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Eur J Haematoll998: 60: 1-6 Copyright 0 Munksgaard 1998
Printed in U K all rights reserved
~

EUROPEAN
JOURNAL OF HAEMATOLOGY
ISSN 0902-4441

Review Article
The management of crisis in sickle cell
disease
Okpala I. The management of crisis in sickle cell disease. lheanyi Okpala
Eur J Haematol 1998: 60: 1-6. 0 Munksgaard 1998. Haematology Department, The Central Sheffield
University Hospitals, Royal Hallamshire Hospital,
Sheffield S10 ZJF, UK
Tel: 44-114 271 1731
Abstract: The symptoms and signs of sickle cell disease are exacerbated in Fax: 44-114 271 1733
times of crisis, characterized by tissue infarction or worsening anaemia.
Prompt medical intervention is required in these distressing situations to
provide relief and comfort to the patient. Effective analgesia is crucial in
treating the painful crisis of sickle cell disease. The haemoglobinopathy may
cause hyposthenuria with reduced ability to excrete the sodium load in
normal saline. A 5% dextrose solution or 5% dextrose in 25% normal saline
is therefore recommended for intravenous hydration. As the leading cause
of morbidity and mortality in sickle cell disease, infections call for vigorous
antibiotic therapy. Oxygen administration should be reserved for hypoxic
patients, and blood transfusion given only when really indicated. Acute chest
syndrome and cerebrovascular accidents are life-threatening complications Key words: sickle cell disease - crisis - treatment
of sickle cell disease whereas priapism can cause important long-term Correspondence: Or I.E. Okpala MSc, MRCPath,
sequelae; all deserve urgent attention. In the long term, comprehensive care FWACP. Haematology Department. The Central
is cost-effective in reducing the frequency and adverse effects of sickle cell Sheffield University Hospitals, Royal Hallamshire
I crisis. Hospital, Sheffield S10 2JF. UK

The first recorded description of the crisis now
recognized as a feature of sickle cell disease was
by Africanus Horton, who noted the bone pains
and the association with fever and cold weather (1).
The illness must have sustained the interest of
medical scientists because by the beginning of this
century Herrick had discovered the cellular basis
of painful crisis (2) and, 75 years after Horton's
account, sickle cell anaemia became the first
human disease to be described at the molecular
level (3). Haemoglobin S (HbS) is the result of a
point mutation in the sixth codon of the P-globin
gene (GAT+G?T), so that the 6th amino acid in
P-globin is valine instead of glutamic acid, as found
in normal haemoglobin (HbA). Sickle cell disease
(SCD) is a generic term which includes sickle cell
anaemia (HbSS), sickle cell haemoglobin C disease
(HbSC), sickle cell thalassqemia disease (Shhal)
and other compound heterozygous conditions
which have in common the inheritance of the sickle
P-globin gene and also cause clinical disease. It
does not include sickle cell trait (HbAS). With the
facility of modern travelling, human societies in
various parts of the globe are becoming more
cosmopolitan and multicultural. There is an
increasing probability of a patient in sickle cell
crisis needing emergency medical treatment in a
geographical region with a historically low preva-
lence of the globin gene disorders. This concise
article will therefore focus on the practical man-
agement of crises in SCD. The clinical and labora-
tory criteria required for initial diagnosis of the
haemoglobinopathy have been discussed in other
publications (4-6).
Crises
Crisis is an acute exacerbation of the symptoms and
signs of sickle cell disease;' usually associated with
pain due to tissue infarction and/or drop in Hb level
below the steady state value. Conditions which
could predispose to crisis include infection, dehy-
dration, cold weather, physical stress and psycho-
logical stress. However, a significant number of
patients in crisis do not present with any identifi-
able precipitating factor. The aims of management
are to keep the patient comfortable in a quiet
environment, achieve adequate pain control, give

1

Okpala
Table 1. Investigations in sickle cell crisis
Full blood count
Reticulocyte count
Examination of blood film
Plasma bilirubin level, total and conjugated
Serum urea, electrolytes and creatinine
Culture of blood, urine and sputum for microbes
Chest radiography
Pulse oximetry
Arterial blood gases if SaO, <92%
optimal hydration, treat intercurrent infections,
transfuse blood if necessary and attend to other
urgent clinical problems such as cerebrovascular
accidents, priapism and the acute chest syndrome.
Some of the investigations which influence specific
diagnosis and treatment are shown in Table 1.
