- Email: [email protected]
Intensive care management of patients with haematological malignancy
Intensive care management of patients with haematological malignancy Martin Beed BM BS FRCA Martin Levitt MB ChB FRCA Syed Waqas Bokhari MB BS MRCP FRCPath
Key points
Estimates of survival to hospital discharge after ICU admission vary but may be as high as 40%. There is presently no way to predict whether or not ICU treatment will be futile, although tracheal intubation with mechanical ventilation and renal replacement therapy are associated with poorer outcomes. Martin Beed BM BS FRCA Consultant in Intensive Care and Anaesthesia Nottingham University Hospital City Campus Nottingham NG5 1PB UK Tel: þ44 115 9691169 Fax: þ44 115 8402620 E-mail: [email protected] (for correspondence) Martin Levitt MB ChB FRCA Consultant in Intensive Care and Anaesthesia Nottingham University Hospital City Campus Nottingham NG5 1PB UK
speaking, the commonest types of malignancies admitted to ICU include acute myeloid and lymphoblastic leukaemias, and non-Hodgkin’s lymphoma. Less common diseases include Hodgkin’s disease, myeloma, and the chronic leukaemias.
Complications of chemotherapy and stem cell transplantation Many chemotherapy agents, either individually or in combination, are commonly used in order to induce cure or remission. They are also used as part of a conditioning regimen with or without total body irradiation before bone marrow transplant. Many drugs can give rise to systemic complications (Table 1); bleomycin merits a special mention as patients who have received extensive doses are at risk of developing pulmonary fibrosis and respiratory failure if high inspired oxygen concentrations are given. Chemotherapy treatment is occasionally administered while on ICU, particularly where there is evidence of airway or mediastinal compression; liver, renal, or brainstem invasion; or a high leukaemic burden. Chemotherapy drugs should only be drawn up and administered by practitioners experienced in their use, and facilities should be in place to safely store chemotherapy agents and to dispose of unused remnants and contaminated body fluids. Designated sharps bins and bags/bins for contaminated linen or containers holding contaminated body fluids should be provided, alongside protective masks, aprons, and gloves and preprepared kits designed for the management of unexpected extravasation or spillage of cytotoxic agents. In a short series of 37 patients receiving chemotherapy while on ICU, 33% were still alive 6 months later.5
Syed Waqas Bokhari MB BS MRCP FRCPath Consultant Haematologist University Hospital Coventry and Warwickshire Coventry CV2 2DX UK
Haematological malignancies
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doi:10.1093/bjaceaccp/mkq034 Advance Access publication 17 September, 2010 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 10 Number 6 2010 & The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
There is a high degree of subclassification of haematological malignancies. Broadly
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Up to 7% of patients admitted to hospital with a diagnosis of haematological malignancy have a critical illness. Up to 13% of haematopoietic stem cell transplant recipients require intensive care unit (ICU) admission.
Serious complications are common among patients admitted to hospital with a diagnosis of haematological malignancy, with one British study of 1437 admissions identifying 7% as being complicated by an episode of critical illness.1 Although most of these episodes did not result in admission to intensive care unit (ICU), an increasing number of patients with a diagnosis of haematological malignancy are being managed within ICU or are receiving critical care input.1 – 3 Complication rates are higher for posthaematopoietic stem cell transplant (HSCT) patients with a recent abstract revealing an overall ICU admission rate for transplant patients of 13.6% among 1671 British patients over a 10 yr period.4 ICU admission for patients with haematological malignancies, and particularly after bone marrow transplantation, has been associated with very poor outcomes, and in some cases, critical care has been withheld because it was perceived to be futile.5 Newer studies suggest that ICU outcomes have improved, probably as a result of changes in both haematological treatments and ICU care.6 Patients with haematological malignancy may develop critical illness either as part of their first presentation with the malignancy or more commonly after chemotherapy or HSCT. Some presentations are specific to each scenario, whereas others may occur in all groups of patients. Respiratory failure is present in approximately half of all referrals to ICU. Between 10% and 50% of the patients have signs of shock, and there is evidence of multiple organ failure in about onefifth. Other causes for admission include neurological failure, gastrointestinal (GI) bleeding, renal failure, and metabolic derangement.3
Matrix reference 3D04
ICU and haematological malignancy
Table 1 Some common complications associated with chemotherapy agents
Table 2 Complications of stem cell transplant
Complications
Associated chemotherapy agents
Early complications (usually ,100 days)
Late complications (usually .100 days)
Idiopathic interstitial pneumonitis Pulmonary fibrosis Haemorrhagic cystitis Hypertension Cardiomyopathy Thrombotic thrombocytopaenic purpura
Cyclophosphamide Bleomycin; high-dose methotrexate Cyclophosphamide Cyclosporin Doxorubicin Cyclosporin, tacrolimus
Infections Haemorrhage Acute GVHD Graft failure (especially aplastic anaemia) Haemorrhagic cystitis Interstitial pneumonitis Others, including veno-occlusive disease, cardiac failure
Infections Chronic GVHD Chronic pulmonary disease Autoimmune disorders Cataract Infertility Second malignancies
Neutropaenia and sepsis There are different definitions of neutropaenia varying between cell counts of 1.5–2109 litre21, although in practice, counts of ,1109 litre21 are considered significantly low. It must be remembered that the absolute relative neutrophil count may still be low in patients with high white cell counts in whom only a small fraction
