL b.d. for mouth and rectum
tranexamic acid 5g in 50mL warm water b.d. for rectal bleeding
1% alum solution for bladder
Systemic:
antifibrinolytic, e.g. tranexamic acid 1.5g p.o. stat and 0.5–1g b.d.–t.d.s. p.o. or slow IV 0.5–1g t.d.s. Do not use if DIC suspected
haemostatic, e.g. etamsylate 500mg q.d.s. (restores platelet adhesiveness)
Haemoptysis
One-third of patients with lung cancer develop haemoptysis, although the incidence of acute fatal bleeds is only 3%, of which some occur without warning
The patient is more likely to die from suffocation secondary to the bleed than from the bleed itself. Bleeding due to cancer, is most commonly from a primary carcinoma of the bronchus. A massive haemoptysis is usually from a squamous-cell lung tumour lying centrally or causing cavitation. Metastases from carcinoma of the breast, colorectum, kidney and melanoma may also cause haemoptysis
Infection in the chest and pulmonary emboli are other causes of haemoptysis
A generalised clotting deficiency seen with thrombocytopaenia, hepatic insufficiency or warfarin therapy can also be contributory factors
Treatments for non-acute haemorrhage include oncological, systemic and local measures. If radiotherapy is inappropriate, coagulation should be enhanced with oral tranexamic acid 1g t.d.s. The risks of encouraging hypercoagulation need to be considered carefully in patients with a history of a stroke or ischaemic heart disease.
Erosion of a major artery can cause acute haemorrhage, which may be a rapidly terminal event. However, it may be possible to anticipate such an occurrence and appropriate medication and a red/green/blue towel to reduce the visual impact should be readily available. Relatives or others who witness such an event will need a great deal of support. If the haemoptysis is not immediately fatal, the aim of treatment is sedation of a shocked, frightened patient.
It may be appropriate to have emergency medication in the home to sedate the acutely bleeding patient, although such a strategy can only be arrived at after discussion with the family, carers and the patient’s GP, and needs to be documented clearly.
Assessment
Consider the commonest causes:
Tumour bleeding
Clotting disorders
Infection
Pulmonary embolism
Treatment
Treat any evidence or signs suggestive of infection
Consider radiotherapy referral (not if multiple lung metastases) or brachytherapy, where the radiation sources are placed close to the tumour within the lungs
Consider and treat other systemic causes of bleeding ( see Chapter 15)
Perform blood tests for clotting screen and platelets
Give tranexamic acid 1g t.d.s. p.o.:
stop if no effect after 1 week
continue for 1 week after bleeding has stopped, then discontinue
continue long term (500mg t.d.s.) only if bleeding recurs and it responds to a second course of treatment
Small bleeds can herald a larger massive haemorrhage; consider siting an IV cannula to administer emergency drugs.
Haematemesis
The incidence is 2% in patients with cancer and may be either directly associated with the cancer and/or secondary to gastroduodenal irritants such as NSAIDs, or aspirin. The management includes stopping NSAIDs if possible or changing to celecoxib (reduced effect on platelets) and adding a proton pump inhibitor or H2-receptor antagonist; a gastroprotective agent such as sucralfate may also be useful.
If the patient’s condition is not stable, and he/she has a history of major haemorrhage or ongoing bleeding:
Consider appropriateness of transfer to an acute medical/endoscopy unit
Site an IV cannula to anticipate the need for emergency drugs
Treat anxiety or distress as needed:
midazolam 2–5mg initially by slow IV titration (10mg diluted to 10mL with sodium chloride 0.9%)
If no IV access, midazolam 5–10mg SC (give IM if shocked or vasoconstricted)
Rectal bleeding
This may be associated with local tumour (radiotherapy may be the treatment of choice to stop the bleeding) and/or radiotherapy. Bloody diarrhoea may occur acutely with pelvic radiotherapy which causes acute inflammation of the rectosigmoid mucosa, but this should be self-limiting. A predsol retention enema 20mg in 100mL o.d.–b.d. or prednisolone 5mg and sucralfate 3g in 15mL b.d. may help.
Bleeding from chronic ischaemic radiation proctitis may respond to tranexamic acid, etamsylate or sucralfate suspension given rectally.
