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URRENT
C
OPINION

Editorial introductions
Current Opinion in Anesthesiology was launched in 1988. It is one of a successful series of review journals whose
unique format is designed to provide a systematic and critical assessment of the literature as presented in the many
primary journals. The field of anesthesiology is divided into 15 sections that are reviewed once a year. Each
section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that
time. Here we are pleased to introduce the Section Editors for this issue.

SECTION EDITORS
Kristin Engelhard
Dr Kristin Engelhard is Professor
of Anesthesiology and ViceChair of the Department of
Anesthesiology at the University Medical Center of the
Johannes Gutenberg-University
Mainz, Germany. She started
her career in 1995 as a resident
at the Department of Anesthesiology at the Technical University
of Munich, Germany, and received her board certification for anesthesiology in 2003. Since 2004
she has been working at the Department of
Anesthesiology, University Medical Center of
the Johannes Gutenberg-University in Mainz,
Germany, first as Associate Professor and now as
Vice-Chair of the department. The research focus of
Prof. Engelhard includes experimental and clinical
neuroprotection and neuromonitoring and she has
published about 90 peer reviewed articles in this
field of research. Professor Engelhard is a member of
the board of directors of the Society of Neuroscience
in Anesthesiology and Critical Care (SNACC) and
has been president of this society since October
2013. Since 2008 she has been an editorial board
member of the Journal of Neurosurgical Anesthesiology
and she serves as a reviewer in more than ten peer
reviewed journals including Anesthesiology, Anesthesia and Analgesia, Stroke, Journal of Cerebral Blood
Flow and Metabolism, and Neuroscience.

Esther Pogatzki-Zahn
Prof. Esther Pogatzki-Zahn is an
Anesthesiologist and Professor in
the Department of Anesthesiology, Critical Care and Pain Medicine of the University Hospital
Muenster, Germany. She is the
Head of the Acute Pain Service
at the University Hospital of
Muenster and has more than
ten years experience in pain management. Furthermore, she runs
an international well established pain research
laboratory focussing on the neurobiology of acute
and chronic pain. The laboratory integrates results
from different methodologies (e.g. in vivo behavioral, pharmacological, in vivo and in vitro neurophysiological, and in vitro studies of neurons in
slices and in culture) each of which provide complementary insight into the neuropathology of pain.
In addition, Prof. Pogatzki-Zahn’s laboratory is
working with human surrogate models of postoperative and neuropathic pain; she is using quantitative
sensory testing (QST) and imaging techniques like
fMRI and MRS to explore acute and chronic pain in
humans. She is Principal Investigator in a number of
clinical studies und performs quantitative metaanalysis including Cochrane analysis. She has
published a number of journal articles and book
chapters related to pain.
Prof. Pogatzki-Zahn won a number of national
and international research awards including the
¨ nenthal grant 2004, the Sertuerner Preis
EFIC-Gru

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Editorial introductions

2005, the ESA research grant 2005, the IARS research
grant 2006, the Carl-Ludwig-Schleich-Preis 2006, the
Clinical Research Grant 2007 and the IASP collaboration grant 2009. Prof. Pogatzki-Zahn is part of
several national and international boards including
the SIG Acute Pain of the IASP, the board of the
German Society of Pain Research (German subchapter of the IASP), the Acute Pain Board of the DGAI and
BDC and the European Society of Anesthesiologists.
She is an active member of several international
pain, anesthesia and neuroscience societies, a board
member of the German Pain Society and on review
boards of leading journals including Anaesthesiology,
The Journal of Neuroscience, Pain, European Journal of
Pain, Journal of Pain, European Journal of Anaesthesiology and Anesthesia & Analgesia.

Jacques E. Chelly
Dr Chelly is Professor and Vice
Chairman of Clinical Research
for the Department of Anesthesia
at the University of Pittsburgh
School of Medicine, Pittsburgh,
Pennsylvania, USA. Before joining the University of Pittsburgh
in July 2002, Dr Chelly was a
member of the Department of
Anesthesiology first at the Baylor
College of Medicine and second at the University of
Texas at Houston. He received his medical degree
from Necker-Enfants Malades Medical School in
Paris, France and did his anesthesiology and intensive care training at Broussais Hospital in Paris. Dr
Chelly also holds a PhD in pharmacology and a
master’s degree in business administration from
the University of Houston, USA.
Dr Chelly serves many roles in the Department
of Anesthesiology at the University of Pittsburgh

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Medical Center: Director of Orthopaedic Anesthesia
at UPMC Shadyside Hospital, Director of the UPMC
Regional Anesthesia Fellowship Program, and Director of the UPMC Division of Acute Interventional
Perioperative Pain and Regional Anesthesia. He also
holds a secondary appointment in the Department
of Orthopaedic Surgery.
Dr Chelly’s recognized expertise are regional
anesthesia, orthopedic anesthesia, acute pain management, and clinical pharmacology. He is a leader
in the use of continuous nerve block techniques.
During his tenure in Pittsburgh Dr Chelly developed
the largest acute pain and regional fellowship in the
country, training 15 fellows in 2013–14. A prolific
author on the topics of orthopaedic anesthesia and
acute pain management, Dr Chelly has been the
lead author and co-author on nearly 200 scientific
articles and has given more than 400 presentations
to national and international conferences and meetings.
He is the editor and co-editor of three
medical books on nerve block techniques: Peripheral
Nerve Block Technique: A Color Atlas, (three editions)
published by Lippincott, Williams and Wilkins;
Continuous Peripheral Nerve Block Techniques: An Illustrated Guide, published by Mosby in 2001; Ultrasound-Guided Regional Anesthesia and Pain Medicine
published by Lippincott, Williams and Wilkins.
He is an active member of numerous national
and international professional societies including
the Association for University Anesthesiologists
and the Royal Society of Medicine. Dr Chelly serves
as a reviewer in more than 10 peer review journals of
the specialty including Anesthesia and Analgesia,
British Journal of Anesthesia and the Clinical Journal
of Anesthesia. He is a member of the Editorial Board
for the Acute and Perioperative Pain Section of
the Pain Medicine journal. Dr Chelly also serves as
President of the Orthopedic Anesthesia, Pain, and
Rehabilitation Society (OAPRS).

Volume 27 Number 5 October 2014

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REVIEW
URRENT
C
OPINION

What’s new in the management of traumatic brain
injury on neuro ICU?
Dhuleep S. Wijayatilake a,b and Stephen J. Shepherd c

Purpose of review
In recent years, we have begun to better understand how to monitor the injured brain, look for less
common complications and importantly, reduce unnecessary and potentially harmful intervention. However,
the lack of consensus regarding triggers for intervention, best neuromonitoring techniques and
standardization of therapeutic approach is in need of more careful study. This review covers the most
recent evidence within this exciting and dynamic field.
Recent findings
The role of intracranial pressure monitoring has been challenged; however, it still remains a cornerstone in
the management of the severely brain-injured patient and should be used to compliment other techniques,
such as clinical examination and serial imaging.
The use of multimodal monitoring continues to be refined and it may be possible to use them to guide novel
brain resuscitation techniques, such as the use of exogenous lactate supplementation in the future.
Summary
Neurocritical care management of traumatic brain injury continues to evolve. However, it is important not
to use a ‘one-treatment-fits-all’ approach, and perhaps look to use targeted therapies to individualize
treatment.
Keywords
brain injury, intracranial pressure, neuromonitoring, traumatic brain injury

INTRODUCTION

TRAUMATIC BRAIN INJURY

The timely transfer of patients to a neurosurgical
center with a dedicated neuro-intensive care unit
(NICU) in the management of brain injury is vital, a
process highlighted by high-profile cases, such as
racing driver Michael Schumacher and actress
Natasha Richardson. The role of dedicated neurointensivists in improving functional outcomes is
evolving; this review highlights key or interesting
publications over the past 2 years.

The epidemiology of traumatic brain injury (TBI) is
changing. Once primarily a disease of the young,
there is a growing representation of older victims
with additional medical problems. The incidence in
low-income and medium-income countries is
increasing with the adoption of motor vehicles
[1]. In the USA, older patients have higher outpatient costs, longer inpatient stays and significantly
higher rates of rehospitalization, particularly for
those aged 75–84 years [2], but there is a general

METHODS
The OVID database and Google Scholar were used to
search for all publications with the term ‘intensive
care’, ‘neurointensive care’, ‘neurocritical care’,
‘NICU’, ‘NITU’, ‘brain injury’ or ‘brain trauma’
from January 2012 to March 2014. Searches were
limited to human adults in the English language.
After exclusion of articles not meeting these
initials, predominantly age criteria, a selection of
the most interesting or pertinent are presented
below.

a
Clinical Lead Neuro Intensive Care, Queens Hospital, Barking Havering
and Redbridge NHS Trust, London, bHonorary Senior Clinical Lecturer,
Queen Mary’s, University of London and cSpecialist Registrar, Anesthesia and Intensive Care Medicine, Barts and The London School of
Anesthesia, London, UK

Correspondence to Dhuleep S. Wijayatilake, Neurointensive Care Unit,
Queens Hospital, Rom Valley Way, Romford, Essex, RM7 0AG, UK.
Tel: +44 1708 503727; fax: +44 1708 503763; e-mail: sanjay.wijaya
tilake@bhrhospitals.nhs.uk
Curr Opin Anesthesiol 2014, 27:459–464
DOI:10.1097/ACO.0000000000000105

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Neuroanesthesia

KEY POINTS
Specialized neurocritical care can and does improve
patient outcomes.
More advanced neuromonitoring techniques are
developing which allow us to better understand the
dynamics of the injured brain.
Consensus guidelines are needed about which
intracranial pressure targets to treat and how best to
individualize therapy, thereby avoiding dangerous
overtreatment.
Albumin appears harmful in the setting of TBI, most
likely due to deleterious effects upon intracranial
pressure.
Early tracheostomy for non-neurological reasons does
not appear beneficial but is a well tolerated option for
those patients in whom level of consciousness is likely
to need ongoing airway protection.