are neutrophils. Neutropaenic patients are at substantial risk of infections, especially unusual or atypical infections, including fungal or viral infections. Patients are often on prophylactic anti-fungal, antiviral, or anti-pneumocystis (pneumocystis jerovicii) medications, and these should be continued while on ICU unless the dose or drug requires adjustment to treat, rather than prevent, active infection. All neutropaenic patients should be reverse-barrier nursed wherever possible; in addition, it is worth noting that they are also at particular risk from individuals infected with varicella. Iatrogenic infections such as ventilator-acquired pneumonia, catheter-related bloodstream infection (CRBSI), and urinary catheter infections are common in neutropaenia; in the early stages of a critical illness, it may be desirable to avoid invasive procedures such as bladder catheterization, tracheal intubation, or central venous access where possible. Neutropaenic patients who develop symptoms of infection (e.g. pyrexia or rigors) should be suspected of having an infection even where there is no evidence of a specific source. They are less likely to develop suppurative symptoms and may not develop classical chest X-ray appearances of pneumonia. A full septic screen of urine, blood, and sputum should be performed, and this is likely to need repeating, sometimes on a daily basis. Broad-spectrum antibiotics which include anti-pseudomonal cover will be required in the first instance, and close liaison with microbiology is essential in tailoring antimicrobial therapy to local resistances (e.g. amikacin may be preferable to gentamicin where there is an increased
Fig 1 Types of HSCT donors.
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Haematopoietic stem cell transplantation can be subdivided according to the origin of the cells ( peripheral or bone marrow), the donor of the cells (Fig. 1), and the intensity of conditioning (myeloablative or reduced intensity conditioning). Myeloablative conditioning involves the pre-transplant destruction of endogenous bone marrow cells using either radiation or drugs, such as busulphan or cyclophosphamide. The use of myeloablative therapy and less well HLA-matched stem cell donation are associated with an increased risk of complications and poorer outcomes if patients are admitted to ICU. Admission to ICU is more likely after myeloablative allografts (39.2%), and reduced intensity conditioning allografts (17.9%), than for autografts (5.1%).4 Although there is a higher chance of the potentially beneficial graft-vs-disease effect in patients with mismatched transplants, this effect is partly off-set by higher risk of developing severe grade II –IV graft-vs-host disease (GVHD) which adversely affects the outcomes. The complications of stem cell transplantation are given in Table 2. Most ICU admissions are for early complications, with at least 50% of admissions being within 30 days of transplantation.
ICU and haematological malignancy
particularly when it is required as part of an emergency resuscitation, although a minimum count of 20–30109 litre21 seems prudent. Despite the potentially increased risk of CRBSI, central venous access via the femoral route is often considered in haematology patients with thrombocytopaenia. In some cases, patients with thrombocytopaenia are sensitized to, and generate antibodies against, transfused platelets resulting in platelet refractoriness. In these cases, it may be valuable to do preand 1 h post-transfusion platelet counts. Where there is little or no increment, specially ordered HLA-matched platelets may be required. It is also worth remembering that other potential causes of thrombocytopaenia may co-exist in haematology patients, for example, idiopathic thrombocytopaenic purpura, heparin-induced thrombocytopaenia, post-transfusion purpura, or drugs such as vancomycin.
Respiratory failure The default diagnosis for the cause of respiratory failure is often infection, although alternative causes include pulmonary oedema, GVHD, and infiltration of the lung by the underlying disease, or pulmonary haemorrhage. Where tracheal intubation and mechanical ventilation are required, they are associated with poorer outcome, except where the cause is transient (i.e. after surgical procedures, or brief neurological failure such as fitting) or where it is associated with an episode of pulmonary oedema. In common with other ICU patients, lung-protective strategies should be adopted where possible. Although it is still unclear, there is some evidence to suggest that avoiding tracheal intubation and mechanical ventilation may improve survival.6 The presence of infection is often hard to prove, and bronchoalveolar lavage may improve detection rates. The diagnosis of lung fibrosis is even harder to prove other than by open-lung biopsy, and by the time this is considered, the patient is often too unstable for the procedure. A review of surgical lung biopsy indicated that where a diagnosis was made, it was as likely to be one of infection as it was to be the underlying malignancy (29% vs 27%). The most common infection diagnosed by biopsy was aspergillosis.7
Thrombocytopaenia The commonest coagulopathy present in haematological malignancy is thrombocytopaenia. Spontaneous bleeding, especially from sites of minor trauma such as nasogastric tubes or arterial line insertion, may occur with very low platelet counts (e.g. 5109 litre21). Where there is active bleeding (e.g. a GI haemorrhage) or when surgical procedures are planned, a minimum platelet count of 50–60109 litre21 should be maintained, using platelet transfusions if required. The safe level at which to maintain patients not expected to undergo such procedures is less clear and counts above 10 –20109 litre21 are often considered acceptable. There is no clear consensus as to what level is required to safely insert a central venous catheter under ultrasound guidance,
Tumour lysis syndrome Tumour lysis syndrome is most associated with the acute leukaemias and high-grade lymphomas especially Burkitt’s lymphoma. In certain rare cases, it can happen spontaneously but most commonly occurs after treatment with chemotherapy (and occasionally with single-therapy dexamethasone treatment). It results in potentially life-threatening hyperkalaemia, renal failure, and acidosis. Serum hyperphosphataemia and hypocalcaemia may also be present along with increased serum and urine uric acid. Aggressive fluid hydration and hyperkalaemia treatment, which may include renal replacement therapy, combined with the administration of rasburicase (a recombinant urate oxidase enzyme) are the mainstays of therapy. Forced alkaline diuresis has previously been advocated, but its use is declining due to variable efficacy, especially where renal function is already compromised, and potential hazards such as fluid overload. Where tumour lysis is likely to occur, close monitoring of renal function, calcium, phosphate, and urate levels is required (e.g. 2, 4, and 8 h after starting chemotherapy). Allopurinol or rasburicase is commonly used as prophylaxis where there is a high tumour load, and thus increased risk of tumour lysis (where rasburicase is used, allopurinol should be withheld).