Vaso-occlusive (painful) crisis
Vaso-occlusive (painful) crisis is the most common
type in sickle cell disease, and the most frequent
reason for hospital attendance (7). It is the result
of tissue ischaemia and infarction caused by the
obstruction of blood vessels, a process in which the
role of sickled erythrocytes has been well recog-
nized (8). Recent findings suggest that, in addition,
the vascular endothelium, humoral factors and
even white blood cells might contribute to the
pathophysiology of vaso-occlusive crisis (9, 10).
The clinical severity of sickle cell anaemia increases
with absolute neutrophil count, and leucocytosis is
associated with a higher mortality rate (11, 12).
Also, clinical improvement in SCD patients on
hydroxyurea trial therapy coincided with decrease
in leucocyte count (13, 14); in some individuals
even before a rise in haemoglobin F level could be
detected. The possible role of white blood cells in
the vaso-occlusive events which characterize SCD
is intriguing and merits further study. The hallmark
of the clinical presentation of vaso-occlusive crisis
is skeletal or soft tissue (infarctive) pain of acute
onset. There may be history or features of the
predisposing factor(s). The most important aspect
of treatment is effective analgesia; providing relief
from the distressing pain wins the patient’s confi-
dence and cooperation. The trick of the trade is not
just to know, but also to apply the fact that each
individual is unique with respect to pain threshold,
and therefore response to pain. This is probably
the reason that patient-controlled analgesia can
produce satisfactory results (15). This personal
variation in pain threshold notwithstanding, some
general suggestions could still be made. For mild/
moderate pain, and in those who request not to
2
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have opiates, a nonsteroidal anti-inflammatory
drug (NSAID) such as diclofenac (voltarol) could
be sufficient. NSAIDs are contraindicated in
patients who have significant impairment of kidney
function. In severe pain morphine is preferred to
pethidine not only because the former has a longer
duration of action, but also because of the accumu-
lation of norpethidine, the toxic neuro-excitatory
metabolite of pethidine (16). An initial subcutane-
ous dose of 10 mg morphine in adults weighing up
to 50 kg (or 5 mg in adults <50 kg) is followed by
infusion of 150 pg/kg/h (about 1mg/h for the aver-
age 70 kg adult), with an antiemetic. In centres
where diamorphine is used equivalent doses are
given. It is crucial to monitor respiratory rate and
oxygen saturation in view of the respiratory depres-
sant effects of these opiates. All patients, and
especially those who have chest pain, should be
encouraged to breathe as deeply as their pain
allows, to facilitate lung expansion and reduce the
chances of developing the acute chest syndrome
(ACS) which has a striking association with vaso-
occlusive crisis in adults (17). With adequate anal-
gesia, most patients can switch to oral drugs within
24h and be discharged if there is no need for
admission. A laxative should be prescribed
together with oral opiates; no more than a 5-d
supply of the latter should be given at a time to
discourage drug dependence and possible addic-
tion. Patients in painful crisis tend to have reduced
intake of food and water. Hydration should be
optimal, but not too vigorous, again to prevent
pulmonary oedema and the development of ACS.
A total daily fluid intake (oral+parenteral) of 1.5
L/m2 is recommended. Equally important is the
type of fluid infused. SCD patients may have
hyposthenuria (inability to concentrate the urine)
and cannot excrete the sodium load in normal
saline (18). High plasma osmolality leads to intra-
cellular dehydration of the erythrocytes, more sick-
ling, increased vaso-occlusion and worsening of the
crisis. A 5% dextrose solution or 5% dextrose in
25% normal saline is the intravenous fluid of
choice. Simple (top-up) blood transfusion is indi-
cated when there are acute symptoms of anaemia
or the absolute haemoglobin concentration is
<6g/dl. The objective of blood transfusion is to
abolish acute symptoms of anaemia, usually by
bringing the Hb level up to the patient’s steady
state value if that is known. To minimize alloanti-
body formation, SCD patients should be given
blood matched for the 6 blood group antigens
which most frequently cause alloimmunization: K,
C, E, S, Fy and Jk (19). Oxygen administration is
needed only if there is hypoxia. HbS has a lower
oxygen affinity than HbA, and so a different
oxygen dissociation curve. As a result correlation

between pulse oximetry readings and arterial blood
oxygen partial pressure in SCD patients is poorer
than in normal individuals. It is therefore important
to confirm desaturation noted on pulse oximetry
by measuring the partial pressure of oxygen in
arterial blood. The presence of hypoxaemia should
alert one to look out for the other features of the
acute chest syndrome. If the patient is febrile
broad-spectrum antibiotic therapy should be
started once samples of blood, urine or other
relevant specimens have been taken for bacteri-
ology. Chike Hedo and co-workers have observed
various immunological abnormalities in sickle cell
anaemia; a number of which correlate with disease
severity (11,20,21). In addition, hyposplenism is a
well-recognized feature of this haemoglobinopathy.