trend toward better outcome across all ages in TBI.
Indeed, although mortality remains higher for elderly patients, the proportion with severe disability is
not increased, perhaps reflecting successful neurorehabilitation [3].
The role of intracranial pressure (ICP) monitoring in the assessment of TBI remains controversial.
Average ICP within the first 48 h of injury predicts
both mortality and neuropsychiatric outcome [4].
The complexity of this issue was highlighted in the
recent multicenter, randomized controlled trial
BEST-TRIP [5]. Conducted in South America, this
study compared monitoring to maintain an ICP up
to 20 mmHg with serial neurological examination
and imaging. No difference was found in survival,
consciousness, functional status or neuropsychological status at 6 months.
Although a relatively innovative design, this
study has a number of limitations. First, BEST-TRIP
was inadequately powered to detect small improvements in the minority with raised ICP. Second,
the generalizability to other developed countries
is limited. Third, mortality across the board was
high. Fourth, prehospital care was poorly developed
in these localities. Fifth, rehabilitation after discharge was not routinely available. However, the
authors did not question the value of knowing the
ICP, or its value as a guide to therapy, prognostic
indicator or research tool. Management without a
bolt has been shown to worsen outcomes [6], and
poor response to treatment predicts mortality [7].
ICP monitors are just that, not a treatment. This
study highlights how the relatively simplified model
through which we manipulate this single variable
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may not improve recovery in the wider population
and the need to adopt a more holistic, multimodal
monitoring approach.
ICP-based therapies remain the cornerstone
of the Brain Trauma Foundation guidelines for
the management of severe TBI [8]. Although well
established and evidence-based, adherence remains
nonuniform [9]. In an 8-year retrospective analysis
from the New York State there was a steady decrease
in case-fatality rate from 22 to 13% (P < 0.0001) as
guideline utilization increased [9]. ICP monitoring and adherence to cerebral perfusion pressure
treatment thresholds improved in particular and
nutritional targets were more likely to be met. The
observation that guidelines-led treatment is beneficial is not new [10].
Similarly, significant heterogeneity exists
regarding optimal surgical management. Evacuation of mass lesions may be life-saving, but timing,
technique and need for decompressive craniotomy
are not fully defined. Authors compared postsurgical course and long-term outcome of differing neurosurgical approaches at two academic centers [11 ].
This UK–USA trial found that the UK patients were
typically older but otherwise patients had similar
prognoses, lesion types and preoperative ICP. Earlier
surgery, larger craniotomy and removal of bone flap
improved outcomes. Those requiring evacuation of
subdural hematomas and contusions seemed to
benefit from decompression even when elevated
ICP was not a factor in the decision to perform a
surgery [11 ], a finding echoed elsewhere [12].
&

&

NEUROMONITORING
Despite its perceived limitations, ICP remains the
most commonly measured intracranial parameter
[13 ]. Definitive class 1 evidence is lacking but
benefit is suggested when used to guide treatment.
The US trauma centers with higher rates of ICP
monitoring demonstrated superior patient outcomes than those less likely to use it [14]. A German
study found that ICP bolts were placed in only 85%
of cases of severe TBI [15]. Technological and interpretative limitations also persist with a fundamental
lack of consensus in how to interpret this information. Although intraventricular catheters remain
the gold standard [16 ], a large North American
survey demonstrated variation in preference of
determining ICP as maximum, mode or mean and
even the transducer reference point [17]. Such a lack
of clarity is worrisome and may have contributed to
problematic data validity in multicenter trials; this
must be urgently addressed. The ‘one-size-fits-all’
approach to ICP triggers is also blunt. It is entirely
plausible that the apparently disappointing results
&&

&

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Neuro ICU management of TBI: what’s new? Wijayatilake and Shepherd

from Decompressive Craniectomy Trial reflect a
distinctly nonphysiologic clinical provocation
[18]. Recent Scandinavian evidence suggested for
patients with only mildly elevated ICP outcome
was not worse [19]. Indeed, overtreatment is not
trivial and a functional or perfusion-guided paradigm may shift us from overreliance on pressure.
Intraparenchymal monitors are well tolerated
than intraventricular but can in certain conditions
be imprecise through zero drift, and still require an
invasive procedure. The incidence of baseline errors
is not insignificant: in a study within subarachnoid
hemorrhage, two separate but identical-type straingauge sensors were placed in the same burr hole [20].
Baseline errors were detected in over 50% of
patients, being 2–5 mmHg in a median of 34% of
observations. Major differences in mean ICP
between the sensors were observed in 44% [20].
The potential clinical consequences of this are significant. Even between invasive modalities, correlation is lacking even in the same patient [21]. When
extra-ventricular drains are used, we are unclear
whether constant opening to allow continuous cerebrospinal fluid (CSF) drainage or intermittent only
in response to increased ICP is the best. The latter
allows continuous ICP measurement and the former
may allow tighter ICP control. This was ratified by a
cohort study with a significant (average 5.6 mmHg)
difference in mean ICP for the open group but
similar survival and 6-month Glasgow Outcome
score [22 ].
Cortical spreading depolarizations are waves
of sustained neuronal activity originating spontaneously and propagating across the cortex in
response to structural or ischemic injury [23]. They
are characterized on electrocorticography by large,
negative and slow potential change followed by
silencing of electrical activity and are associated
with poor outcome in TBI [24]. Spreading depolarizations have been directly measured in brain parenchyma using cortical and depth electrode arrays
inserted at craniotomy [25 ]. In the future, it may
be possible to introduce an electrode array via a
burr hole.
Invasiveness is a flaw of many neuromonitoring
modalities and an accurate, noninvasive method
is desirable. Computed tomography (CT) and MRI
can provide some assessment, but the utility of
transcranial Doppler, power electrocorticography
analysis and ophthalmological-based methods is
increasing [16 ] with issues of interobserver variability reduced by using the same technician. Combination neuromonitoring may yield the most
benefits. A recent systematic review suggested that
the addition of brain tissue oxygen (PbtO2)-guided
therapy to ICP may provide better functional
&

&&

&

outcomes [26]. Individualization of ICP targets
has theoretical benefits but has not yet been subject
to a true randomized trial. Cerebrovascular pressure
reactivity index technology examines for cerebral
autoregulation in just this way, and a recent small
study showed a strong link with the brain’s ability to
control for its extracellular oxygen content [27].
This technology may identify those who would
benefit from hyperoxia treatment.

OSMOTHERAPY
Administration of osmotic agents to reduce ICP is
frequently used yet hard evidence is lacking. Physician and institutional variation in therapeutic
practice and a lack of standardized protocols and
indications mean that most data are derived from
retrospective and case series [28]. Traditionally,
mannitol has been used. It is well tolerated and
effective, but its mechanism of action remains
unclear; it may reduce blood volume, brain water
or both. This former theory has been disproved by a
small PET CT study in which a single bolus of 1 g/kg
20% mannitol did not alter cerebral blood volume
significantly [29]. A single bolus dose of 14.6 or
23.4% hypertonic saline is an alternative, but many
centers lack experience and few published studies
have evaluated the safety of repeated bolusing. A
retrospective review demonstrated repeated administration to be safe without increased incidence
of demyelination, although there was a marked
increase in serum sodium concentration [30]. The
optimal dose, method of administration and superiority to mannitol remains unclear [28,31,32].
Indeed, the efficacy of routine osmotherapy is questionable [31]. Rebound intracranial hypertension is
a significant concern with all agents [33] and their
role undoubtedly is as a rescue measure pending
definitive (usually surgical) treatment.

INTRACEREBRAL BLEEDING
Both primary and traumatic intracerebral bleeds
remain a common indication for intensive care
admission, although outside aneurysm-associated
etiologies’ therapeutic option was perhaps until
relatively recently more limited. Traditionally,
standard practice for isolated traumatic subarachnoid hemorrhage includes neurosurgical consultation which may involve tertiary trauma center
transfer. However, a cross-sectional study of patients
with isolated traumatic subarachnoid hemorrhage
demonstrated a low risk of deterioration [34].
Although traditionally associated with aneurysmal
subarachnoid hemorrhage, cerebral vasospasm
may be a significant contributor to mortality in

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Neuroanesthesia

traumatic disease, with an incidence proportional to
the severity of TBI [35]. However other researchers
argue that the association of angiographic vasospasm
which is sometimes seen in patients with traumatic
sub arachnoid haemorhage and neurological deficits
is poorly understood and may be associative rather
than causative [36]. Cerebral ischemia often involves
more than one arterial territory with both microthrombosis and impaired autoregulation contributing to the clinical picture [37].
Magnesium may be protective in vasospasm by
modulating vascular reactivity and inhibiting Nmethyl-D-aspartate-glutamate receptors and voltage-dependent calcium channels. Trials of magnesium in aneurysmal subarachnoid hemorrhage have
failed to affect mortality or neurological outcome
[38]. However, the neuroprotective effects of magnesium rely on adequate CSF concentration which is
limited by systemic toxicity before these levels are
reached. Intracisternal administration offers an
alternative [39,40]. Supplementation may also be
significantly delayed after the initial ictus by up
to 30–40 h in most trials; more rapid administration
may be beneficial.