Other organ failures Temporary neurological dysfunction and seizures are relatively common and may have a whole variety of causes. Given the possibility of thrombocytopaenia, or other coagulopathic states, a CT is often required to rule out the presence of an intracranial bleed. This is especially true in the presence of trauma, no matter how minor. Hypercoagulable states may give rise to cerebral infarction or venous thrombosis. Hyperviscosity syndrome may lead to drowsiness, coma, and neurological defects and may require therapeutic apheresis ( plasmapheresis or leucopheresis depending on the underlying haematological condition). Neurological failure may
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risk of resistant pseudomonal infections). Even when a likely pathogen is isolated, it is common for a broad range of antimicrobial therapy to be maintained. Persistent or recurrent fever in neutropaenic patients despite adequate antibacterial cover should prompt consideration of fungal infection with a computed tomography (CT) chest and empirical treatment with anti-fungal agents. The choice and dosage of these anti-fungal agents will depend upon the liver and renal functions of the individual patient and the type of fungal infection suspected, but should cover Aspergillus and resistant Candida species. Granulocyte colony-stimulating factor (GCSF) is often used to promote neutrophil recovery, except in conditions where there is a low absolute neutrophil count but a high overall white cell count. GCSF has, rarely, been associated with splenic rupture especially in myeloproliferative disorders with associated splenomegaly.
ICU and haematological malignancy
Graft-vs-host disease Acute GVHD typically presents with skin rash, diarrhoea, and hepatitis. It can also lead to significant thrombocytopaenia, conjunctivitis, and even microangiopathic haemolysis. Incidence of GVHD increases with HLA incompatibility, unrelated rather than related donor, donor–recipient sex mismatch, inadequate GVHD prophylaxis, myeloablative conditioning, peripheral blood as stem cell source, increasing age of donor and recipient, and cytomegalovirus-positive status. Acute GVHD (,100 days post-HSCT) can be diagnosed histologically, but in the acute setting, a clinical diagnosis and staging system, such as the Seattle scoring system, are more commonly used. The overall grade of acute GVHD is predictive of day 100 survival (Table 3). The peak time for developing acute GVHD is 30 –50 days posttransplant, although it can occur later than 100 days after transplant especially if donor lymphocyte transfusions are required. Identifying acute GVHD as the cause of a critical illness is often difficult (e.g. where there is hepatic dysfunction which could be due to drugs such as cyclosporin or infection or veno-occlusive disease) and low threshold should be kept to pursue a histological diagnosis with a skin, rectal, or liver biopsy if in doubt. Where GVHD requires treatment within ICU, options include increased doses of steroids, immunosuppressants such as cyclosporin or mycophenolate mofetil, and occasionally extra-corporeal phototherapy, although the latter requires the patient to be
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Table 3 Scoring systems for GVHD The Seattle scoring system for graft-vs-host disease Stage
1 2 3 4
Skin rash (typically face, palms, soles, ears)
Liver (bilirubin, mmol litre21)
Gut (diarrhoea, litre day21)
Rash ,25% Rash 25 –50% Erythroderma Bullae, desquamation
20 –35 35 –80 80 –150 .150
0.5 – 1 1 –1.5 1.5 – 2.5 .2.5 (pain, ileus)
Overall grading of acute graft-vs-host disease 100 day survival I II III IV
Stage 1 or 2 skin, no gut or liver involvement Stage 1–3 skin; with stage 1 gut or liver; mild decrease in performance status Stage 2–3 skin; with stage 2– 4 gut or stage 2–3 liver; marked decrease in performance status Similar to grade III; with stage 4 gut or liver; extreme decrease in performance status
78 – 90% 66 – 92% 29 – 62% 23 – 25%
haemodynamically stable enough to tolerate aliquots of blood removal for treatment. GI involvement may necessitate the need for parenteral nutrition to rest the gut. Octreotide may be useful for severe diarrhoea. Chronic GVHD, a multiorgan syndrome resembling autoimmune disorders, occurs in 30–50% of matched sibling grafts. It may be limited or extensive and these patients are usually quite significantly immunocompromised, despite normal neutrophil counts.