Haematuria ( see Chapter 6g Genitourinary problems)
This may occur with carcinoma of the bladder or prostate or as a result of chronic radiation cystitis. Urinary infection will aggravate the situation. Tranexamic acid or etamsylate may be useful, although there is the risk of clot formation and urinary retention. Alum 50mL of a 1% solution can be useful if retained in the bladder via a catheter for 1 hour.
Massive terminal haemorrhage
Massive terminal haemorrhage occurs as a result of a major arterial haemorrhage and usually causes death in minutes. For patients who have undergone all possible treatment options, this inevitably terminal event should be treated palliatively, the main aim being comfort for the patient and support for the family.
It is usually associated with tumour erosion into the aorta or into the pulmonary artery (causing haematemesis or haemoptysis) or carotid or femoral artery (causing external bleeding). If a massive haemorrhage is unexpected, the only appropriate management may be to stay with the patient and attempt to comfort any distress.
Major haemorrhage may be preceded by smaller bleeds. Patients may have been receiving platelets and blood products, which have now been discontinued. If major haemorrhage is anticipated, it may be appropriate to warn family members of the possibility. Appropriate drugs, already drawn up in a syringe, should be kept available at the bedside to ensure fast administration.Red, blue or green towels (which mask the colour of blood) should be available to help control the spread of blood.
In the event of a massive bleed, the aim of treatment will be to rapidly sedate and relieve patient distress from what will, by definition, be the terminal event. Where possible, drugs should be given IV or else by deep IM injection.
Drug options
Midazolam
Midazolam 10mg SC, IV or bucally will sedate most patients. Heavy alcohol drinkers and patients on regular benzodiazepines may require larger doses.
Ketamine
The effect of ketamine is more predictable in palliative care patients than benzodiazepines and opioids, since the patient is unlikely to have been taking it regularly. Ketamine 150–250mg IV will rapidly sedate a patient dying from a terminal haemorrhage. If the IM route is deemed necessary, a larger dose of 500mg will be required.
Opioids
These are less recommended for the management of terminal haemorrhage for the following reasons:
As a controlled drug, nurses may not be able to leave a dose by the bedside or to check doses quickly
Variable doses will be required depending on how opioid-naïve the patient is
Diamorphine needs to be dissolved, leading to further delay
Summary
Midazolam 10–20mg IV, SC, IM or buccal
Ketamine 150–250mg IV or 500mg IM
Opioid dose will vary
Thromboembolism
It is over 130 years since Trousseau first noticed the association between cancer and thrombosis. Patients with cancer are at high risk of developing venous thromboembolism (VTE) and the risk increases as malignancy advances. Therefore, it follows that palliative care patients are extremely thrombogenic.
Studies have suggested that the incidence of deep vein thrombosis (DVT) may be as high 52% (with 33% of those being bilateral) in palliative care.
Thrombogenic risk
Virchow’s triad describes the predisposing factors for VTE as:
Stasis
Endothelial perturbation
Hypercoaguability
The following list suggests some of the reasons that patients with cancer are at such high risk.
Prothrombotic risk in cancer
Stasis:
Immobility due to weakness, lethargy
Compression of vessels by tumour, e.g. pelvic disease
Extrinsic compression from oedematous legs
Endothelial perturbation:
Recent surgery
Central venous access
Direct tumour invasion of vessel
Hypercoagulable state:
Dehydration
Tissue factor/tumour procoagulant release
Increased platelet activation
DIC
Cytokine-related thrombotic changes
Prothombotic changes from certain chemotherapeutic agents
Deep vein thrombosis (DVT)
Signs and symptoms vary depending upon the severity of DVT. It should be suspected in those patients with a swollen, tender, warm, erythematous leg, although it is unreliable to make a firm clinical diagnosis on the basis of these findings alone. Some are asymptomatic, whilst extreme cases may lead to vascular insufficiency and gangrene. The risk of a pulmonary embolus from a distal DVT (i.e. below knee) is low; and only about 20% of calf vein thromboses progress to a proximal thrombosis.