BRAIN RESUSCITATION
Goal-directed resuscitation is an emerging field [41].
Post-hoc analysis of the 2004 Saline versus Albumin
Fluid Evaluation study previously demonstrated an
increased mortality for TBI patients resuscitated
with albumin rather than 0.9% saline [42]. The
mechanism behind this was unclear, but a significant increase in mean ICP and subsequent deaths in
patients who received albumin coupled with higher
sedative and vasopressor requirements, presumably
suggest that this effect is due to increasing ICP [43].
PbtO2 or lactate-guided resuscitation is increasingly popular, but again targets remain controversial [44]. Exogenous lactate supplementation may
offer a potential therapeutic option. Preferential
aerobic utilization of this substrate is seen in injured
brain tissue; in a small pilot study, hypertonic
sodium lactate was administered to increase arterial
lactate to supraphysiological levels subsequently
improved PbtO2 with a reduction in ICP [45 ].
Adopting this approach may provide positive effects
on brain energy metabolism although avoiding the
complications of commonly used fluids, such as
0.9% sodium chloride [46].
&

EARLY TRACHEOSTOMY
Many ICU patients require tracheostomy for reasons
not least of which is to facilitate ventilatory weaning. Patients admitted to NICU are more likely to
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undergo tracheostomy than general ICU patients
[47]. The TracMan trial suggested no benefit to early
rather than late tracheostomy [48]. However,
patients with chronic neurological conditions were
excluded and although no difference was demonstrated in the duration of mechanical ventilation or
mortality, of those randomized to late tracheostomy
only 45% still required the procedure at 10 days.
Although those with acute intracranial lesions or
peripheral neuromuscular disorders were included,
they were the minority. Most patients underwent
tracheostomy for ‘pulmonary’ reasons which may
show more rapid reversal.
The SETPOINT study examined this in more
detail. Sixty patients with severe stroke predicted
to require ventilation for more than 2 weeks underwent tracheostomy within 1–3 days rather than
standard practice of 7–14 days [49]. Both ICU and
6-month mortality were lower in the early group
alongside the requirement for sedatives which was
postulated to account for much of this effect. A
larger retrospective analysis of TBI patients similarly
suggested that tracheostomy within 7 days reduced
length of stay and increased the likelihood of functional independence [50]. These factors involved a
Rey complex, not least including predicted survival
but this database is large, covering a 15-year period.

PROGNOSTICATION
Predicting survival from cerebral injury remains
challenging yet a frequently sought after role for
the neurointensivist.

Biomarkers
A number of biomarkers, including S110B, neuronspecific enolase and myelin basic protein, have been
proposed as potentially prognostic but proven disappointing with only ubiquitin carboxyl-terminal
hydroxylase L1 deemed worthy of further study
[51]. Nitric oxide may have both protective and
damaging effects in the injured brain and its metabolites have shown promising early results as prognostic indicators [52,53]. Glucose management also
remains of relevance, whereas hyperglycemia is
associated with poor outcomes, tight glycemic
control offers little benefit [54,55]. Microdialysis
studies have corroborated the attendant risk of hypoglycemia with intensive insulin therapy [56,57]. A
brain: serum glucose ratio less than 0.12 predicts
cerebral metabolic distress and mortality after severe
TBI [58].

Imaging
No single-imaging technique ideally suits the role of
prognostication. In a Dutch study of 605 patients,
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Neuro ICU management of TBI: what’s new? Wijayatilake and Shepherd

the aspect of the ambient cisterns on CT predicted
death in TBI but disability in survivors [59]. The
utility of MRI is improved with more advanced
diffusion tensor techniques [60] and identification
of brainstem lesions strongly predicts poor outcome
[61].

Genetic predisposition
ATP-binding cassette transporters are important
mediators of blood–brain barrier solute transport.
A variety of polymorphisms (ABCB1, ABCC1 and
ABCC2) exist which impact the bioavailability of
both drugs and endogenous substrates in the brain
[62]. Patients homozygous for the T allele of ABCB1
or the G allele of ABCC1 appear to have better
outcomes after severe TBI [63]. Further work is
required to move this outside the experiment.

Ethical considerations
Policies on withdrawal of care vary greatly. In an
extremely thought-provoking study, factors contributing to variability in outcome prognostication in
moderate to severe TBI were examined [64 ]. Treatment withdrawal was the major determinant of inhospital mortality, negating all other predictors.
Patients in whom withdrawal was more likely
included those with included coagulopathy on
admission, cardiac arrest on NICU, brain herniation
and ICP crisis. Significant interhospital and interspecialty variation was seen; clinical nihilism is an
important entity and the role of the multidisciplinary team in discussions of withdrawal remains
paramount.
&&

CONCLUSION
Excellence in NICU improves life after neurological
injury, perhaps more relevant than crude mortality.
Our patients are older with increasingly complex
requirements yet outcomes are improving. We still
suffer from a lack of consensus in which monitors to
use, how to standardize their interpretation, when
to intervene upon the information they provide
and when not to. Translation of what we are coming
to know as a good practice on paper into good
practice at the bedside is essential if we are to continue to gain good outcomes for those who can
benefit.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
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brain injury. Lancet 2012; 380:1088–1098.
2. Thompson HJ, Weir S, Rivara FP, et al. Utilization and costs of health care after
geriatric traumatic brain injury. J Neurotrauma 2012; 29:1864–1871.
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population. J Neurotrauma 2012; 29:1119–1125.
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severe traumatic brain injury treated without intracranial pressure monitoring.
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&
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Interesting United Kingdom/United States study comparing two different approaches to the management of TBI.
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in traumatic brain injury with or without mass lesion. Br J Neurosurg 2013;
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13. Kirkman MA, Smith M. Intracranial pressure monitoring, cerebral perfusion
&&
pressure estimation, and ICP/CPP-guided therapy: a standard of care or
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A well balanced opinion piece examining the ideals behind cerebral perfusion
pressure optimization.
14. Alali AS, Fowler RA, Mainprize TG, et al. Intracranial pressure monitoring in
severe traumatic brain injury: results from the American College of Surgeons
Trauma Quality Improvement Program. J Neurotrauma 2013; 30:1737–1746.
15. Kowoll CM, Dohmen C, Kahmann J, et al. Standards of scoring, monitoring,
and parameter targeting in german neurocritical care units: a national survey.
Neurocrit Care 2014; 20:176–186.
16. Kristiansson H, Nissborg E, Bartek J Jr, et al. Measuring elevated intracranial
&
pressure through noninvasive methods: a review of the literature. J Neurosurg
Anesthesiol 2013; 25:372–385.
Explains the current noninvasive ICP measures in greater depth.
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neurocritical care: results from a national practice survey. Neurocrit Care
2014; 20:15–20.
18. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive craniectomy in
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&&
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Excellent article examining the potentially inbuilt nihilism seen within NICU.
&

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REVIEW
URRENT
C
OPINION

Anesthesia for intracranial surgery in infants
and children
Craig D. McClain and Sulpicio G. Soriano

Purpose of review
Age-related differences in the surgical lesions, anatomy and physiological responses to surgery and
anesthesia underlie the clinically relevant differences between pediatric patients and their adult
counterparts. Anesthesiologists need to be aware of the unique challenges in the anesthetic management of
the pediatric neurosurgical patient.
Recent findings
Neurosurgeons with subspecialty training in pediatrics have driven advances in intracranial surgery in
infants and children. Subspecialization in pediatric neurosurgery and critical care has resulted in more
favorable outcomes. Innovations in tumor, epilepsy and endoscopic and cerebrovascular neurosurgery are
constantly being adapted to the pediatric patient. The highly specialized nature of these and other
pediatric neurosurgical procedures prompt calls for similarly trained anesthesiologists for management of
these infants and children.
Summary
The aim of this review is to highlight the impact of these techniques on the intraoperative management of
the pediatric neurosurgical patient. These issues are essential in minimizing perioperative morbidity and
mortality.
Keywords
childhood tumors, epilepsy surgery, neuroanesthesia, pediatric anesthesia

INTRODUCTION
Childhood intracranial lesions are different from
adults’. Brain tumors are the most common solid
malignancies in pediatric patients [1], and the
histology and location of these tumors are significantly different from adults. Infants and children
with medically intractable seizure disorders are
increasingly benefiting from epilepsy surgery [2].
Finally, advances in diagnosis and interventional
neuroradiology have increased survival of infants
and children with neurovascular lesions. The highly
specialized nature of these and other pediatric
neurosurgical procedures prompted calls for likeminded and trained perioperative team for management of these infants and children [3]. This notion
has been supported by reports noting that subspecialzation in pediatric neurosurgery and critical
care has resulted in decreased morbidity [4 ,5].
The developmental stage impacts the anesthetic
management of infants and children undergoing
intracranial neurosurgery. Age-dependent differences in anatomy, cerebrovascular physiology and

neurologic lesions distinguish neonates, infants and
children from their adult counterparts. The goal of
this review is to highlight these age-dependent
differences and their effect on the anesthetic management of the pediatric neurosurgical patient.

PREOPERATIVE PREPARATION AND
INTRAOPERATIVE MANAGEMENT
The preoperative assessment of the pediatric neurosurgical patients requires a focused approach on
areas unique to this surgical cohort. Childhood
tumors present with a variety of signs and symptoms
that may affect the conduct of anesthesia [6]. These
Department of Anesthesiology, Boston Children’s Hospital and Harvard
Medical School, Boston, Massachusetts, USA

&

Correspondence to Sulpicio G. Soriano, MD, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 617 355
6457; e-mail: sulpicio.soriano@childrens.harvard.edu
Curr Opin Anesthesiol 2014, 27:465–469
DOI:10.1097/ACO.0000000000000112

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Neuroanesthesia

KEY POINTS
A thorough preoperative organ system-based
evaluation of the pediatric patient is essential to
minimize perioperative morbidity.

