Paediatric Anaesthesia 2003 13: 375–383

Review article
Considerations for anaesthesia in children
with haematological malignancy undergoing
short procedures
V A L E R I E C U LS H A W F R C A * , M U R R A Y Y U L E MRCPaed†
AND ROS LAWSON FRCA‡
*Department of Anaesthesia, Victoria Infirmary, Glasgow, †Medical Advisor )
Oncology ⁄ Haematology, Eisai Ltd, London and ‡Department of Anaesthesia,
Royal Hospital for Sick Children, Glasgow, UK

Summary
As a result of increased use of risk-directed treatment regimes, there is
a regular requirement for short-lasting but painful procedures to be
performed on children to aid in diagnosis or treatment. The aim of any
anaesthetic technique is to provide analgesia and amnesia with
minimal side-effects and early return to former activity levels. We
review the implications of haematological malignancy in children
with regard to anaesthesia and the consequences arising from both the
disease and ensuing treatment. We outline some of the current
anaesthetic techniques in use and review the advantages and
disadvantages of each.

Keywords: haematology; malignancy; anaesthesia; children

invasive procedures, particularly bone marrow as-

Introduction
pirates and lumbar punctures for the administration
In the UK, cancer affects one in every six hundred of intrathecal chemotherapy. Parental preference and
children prior to their sixteenth birthday. The most an increased awareness of the limitations of sedation
common paediatric malignancy is acute leukaemia, have led to many of these investigations being
which has a peak incidence between 2–5 years of age. performed under general anaesthesia. The wide-
Intracranial tumours are the most frequent nonhaem- spread use of intrathecal methotrexate as central
atological malignancy followed by neuroblastoma, nervous system prophylaxis in preference to cranial
Wilm’s tumour, non-Hodgkin’s Lymphoma (NHL) irradiation has considerably increased the number of
and various bone and soft tissue sarcomas. During children receiving repeated lumbar punctures dur-
the last two decades, the development of centralized ing therapy. In addition, treatment strategies have
care facilities, national treatment protocols and become increasingly
risk-directed in an effort to
multidisciplinary therapies has produced overall individualize therapy to patients and their disease
5-year survival rates in excess of 60% (1). This has (2). This approach requires multiple marrow aspir-
been achieved at the expense of a wider use of ates during treatment in order to assess ongoing
response upon which subsequent chemotherapy
Correspondence to: Valerie Culshaw, Department of Anaesthesia,
Victoria Infirmary, Langside Road, Glasgow G42 9TY, UK (email: decisions are based. These changes have produced
[email protected]). an increasing number of children requiring short and

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376 V. CULSHAW ET AL.

repeated anaesthetics for invasive procedures. For- (Figure 1). Patients at particular risk are those with
tunately, most of these investigations are performed acute lymphoblastic leukaemia (especially those with
electively and can be postponed in the face of a T-cell phenotype and a high white cell count), NHL,
intercurrent illness. The most common exceptions Hodgkin’s disease, neuroblastoma and, more rarely,
to this are the newly presenting patient in whom a intrathoracic germ cell tumours. In these cases, it is
tissue diagnosis is often paramount in order to start well documented that anaesthesia may cause sudden
treatment and children with an ongoing central and potentially fatal respiratory embarrassment as
venous line infection requiring urgent removal. resting airway muscle tone is abolished (3,4).
The aim of this review is to identify suitable Computed tomagraphy (CT) is often advocated in
techniques for children with haematological malig- the initial assessment of the severity of the obstruc-
nancy who require anaesthesia and to highlight tion (5). In the small child, however, anaesthesia may
some of the potential hazards presented by this still be required to obtain adequate CT imaging.
group of patients. Careful preoperative assessment is essential to elu-
cidate the potential risks, although the severity of a
lesion may not become apparent until loss of
Disease and treatment factors influencing consciousness has ensued (Figure 2).
anaesthesia In such cases, full provision for a potentially
obstructed airway must be in place. This usually
Airway obstruction
means the presence of an ENT surgeon capable of
The most common cause of airway obstruction in inserting a rigid bronchoscope and some centres
children with cancer is the presence of a mediastinal even advocate the availability of cardiopulmonary
mass, which is most often found at presentation bypass (6). An inhalational induction with the main-
tenance of spontaneous respiration is recommended

Figure 1 Figure 2
Chest X-ray of a 3-year-old girl with T-cell acute lymphoblastic CT scan of an 11-year-old boy with NHL who presented with a
leukaemia who presented with respiratory distress as a result of mediastinal mass, following treatment with steroids demonstra-
an extensive mediastinal mass. ting patency of the major airways.