It is therefore hardly surprising that infection is the
most common cause of morbidity among all indi-
viduals with SCD, and of mortality in paediatric
patients (22). It is pertinent to point out that the
differential diagnosis of abdominal soft tissue vaso-
occlusive crisis from a surgical acute abdomen can
sometimes be difficult. In such cases a surgeon
should be invited to join in the management.
Surgical operation should be delayed for as long as
it is safe to do so, while medical treatment of vaso-
occlusive crisis is continued. If the patient’s clinical
condition deteriorates despite conservative man-
agement, surgical intervention is warranted.
Sequestration crisis
Sequestration crisis results from an acute seques-
tration of large amounts of blood, usually in the
spleen, and sometimes in the liver. The clinical
features are marked pallor, sudden and progressive
enlargement of the spleen or liver and “hypovol-
aemic” shock, since much of the blood volume is
pooled in the spleen. The fall in haemoglobin level
is precipitous, and can reach 1.5 g/dl within 6 h. This
type of crisis usually occurs in children under 6 yr,
but could be seen in adult HbS+C and S/B thalas-
saemia patients who are more likely to have
enlarged spleens. It is unusual in adult Hb SS
individuals because of autosplenectomy. Since
erythropoiesis is not shut down, there is reticulo-
cytosis and/or increased number of nucleated
RBCs in the blood film. These differentiate seques-
tration from aplastic crisis, and are of practical
importance because aplastic crisis could develop in
a patient with pre-existing splenomegaly or
hepatomegaly. Rapid (simple) transfusion of red
cell concentrate confers clinical benefit and may be
the only practicable life-saving measure in a child
who needs immediate treatment. The Hb usually
rises = 3 g/dl more than would be expected from
the number of units transfused, as the spleen
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Treatment of sickle cell crisis
shrinks and pushes out the red cells it trapped.
When feasible, emergency exchange blood transfu-
sion (EBT) is an alternative measure. Sequestra-
tion crisis is a life-threatening event and was the
leading cause of early mortality in the Jamaican
cohort study (23). In view of the high rate of
recurrence (about 50%), splenectomy has been
advocated in children aged >2 yr who have a single
severe episode or less severe recurrent episodes
(24). In Jamaica this practice has reduced mortality
from sequestration crisis (25). There is no obvious
reason why this cannot be achieved in other parts
of the world which, like Jamaica, are non-endemic
for malaria. For patients who live in or regularly
visit malaria endemic regions, childhood splenec-
tomy may not be advisable because of the risk of
mortality from cerebral malaria. In such cases
elective E B T followed by a hyper-transfusion pro-
gramme could reduce the incidence of recurrent
sequestration crises and the associated mortality
(24). Whatever the geographical location, educa-
tion of parents and other carers on how to detect
conjuctival pallor and a rapidly enlarging spleen or
liver in the early phases of sequestration crisis is a
worthwhile, life-saving exercise.
Aplastic crisis
Aplastic crisis is a misnomer because only the red
cell count is reduced; the leucocyte and platelet
counts are usually unchanged. The condition is an
acutely acquired type of pure red cell aplasia which
results from a maturation arrest of bone marrow
erythroid precursor cells at the pronormoblast/
early normoblast stage. The majority of cases are
associated with infection by the parvovirus B19
(26), although other pathogens have been reported
to cause a similar illness (27).The only parvovirus
known to be pathogenic in humans, B19 replicates
exclusively in the bone marrow red cell precursors.
The biological basis of this erythroid tropism is that
the P blood group antigen (globoside) serves as the
receptor for the parvovirus (28).Aplastic crisis is
characterized by reticulocytopenia (retic count
<2%), symptomatic anaemia, serum IgM antibod-
ies to parvovirus B19, the presence of B19 DNA
in the serum or bone marrpw cells and fever due
to the viral infection. It is more common in children
than in adults, possibly because of previous expo-
sure and immunity to the virus. Transfusion of red
cell concentrate is the mainstay of treatment. The
target Hb level is the patient’s steady state value.
Higher concentrations could inhibit red cell pro-
duction and delay marrow recovery. The parvovirus
infection usually runs its natural course and has no
effective specific treatment. Although intravenous
immunoglobulin has been used in immunodeficient
3

Okpala
individuals this has not been found necessary in
SCD. Aplastic crisis hardly recurs probably because
the immunity acquired from a single parvovirus
infection is lifelong in people who do not have
severe immune deficiency. A vaccine against par-
vovirus B19 has been developed and is awaiting
clinical trial.