Table 1. Coexisting conditions that impact anesthetic
management
Condition

Anesthetic implications

Congenital heart disease

Hypoxia
Arrhythmias

Neonate and infants are at risk of intraoperative
cerebral hypoperfusion due to inadequate systolic
blood pressure and inadvertent hypocarbia.
New innovations in surgical approached and
intraoperative technology are constantly being adapted
to pediatric neurosurgical patients.

include lethargy, seizures, cranial nerve palsies,
focal muscle weakness, hypothalamic-pituitary axis
hormonal deficiencies, nausea and vomiting
(Table 1 ) [7]. A complete history and physical
examination should reveal these symptoms and
provide a framework for the well tolerated conduct
of anesthesia. Pediatric patients have a higher risk
for perioperative respiratory and cardiovascular
morbidity and mortality than adult cohorts [8].
The systemic effects of general anesthesia and the
physiological stress of surgery impact this vulnerable group. Therefore, a thorough review of the
patient’s history can reveal conditions that may
increase the risk of adverse reactions to anesthesia
and identify patients who require more extensive
evaluation or whose medical condition needs to be
optimized before surgery.
The age of the patient has a major impact on the
conduct of anesthesia. The level of anxiety and
the cognitive development and age of the pediatric
patient dictate the type of sedation and induction
medications. Children between the ages of 9–12
months and 6 years may have separation anxiety
and may need orally or intravenously administered
benzodiazepine. Parental presence during induction
of anesthesia is common and a viable alternative to
ease both patient and parental anxiety but requires
full engagement of the operating room team.
Obtunded and lethargic patients should have a
rapid anesthetic induction in order to minimize
cerebral hypoperfusion and pulmonary aspiration.
Anesthesia can be induced with sevoflurane,
nitrous oxide and oxygen by mask in neurologically
stable patients. Although some neuroanesthesia
practices avoid the use of nitrous oxide, its brief
use during induction of anesthesia should not be
clinically significant. More importantly, intracranial hypertension may be exacerbated by hypercarbia and hypoxia, which may occur if the airway
becomes obstructed during induction. Patients with
lethargy or nausea and vomiting are at risk for
aspiration of gastric contents and will benefit from
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Cardiovascular instability
Paradoxical air emboli
Prematurity

Postoperative apnea

Gastrointestinal reflux

Aspiration pneumonia

Upper respiratory tract
infection

Laryngospasm,
bronchospasm
hypoxia, pneumonia

Craniofacial abnormality

Difficult tracheal intubation

Denervation injuries

Hyperkalemia after
succinylcholine,
Resistance to
nondepolarizing
muscle relaxants
Abnormal response to
nerve stimulation

Epilepsy

Hepatic and
hematological abnormalities
Increased metabolism of
anesthetic agents
Ketogenic diet

Arteriovenous malformation
Neuromuscular disease

Congestive heart failure
Malignant hyperthermia
Respiratory failure
Sudden cardiac death

Chiari malformation

Apnea

Hypothalamic/pituitary

Diabetes insipidus

Aspiration pneumonia
lesions

Hypothyroidism
Adrenal insufficiency

Reproduced with permission from [7].

a rapid-sequence induction of anesthesia with
succinylcholine. Contraindications to the use of
succinylcholine include malignant hyperthermia
susceptibility, muscular dystrophies, burns and
recent denervation injuries.
The most important tenet in neuroanesthesia is
to preserve neurological function [9 ]. As the lower
limit of cerebral autoregulation pediatric patients is
unknown, they are at risk for cerebral hypoperfusion, especially when they are deeply anesthetized
during periods of massive blood loss [10]. The most
frequently used technique during neurosurgery
consists of an opioid (i.e., fentanyl, sufentanil or
remifentanil) and low-dose isoflurane or sevoflurane. Dexmedetomidine can be used as an adjunct. It
does not significantly affect most intraoperative
&&

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Pediatric neuroanesthesia McClain and Soriano

neurophysiologic monitoring and reduces opioid
requirements. The use of adjuvant infusions of
dopamine to provide vasoactive support is beneficial during hemodynamically tenuous intervals.
Patients on chronic anticonvulsant therapy usually
require a larger dose of neuromuscular-blocking
agents and opioids because of induced enzymatic
metabolism of these agents. The use of neuromuscular-blocking agents should be discussed with the
surgical and neuromonitoring teams, if assessment
of motor function is planned.
Hemodynamic collapse due to massive blood
loss or venous air embolism looms as a catastrophic
complication for any major craniotomy. Large-bore
intravenous access and arterial blood pressure
monitoring are, therefore, essential for these procedures. Should initial attempts fail, central venous
cannulation may be necessary. Femoral vein catheterization avoids the risk of pneumothorax and does
not interfere with cerebral venous return. Furthermore, femoral catheters are more easily accessible to
the anesthesiologist. Routine insertion of central
venous catheters is not a reliable measure of preload
and is not routinely indicated for this reason alone
[11 ].
Patient positioning requires a careful preoperative planning to allow adequate access to the patient
for both the neurosurgeon and the anesthesiologist.
The prone position can lead to decreased lung compliance, venocaval compression and bleeding due
to increased epidural venous pressure. Supportive
lateral rolls can alleviate these problems by minimizing abdominal and thoracic pressure. Elevating
the head facilitates venous and cerebrospinal fluid
drainage from the surgical site. However, this
increases the likelihood of venous air emboli
(VAE). Maintaining normolemia minimizes this
risk. Early detection of a VAE with continuous precordial Doppler ultrasound may allow treatment
to be instituted before large amounts of air are
entrained. Should a VAE produce hemodynamic
instability, the operating table must be placed in
the Trendelenburg position in order to improve
cerebral perfusion and prevent further entrainment
of intravascular air. Special risks exist in neonates
and young infants as right-to-left cardiac mixing
lesions can result in paradoxical emboli. Significant
rotation of the head can also impede venous return
via compression of the jugular veins and can lead to
impaired cerebral perfusion, increased intracranial
pressure and venous bleeding. Obese patients may
be difficult to ventilate in the prone position and
may benefit from the sitting position. In addition to
the physiological sequelae of the sitting position, a
whole spectrum of neurovascular compression and
stretch injuries can occur.
&

Massive blood loss should be aggressively
treated with crystalloid and blood replacement, as
well as vasopressor therapy (e.g., dopamine, phenylephrine, epinephrine and norepinephrine). Isotonic
saline is generally chosen as an intraoperative maintenance fluid because it is mildly hyperosmolar and
should minimize cerebral edema. However, rapid
infusion of more than 60 ml/kg of isotonic saline
may cause hyperchloremic acidosis. Patients with
diabetes mellitus, total parenteral alimentation and
premature and small newborn infants may require
glucose-containing intravenous fluids. Transfusion
of 10 ml/kg of packed red blood cells increases
hemoglobin concentration by 2 g/dl. Pediatric
patients are susceptible to dilutional thrombocytopenia in the setting of massive blood loss and
multiple red blood cell transfusions. Administration
of 5–10 ml/kg of platelets increases the platelet
count by 50 000–100 000/mm3. The routine use
of the antifibrinolytic agent, tranexamic acid, in
surgical procedures with excessive blood loss, such
as posterior spine fusions, cardiac surgery and
craniofacial reconstructive procedures, has been
shown to decrease blood loss in pediatric patients
[12 ]. In the case of severe cardiovascular collapse,
some pediatric centers have rapid response extracorporeal membrane oxygenation teams that can
provide rescue therapy when the crisis is refractory
to standard cardiopulmonary resuscitation algorithms. However, the use of anticoagulation in
the setting of ongoing bleeding may be problematic.
&&

ANESTHETIC MANAGEMENT OF SPECIFIC
NEUROSURGICAL PROCEDURES
A majority of brain tumors in pediatric patients are
located in the posterior fossa. These tumors have a
mass effect and often obstruct cerebrospinal fluid
flow, which can lead to hydrocephalus and intracranial hypertension. If the patient is symptomatic,
measures to reduce hydrocephalus and intracranial
hypertension include intravenous steroid therapy
and a ventricular shunt or external ventricular drain
in severe cases. Brain stem tumors may impinge
upon the respiratory control centers and cranial
nuclei. These structures are also vulnerable to surgical manipulations and dissection. Stimulation of
the nucleus of cranial nerve V can cause hypertension and tachycardia. Irritation of the nucleus of the
cranial nerve X may result in bradycardia and vocal
cord paralysis. Continuous observation of the blood
pressure and ECG are essential to detect encroachment upon these structures. Elevation of the bone
flap can result in sinus tears, massive blood loss
and/or VAE. Inadvertent entry into the straight
and transverse sinus can precipitate massive VAE.

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Neuroanesthesia

Damage to the respiratory centers and cranial nerves
can lead to apnea and airway obstruction after extubation of the patient’s trachea.
Supratentorial tumors are more common in
infants and adolescents. Infants predominantly have
embryonal tumors; whereas craniopharyngiomas
occur more frequently in toddlers and children and
may be associated with hypothalamic and pituitary
dysfunction. Steroid replacement therapy with either
dexamethasone or hydrocortisone may be required
as the integrity of the hypothalamic-pituitaryadrenal axis may be disrupted. Perioperative diabetes
insipidus can lead to electrolyte and hemodynamic
derangements due to excessive fluid loss through
polyuria. Laboratory studies should therefore include
serum electrolytes and osmolality, urine-specific
gravity and urine output. Diabetes insipidus is
marked by a sudden polyuria (> 4 ml/kg/h), hypernatremia and hyperosmolarity. Initial management consists of infusion of aqueous vasopressin
(1–10 mU/kg/h) and judicious fluid administration
that matches urine output and estimated insensible
losses.
Advances in intraoperative MRI provide the
opportunity to define the margins of tumors during
the surgical section. This provides the opportunity
to conservatively resect the lesions without causing
iatrogenic damage to normal tissue or residual
tumors in single operative session. However, this
combined surgical and imaging procedure is associated with prolonged anesthesia times and hazards in
a MRI environment [13 ]. Ongoing investigations
are examining the efficacy and cost-effectiveness of
this hybrid environment.
Epilepsy surgery poses several anesthetic management issues [14]. General anesthetics can
compromise the effectiveness of intraoperative
neurophysiologic monitors that guide the resection
of the epileptogenic focus. High levels of volatile
anesthetics and neuromuscular blockade may also
suppress cortical stimulation. Nitrous oxide can precipitate pneumocephalus after a recent craniotomy
(up to 3 weeks later) and should be avoided until
after the dura is opened.
A variety of techniques have been advocated to
facilitate intraoperative assessment of motor-sensory function and speech, including awake craniotomies. In the ‘sleep-awake-asleep’ technique the
patient undergoes general anesthesia for the surgical
exposure. The patient is then awakened for functional testing and general anesthesia is reinstituted
when patient cooperation is no longer needed. Most
cooperative patients will tolerate sedation with propofol or dexmedetomidine. Propofol does not interfere with the electrocorticogram, if it is discontinued
20 min before monitoring in children undergoing
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an awake craniotomy [15]. Supplemental opioids are
administered to provide analgesia. It is, however,
imperative that candidates for craniotomy under
local anesthesia or sedation be mature and psychologically prepared to participate in this procedure.
Cerebral hemispherectomy for the management
of medically intractable seizures has evolved over
the last decade, with a trend from anatomic (total)
toward minimally invasive functional resections
[16,17]. Significant intraoperative blood loss and
hemodynamic instability of both techniques
have an impact on the anesthetic management of
these patients [18,19]. Coexisting comorbidities,
concurrent anticonvulsant therapy and evolving
coagulopathies must also be of concern to the anesthesiologist [14]. Tranexamic acid has been recently
shown to attenuate massive blood loss in a variety of
surgical procedures in infants and children [20,21]
and has been empirically administered in surgical
procedures associated with massive blood loss [12 ].
The primary goal of the anesthesiologist during
cerebrovascular surgery is to optimize cerebral perfusion while minimizing the risk of bleeding. Large
arteriovenous malformation may be associated with
high-output congestive heart failure requiring vasoactive support. Hypertensive crisis after embolization
or surgical resection of the arteriovenous malformation should be rapidly treated with vasodilators.
These lesions are often managed by combined neurointerventional and neurosurgical approach, which
start with endovascular occlusion of the lesion followed by surgical resection and ending with a
postoperative angiography.
The goal of anesthetic management of patients
with moyamoya syndrome is to optimize cerebral
perfusion with aggressive preoperative hydration
and maintaining normotension or mild hypertension during surgery and the postoperative period
[22]. Intraoperative normocapnia is essential because
both hypercapnia and hypocapnia can lead to steal
phenomenon from the ischemic region. Intraoperative electroencephalogram monitoring may be
utilized during surgery to detect cerebral ischemia.
Optimization of cerebral perfusion should be extended into the postoperative period by maintaining
euvolemia and using sedatives and opioids to prevent
hyperventilation induced by pain and crying.
Technological advances in endoscopic surgery
have provided minimally invasive approaches to the
surgical management of central nervous system
lesions. Endoscopic-guided biopsies of deep-seated
brain lesions have been adapted to pediatric patients
[23]. Endoscopic third ventriculostomies have been
proposed as a viable and efficacious alternative
to ventricular shunts. Despite the relative safety
of this procedure, hypertension, arrhythmias and
&&