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 A N A E S T H E S I A IN C H I L D R E N WI T H H A E M A T O L O G I C A L M A L I G N A N C Y 377

because this minimizes the loss of airway tone and pitation with a rapidly rising serum potassium.
thus compression of the airway. This may best be Increased serum phosphate concentrations may be
performed with the patient in a semisitting position. accompanied by hypocalcaemic seizures. Haemofil-
In a proportion of patients, the diagnosis may have tration can be avoided in the majority of cases by
to be made from cells obtained from an accompany- prophylactic allopurinol and hyperhydration.
ing pleural effusion or a marrow aspirate performed Patients considered to be at high risk of urate
under local anaesthesia. In an emergency situation nephropathy are often alkalinized with sodium
where no diagnostic procedures are without risk, bicarbonate, which may result in problematic carbon
lymphoid malignancies may be identified by their dioxide retention (10,11). Red cell transfusion may
location as an anterior mediastinal mass and their be inappropriate in children with acute leukaemia
rapid response to corticosteroids. who present with peripheral blast counts of greater
than 100 · 109Æl)1 because of the risk of precipitating
the hyperviscosity syndrome.
Coagulopathy
Thrombocytopaenia is an invariable consequence of
Infection
most cytotoxic drugs and should be screened for
preoperatively. In order to reduce the risk of The intensification of paediatric chemotherapy reg-
paraspinal haematoma formation, it is our practice imens has resulted in periods of prolonged neutro-
only to perform lumbar punctures in the presence of paenia accompanied by bacterial and fungal sepsis
a normal coagulation screen and a platelet count of (12). In many cases, the risk of infection is heigh-
at least 50 · 109Æl)1. Children who have received tened by the presence of an indwelling central
multiple platelet transfusions may become refractory venous catheter which may necessitate urgent atten-
to random donor platelets and, in such cases, single- tion. Although it is possible to control florid sepsis
donor or human leukocyte antigen-matched plate- prior to surgery in the majority of cases, often by
lets may be required (7). It is prudent to confirm an ceasing to use an infected central line, a small
adequate increment immediately following platelet number of patients may not respond to antibiotics
transfusion in multiply transfused children prior to prior to its removal. In these circumstances, it may
invasive procedures. The consequences of local be unavoidable to administer a general anaesthetic
bleeding following marrow aspiration are less severe to a febrile septic patient. It is wise to avoid using a
and this technique can performed safely by an central line which is known to be infected. Other
experienced operator in the presence of a platelet indications for surgery in infected neutropaenic
count as low as 20 · 109Æl)1. Several groups of patients are rare but include gastrointestinal com-
children are at particular risk from ongoing coagul- plications of treatment, such as volvulus and
opathy, especially patients with active infection, appendicitis. Whilst bacterial pneumonias are com-
acute promyelocytic leukaemia and disseminated mon, particular care should also be taken in children
neuroblastoma (8,9). Where possible, deranged with Streptococcal septicaemias because these are
coagulation parameters should be corrected preop- often accompanied by more subtle respiratory
eratively using group-matched fresh frozen plasma embarrassment (13). Children with neutropaenic
or cryoprecipitate (if plasma fibrinogen is less than sepsis may have a subclinical coagulopathy that
1.5 gÆl)1) using increments of 20 mlÆkg)1. should be corrected prior to theatre. Furthermore,
they are frequently affected by electrolyte distur-
bances, particularly hypokalaemia, following treat-
Tumour lysis syndrome
ment with diuretics, aminoglycoside antibiotics and
Patients with a large tumour bulk at presentation, amphotericin B.
usually those with acute leukaemia or NHL, may
experience the rapid death of large numbers of
Complications of therapy
malignant cells following induction chemotherapy.
This tumour lysis leads to progressive renal impair- Most currently used cytotoxic agents produce
ment from urate nephropathy and phosphate preci- varying degrees of dose-dependent bone marrow