Differential diagnosis
Cellulitis
Lymphoedema
Oedema due to hypoproteinaemia
Ruptured Baker’s cyst
Diagnosis
It is not always practical to confirm the presence of a DVT if the patient is in the terminal stages of illness or to treat all patients with VTE. If a patient is not going to be anticoagulated there is little point in investigating a suspected thrombus. Anticoagulation carries risks as well as benefits and these should be weighed up on an individual basis first.
Doppler ultrasound:
non-invasive; no ionizing radiation; easily repeatable
can be performed at the bedside if suitable equipment is available
accuracy is lower for non-occlusive iliac thrombus and calf vein assessment than ascending venography
Venography:
invasive; involves ionizing radiation; contrast media is injected into a vein on the dorsum of the foot; low risk of allergic reaction
no longer the first-line investigation; useful when Doppler is inconclusive, for example in patients with large oedematous legs or with previous deep vein thrombosis
gives excellent visualization of all the leg veins
Light reflection rheography:
non-invasive
can be done at bedside
high sensitivity but poor specificity and therefore not used greatly in clinical practice
cannot localize thrombus or distinguish intrinsic from extrinsic compression
D-dimers:
use in cancer patients is limited due to high false-positive rate in malignancy
Magnetic resonance angiography:
non-invasive
good at imaging leg vessels
use in palliative care patients is yet to be evaluated
Pulmonary embolus (PE)
Evidence from post-mortem studies suggests that pulmonary emboli are underdiagnosed clinically in the palliative care setting.
This may be due to several factors:
Patient not well enough for investigation
Other lung pathologies make radiological diagnosis problematic
Concerns over anticoagulation in some patients
Breathlessness assumed to be due to other causes
Most PEs occur as a complication of DVT in the legs or pelvis. The risk of PE from untreated DVT is estimated at 50% and the mortality rate of untreated PE at 30–40%. Most deaths from PE occur in the first hour.
Signs and symptoms
These will vary depending upon the extent of thrombus, the general condition of the patient, other respiratory/cardiovascular co-morbidity and whether chronic pulmonary emboli or an acute event has occurred.
In some patients pulmonary emboli may go unnoticed, causing mild breathlessness, whilst in more severe cases, sudden cardiovascular collapse and death occur. Features suggestive of pulmonary emboli include:
Breathlessness and cough
Haemoptysis
Palpitations
Chest pain
Clinical signs may vary and are useful if present, but absence of signs should not exclude the diagnosis if there is a strong clinical suspicion. Likewise many of the signs could be accounted for by other co-morbidities. Signs may include:
Tachycardia
Tachypnoea
Atrial fibrillation
Raised JVP
Hypotension
Loud P2 heart sound
Cyanosis
Syncope
Investigations
It is important to decide whether an investigation is going to alter management and, if so, which test would be the most appropriate and best tolerated by the patient. A balance between the test most likely to confirm the diagnosis and that with the least disruption/burden to the patient may need to be considered. Several tests that may be done in the acute setting may be less appropriate near the end of life.
Arterial blood gases:
painful and unlikely to give much useful information in presence of coexisting lung disease
Pulse oximeter O2 saturation
non-invasive, rapid result
ECG
majority of ECGs are normal
most common abnormality is sinus tachycardia
S1Q3T3 phenomenon rare
atrial fibrillation may be present
D-dimers:
a negative result is helpful in excluding the diagnosis. A positive result does not confirm the diagnosis in the presence of malignancy, infection, increasing age or impaired renal function
Chest X-ray
useful in considering other causes of breathlessness besides PE
Objective testing for PE
All imaging techniques have their limitations and different degrees of burden on the patient:
Spiral CT:
first-line investigation
requires large volume of IV contrast
gives assessment of pulmonary veins
other chest pathologies identified
can be used to assess lower limb veins and inferior vena cava (IVC) at the same time
Ventilation/Perfusion (V/Q) scan:
usually well-tolerated procedure
use falling due to CT and pulmonary angiography
Pulmonary angiography:
‘gold standard’ investigation
invasive
complication rate 0.5%, mortality 0.1%
limited use in palliative care population
rarely used now with advent of CT pulmonary angiography
Magnetic resonance angiography:
under evaluation
limited use in palliative population
Chronic venous thrombosis
Patients with hypercoagulability related to disseminated malignancy or with cancers obstructing veins may have chronic venous thrombosis requiring warfarin and/or low molecular weight heparin (LMWH). Migratory thrombophlebitis affecting superficial veins, which is largely associated with disseminated bronchogenic adenocarcinoma, may also cause venous and arterial clotting.