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Pediatric neuroanesthesia McClain and Soriano

neurogenic pulmonary edema have been reported
in conjunction with acute intracranial hypertension
due to lack of egress of irrigation fluids and/or
manipulation of the floor of the third ventricle.

CONCLUSION
The anesthetic management of infants and children
for intracranial surgery is based on age-dependent
factors that are unique to the neurosurgical lesions
and the anesthetic approach to these patients.
Advances in subspecialty training in pediatric neurosurgery mandate that anesthesiologists be well versed
in this evolving field [24 ]. Thorough preoperative
evaluation and open communication among members of the healthcare team are essential for minimizing perioperative morbidity and mortality.
&&

Acknowledgements
C.D.C. and S.G.S. have no conflicts of interest to declare.
This work was supported by the Boston Children’s Hospital Endowed Chair in Pediatric Neuroanesthesia (S.G.S.).
Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
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&
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&&
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10. McCann ME, Schouten AN. Beyond survival; influences of blood pressure,
cerebral perfusion and anesthesia on neurodevelopment. Pediatr Anesth
2014; 24:68–73.
11. Stricker PA, Lin EE, Fiadjoe JE, et al. Evaluation of central venous pressure
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monitoring in children undergoing craniofacial reconstruction surgery. Anesth
Analg 2013; 116:411–419.
This report demonstrates the lack of efficacy in the routine placement of central
venous catheters in specific surgical procedures.
12. Faraoni D, Goobie SM. The efficacy of antifibrinolytic drugs in children
&&
undergoing noncardiac surgery: a systematic review of the literature. Anesth
Analg 2014; 118:628–636.
This review discusses the utility of TXA in decreasing blood loss in major surgery.
13. McClain CD, Rockoff MA, Soriano SG. Anesthetic concerns for pediatric
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patients in an intraoperative MRI suite. Curr Opin Anaesthesiol 2011;
24:480–486.
This review discusses the evolving nature of the neurosurgical operating room
environment.
14. Soriano SG, Bozza P. Anesthesia for epilepsy surgery in children. Childs Nerv
Syst 2006; 22:834–843.
15. Soriano SG, Eldredge EA, Wang FK, et al. The effect of propofol on
intraoperative electrocorticography and cortical stimulation during awake
craniotomies in children. Paediatr Anaesth 2000; 10:29–34.
16. Cook SW, Nguyen ST, Hu B, et al. Cerebral hemispherectomy in pediatric
patients with epilepsy: comparison of three techniques by pathological
substrate in 115 patients. J Neurosurg 2004; 100:125–141.
17. Beier AD, Rutka JT. Hemispherectomy: historical review and recent technical
advances. Neurosurg Focus 2013; 34:E11.
18. Brian JE Jr, Deshpande JK, McPherson RW. Management of cerebral hemispherectomy in children. J Clin Anesth 1990; 2:91–95.
19. Flack S, Ojemann J, Haberkern C. Cerebral hemispherectomy in infants and
young children. Paediatr Anaesth 2008; 18:967–973.
20. Sethna NF, Zurakowski D, Brustowicz RM, et al. Tranexamic acid reduces
intraoperative blood loss in pediatric patients undergoing scoliosis surgery.
Anesthesiology 2005; 102:727–732.
21. Goobie SM, Meier PM, Pereira LM, et al. Efficacy of tranexamic acid in
pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial.
Anesthesiology 2011; 114:862–871.
22. Soriano SG, Sethna NF, Scott RM. Anesthetic management of children with
moyamoya syndrome. Anesth Analg 1993; 77:1066–1070.
23. Al-Tamimi YZ, Bhargava D, Surash S, et al. Endoscopic biopsy during third
ventriculostomy in paediatric pineal region tumours. Childs Nerv Syst 2008;
24:1323–1326.
24. Soriano SG(Guest Editor). Pediatric Neuroanesthesia. Pediatr Anesth 2014;
&&
24:645-793.
This is special themed issue on the latest advances in Pediatric Neuroanesthesia.
It features state of the art reviews, original papers and case reports.

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REVIEW
URRENT
C
OPINION

Red blood cell transfusion in neurosurgical patients
Shaun E. Gruenbaum and Keith J. Ruskin

Purpose of review
Anemia is common in neurosurgical patients, and is associated with secondary brain injury. Although
recent studies in critically ill patients have shifted practice toward more restrictive red blood cell (RBC)
transfusion strategies, the evidence for restrictive versus liberal transfusion strategies in neurosurgical
patients has been controversial. In this article, we review recent studies that highlight issues in RBC
transfusion in neurosurgical patients.
Recent findings
Recent observational, retrospective studies in patients with traumatic brain injury, subarachnoid
hemorrhage, and intracranial hemorrhage have demonstrated that prolonged anemia and RBC transfusions
were associated with worsened outcomes. Anemia in patients with ischemic stroke was associated with
increased ICU length of stay and longer mechanical ventilation requirements, but mortality and functional
outcomes did not improve with RBC transfusion. In elective craniotomy, perioperative anemia was
associated with increased hospital length of stay but no difference in 30-day morbidity or mortality.
Summary
There is a lack of definitive evidence to guide RBC transfusion practices in neurosurgical patients. Large
randomized control trials are needed to better assess when and how aggressively to transfuse RBCs in
neurosurgical patients.
Keywords
neurosurgery, red blood cell, subarachnoid hemorrhage, transfusion, traumatic brain injury

INTRODUCTION
Anemia is common among patients in the ICU. Up
to half of ICU patients are transfused with red blood
cells (RBCs) during their hospital stay [1]. Patients
with traumatic brain injury (TBI), subarachnoid
hemorrhage (SAH), intracranial hemorrhage (lCH),
and acute ischemic stroke admitted to the Neurosurgical Intensive Care Unit (NICU) commonly
develop anemia and require RBC transfusion. A
recent large-scale study examined 38 000 neurosurgical cases from the National Surgical Quality
Improvement Program database, and reported that
the need for preoperative transfusion with more
than 4 units of RBCs is significantly associated with
complications in neurosurgery [2]. It remains
unclear whether anemia is a marker of disease
severity, or an independent predictor of worsened
outcomes. What is clear, however, is that RBC transfusion in neurosurgical patients deserves special
attention and considerations.
The brain is especially vulnerable to decreased
perfusion and hypoxia, and brain oxygenation is
highly dependent on adequate cerebral blood flow.
The risks associated with both transfusion and anemia should be carefully weighed when deciding
www.co-anesthesiology.com

when, and how aggressively to transfuse RBCs in
neurosurgical patients. However, transfusion goals
in neurosurgical patients are controversial and vary
depending on the type of neurological injury or
surgery [3]. Furthermore, RBC transfusion strategies
for neurosurgical patients vary greatly among clinicians [4,5].
There has been a considerable debate about the
optimal hemoglobin (Hb) trigger for transfusion in
neurosurgical patients, and both anemia and RBC
transfusion appear to negatively impact clinical outcomes. There are, therefore, convincing arguments
for using both liberal and restrictive transfusion
guidelines [4]. In recent years, several articles have
emphasized the risks associated with RBC transfusion in hospitalized patients. A recent meta-analysis
reported that a restrictive RBC transfusion strategy
Department of Anesthesiology, Yale University School of Medicine, New
Haven, Connecticut, USA
Correspondence to Keith J. Ruskin, MD, Department of Anesthesiology,
Yale University School of Medicine, New Haven, CT 06511, USA. Tel: +1
203 785 2802; fax: +1 203 785 6664; e-mail: keith.ruskin@yale.edu
Curr Opin Anesthesiol 2014, 27:470–473
DOI:10.1097/ACO.0000000000000109
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RBC transfusion Gruenbaum and Ruskin