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378 V. CULSHAW ET AL.

suppression and, in particular, some are associated drug mixing. At present, the most commonly
with severe mucositis (cytarabine, melphalan, anth- encountered situations are children receiving pro-
racyclines). Several categories of drugs pose further longed infusions of
high-dose methotrexate for the
hazards to anaesthesia, as outlined in Table 1. treatment of acute leukaemia or NHL. Although the
Refractory emesis is now rare following the intro- methotrexate infusion must be completed prior to
duction of 5-hydroxytryptamine antagonists. the patient’s arrival in theatre (see below), it is
Despite the widespread use of corticosteroids for necessary to continue with intravenous bicarbonate
their lymphocytoxic, antiemetic and immunosup- hydration for at least 72 h in order to increase renal
pressive properties, the incidence of steroid-induced elimination of methotrexate. All patients undergoing
adrenal crisis in children receiving chemotherapy is such therapy will have a double-lumen central
very low. We were unable to find a single docu- venous line in situ and, whilst the bicarbonate
mented report of this in the literature. This may infusion should not be discontinued, the uninvolved
reflect their use in short courses lasting up to 1 week. lumen may be used for the administration of
Routine hydrocortisone supplementation is not anaesthetic drugs. It is also imperative to flush any
given prior to a short procedure. anaesthetic agents through the line deadspace after
Ideally, children undergoing elective procedures administration. Anthracyline infusions (most com-
should not arrive in theatre with infusions of monly involving daunorubicin or doxorubicin)
cytotoxic drugs or hydration regimens still running should be discontinued prior to theatre because of
because it is often unclear as to whether these can be their cardiodepressant property (14).
interrupted to provide venous access or whether A minority of patients, usually those with bone
individual drugs are compatible with anaesthetic and soft tissue sarcomas, will have received prior
agents. The literature is scarce regarding the com- radiotherapy. Although severe mucositis may occur
patibility of individual cytotoxic agents with anaes- as an acute complication, the long-term effects of
thetic agents and it is prudent to avoid any form of localized radiotherapy are unlikely to increase

Table 1
Potential anaesthetic hazards of commonly used cytotoxic drugs

Cytotoxic drug Common usage Early complications of therapy Long-term hazards

Vincristine ALL SIADH Peripheral neuropathy

Anthracyclines (daunorubicin, Acute leukaemia, STS, NHL, Cardiomyopathy, Cardiac failurea
doxorubicin, epirubicin, bone tumours, Wilms’ tumour, cardiac arrhythmias
mitozantrone) neuroblastoma, Hodgkin’s disease
Cyclophosphamide NHL, BMT, STS, neuroblastoma Cardiomypathyb, Pulmonary fibrosis
cardiac arrhythmiasb
Ifosfamide NHL, STS, bone tumours Fanconi’s syndrome, Fanconi’s syndrome,
renal failure renal failure
Cisplatin Germ cell tumours, Seizures, hypomagnesaemia, Hypomagnesaemia,
neuroblastoma, renal failure renal failure
bone tumours
Nitrosoureas Intracranial tumours None Pulmonary fibrosis,
(carmustine, lomustine) renal failure
Bleomycin Germ cell tumours, Allergic reactions Pulmonary fibrosisc,
Hodgkin’s disease Raynauds phenomenon
L-Asparaginase ALL Coagulopathy, hepatitis, None
pancreatitis, allergic reactions
Actinomycin D Wilms’ tumour, STS Coagulopathy, liver failure, RDS None
Busulphan BMT Hepatic veno-occlusive disease, None
seizures
a
Girls, patients treated under the age of 5 years and children who have received high cumulative doses (> 240 mgÆm2 of daunorubicin or
doxorubicin) are at particular risk. bFollowing high-dose therapy, such as that employed as conditioning for bone marrow transplantation
only. cFibrosis may be progressive and oxygen exposure may precipitate respiratory failure. ALL, acute lymphoblastic leukaemia; SIADH,
syndrome of inappropriate antidiuretic hormone secretion; NHL, non-Hodgkin’s lymphoma; BMT, bone marrow transplant; STS, soft
tissue sarcoma; RDS, respiratory distress syndrome.

