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
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.
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: martin.beed@nottingham.ac.uk
(for correspondence)
Martin Levitt MB ChB FRCA
Consultant in Intensive Care and
Anaesthesia
Nottingham University Hospital
City Campus
Nottingham NG5 1PB
UK
Syed Waqas Bokhari MB BS MRCP
FRCPath
Consultant Haematologist University
Hospital Coventry and Warwickshire
Coventry CV2 2DX
UK
167
Serious complications are common among pati-
ents admitted to hospital with a diagnosis of hae-
matological malignancy, with one British study of
1437 admissions identifying 7% as being compli-
cated 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 haematolo-
gical malignancy are being managed within ICU
or are receiving critical care input.1 – 3
Complication rates are higher for post-
haematopoietic 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 haematolo-
gical 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 com-
monly after chemotherapy or HSCT. Some pre-
sentations 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 one-
fifth. Other causes for admission include neuro-
logical failure, gastrointestinal (GI) bleeding,
renal failure, and metabolic derangement.3
Haematological malignancies
There is a high degree of subclassification
of haematological malignancies. Broadly
doi:10.1093/bjaceaccp/mkq034
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& The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
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Matrix reference 3D04
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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 develop-
ing 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 com-
pression; 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 che-
motherapy agents and to dispose of unused
remnants and contaminated body fluids.
Designated sharps bins and bags/bins for con-
taminated linen or containers holding contami-
nated body fluids should be provided, alongside
protective masks, aprons, and gloves and pre-
prepared kits designed for the management of
unexpected extravasation or spillage of cyto-
toxic agents.
In a short series of 37 patients receiving
chemotherapy while on ICU, 33% were still
alive 6 months later.5
Advance Access publication 17 September, 2010
ICU and haematological malignancy
Table 1 Some common complications associated with chemotherapy agents
Complications Associated chemotherapy agents
Idiopathic interstitial pneumonitis Cyclophosphamide
Pulmonary fibrosis Bleomycin; high-dose methotrexate
Haemorrhagic cystitis Cyclophosphamide
Hypertension Cyclosporin
Cardiomyopathy Doxorubicin
Thrombotic thrombocytopaenic purpura Cyclosporin, tacrolimus
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 busul-
phan 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 myeloabla-
tive allografts (39.2%), and reduced intensity conditioning allo-
grafts (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.
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 remem-
bered that the absolute relative neutrophil count may still be low in
patients with high white cell counts in whom only a small fraction
Fig 1 Types of HSCT donors.
168 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 10 Number 6 2010
Table 2 Complications of stem cell transplant
Early complications (usually ,100 days) Late complications
(usually .100 days)
Infections Infections
Haemorrhage Chronic GVHD
Acute GVHD Chronic pulmonary disease
Graft failure (especially aplastic anaemia) Autoimmune disorders
Haemorrhagic cystitis Cataract
Interstitial pneumonitis Infertility
Others, including veno-occlusive disease, Second malignancies
cardiac failure
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are neutrophils. Neutropaenic patients are at substantial risk of infec-
tions, especially unusual or atypical infections, including fungal or
viral infections. Patients are often on prophylactic anti-fungal, anti-
viral, 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 catheteriza-
tion, 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 clas-
sical 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 essen-
tial in tailoring antimicrobial therapy to local resistances (e.g. ami-
kacin may be preferable to gentamicin where there is an increased

risk of resistant pseudomonal infections). Even when a likely
pathogen is isolated, it is common for a broad range of antimicro-
bial therapy to be maintained. Persistent or recurrent fever in neu-
tropaenic patients despite adequate antibacterial cover should
prompt consideration of fungal infection with a computed tomogra-
phy (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.
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 mechan-
ical 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 mechan-
ical ventilation may improve survival.6
The presence of infection is often hard to prove, and bronchoal-
veolar 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 malig-
nancy 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 haem-
orrhage) 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 main-
tain patients not expected to undergo such procedures is less clear
and counts above 10 –20109 litre21 are often considered accepta-
ble. There is no clear consensus as to what level is required to
safely insert a central venous catheter under ultrasound guidance,
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 10 Number 6 2010
ICU and haematological malignancy
particularly when it is required as part of an emergency resuscita-
tion, 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 haema-
tology 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 pre-
and 1 h post-transfusion platelet counts. Where there is little or no
increment, specially ordered HLA-matched platelets may be
required.
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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.
Tumour lysis syndrome
Tumour lysis syndrome is most associated with the acute leukae-
mias and high-grade lymphomas especially Burkitt’s lymphoma.
In certain rare cases, it can happen spontaneously but most com-
monly occurs after treatment with chemotherapy (and occasionally
with single-therapy dexamethasone treatment). It results in poten-
tially 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 main-
stays of therapy. Forced alkaline diuresis has previously been advo-
cated, 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 possi-
bility 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 drow-
siness, coma, and neurological defects and may require therapeutic
apheresis ( plasmapheresis or leucopheresis depending on the
underlying haematological condition). Neurological failure may
169
ICU and haematological malignancy
also be caused by the underlying malignancy or by electrolyte
imbalance.
Hypercoagulable states are associated with many of the under-
lying 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 hypo-
tension. 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 haema-
tological malignancy, although renal failure suspected to be as a
result of the disease itself is not necessarily a bar to treatment.8
Graft-vs-host disease
Acute GVHD typically presents with skin rash, diarrhoea, and
hepatitis. It can also lead to significant thrombocytopaenia, con-
junctivitis, 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 histo-
logically, 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 post-
transplant, 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 cyclos-
porin or mycophenolate mofetil, and occasionally extra-corporeal
phototherapy, although the latter requires the patient to be
170 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 10 Number 6 2010
Table 3 Scoring systems for GVHD
The Seattle scoring system for graft-vs-host disease
Stage Skin rash Liver Gut (diarrhoea,
(typically face, palms, soles, ears) (bilirubin, litre day21)
mmol litre21)
1 Rash ,25% 20 –35 0.5 – 1
2 Rash 25 –50% 35 –80 1 –1.5
3 Erythroderma 80 –150 1.5 – 2.5
4 Bullae, desquamation .150 .2.5 (pain, ileus)
Overall grading of acute graft-vs-host disease
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100 day survival
I Stage 1 or 2 skin, no gut or liver involvement 78 – 90%
II Stage 1–3 skin; with stage 1 gut or liver; mild 66 – 92%
decrease in performance status
III Stage 2–3 skin; with stage 2– 4 gut or stage 29 – 62%
2–3 liver; marked decrease in performance status
IV Similar to grade III; with stage 4 gut or liver; 23 – 25%
extreme decrease in performance status
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 differ-
ent 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 malig-
nancy requiring ICU support.
A review in 2003 found a wide variation in the reported survi-
val 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

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 predo-
minantly 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 pres-
ence of co-morbidities, and their current condition and should be
made after informed discussion with the referring team and the
patient or their representative.
Conflict of interest
None declared.
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Please see multiple choice questions 1– 4.
171