KEY POINTS
The brain is highly dependent on adequate cerebral
blood flow, and anemia may worsen secondary
brain injury.
Although the risks associated with RBC transfusion may
warrant restrictive transfusion strategies in many
critically ill patients, the optimal Hb trigger to transfuse
neurosurgical patients is unknown.
In patients with TBI, SAH, and ICH, both prolonged
anemia and RBC transfusion were associated with
worsened outcomes.
Although few alternatives to RBC transfusion have been
demonstrated to be effective in improving outcomes in
neurosurgical patients, some evidence suggests that
normovolemic hemodilution may be safe.
Although anemia is associated with a poor outcome,
especially in the presence of cerebral ischemia, RBC
transfusion is also associated with a worsened
outcome.
Large randomized controlled trials (RCTs) are needed
of which neurosurgical patients may benefit from more
restrictive or liberal transfusion strategies.

was associated with a reduced risk of healthcareassociated infections as compared with a more
liberal transfusion strategy [6 ]. Similarly, another
meta-analysis and systematic review concluded that
restrictive RBC transfusion criteria, in which a Hb
trigger of less than 7 g/dl was used, were associated
with a significant reduction in cardiac events,
rebleeding, bacterial infections, and mortality [7 ].
In the absence of cardiac disease, many authors have
cited these studies as a reason to use more restrictive
transfusion protocols in critically ill patients. In this
article, we will discuss some recent articles that have
highlighted the important issues in RBC transfusion
in neurosurgical patients.
&

&

stays, decreased ventilator-free days, and multiple
organ failure.
The threshold for RBC transfusion in patients
with TBI is controversial, and the optimal transfusion trigger is unknown [9]. In a recent retrospective review of 635 patients with isolated, severe TBI
(Glasgow Coma Scale 3–8), the association between
Hb levels and mortality was assessed [10]. In the 38%
of patients who received RBC transfusion during
their hospitalization, 5-day mean Hb levels less than
10 g/dl were associated with a two-fold increase in
mortality. However, another large retrospective
review of TBI patients found that RBC transfusion
when the Hb level was greater than 10 was associated with worse outcomes [11 ]. This emphasizes the
importance of implementing guidelines to prevent
and treat sustained anemia in TBI.
Very less is known regarding optimal RBC transfusion practices in pediatric patients with TBI. A
recent retrospective study reviewed outcomes in
1607 pediatric patients with TBI, of which 178
received RBC transfusion [9]. The authors demonstrated that RBC transfusions in these patients were
associated with poor outcomes and increased
mortality. They, therefore, suggested that a transfusion trigger of 8.0 g/dl be considered in children
with TBI.
&

SUBARACHNOID HEMORRHAGE
Anemia is common in patients with SAH, and may
be caused by hemodilution, occult hemorrhage,
drug effects, surgical blood loss, and aneurysm rupture and rebleeding [12 ]. As with TBI, both anemia
and RBC transfusion in SAH have been associated
with increased mortality. Historically, the threshold
for RBC transfusion in patients with SAH was on the
basis of expert opinion, and there is a lack of clinical
guidelines to guide RBC transfusions in these
patients.
A recent retrospective study examined 318
patients with SAH, of which 23% received RBC
transfusion [12 ]. The study demonstrated that
patients who received RBC transfusion had a
three-fold increase in mortality as compared with
patients who were not transfused. The authors
suggest that anemia might have a ‘protective’ effect
by increasing cerebral blood flow, decreasing blood
viscosity, and inducing cerebral vasodilation by
upregulating nitric oxide production. Another
recent retrospective study demonstrated that RBC
transfusion in patients with SAH was associated with
a dose-dependent increased risk of thrombotic
events and venous thromboembolism [13 ].
Although other studies have demonstrated a
strong association between anemia and poor
&

&

TRAUMATIC BRAIN INJURY
Anemia is common in patients with severe TBI, and
can result in decreased cerebral oxygen delivery and
secondary brain injury [4]. Acute traumatic coagulopathy (ATC) is an acquired coagulation disorder
that has been described in the context of isolated
TBI, and coagulopathy increases the possibility that
a patient will require an RBC transfusion. In a recent
systematic review and meta-analysis, Epstein et al.
[8 ] reported that ATC was uniformly associated
with worse outcomes and high mortality that
ranged from 17 to 86%. ATC was also associated
with transfusion rates of 41%, as well as longer ICU
&&

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&

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Neuroanesthesia

outcomes, it is difficult to establish causal relationships in these retrospective studies [14]. Currently,
the threshold to transfuse RBCs in patients with SAH
is still debated and varies among practitioners.
These studies highlight the need for large, prospective RCTs that address which patients might
benefit from more restrictive or liberal transfusion
strategies.

INTRACRANIAL HEMORRHAGE
Very few studies have examined the impact of anemia on clinical outcomes in patients with ICH. A
recent observational study retrospectively examined
435 patients with spontaneous ICH, and demonstrated that the presence of anemia (defined as Hb
<12 mg/dl for women and <13 mg/dl for men)
resulted in a seven-fold increase in the risk of a poor
outcome [1]. Even in minor-volume ICH, anemia
was a strong predictor of unfavorable functional
outcome. Another retrospective study demonstrated that low nadir Hb, not admission Hb, can
be used to predict poor functional outcomes in
patients with ICH [15].
Despite this fact, a recent retrospective study
failed to demonstrate an improvement in outcomes
with RBC transfusion in patients with ICH [16].
Outcomes in patients with ICH who receive RBC
transfusion have been contradictory. In one study,
RBC transfusion was associated with a trend toward
worse outcomes compared with patients who were
not transfused [16]. In another study, however, RBC
transfusion was not an independent predictor of
poor outcomes [15].
A retrospective study analyzed various factors
associated with an increased risk of developing
acute respiratory distress syndrome after ICH [17].
They found that RBC transfusion was a modifiable
risk factor associated with increased risk of acute
respiratory distress syndrome. The authors did
not examine the indication or Hb level at the
time of transfusion, so the relative necessity of
the transfusions could not be ascertained. Large,
prospective trials are needed to further examine the
risks of anemia and RBC transfusion in patients
with ICH.

CEREBRAL ISCHEMIA
Patients in the neurological ICU frequently present
with ischemic stroke, and these patients often
require endovascular or decompressive surgery
during their hospital stay. These patients generally
have a poor prognosis, and prevention of secondary
brain injury is vital [18]. To date, there have been no
RCTs or large-scale studies that have investigated
the role of anemia RBC transfusion strategies in
NICU patients with ischemic stroke.
472

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A recent observational, retrospective study
examined the effects of anemia and RBC transfusion
in 109 patients admitted to the NICU with ischemic
stroke [18]. Nearly every patient in their cohort
developed anemia, defined as Hb less than 12 g/dl
in women and 13 g/dl in men. About one-third of
patients were transfused RBCs, at the discretion of
the attending physician, during their hospital stay.
They found that decreasing Hb and hematocrit (Hct)
were associated with increased NICU length of stay
and longer mechanical ventilation requirements.
There were no differences in mortality or functional
outcomes, and patients who were administered RBC
transfusions did not experience any benefits. Their
limited data suggest that anemia should probably be
avoided in patients with cerebral ischemia, but until
larger prospective studies are done, no specific transfusion strategies for these patients can be recommended at this time.

ELECTIVE CRANIAL SURGERY
There have been no RCTs to date that have
examined whether patients undergoing elective
craniotomy benefit from either aggressive or
restrictive perioperative RBC transfusion criteria.
Alan et al. [19 ] recently published the first largescale study examining the effect of perioperative
anemia on outcomes in patients undergoing elective cranial surgery. Using the National Surgical
Quality Improvement Program database, they
identified more than 6500 patients who underwent
elective craniotomy for brain tumor, developed
perioperative anemia, but were not transfused.
Anemia was defined as mild (Hct 30–38%), moderate (Hct 26–30%), and severe (Hct <26%). The study
found that perioperative anemia, irrespective of
severity, was associated with increased hospital
length of stay but not increased 30-day morbidity
or mortality.
&

OTHER CONSIDERATIONS
Currently, there are few alternatives to RBC transfusion for anemic patients. Although RBCs are being
transfused less frequently in recent years because of
adverse patient outcomes and their associated costs,
the use of alternatives to RBCs that is currently
under investigation will likely also be driven by
patient costs and clinical outcomes [20]. Autologous
blood procurement, erythropoiesis-stimulating
agents, and hemostatic agents have shown some
promise in preventing sustained anemia in neurosurgical patients, but larger RCTs are needed to
evaluate their efficacy. For patients undergoing
neurosurgical procedures, there is limited evidence
that blood conservation methods, such as acute
normovolemic hemodilution, may be safe [21].
Volume 27 Number 5 October 2014

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RBC transfusion Gruenbaum and Ruskin

AGE OF STORED BLOOD
Many have questioned whether RBC age alters RBC
function, thereby possibly increasing morbidity
and mortality in neurosurgical patients [14]. It has
been argued that progressively decreasing levels of
2–3 diphosphoglycerate in older blood may impair
oxygen unloading and the release of vasodilators.
However, patients transfused with older blood have
not consistently demonstrated worse outcomes
compared with transfusion of younger blood. A
recent systematic review concluded that the quality
of evidence is too poor to implement changes in
current transfusion practices [22 ].
&&

CONCLUSION
Anemia and RBC transfusion in neurosurgical
patients are common. The brain is especially sensitive to hypoperfusion and hypoxia, and anemia may
be associated with an increased risk of secondary
brain injury. However, the inherent risks associated
with RBC transfusion should not be underestimated. Although anemia is associated with a poor
outcome, especially in the presence of cerebral
ischemia, RBC transfusion is also associated with
a worsened outcome. Currently, there is no level 1
evidence by which definitive RBC transfusion
guidelines for neurosurgical patients can be recommended. Large RCTs are needed to better understand the balance between the risks associated
with anemia and RBC transfusion in neurosurgical
patients. Although some authors have recently
advocated for a more liberal transfusion trigger
(Hb of 9 g/dl) in patients with TBI, SAH, and acute
ischemic stroke, there are also studies that suggest
that a restrictive transfusion trigger (Hb of 7–8 g/dl)
does not worsen outcome and may be of benefit to
some patients. RBC transfusion decisions should be
guided by risk and benefit analysis should be determined for each patient.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
1. Kuramatsu JB, Gerner ST, Lucking H, et al. Anemia is an independent
prognostic factor in intracerebral hemorrhage: an observational cohort study.
Crit Care 2013; 17:R148. [Epub ahead of print]