Outcomes and survival after ICU admission Patients with haematological malignancies presenting to the ICU are clearly not a homogenous population. It is difficult to estimate ICU and hospital survival in a group of patients with such a wide range of underlying diseases and disease severity, requiring different treatment regimens, and in whom, the presenting complaint requiring ICU intervention also varies. Most studies conclude that high acute physiology and chronic health evaluation (APACHE) scores are associated with increased mortality (and indeed may even underestimate it in this cohort), as are increased number of organ failures, the need for mechanical ventilation, and the need for renal replacement therapy. There is no single clinical feature, or combination of features, that can be used to reliably predict futility in patients with haematological malignancy requiring ICU support. A review in 2003 found a wide variation in the reported survival to hospital discharge for ICU patients with haematological malignancy, ranging from 17% to 44%.9 A similar review in 2004 concentrating just on HSCT recipients revealed hospital discharge survival ranges of 4–20%.2 In both these reviews, many of the absolute numbers in individual studies were small; nevertheless, there would appear to be a trend towards improved survival over
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also be caused by the underlying malignancy or by electrolyte imbalance. Hypercoagulable states are associated with many of the underlying malignancies, chemotherapy treatment and HSCT, and may also cause veno-occlusive disease of peripheral, pulmonary, or hepatic veins; even in patients who have thrombocytopaenia. GI dysfunction is associated with chemotherapy, GVHD, and infection. Typhlitis, a neutropaenic enterocolitis (sometimes referred to as caecitis or caecenteritis), commonly occurs between 10 and 14 days after cytotoxic chemotherapy and is especially associated with the use of cytosine, vinca alkaloids, and doxorubicin, although other agents are known to cause it. Typhlitis may be very difficult to differentiate from appendicitis or infection with Clostridium difficile; abdominal CT may be helpful in confirming the diagnosis. Acute renal failure may be as a result of the underlying disease, administration of nephrotoxic agents, or related to sepsis and hypotension. It is often associated with hepatic failure, especially after HSCT therapy. Renal replacement therapy may be required to support the patient, although anti-coagulation of the filter may be relatively contraindicated in patients with a coagulopathy, in whom haemofiltration using pre-dilution alone may be a safer option. Many studies have shown the need for renal replacement therapy to be an independent predictor of mortality in patients with haematological malignancy, although renal failure suspected to be as a result of the disease itself is not necessarily a bar to treatment.8
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time.6 Of those patients who do survive for a prolonged period after ICU discharge, a significant number are cured or in complete remission. The aetiology and severity of that acute illness does not affect the long-term prognosis or quality of life, these being predominantly affected by the underlying nature of their malignancy.10 A decision not to treat an episode of critical illness in a patient with haematological malignancy should be made with due regard to both their underlying condition, physiological reserve, the presence of co-morbidities, and their current condition and should be made after informed discussion with the referring team and the patient or their representative.
3. Kroschinsky F, Weise M, Illmer T et al. Outcome and prognostic features of intensive care unit treatment in patients with hematological malignancies. Intensive Care Med 2002; 28: 1294– 300 4. Holroyd A, Townsend W, Naik P et al. Favourable outcome for haematopoietic transplant recipients requiring intensive therapy unit admission: a 10-year single-centre experience. Bone Marrow Transplant 2009; 43: S23 5. Benoit DD, Depuydt PO, Vandewoude KH et al. Outcome in severely ill patients with haematological malignancies who received intravenous chemotherapy in the intensive care unit. Intensive Care Med 2006; 32: 93– 9 6. Azouley E, Alberti C, Bornstain C et al. Improved survival in cancer patients requiring mechanical ventilator support: impact of noninvasive mechanical ventilator support. Crit Care Med 2001; 29: 519– 25
None declared.
8. Mallick NP, Olujohungbe A, Drayson MT. Renal impairment in myeloma: time for a reappraisal. Nephrol Dial Transplant 1998; 13: 30– 2
References 1. Gordon AC, Oakervee HE, Kaya B et al. Incidence and outcome of critical illness amongst hospitalised patients with haematological malignancy: a prospective observational study of ward and intensive care unit based care. Anaesthesia 2005; 60: 340–7 2. Soubani AO, Kseibi E, Bander JJ et al. Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest 2004; 126: 1604– 11
9. Silfvast T, Pettil V, Ihalainen A et al. Multiple organ failure and outcome of critically ill patients with haematological malignancy. Acta Anaesthesiol Scand 2003; 47: 301– 6 10. Yau E, Rohatiner AZ, Lister TA, Hinds CJ. Long term prognosis and quality of life following intensive care for life-threatening complications of haematological malignancy. Br J Cancer 1991; 64: 938 –42
Please see multiple choice questions 1– 4.