Urgent clinical problems
Acute chest syndrome
Acute chest syndrome (ACS) is the leading cause
of mortality in adults who have sickle cell disease
(29). It is characterized by fever, cough, chest pain,
respiratory distress, hypoxia, new pulmonary opac-
ities on the chest radiograph, worsening anaemia,
rapid clinical progression and antecedent painful
crisis in about 50% of adults but less than 20% of
children (17). The causes include lung infection,
lung infarction, and pulmonary fat embolisim (30).
With respect to the causative role of fat emboli,
Styles and co-workers have observed that serum
levels of secretory phospholipase A, (sPLA,) are
markedly raised in ACS, and that the rise often
occurs in patients who had a preceding painful
crisis before the features of the chest syndrome are
apparent (31). Serial measurement of serum sPLA,
during vaso-occlusive crisis may therefore have the
potential to enable clinicians to predict impending
ACS and institute early treatment. As far as treat-
ment in the emergency situation is concerned, it is
largely academic whether the underlying cause is
lung infection or infarction. In practice both are
assumed to be present and treated. Oxygen admin-
istration is required if there is hypoxia. Routine 0,
therapy in nonhypoxic patients has not shown
unequivocal benefit, and high blood PaO, might
suppress erythropoiesis. Broad-spectrum antibiotic
therapy (e.g cefuroxime + erythromycin) is impor-
tant because various bacteria, as well as myco-
plasma and chlamydia, have been implicated in the
aetiology (32). Optimal hydration with appropriate
fluids is desirable, taking care to avoid lung
oedema. Fluid balance should be monitored and
the patient weighed daily. For pulmonary oedema
or fluid overload gentle diuresis is recommended,
to avoid tipping the balance towards dehydration.
Effective analgesia is needed for painful crisis,
especially when there is chest pain which may
inhibit chest expansion. The patient should be
encouraged to breathe as deeply as possible to
minimize the chances of atelectesis. Some authori-
ties recommend a nebulized bronchodilator (33).
Considering the risks of post-transfusion lung
oedema, blood-borne infections from multiple
donor exposure and transfusion reactions, EBT
4
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should not be performed routinely in all cases of
ACS. Patients with P,O, >60mmHg (>8 kPa)
could have a simple blood transfusion to raise the
Hb level to 10g/dl. EBT is recommended
for individuals who have severe hypoxia
(P,O, <60 mmHg) (reference values: 75- 100 mmHg;
10-13.3 kPa). The prevention of acute chest syn-
drome is clearly desirable because it is a major
cause of death in SCD. Hydroxyurea therapy (13)
and chronic hypertransfusion (34) have each
proven effective in reducing the incidence of recur-
rent ACS. Haemopoietic cell transplantation is
being assessed.
Cerebrovascular accident
Cerebrovascular accident (CVA) is caused by the
occlusion of an intracranial blood vessel by sickled
red cells, resulting in acute cerebral infarction.
Intracranial bleeding could also occur. It is a
devastating complication of SCD and needs urgent
medical attention. The presenting features include
headache, vomiting, convulsion, transient ischae-
mic attacks, sudden diminution or loss of conscious-
ness, and even sudden death. Cerebral infarction
or haemorrhage may be detected with the aid of
computed tomography (CT) or magnetic resonance
imaging (MRI). Joint management with neurolo-
gists is desirable. Cerebrovascular accident is an
indication for urgent EBT to reduce the HbS to
<30% while keeping the haematocrit <0.33. In an
adult SCD patient weighing at least 50 kg with
haematocrit 0.20-0.27, 500 ml of blood is removed
by venesection, followed by the intravenous infu-
sion of 500 ml of 5% dextrose in 25% normal
saline. A second 500 ml of blood is then removed
and the patient rapidly transfused with 5 units of
red cell concentrate, prewarmed to prevent the
development of chills. Blood cell apheresis
machines are becoming more widely available and
can be used for EBT. Automated EBT using an
apheresis machine achieves a higher volume
exchange, is more efficient, and certainly less labo-
rious than the manual method. The YOHbS in the
patient after the EBT qnd the haematocrit should
be determined on a blood sample taken when
adequate time has been given for thorough equili-
bration in vivo. Recovery from CVA could be
incomplete with residual paralysis or paresis,
although some patients achieve apparently full
recovery with no gross neurological deficits. In the
long term, hypertransfusion is required to prevent
recurrence.