2. Rolston JD, Han SJ, Lau CY, et al. Frequency and predictors of complications
in neurological surgery: national trends from 2006 to 2011. J Neurosurg
2014; 120:736–745.
3. Chang TR, Naval NS, Carhuapoma JR. Controversies in neurosciences
critical care. Anesthesiol Clin 2012; 30:369–383.
4. LeRoux P. Haemoglobin management in acute brain injury. Curr Opin Crit
Care 2013; 19:83–91.
5. Desjardins P, Turgeon AF, Tremblay MH, et al. Hemoglobin levels and
transfusions in neurocritically ill patients: a systematic review of comparative
studies. Crit Care 2012; 16:R54.
6. Rohde JM, Dimcheff DE, Blumberg N, et al. Healthcare-associated infection
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after red blood cell transfusion: a systematic review and meta-analysis. JAMA
2014; 311:1317–1326.
Systematic review and meta-analysis demonstrated that RBC transfusion was
associated with an increased risk of healthcare-associated infection.
7. Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood
&
transfusion strategies on clinical outcomes: a meta-analysis and systematic
review. Am J Med 2014; 127:124–131; e3.
Systematic review and meta-analysis demonstrated the many benefits of restrictive
RBC transfusion strategies on outcomes.
8. Epstein DS, Mitra B, O’Reilly G, et al. Acute traumatic coagulopathy in the
&&
setting of isolated traumatic brain injury: a systematic review and metaanalysis. Injury 2014; 45:819–824.
Systematic review and meta-analysis demonstrated the effect of acute traumatic
coagulopathy on clinical outcomes.
9. Acker SN, Partrick DA, Ross JT, et al. Blood component transfusion increases
the risk of death in children with traumatic brain injury. J Trauma Acute Care
Surg 2014; 76:1082–1088.
10. DeCuypere M, Phillips G, Muhlbauer MS. Anemia and associated hospital
mortality after severe traumatic brain injury. Surg Forum Abstracts 2013;
217:S69.
11. Elterman J, Brasel K, Brown S, et al. Transfusion of red blood cells in patients
&
with a prehospital Glasgow Coma Scale score of 8 or less and no evidence of
shock is associated with worse outcomes. J Trauma Acute Care Surg 2013;
75:8–14; Discussion.
Large, retrospective study demonstrated that RBC transfusion when Hb more than
10 g/dl was associated with worse outcomes.
12. Festic E, Rabinstein AA, Freeman WD, et al. Blood transfusion is an important
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predictor of hospital mortality among patients with aneurysmal subarachnoid
hemorrhage. Neurocrit Care 2013; 18:209–215.
Retrospective study demonstrated that RBC transfusion was independently
associated with increased mortality compared with patients who were not transfused.
13. Kumar MA, Boland TA, Baiou M, et al. Red blood cell transfusion increases the
&
risk of thrombotic events in patients with subarachnoid hemorrhage. Neurocrit
Care 2014; 20:84–90.
Retrospective, observational cohort study demonstrated an increased risk of
thrombotic events and venous thromboembolism with RBC transfusion in patients
with SAH.
14. Rosenberg NF, Koht A, Naidech AM. Anemia and transfusion after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol 2013; 25:66–
74.
15. Chang TR, Boehme AK, Aysenne A, et al. Nadir hemoglobin is associated
with poor outcome from intracerebral hemorrhage. Springerplus 2013;
2:379.
16. Mohamed W, Reddy S, Sivakumar S, et al. Blood transfusion does not
improve outcomes in patients with spontaneous intracerebral hemorrhage.
Neurology 2014; 82 (Suppl):143; P7.
17. Elmer J, Hou P, Wilcox SR, et al. Acute respiratory distress syndrome after
spontaneous intracerebral hemorrhage . Crit Care Med 2013; 41:1992–
2001.
18. Kellert L, Schrader F, Ringleb P, et al. The impact of low hemoglobin levels and
transfusion on critical care patients with severe ischemic stroke: STroke:
RelevAnt Impact of HemoGlobin, Hematocrit and Transfusion (STRAIGHT)–
an observational study. J Crit Care 2014; 29:236–240.
19. Alan N, Seicean A, Seicean S, et al. Impact of preoperative anemia on
&
outcomes in patients undergoing elective cranial surgery. J Neurosurg
2014; 120:764–772.
Large, retrospective study demonstrated that anemia was associated with prolonged hospitalization after elective cranial surgery but not an increased risk for
adverse outcomes.
20. Spahn DR, Goodnough LT. Alternatives to blood transfusion. Lancet 2013;
381:1855–1865.
21. Oppitz PP, Stefani MA. Acute normovolemic hemodilution is safe in neurosurgery. World Neurosurg 2013; 79:719–724.
22. Lelubre C, Vincent JL. Relationship between red cell storage duration and
&&
outcomes in adults receiving red cell transfusions: a systematic review. Criti
Care 2013; 17:R66. [Epub ahead of print]
Systematic review demonstrated that no definitive studies supported that transfusion with fresh RBCs improved outcomes over transfusion with older RBCs.

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473

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REVIEW
URRENT
C
OPINION

Craniotomy in sitting position: anesthesiology
management
Isabel Gracia and Neus Fabregas

Purpose of review
Sitting position to surgically approach posterior fossa disorder continues to be the first choice for some
neurosurgical teams. We underwent a literature research for recent published studies involving
neurosurgical patients operated on in this position. Preoperative evaluation, anesthetic technique,
intraoperative monitoring, detection and treatment of venous or arterial air embolism episodes, and all the
reported complications were recorded.
Recent findings
A modified semisitting (lounging) position aiming to create a positive pressure in the transverse and
sigmoid sinuses, with lower head and higher legs positioned above the top of the head, decreases the
incidence and severity of venous air embolism. Hyperventilation, compromising cerebral blood flow, has to
be avoided during a sitting position. Precordial Doppler or transesophageal echocardiography monitoring
improves the detection of small venous air embolism enabling its early treatment and diminishing its
consequences. Patients with known patent foramen ovale can be operated on in a sitting position, under
strict protocol, with few reported clinical venous air embolism and no paradoxical air embolism.
Summary
Sitting position for neurosurgical procedures may be a well tolerated approach for the patient if
neurosurgeons and neuroanesthesiologists undergo a strict team protocol, including all necessary
monitoring and meticulously followed.
Keywords
neuroanesthesia, patent foramen ovale, posterior fossa surgery, sitting position, venous air embolism

INTRODUCTION

enhance safer and finer dissection [1]. The rate of
nerve cranial preservation is higher [3 ], gives an
optimal access to the airway, and improves ventilation because of the diminution of the intrathoracic pressure.
The major risks of the sitting position include
hemodynamic instability, which could affect the
cerebral perfusion pressure (CPP); increased incidence of venous air embolism (VAE); favor the postoperative occurrence of pneumocephalus, subdural
hematoma, tetraplegia, macroglosia and peripheral
neuropathy [5,6].
&&

There is a great difference between countries in the
use of the sitting position for craniotomies. In Japan,
for instance, the position is used only in a small
number of institutions; neurosurgeons and neuroanesthesiologists may not choose the position
because they know that the risk may be different
depending on clinical team members and their
experience [1]. The results of a recently published
survey highlight that whether in Germany it is a
common practice, only 27% of UK centers offer the
sitting position nowadays [2].
The sitting position has several advantages compared with supine, especially for surgery of large and
vascularized tumors in the posterior cranial fossa
[3 ]; lowers intracranial pressure and reduces bleeding field due to gravity-assisted blood drainage and
cerebellar retraction; reduces need for coagulation
allowing a well defined tumour-brain interface [4 ];
bimanual microsurgical procedures in an operative
field with less blood and less retraction that may
&&

&&

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Anesthesiology Department, Hospital Clinic Barcelona, Barcelona University, Barcelona, Spain
Correspondence to Neus Fabregas, MD, PhD, Anesthesiology Department, Villarroel, 170, 08036 Barcelona, Spain. Tel: +34 932275558;
fax: +34 932279184; e-mail: fabregas@clinic.ub.es, fabregas@ub.edu
Curr Opin Anesthesiol 2014, 27:474–483
DOI:10.1097/ACO.0000000000000104
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Craniotomy in sitting position Gracia and Fabregas
&&

KEY POINTS
The presence of a PFO should be known before
positioning the patient in a sitting position; it does not
contraindicate this surgical approach, but a strict
perioperative protocol is needed to detect and treat
VAE and avoid paradoxical air embolism.
Maintaining lower head and higher legs position
diminishes VAE incidence; monitoring sensitive and
motor evoked potentials for the positioning and during
the surgery is recommended.
Specific monitoring such as a precordial Doppler or
transesophageal echocardiography and a central
venous line with tip in right atrium are mandatory.

&&

&&

&

&&

A patient safety approach for a procedure in sittingposition surgery needs a team-coordinated work; early
diagnosis and treatment of any complication secondary
to the positions are needed to minimize its severity and
improve outcomes.

MODIFIED SITTING POSITION
To increase position safety, Jadik et al. [7] developed,
as part of a standardized perioperative protocol, a
modified semisitting position aiming to achieve a
positive venous pressure at the operation site. The
positioning requires a combination of adjustments;
upper body and legs elevated by bending the operating table to a position in which the hip is flexed to
a maximum of 908. A 308 flexion of the knees is
maintained to avoid overstretching of the tendons
and nerves of the leg. The patient’s head is flexed
anteriorly and a two-finger space between the sternal notch and the chin is left to avoid venous outflow obstruction. Arms are supported to avoid
traction of the shoulders; legs, arms and heels are
padded. Finally, the inclination of the whole operating table is changed to a lower head and higher
legs position, in which the legs of the patients are as
high as the vertex. This modified positioning has
been included in quite all recent prospective published series from different countries [3 ,4 ,8 ],
demonstrating that strict adherence to standardized
protocols minimizes perioperative complications.
&&

&&

&&

Hyperventilation, compromising cerebral blood flow,
has to be avoided during sitting position; noninvasive
monitoring of cerebral oxygenation adequacy
is needed.