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7. Zihlif M, Khanchandani G, Ahmed HP, Soubani AO. Surgical lung biopsy in patients with hematological malignancy or hematopoietic stem cell transplantation and unexplained pulmonary infiltrates: improved outcome with specific diagnosis. Am J Hematol 2005; 78: 94–9
Conflict of interest
Key points
Estimates of survival to hospital discharge after ICU admission vary but may be as high as 40%. There is presently no way to predict whether or not ICU treatment will be futile, although tracheal intubation with mechanical ventilation and renal replacement therapy are associated with poorer outcomes. Martin Beed BM BS FRCA Consultant in Intensive Care and Anaesthesia Nottingham University Hospital City Campus Nottingham NG5 1PB UK Tel: þ44 115 9691169 Fax: þ44 115 8402620 E-mail: [email protected] (for correspondence) Martin Levitt MB ChB FRCA Consultant in Intensive Care and Anaesthesia Nottingham University Hospital City Campus Nottingham NG5 1PB UK
speaking, the commonest types of malignancies admitted to ICU include acute myeloid and lymphoblastic leukaemias, and non-Hodgkin’s lymphoma. Less common diseases include Hodgkin’s disease, myeloma, and the chronic leukaemias.
Complications of chemotherapy and stem cell transplantation Many chemotherapy agents, either individually or in combination, are commonly used in order to induce cure or remission. They are also used as part of a conditioning regimen with or without total body irradiation before bone marrow transplant. Many drugs can give rise to systemic complications (Table 1); bleomycin merits a special mention as patients who have received extensive doses are at risk of developing pulmonary fibrosis and respiratory failure if high inspired oxygen concentrations are given. Chemotherapy treatment is occasionally administered while on ICU, particularly where there is evidence of airway or mediastinal compression; liver, renal, or brainstem invasion; or a high leukaemic burden. Chemotherapy drugs should only be drawn up and administered by practitioners experienced in their use, and facilities should be in place to safely store chemotherapy agents and to dispose of unused remnants and contaminated body fluids. Designated sharps bins and bags/bins for contaminated linen or containers holding contaminated body fluids should be provided, alongside protective masks, aprons, and gloves and preprepared kits designed for the management of unexpected extravasation or spillage of cytotoxic agents. In a short series of 37 patients receiving chemotherapy while on ICU, 33% were still alive 6 months later.5
Syed Waqas Bokhari MB BS MRCP FRCPath Consultant Haematologist University Hospital Coventry and Warwickshire Coventry CV2 2DX UK
Haematological malignancies
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doi:10.1093/bjaceaccp/mkq034 Advance Access publication 17 September, 2010 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 10 Number 6 2010 & The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
There is a high degree of subclassification of haematological malignancies. Broadly
Downloaded from http://ceaccp.oxfordjournals.org/ at New York University on June 3, 2015
Up to 7% of patients admitted to hospital with a diagnosis of haematological malignancy have a critical illness. Up to 13% of haematopoietic stem cell transplant recipients require intensive care unit (ICU) admission.
Serious complications are common among patients admitted to hospital with a diagnosis of haematological malignancy, with one British study of 1437 admissions identifying 7% as being complicated by an episode of critical illness.1 Although most of these episodes did not result in admission to intensive care unit (ICU), an increasing number of patients with a diagnosis of haematological malignancy are being managed within ICU or are receiving critical care input.1 – 3 Complication rates are higher for posthaematopoietic stem cell transplant (HSCT) patients with a recent abstract revealing an overall ICU admission rate for transplant patients of 13.6% among 1671 British patients over a 10 yr period.4 ICU admission for patients with haematological malignancies, and particularly after bone marrow transplantation, has been associated with very poor outcomes, and in some cases, critical care has been withheld because it was perceived to be futile.5 Newer studies suggest that ICU outcomes have improved, probably as a result of changes in both haematological treatments and ICU care.6 Patients with haematological malignancy may develop critical illness either as part of their first presentation with the malignancy or more commonly after chemotherapy or HSCT. Some presentations are specific to each scenario, whereas others may occur in all groups of patients. Respiratory failure is present in approximately half of all referrals to ICU. Between 10% and 50% of the patients have signs of shock, and there is evidence of multiple organ failure in about onefifth. Other causes for admission include neurological failure, gastrointestinal (GI) bleeding, renal failure, and metabolic derangement.3
Matrix reference 3D04
ICU and haematological malignancy
Table 1 Some common complications associated with chemotherapy agents
Table 2 Complications of stem cell transplant
Complications
Associated chemotherapy agents
Early complications (usually ,100 days)
Late complications (usually .100 days)
Idiopathic interstitial pneumonitis Pulmonary fibrosis Haemorrhagic cystitis Hypertension Cardiomyopathy Thrombotic thrombocytopaenic purpura
Cyclophosphamide Bleomycin; high-dose methotrexate Cyclophosphamide Cyclosporin Doxorubicin Cyclosporin, tacrolimus
Infections Haemorrhage Acute GVHD Graft failure (especially aplastic anaemia) Haemorrhagic cystitis Interstitial pneumonitis Others, including veno-occlusive disease, cardiac failure
Infections Chronic GVHD Chronic pulmonary disease Autoimmune disorders Cataract Infertility Second malignancies
Neutropaenia and sepsis There are different definitions of neutropaenia varying between cell counts of 1.5–2109 litre21, although in practice, counts of ,1109 litre21 are considered significantly low. It must be remembered that the absolute relative neutrophil count may still be low in patients with high white cell counts in whom only a small fraction