Treatment of VTE
Treatment goals should be to relieve symptoms and prevent further thrombotic events:
DVT:
consider leg elevation
analgesia for swelling and tenderness (NSAIDs may interfere with the INR)
compression stockings if tolerated, ease the symptoms of venous hypertension
consider anticoagulation
venocaval filters may prevent a pulmonary embolism if recurrent DVTs are a problem despite anticoagulation, but are associated with painful engorgement of both lower limbs
PE:
oxygen
opioids ± benzodiazepines for breathlessness and fear
consider anticoagulation
Recurrence of thrombotic episodes while on warfarin may be managed by increasing the dose to achieve an INR in the higher therapeutic range e.g. 3.0–4.0 (see p.505).If there are problems achieving a therapeutic range e.g. because of compliance, the necessity for medication which potentiates warfarin, poor nutrition, poor venous access, then consider long-term LMWH in therapeutic dose.This also eliminates the need for INR monitoring. Rarely, patients experiencing recurrent thrombotic episodes despite the above may require LMWH in addition to warfarin. Anticoagulation in a patient with advanced malignancy should be considered carefully prior to initiation. Palliative care patients are at a high risk of haemorrhage for several reasons:
Presence of DIC
Consumption of clotting factors
Platelet dysfunction/thrombocytopenia
Tumours may be vascular
Liver metastases
Each patient should be considered on an individual basis taking into account the following:
Prognosis
Bleeding risk
Ability to control symptoms and the patient’s quality of life without anticoagulation
Perceived burden of anticoagulation
Patient’s views
Local haematology department guidelines should be sought regarding anticoagulation. Traditionally in palliative care, patients were initially treated with LMWH and, depending on the clinical circumstances, considered for commencing warfarin at the same time. Once the INR was stable at a therapeutic dose, the LMWH would then be discontinued. Emerging evidence from three RCTs comparing warfarin with LMWH in the management of cancer-related VTE have suggested that LMWHs reduces the recurrence of VTE whilst anticoagulated by 50% without significant difference in bleeding complications. Within the palliative care setting long-term LMWH should be the first-line anticoagulant of choice.
Never commence anticoagulant therapy without first checking the INR or platelet count.
Warfarin in patients with cancer
Despite being the mainstay of long-term anticoagulation for VTE, extreme caution should be used when recommending warfarin. Several studies have demonstrated significant increases in rates of bleeding amongst cancer patients on warfarin (in the order of 20%). Therefore, more frequent monitoring of the International Normalized Ratio (INR) (which should be maintained between 2 and 3) is often needed in patients with cancer (i.e. every 2–3 days) to reduce the risk of bleeding ( see Table 6l.2).
| Target INR | Indication |
|---|---|
2.0–2.5 | DVT prophylaxis |
2.5 | Treatment of DVT and PE (or recurrence in patients not on warfarin) |
3.5 | Recurrent DVT and PE in patients receiving warfarin Mechanical prosthetic heart valves |
| Target INR | Indication |
|---|---|
2.0–2.5 | DVT prophylaxis |
2.5 | Treatment of DVT and PE (or recurrence in patients not on warfarin) |
3.5 | Recurrent DVT and PE in patients receiving warfarin Mechanical prosthetic heart valves |
Problems with using warfarin in patients with advanced cancer
High risk of bleeding. Even higher if thrombocytopenia or liver metastases present
Unpredictable metabolism of warfarin
Interaction with other drugs
Difficulty maintaining INR in therapeutic range
Burden of repeated INR checks to optimize safety
Progression of thrombus despite therapeutic INR in a proportion of patients
Rapid reversal of warfarin
Give 12–15mL/kg FFP, 1 unit 300mL—usually 3–4 units of fresh plasma and 10mg vitamin K by slow IV injection.
Low molecular weight heparin in patients with cancer
Although the mainstay of treatment of VTE in patients with cancer remains long-term anticoagulation with warfarin, this is likely to change. There is now level 1a evidence comparing long-term LMWH with warfarin in this patient group. LMWH has been shown to reduce the recurrence of VTE from 17% to 9% with no stastistical difference in bleeding when compared with warfarin.