In contrast to CVA, another “cranial” event
which occurs in SCD, but is not life-threatening, is
cephalhaematoma (35, 36). These subperiosteal
haemorrhages of the skull bones do not cross the

suture lines. Headache is the main presenting com-
plaint, the haematoma usually resolves within a
fortnight, and no coagulation abnormalities were
detected in one series (37). The parietal bone is
most often affected and, when bilateral, the patient
has a “mickey mouse” appearance, if alarmed by
the rather perplexing swellings. Management is
conservative with analgesics and intravenous fluids.
There is no need to aspirate the cephalhaematoma
because spontaneous resolution is the rule, and
infection may be introduced by the procedure.
Priapism
A significant but difficult to ascertain proportion
of males with SCD have recurrent but short-lived
episodes of (stuttering) priapism. These do not
always come to the attention of doctors because
the patients have devised their own ways of dealing
with the problem, or are simply shy. Patients should
be encouraged to seek medical attention for pria-
pism lasting >2 h, to facilitate early treatment and
minimize the chances of permanent loss of erectile
function and its psychosocial effects on affected
people (38). Much of the treatment is within the
province of the urosurgeon, who should be
involved as early as possible. Even with early
medical attention the results of treatment are not
satisfactory, and randomized clinical studies are
required to guide us in the future (39). During
history-taking from an SCD patient with priapism
one should find out when the priapism started,
whether there has been a previous prolonged epi-
sode of more than 2 h duration (especially episodes
lasting >6 h, known as fulminant priapism), and if
there is inability to pass urine. Physical examina-
tion, in addition to the general, should be aimed at
ascertaining whether the glans penis is soft, i.e. only
the cavernosa area is painful and hard. This is
important because if the glans is soft and the
patient is able to micturate, the corpus spongiosum
is not involved, and a glans-cavernosa shunt could
be beneficial. Urinary obstruction and engorge-
ment of the glans imply involvement of the corpus
spongiosum, suggesting that the cavernosa is prob-
ably infarcted, and a glans-cavernosa shunt will
not produce a good result. Conservative manage-
ment of priapism includes analgesia, optimal
hydration, anxiolytic therapy and EBT. In young
children such measures are usually effective and
should be tried during the first 12 h. If the child
improves it is continued until detumescence is
achieved. If the penile shaft has not softened after
12 h, the urosurgeon should aspirate and irrigate
the cavernosa. In adults, earlier surgical interven-
tion is warranted because medical treatment is less
beneficial. However, recent reports suggest that the
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Treatment of sickle cell crisis
alpha adrenergic stimulant etilefrine, injected into
the corpus cavernosum, is beneficial in prolonged
priapism (40). Other workers have used phenyle-
phrine 0.5 mg intracorporally for fulminant cases
(41). EBT is not of proven efficacy in adults,
possibly because the greatly reduced penile blood
circulation which occurs in priapism does not allow
inflow of a significant amount of the transfused
normal red cells. There might be subtle differences
in the physiology of penile erection between sexu-
ally mature adults and prepubertal children, which
may underlie the better response to conservative
treatment of priapism in the latter. There are a
number of options in surgical treatment. Aspira-
tion and irrigation of the corpora cavernosa
reduces the turgidity, pain, discomfort and anxiety.
It is most effective if performed within hours of
onset, and is seldom helpful 2 d after the priapism
started, or if there has been a previous prolonged
episode. Glans-cavernosa shunting is beneficial if
the corpus spongiosum is not affected, and gives
best results within a day of the onset (42). Other
types of shunting (e.g. dorsal vein-cavernosa
shunt) are needed when the spongiosum is
involved. Oral etilefrine 25 mg at night has been
found effective in preventing recurrent priapism
(40, 41). Patients who have permanent erectile
failure could benefit from penile prostheses.
Beyond the emergency room
A holistic approach is required for efficient man-
agement of sickle cell disease (43). This strategy is
similar to the comprehensive care of haemophili-
acs. Counselling the patient on the need to avoid
the conditions which predispose to crisis, as well as
psychosocial support services help to reduce the
frequency of crises. In the final analysis these
measures are cost effective and worth the time
spent. Education of parents and other carers is also
important. For example, in Jamaica, the parents’
ability to detect the rapidly enlarging spleen in the
early phase of sequestration crisis reduced the
mortality from this life-threatening event by 90%
(44). Simple measures can be that effective.
Acknowledgements
The author would like to thank Drs D.A. Winfield, J.T. Reilly,
M. Makris, A.J. Vora, G.U. Lekwuwa, G.C. Lekwuwa and J.U.
Okpala for helpful comments, and Janet Woolley for secretarial
assistance.
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