are neutrophils. Neutropaenic patients are at substantial risk of infections, especially unusual or atypical infections, including fungal or viral infections. Patients are often on prophylactic anti-fungal, antiviral, or anti-pneumocystis (pneumocystis jerovicii) medications, and these should be continued while on ICU unless the dose or drug requires adjustment to treat, rather than prevent, active infection. All neutropaenic patients should be reverse-barrier nursed wherever possible; in addition, it is worth noting that they are also at particular risk from individuals infected with varicella. Iatrogenic infections such as ventilator-acquired pneumonia, catheter-related bloodstream infection (CRBSI), and urinary catheter infections are common in neutropaenia; in the early stages of a critical illness, it may be desirable to avoid invasive procedures such as bladder catheterization, tracheal intubation, or central venous access where possible. Neutropaenic patients who develop symptoms of infection (e.g. pyrexia or rigors) should be suspected of having an infection even where there is no evidence of a specific source. They are less likely to develop suppurative symptoms and may not develop classical chest X-ray appearances of pneumonia. A full septic screen of urine, blood, and sputum should be performed, and this is likely to need repeating, sometimes on a daily basis. Broad-spectrum antibiotics which include anti-pseudomonal cover will be required in the first instance, and close liaison with microbiology is essential in tailoring antimicrobial therapy to local resistances (e.g. amikacin may be preferable to gentamicin where there is an increased
Fig 1 Types of HSCT donors.
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Haematopoietic stem cell transplantation can be subdivided according to the origin of the cells ( peripheral or bone marrow), the donor of the cells (Fig. 1), and the intensity of conditioning (myeloablative or reduced intensity conditioning). Myeloablative conditioning involves the pre-transplant destruction of endogenous bone marrow cells using either radiation or drugs, such as busulphan or cyclophosphamide. The use of myeloablative therapy and less well HLA-matched stem cell donation are associated with an increased risk of complications and poorer outcomes if patients are admitted to ICU. Admission to ICU is more likely after myeloablative allografts (39.2%), and reduced intensity conditioning allografts (17.9%), than for autografts (5.1%).4 Although there is a higher chance of the potentially beneficial graft-vs-disease effect in patients with mismatched transplants, this effect is partly off-set by higher risk of developing severe grade II –IV graft-vs-host disease (GVHD) which adversely affects the outcomes. The complications of stem cell transplantation are given in Table 2. Most ICU admissions are for early complications, with at least 50% of admissions being within 30 days of transplantation.
ICU and haematological malignancy
particularly when it is required as part of an emergency resuscitation, although a minimum count of 20–30109 litre21 seems prudent. Despite the potentially increased risk of CRBSI, central venous access via the femoral route is often considered in haematology patients with thrombocytopaenia. In some cases, patients with thrombocytopaenia are sensitized to, and generate antibodies against, transfused platelets resulting in platelet refractoriness. In these cases, it may be valuable to do preand 1 h post-transfusion platelet counts. Where there is little or no increment, specially ordered HLA-matched platelets may be required. It is also worth remembering that other potential causes of thrombocytopaenia may co-exist in haematology patients, for example, idiopathic thrombocytopaenic purpura, heparin-induced thrombocytopaenia, post-transfusion purpura, or drugs such as vancomycin.
Respiratory failure The default diagnosis for the cause of respiratory failure is often infection, although alternative causes include pulmonary oedema, GVHD, and infiltration of the lung by the underlying disease, or pulmonary haemorrhage. Where tracheal intubation and mechanical ventilation are required, they are associated with poorer outcome, except where the cause is transient (i.e. after surgical procedures, or brief neurological failure such as fitting) or where it is associated with an episode of pulmonary oedema. In common with other ICU patients, lung-protective strategies should be adopted where possible. Although it is still unclear, there is some evidence to suggest that avoiding tracheal intubation and mechanical ventilation may improve survival.6 The presence of infection is often hard to prove, and bronchoalveolar lavage may improve detection rates. The diagnosis of lung fibrosis is even harder to prove other than by open-lung biopsy, and by the time this is considered, the patient is often too unstable for the procedure. A review of surgical lung biopsy indicated that where a diagnosis was made, it was as likely to be one of infection as it was to be the underlying malignancy (29% vs 27%). The most common infection diagnosed by biopsy was aspergillosis.7
Thrombocytopaenia The commonest coagulopathy present in haematological malignancy is thrombocytopaenia. Spontaneous bleeding, especially from sites of minor trauma such as nasogastric tubes or arterial line insertion, may occur with very low platelet counts (e.g. 5109 litre21). Where there is active bleeding (e.g. a GI haemorrhage) or when surgical procedures are planned, a minimum platelet count of 50–60109 litre21 should be maintained, using platelet transfusions if required. The safe level at which to maintain patients not expected to undergo such procedures is less clear and counts above 10 –20109 litre21 are often considered acceptable. There is no clear consensus as to what level is required to safely insert a central venous catheter under ultrasound guidance,
Tumour lysis syndrome Tumour lysis syndrome is most associated with the acute leukaemias and high-grade lymphomas especially Burkitt’s lymphoma. In certain rare cases, it can happen spontaneously but most commonly occurs after treatment with chemotherapy (and occasionally with single-therapy dexamethasone treatment). It results in potentially life-threatening hyperkalaemia, renal failure, and acidosis. Serum hyperphosphataemia and hypocalcaemia may also be present along with increased serum and urine uric acid. Aggressive fluid hydration and hyperkalaemia treatment, which may include renal replacement therapy, combined with the administration of rasburicase (a recombinant urate oxidase enzyme) are the mainstays of therapy. Forced alkaline diuresis has previously been advocated, but its use is declining due to variable efficacy, especially where renal function is already compromised, and potential hazards such as fluid overload. Where tumour lysis is likely to occur, close monitoring of renal function, calcium, phosphate, and urate levels is required (e.g. 2, 4, and 8 h after starting chemotherapy). Allopurinol or rasburicase is commonly used as prophylaxis where there is a high tumour load, and thus increased risk of tumour lysis (where rasburicase is used, allopurinol should be withheld).