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the risk of subsequent anaesthesia unless prior if intravenous cannulation is required (19). These
treatment has altered head and neck anatomy. The agents also have a useful place in the provision of
widespread use of bone marrow transplantation has surface anaesthesia when applied to bone marrow or
produced an increasing number of long-term survi- lumbar puncture sites preoperatively (20).
vors who received total body irradiation as condi-
tioning prior to transplant. Many of these patients
Sedation or anaesthesia?
have restrictive defects in pulmonary function that
require monitoring perioperatively (15). Sedation and anaesthesia have been differentiated
by the fact that verbal contact is supposed to be
maintained during sedation but lost during anaes-
Anaesthetic techniques thesia (17). This is an arbitrary definition and has
little application in paediatric practice. Moreover,
General preparation
there is a continuous spectrum between the sedated
Regardless of the proposed technique, normal fast- child and the anaesthetized child and it is difficult to
ing regimes and minimal monitoring standards predict the degree of sedation or anaesthesia that
should apply throughout the perioperative period. will ensue when the patient is given a particular
Many children may be on complicated treatment agent. For this reason, the term anaesthesia is used
protocols and the timing of the procedure may need when describing pharmacological regimes and we
to be based on adherence to a specific protocol. Full advocate the presence of an anaesthetist during all
resuscitation facilities, anaesthetic personnel and procedures.
skilled assistance should be available for all proce- However, a protocol driven sedation regime using
dures where anaesthesia is administered. Documen- chloral hydrate has recently been described with
tation of vital signs and the technique used is regard to the management of children undergoing
mandatory until the child has fully recovered magnetic resonance imaging (MRI) (21).
(16,17).
In our unit, patients are assessed 24 h prior to
Intravenous techniques
anaesthesia. Past medical history, progress of dis-
ease and previous anaesthetic history are evaluated. The most frequently used agents administered
Routine measurements of serum biochemistry, hae- intravenously to provide short-acting anaesthesia
matology and coagulation are made to allow correc- with or without analgesia are propofol, ketamine and
tion of abnormal indices as far as possible and midazolam. These drugs are often used in various
preordering of blood products for the following day. combinations and dosage regimes but are also used
Fit children are then discharged, to return fasted the as the sole anaesthetic agent by some operators.
following morning. Propofol can be used successfully as a single agent
given as an infusion (TIVA) (22–24) or more simply
in increments by the anaesthetist. TIVA compared
Topical analgesia
favourably with a thiopentone and isoflurane tech-
In those children undergoing intensive therapy, nique (25). The use of an infusion pump, providing a
there will be an indwelling tunnelled line obviating controlled rate of infusion, is cited as being inher-
the need for repeated venepuncture (18). Lumens ently safer than bolus dosing (22). However, from a
should be patent and show no evidence of infection. practical point of view with a rapid turnover of
They should be flushed with heparinized saline patients, anaesthetist administered boluses of prop-
prior to anaesthesia, and again subsequent to the ofol can be used efficiently and safely. An initial
procedure, paying particular attention to an aseptic dose of 4 mgÆkg)1 is often required with subsequent
technique. In our unit, it is common practice to use a increments of 1 mgÆkg)1 to maintain anaesthesia
clean but not sterile technique in uncomplicated depending on the stimulus and duration of the
cases with no neutropaenia or suspicion of sepsis. It procedure. The documented antiemetic effect of
is regarded as a standard of care to use topical local propofol, when used without nitrous oxide, has
analgesia, such as EMLA cream or amethocaine gel, an advantage in this patient population (24). As

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380 V. CULSHAW ET AL.