LMWH may be of particular benefit in palliative care since there is no need to measure the INR, and the drug does not react with other medicines.
The progressive nature of advanced malignancy invariably heralds changing symptoms, which necessitate drug alterations. This is a particular area of risk in warfarinized patients, where drug interactions may increase the INR.
There have been concerns that the once-daily injection of LMWH is too invasive, burdensome and detrimental to patients’ quality of life, while others would argue that this is less of a burden than the alternate-day INR checks that may be required to minimize the risk of warfarin-related haemorrhage.
A phenomenological study amongst palliative care patients receiving long-term LMWH suggests it is an acceptable intervention and does not have an adverse impact on quality of life.
LMWH is more costly than warfarin. However, this does not take into account costs of repeated blood monitoring and prolonged length of hospital stay whilst loading warfarin to therapeutic levels.
Potential benefits for LMWH
Reliable pharmacokinetics
Anticoagulant effect not altered by diet or concomitant drug use
Fast onset of action
Repeated blood test monitoring not required
At present, there are no guidelines defining which patients should receive LMWH for long-term anticoagulation. Each patient should be considered individually, but the following patients should be considered for LMWH rather than warfarin:
Continued thrombosis despite the INR being within the therapeutic range
Liver metastases
Symptoms that are difficult to control adequately with regular medication
Regular INR checks considered too great a burden
Poor venous access for blood testing
VTE and brain metastases
The management of VTE in those patients with brain metastases is complicated and there is no consensus. Studies comparing the use of venacaval filters with anticoagulation, show that 40% of patients with filters may experience further thrombotic events and 7% of those anticoagulated may develop neurological deterioration from intracerebral bleeding. The role of LMWH in these patients is yet to be clarified.
Length of anticoagulation
A patient should remain anticoagulated as long as the prothrombotic risk leading to VTE persists. In cancer, the prothrombotic risk increases as disease advances and so anticoagulation should, in theory, continue indefinitely. The decision should be made taking into account the patient’s views, effect of treatment, logistics of treatment and the complications. As the disease progresses and the bleeding tendency increases, stopping anticoagulation may be the lesser of two evils.
Developing a good relationship with haematology colleagues
In order to provide the best possible care for patients with end-stage haematological disease, palliative care teams need to build close working relationships with colleagues in haematology
Historically, this relationship has been challenging, as there has been a lack of understanding of the respective roles
Many patients may benefit in terms of symptom control and the prolongation of life resulting from aggressive active haematological intervention (including invasive procedures and frequent infusion of blood products) even in the terminal stages. This may be difficult for palliative care teams, whose aim for dying patients is to control symptoms in the least burdensome manner
The stereotypical prejudices inherent in both specialties are not helpful
It is crucial for the benefit of patients that there are good working relationships between haematology and palliative care specialists, so that patients and their families can have access to and the support of both approaches, and are aware of all the issues and choices
There are reasons why palliative care involvement in haematological patients is challenging, as outlined below:
There may be a misperception that palliative care teams only provide terminal care and therefore referrals should only be made when the patient is ‘actively dying’
Problems may have occurred previously with well intentioned but perhaps misguided palliative interventions, e.g. thrombocytopenic patients bleeding or myeloma patients developing renal failure after having been started on NSAIDs
Communication issues. The palliative care team may inadvertently question the patient’s knowledge and understanding of their illness and attitude to continuation of treatment, which might overtly or covertly be seen to undermine the haematology treatment plan
Fear that the palliative care team will take over patients who have often been managed for many years by the haematology team
It is important to fully appreciate that the haematology team may have looked after their patient through several near-death crises. The patients may have responded to previous treatments in extremis and, for instance, offering further chemotherapy may be totally appropriate
During treatment and as disease progresses haematology patients can become very ill, very quickly. This may not be the terminal stage, however, as patients may respond to active support with antibiotics, fluids and blood products
In the haematology context it is often very difficult to identify when a patient is dying.
Haematology colleagues need to be aware that palliative care specialists do not take over patients, or undermine their colleagues, or use medication to shorten the lives of patients
Palliative care teams should work alongside haematology teams, amicably negotiating the treatment path with patients and families