Other organ failures Temporary neurological dysfunction and seizures are relatively common and may have a whole variety of causes. Given the possibility of thrombocytopaenia, or other coagulopathic states, a CT is often required to rule out the presence of an intracranial bleed. This is especially true in the presence of trauma, no matter how minor. Hypercoagulable states may give rise to cerebral infarction or venous thrombosis. Hyperviscosity syndrome may lead to drowsiness, coma, and neurological defects and may require therapeutic apheresis ( plasmapheresis or leucopheresis depending on the underlying haematological condition). Neurological failure may
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risk of resistant pseudomonal infections). Even when a likely pathogen is isolated, it is common for a broad range of antimicrobial therapy to be maintained. Persistent or recurrent fever in neutropaenic patients despite adequate antibacterial cover should prompt consideration of fungal infection with a computed tomography (CT) chest and empirical treatment with anti-fungal agents. The choice and dosage of these anti-fungal agents will depend upon the liver and renal functions of the individual patient and the type of fungal infection suspected, but should cover Aspergillus and resistant Candida species. Granulocyte colony-stimulating factor (GCSF) is often used to promote neutrophil recovery, except in conditions where there is a low absolute neutrophil count but a high overall white cell count. GCSF has, rarely, been associated with splenic rupture especially in myeloproliferative disorders with associated splenomegaly.
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Graft-vs-host disease Acute GVHD typically presents with skin rash, diarrhoea, and hepatitis. It can also lead to significant thrombocytopaenia, conjunctivitis, and even microangiopathic haemolysis. Incidence of GVHD increases with HLA incompatibility, unrelated rather than related donor, donor–recipient sex mismatch, inadequate GVHD prophylaxis, myeloablative conditioning, peripheral blood as stem cell source, increasing age of donor and recipient, and cytomegalovirus-positive status. Acute GVHD (,100 days post-HSCT) can be diagnosed histologically, but in the acute setting, a clinical diagnosis and staging system, such as the Seattle scoring system, are more commonly used. The overall grade of acute GVHD is predictive of day 100 survival (Table 3). The peak time for developing acute GVHD is 30 –50 days posttransplant, although it can occur later than 100 days after transplant especially if donor lymphocyte transfusions are required. Identifying acute GVHD as the cause of a critical illness is often difficult (e.g. where there is hepatic dysfunction which could be due to drugs such as cyclosporin or infection or veno-occlusive disease) and low threshold should be kept to pursue a histological diagnosis with a skin, rectal, or liver biopsy if in doubt. Where GVHD requires treatment within ICU, options include increased doses of steroids, immunosuppressants such as cyclosporin or mycophenolate mofetil, and occasionally extra-corporeal phototherapy, although the latter requires the patient to be
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Table 3 Scoring systems for GVHD The Seattle scoring system for graft-vs-host disease Stage
1 2 3 4
Skin rash (typically face, palms, soles, ears)
Liver (bilirubin, mmol litre21)
Gut (diarrhoea, litre day21)
Rash ,25% Rash 25 –50% Erythroderma Bullae, desquamation
20 –35 35 –80 80 –150 .150
0.5 – 1 1 –1.5 1.5 – 2.5 .2.5 (pain, ileus)
Overall grading of acute graft-vs-host disease 100 day survival I II III IV
Stage 1 or 2 skin, no gut or liver involvement Stage 1–3 skin; with stage 1 gut or liver; mild decrease in performance status Stage 2–3 skin; with stage 2– 4 gut or stage 2–3 liver; marked decrease in performance status Similar to grade III; with stage 4 gut or liver; extreme decrease in performance status
78 – 90% 66 – 92% 29 – 62% 23 – 25%
haemodynamically stable enough to tolerate aliquots of blood removal for treatment. GI involvement may necessitate the need for parenteral nutrition to rest the gut. Octreotide may be useful for severe diarrhoea. Chronic GVHD, a multiorgan syndrome resembling autoimmune disorders, occurs in 30–50% of matched sibling grafts. It may be limited or extensive and these patients are usually quite significantly immunocompromised, despite normal neutrophil counts.