apnoea can occur initially, it is imperative that an Midazolam may be used in abating emergence
anaesthetist is present to maintain and secure the phenomena when ketamine is used (29).
airway if required. Supplemental oxygen is often Ketamine has been studied in combination with
necessary. The combination of propofol and the ultra midazolam. Pellier et al. successfully used ketamine
short-acting opioid remifentanil has been evaluated doses of 1–2 mgÆkg)1 along with 0.025 mgÆkg)1 of
for use in short painful procedures and this further midazolam. The advantages were reported to be a
increases the risk of apnoea, albeit improving con- reduced dose of midazolam, and hence more rapid
ditions and reducing the amount of propofol recovery times, and a reduced incidence of dysphor-
required (26,27). ic reactions (31). In the study of Parker et al., no
Pain on injection when propofol is given into a respiratory support or reversal of sedation was
peripheral vein is commonly experienced. If a claimed to be necessary using a combined keta-
peripheral line is being used, it is important to add mine ⁄ midazolam technique (30).
lidocaine (0.2 mgÆkg)1) to the syringe to attempt to Methohexitone and etomidate have also been
attenuate the discomfort. This complication is obvi- described in techniques for paediatric oncology
ously avoided if given centrally, although the speed procedure management but appear to confer little
of injection may influence how comfortable the child advantage over existing newer agents (32).
finds the induction. A slow induction may avoid Stress and anxiety may affect anaesthetic require-
unpleasant sensations. ment and supplementation of an intravenous tech-
The phencyclidine derivative ketamine has both nique with volatile agent during the procedure may
analgesic and anaesthetic properties, making it a be required.
useful agent for this type of procedure. It also usually
preserves airway reflexes, respiration and cardiovas-
Inhalational agents
cular stability. An initial bolus of 2 mgÆkg)1 will
provide good analgesia for 5–10 min and the drug Induction with an intravenous induction agent and
can easily be given in increments to prolong anaes- maintenance with a volatile agent is frequently used
thesia. Ketamine would appear to potentially have a but, if intravenous access is not preexisting, it is
major role as the main agent in these procedures. often simpler to perform a gaseous induction on a
However, it use is limited by the complication of suitably prepared child. With the introduction of
emergence dreams and hallucinations, making a sevoflurane, this can be well tolerated with an
quiet recovery environment and perhaps the use of extremely rapid induction due to the the low blood
a benzodiazepine imperative. In addition, excessive gas solubility and acceptable odour of the agent.
salivation and hypertension can occur and an anti- Recovery from a short procedure is also rapid for the
sialogogue is recommended. Using a combination of same reason. There is an observed incidence of
drugs may mean that the child takes longer to excitement following sevoflurane anaesthesia but
recover than when a single agent is used and this adequate analgesia postprocedure may minimize
may be less acceptable if early discharge and return this (33). Studies using the other volatile agents
to
street-fitness is desired. The use of ketamine is not have been described but there appears to be little
recommended in intracranial malignancy due to the advantage over sevoflurane other than cost. Recent
consequent effect on intracranial pressure. studies have tended to concentrate on intravenous
The short-acting, water-soluble benzodiazepine, techniques. Prior to the introduction of sevoflurane,
midazolam, has a rapid onset and short duration of Fisher et al. studied 60 children, comparing isoflura-
action and a role in the provision of anxiolysis and ne, enflurane and halothane, and concluded that
amnesia (28,29). It may be usefully employed in rapid recovery times and minimal airway related
combination with a short-acting opioid or ketamine complications made halothane an excellent agent for
(30,31). Adverse effects are few, but will obviously short procedures (34). In their study, isoflurane
increase if given with other sedative agents. The showed the greatest incidence of laryngospasm
recommended dose is up to 0.1 mgÆkg)1, although and coughing. Enflurane had the most rapid recov-
this should be titrated to effect with careful evalu- ery times. There was no difference in nausea or
ation of physical health and concomitant medication. vomiting.