Outcomes and survival after ICU admission Patients with haematological malignancies presenting to the ICU are clearly not a homogenous population. It is difficult to estimate ICU and hospital survival in a group of patients with such a wide range of underlying diseases and disease severity, requiring different treatment regimens, and in whom, the presenting complaint requiring ICU intervention also varies. Most studies conclude that high acute physiology and chronic health evaluation (APACHE) scores are associated with increased mortality (and indeed may even underestimate it in this cohort), as are increased number of organ failures, the need for mechanical ventilation, and the need for renal replacement therapy. There is no single clinical feature, or combination of features, that can be used to reliably predict futility in patients with haematological malignancy requiring ICU support. A review in 2003 found a wide variation in the reported survival to hospital discharge for ICU patients with haematological malignancy, ranging from 17% to 44%.9 A similar review in 2004 concentrating just on HSCT recipients revealed hospital discharge survival ranges of 4–20%.2 In both these reviews, many of the absolute numbers in individual studies were small; nevertheless, there would appear to be a trend towards improved survival over
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also be caused by the underlying malignancy or by electrolyte imbalance. Hypercoagulable states are associated with many of the underlying malignancies, chemotherapy treatment and HSCT, and may also cause veno-occlusive disease of peripheral, pulmonary, or hepatic veins; even in patients who have thrombocytopaenia. GI dysfunction is associated with chemotherapy, GVHD, and infection. Typhlitis, a neutropaenic enterocolitis (sometimes referred to as caecitis or caecenteritis), commonly occurs between 10 and 14 days after cytotoxic chemotherapy and is especially associated with the use of cytosine, vinca alkaloids, and doxorubicin, although other agents are known to cause it. Typhlitis may be very difficult to differentiate from appendicitis or infection with Clostridium difficile; abdominal CT may be helpful in confirming the diagnosis. Acute renal failure may be as a result of the underlying disease, administration of nephrotoxic agents, or related to sepsis and hypotension. It is often associated with hepatic failure, especially after HSCT therapy. Renal replacement therapy may be required to support the patient, although anti-coagulation of the filter may be relatively contraindicated in patients with a coagulopathy, in whom haemofiltration using pre-dilution alone may be a safer option. Many studies have shown the need for renal replacement therapy to be an independent predictor of mortality in patients with haematological malignancy, although renal failure suspected to be as a result of the disease itself is not necessarily a bar to treatment.8
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time.6 Of those patients who do survive for a prolonged period after ICU discharge, a significant number are cured or in complete remission. The aetiology and severity of that acute illness does not affect the long-term prognosis or quality of life, these being predominantly affected by the underlying nature of their malignancy.10 A decision not to treat an episode of critical illness in a patient with haematological malignancy should be made with due regard to both their underlying condition, physiological reserve, the presence of co-morbidities, and their current condition and should be made after informed discussion with the referring team and the patient or their representative.
3. Kroschinsky F, Weise M, Illmer T et al. Outcome and prognostic features of intensive care unit treatment in patients with hematological malignancies. Intensive Care Med 2002; 28: 1294– 300 4. Holroyd A, Townsend W, Naik P et al. Favourable outcome for haematopoietic transplant recipients requiring intensive therapy unit admission: a 10-year single-centre experience. Bone Marrow Transplant 2009; 43: S23 5. Benoit DD, Depuydt PO, Vandewoude KH et al. Outcome in severely ill patients with haematological malignancies who received intravenous chemotherapy in the intensive care unit. Intensive Care Med 2006; 32: 93– 9 6. Azouley E, Alberti C, Bornstain C et al. Improved survival in cancer patients requiring mechanical ventilator support: impact of noninvasive mechanical ventilator support. Crit Care Med 2001; 29: 519– 25
None declared.
8. Mallick NP, Olujohungbe A, Drayson MT. Renal impairment in myeloma: time for a reappraisal. Nephrol Dial Transplant 1998; 13: 30– 2
References 1. Gordon AC, Oakervee HE, Kaya B et al. Incidence and outcome of critical illness amongst hospitalised patients with haematological malignancy: a prospective observational study of ward and intensive care unit based care. Anaesthesia 2005; 60: 340–7 2. Soubani AO, Kseibi E, Bander JJ et al. Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest 2004; 126: 1604– 11
9. Silfvast T, Pettil V, Ihalainen A et al. Multiple organ failure and outcome of critically ill patients with haematological malignancy. Acta Anaesthesiol Scand 2003; 47: 301– 6 10. Yau E, Rohatiner AZ, Lister TA, Hinds CJ. Long term prognosis and quality of life following intensive care for life-threatening complications of haematological malignancy. Br J Cancer 1991; 64: 938 –42
Please see multiple choice questions 1– 4.
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7. Zihlif M, Khanchandani G, Ahmed HP, Soubani AO. Surgical lung biopsy in patients with hematological malignancy or hematopoietic stem cell transplantation and unexplained pulmonary infiltrates: improved outcome with specific diagnosis. Am J Hematol 2005; 78: 94–9
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