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The issue of adequate anaesthetic gas scavenging Midazolam and S-(+)-ketamine have been used in
arises if these procedures are not being performed in combination rectally for anaesthesia during MRI (38).
the operating department environment, and this is
particularly relevant with respect to the use of
Adjuvant techniques
nitrous oxide.
There have been attempts to analyse individual
patient response to these procedures (41). Beha-
The use of nitrous oxide
vioural technique training has been used in addition
Nitrous oxide with oxygen in the form of Entonox (42). There is little evidence that children as a group
has been advocated as the sole method of anaesthe- habituate to multiple procedures. This may be due to
sia in older children with some success (35). the fact that there is no static stimulus and that there
However, nitrous oxide impairs methionine syn- is a tendency for inconsistencies. For example, there
thetase activity, disturbing folate metabolism and may be a different operator or anaesthetist on
thus vitamin B12 metabolism. Bone marrow sup- several occasions. The number of previous vene-
pression is more likely to occur when exposure to punctures or the presence of scarring from previous
the agent is prolonged but, theoretically, this can still operations also have a role in the stress response.
occur with short periods of administration. In Factors described that influence the response of
patients receiving methotrexate, which also acts by the child, and which may be manipulated, include
impairing folate metabolism and with additional the behaviour of the personnel in the immediate
causes for bone marrow suppression, it would theatre environment, overreassurance, criticism of
appear that the use of nitrous oxide as an adjunct the child and parental anxiety (42). Coping tech-
to anaesthesia should be applied with caution. It is niques for parents are available.
also conceivable that nitrous oxide may reduce the
therapeutic benefit and increase the side-effects of
Postprocedure complications
methotrexate therapy (36,37).
As already emphasized, a full recovery area with
trained staff is mandatory.
Alternative routes of administration
The oral, transmucosal and rectal routes of drug
Postoperative nausea and vomiting (PONV)
administration have also been utilized in the anaes-
thetic management of short procedures using mid- Nausea and vomiting should be treated early. Those
azolam, ketamine and fentanyl (38–40). However, children who have had a prolonged fast and who
the induction may be less predictable and unsuited vomit may require intravenous rehydration. Using a
to longer or more technically difficult procedures. single agent technique without nitrous oxide, the
An alternative to intramuscular injection is always incidence of PONV is very low (24).
preferable.
Midazolam is available only as the bitter-tasting
Pain
i.v. preparation in the UK. For oral use, it can be
disguised in a small amount of sweetened juice or In our experience, children do not experience signi-
paracetamol syrup. This should be administered ficant discomfort following a single bone marrow
30 min before performing the procedure and has a aspirate. Our practice is to infiltrate local anaesthetic

window of full effect of approximately 30 min. only following multiple aspirates and trephine
The fentanyl lollipop for transmucosal adminis- biopsies.
tration as a premedicant or adjunct to anaesthesia
has been studied. The main side-effect is a signifi-
Postdural puncture headache (PDPH)
cant incidence of vomiting. Usual doses are 15–
20 lgÆkg)1. Vital signs remain stable and it has been The incidence of PDPH in children has not been
shown to reduce the pain of minor procedures in studied extensively. This may be the result of under
older children (39). At present, it is not widely used. reporting or a failure to recognize the less-well

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382 V. CULSHAW ET AL.

defined symptoms of this type of headache in the and isolation techniques, one retrospective analysis
younger child. Reported incidences range from reported an improved survival in adults undergoing
8–50% and vary with age (43,44). However, a recent allogeneic bone marrow transplantation nursed in
study has shown that age bears no relation to laminar air flow or HEPA rather than a side room
whether a child experiences a headache after lumbar (48). On a practical level, bedside anaesthesia is
puncture (45). usually rendered impossible by the lack of space
As with adults, the factors influencing PDPH are within air filtration units and there is no alternative
gauge and type of spinal needle and its orientation to using a ward side room or the theatre suite. In the
to dural fibres when lumbar puncture is performed. absence of evidence to the contrary, it is our practice
In addition, the volume of cerebrospinal fluid to transfer patients to the theatre suite where all
drained for sampling, relative to a chemotherapeutic appropriate equipment is readily available, at the
agent injected, may be of relevance. same time ensuring that no unnecessary delays
Children who experience prolonged vomiting occur.
after lumbar puncture may be experiencing PDPH
symptoms. There has been one reported case of
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