&&

known. Ammirati et al. [4 ] are the only group that
perform a preoperative flexo-extension cervical
radiograph to diagnose spinal instability in all
patients. Preoperative transcranial Doppler (TCD)
can be used [9].
Three groups perform a preoperative screening
to determine the presence of a right-to-left cardiac
shunt in all patients planned to be operated on in a
sitting position [3 ,8 ,10 ]. Some centers have
recommended closing the patent foramen ovale
(PFO) before surgery [11]. In two centers, the PFO
search is done only after anesthesia induction
¨ rgens and Basu [2] survey, six
[4 ,12 ]. In the Ju
centers (55%) in the UK performed preoperatively
transthoracic bubble screening. Confirmation of a
PFO not always implied change in the planned
surgical position; moreover, the Feigl et al. study
[3 ] was performed including only patients with
this condition (Table 1). Testing previously to the
surgery the planned positioning in the patient
awake and looking for a PFO is always advisable.

&&

PREOPERATIVE EVALUATION
There is not a uniform approach on what special
preoperative evaluation is necessary for patients to
be operated on in a sitting position. We need to
minimize complications that can be preventable if

INTRAOPERATIVE MONITORING
During sitting-position surgeries specific intraoperative monitoring is required to increase the safety of
the procedure. Invasive arterial blood pressure
monitoring was used by all groups, some of them
specify the transducer zeroed and located at the
foramen of Monro level [3 ,8 ,12 ]. A central
venous line (CVL) is also a standard monitoring
(Table 2). Only one study included a Swan Ganz
catheter [13].
Sensory-evoked and motor-evoked potentials
with transcranial electrical stimulation during
positioning and intraoperatively were used in the
Jadik et al. [7] and Feigl et al. [3 ] studies as a
standard protocol.
Intraoperative transesophageal echocardiography (TEE) to identify air bubbles is a standard of
care for a sitting position in different German hospitals [3 ,7,14]; it is not the case in other countries,
being precordial Doppler monitoring the standard
[2,4 ,12 ] (Table 2). In a recently published case
report [14], both monitors were applied to their
patient. Patients should not be operated on in a
sitting position if no specific monitoring is available.
&&

&&

&

&&

&&

&&

&

ANESTHETIC MANAGEMENT
We cannot conclude from the literature what is the
best anesthetic approach for sitting position; nevertheless, intravenous anesthesia is predominantly
referred to in recent studies (Table 3). Nitrous oxide
is not used and sevoflorane is mentioned as
occasional in only two centers [8 ,10 ]. FiO2 goes

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&&

&&

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Neuroanesthesia
Table 1. Sitting position neurosurgical studies design and search of a patent foramen ovale
Lindroos
&&
et al. [8 ]

Ganslandt
&&
et al. [10 ]

Scha¨fer
et al. [13]

Ammirati
&&
et al. [4 ]

Hervias
&
et al. [12 ]

Feigl
&&
et al. [3 ]

Study design

Prospective

Retrospective

Retrospective

Retrospective

Prospective

Prospective

Retrospective

number of patients
included

15/15

600

799

41 (85%)
semisitting

136

52

187

Craniotomy

All

482 (80%)

All

All

93 (68%)

All

All

cervical spine

0

118 (20%)

0

0

43 (32%)

0

0

preoperative
PFO search

Yes (test
not specified)

Yes (test not
specified)

ND

ND

No

TTE (þVM)
52 PFOa

ND

Postinduction
PFO search

No

No

ND

TEE
PFO in10b (20.8%)

TCD (þVM)
PFO in 2c (1.4%)

TEE

TEE (þVM)
PFO (21.5%)d

‘material’ for
test bubbling

ND

ND

ND

Foaming patient‘s
blood or albumin
and reinjection
into a central line

Agitated saline
into a central
line

Cold saline
solution

Intravenous
echo-contrast

Jadik
et al. [7]

7 (15%) prone

24 PFO (4%)

ND, no data; PFO, patent foramen ovale; TCD, transcranial Doppler; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography; VM,
valsalva manoeuvre.
a
(All operated on in sitting position).
b
(Six patients with large PFO were operated prone).
c
(Operated on in semisitting position).
d
(Excluded and operated prone or park bench position).

from 0.4 to 1 (Table 3). Different authors have
shown that hyperoxia may prevent or reduce blood
flow through arteriovenous pathways bypassing the
capillary system when they are exercise induced. It
remains unknown whether FiO2 or oxygen tension
specifically regulates these recruited anastomoses or
opens them indirectly [14].
Prepositioning fluid load is referred to in three
studies [7,8 ,13]. Antigravity devices are used in
Lindroos et al. study [8 ] and in two UK centers
[2]. The intermittent sequential compression device
on the lower extremities has been also used in sitting-position surgery for shoulder arthroscopy; its
use decreased hypotensive episodes and improved
cerebral brain oxygenation [15]. A controlled fluid
load, knowing patient intravascular volume status,
and compression devices are both suitable during
these procedures.
&&

&&

HAEMODYNAMIC MANAGEMENT
Cerebral ischemic injuries from relative hypotension have opened a debate about the adequacy of
CPP in head up positions, and there are differences
of opinion on the physiology and monitoring for
cerebral circulation [5,16]. Changing from the
supine to the sitting position during neurosurgical
procedures induces a significant decrease of cardiac
index (CI), stroke volume index (SVI), right atrial
pressure, mean arterial blood pressure (MAP), mean
476

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pulmonary arterial pressure and pulmonary wedge
pressure, and an increase in systemic vascular and
pulmonary resistances [17]. Sitting may affect brain
arterial and venous pressure and alter the venous or
arterial ratio with different blood distributions [18 ].
The pooling of venous blood in lower extremities,
VAE or cranial nerve manipulation aggravates
hemodynamic alterations jeopardizing cerebral
blood flow (CBF), especially in patients with disturbed autoregulation. ‘Beach-chair’ position for
shoulder surgery is nowadays spreading and shows
similar hemodynamic effects needing to be aware of
[18 ]. It is important to take into account that 50o
head-of-bed elevation leads to an 18-mmHg difference in MAP measured at the level of the tragus
compared with the level of the right atrium. Failure
to appreciate this concept can produce devastating
consequences [19]. Therefore, a reported CPP of
60 mmHg may vary from a true head-level value
of 43–60 mmHg, depending on reference point,
head-of-bed elevation and height of the patient.
This added variability might have affected patient
outcomes and conceals treatment effects in clinical
research trials [20].
Only a few studies recommend a fluid preloading before changing from supine. Lindroos et al. [8 ]
determined stroke volume (SV), measured by arterial
pressure waveform analysis, before positioning and
administered boluses of fluid (either 6% hydroxyethyl starch (HES) or Ringer’s acetate (RAC) after
&

&

&&

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PAE

No

No

3 (0.5%)

Flooding with saline;
head tilt to heart
level; catecholamine
bolus

20 (3.3%)

20 (3.3%)

ND

No

ND

ND

ND

ND

114 (19%); craniotomy 52 (6.5%)
101(21%); spinal
surgery 13 (11%)
(In PFO patients
VAE:16.6%)

ND

Yes/ECG

No

No

No

Bone waxed, jugular
vein, compression,
wet gauze field,
FiO2 1; fluid load,
CVL aspiration,
Trendelenburg

Yes

Yes

2 (4.9%) air
aspiration;
5 (12.8%) no
air aspiration

Sudden drop in
systolic BP of at
least 20 mmHg;
23 (56.1%)

fall 5 mmHg;
11 (26.8%)

Yes

No

2 p (4.9%).not in
PFO patients
All patients air bubbles in
29 p (55.7%), 63 events$
(1-7 events per patient)

Yes

No

b

Not possible

Yes /TEE

Feigl
&&
et al. [3 ]

No

No

No

No

No

No

No

No

No

1 (0.5%)

In one (1.9%)

If air bubbles in TEE:
Bone waxed, gelatine
irrigation surgical site;
foam, cauterizing
FiO2: 1; jugular vein
bleeding sites
compression, gelatine or
glue foam; CVL aspiration.
bone waxed.

ND

3 (1.6%)

Yes

Yes

3 (13.7%)

In one (1.9%)

All patients intermittent
jugular compression
to detect bleeding
No

c

ND

Yes/ECG

Jadik
et al. [7]

Bone waxed, jugular
vein compression,
FiO2 1; fluid load,
CVL aspiration.

4 (18%)

22 (16.2%); craniotomies; 5 (9.6%)
20 (21.5%); spinal
surgery; 2 (4.7%)

Sudden drop in systolic
Yes
BP of at least 20 mmHg

6 (27.3%); 12 (54.5%)
PCD þ drop ETCO2

Yese; positive in
4 (18.2%)

No

Yes, in 59% VAE

Yes/ECG

Hervias
&
et al. [12 ]

ABP, arterial blood pressure; BP, blood pressure; CVL, central venous line; ECG, intracardiac electrocardiographic recordings; ETCO2, end-tidal CO2; $, ‘minor’; ND, no data; PAE, paradoxical air embolism; PCD,
precordial Doppler; PFO, patent foramen ovale; TEE, transoesophageal echocardiography; VAE, venous air embolism.
a
(View of the right ventricular inflow-outflow tract).
b
(Placed in supine, superior cava or right atrium and left ventricle visible in the semisitting position. Bolus of cold saline test); $(In 30 events (47.6%) a venous leak was found under bilateral compression of the jugular
veins).
c
(After semisitting position 0.25 ml of air is intravenously injected).
d
(Right of sternum, over fifth intercostal space).
e
(Second to fourth intercostal spaces, better sound injecting agitated saline).

No

No

Death for VAE

ND

VAE treatment

No

No

VAE with hypotension

STOP SURGERY

No

VAE with hypoxemia

ND

14 (50%) $$

ND

fall 2.25 mmHg fall 4 mmHg;
61 (10.2%)

ETCO2 threshold;
patients
(percentage)
Diagnosis by ABP

VAE patients
(percentage)

Yes

In 245 p (until 2000);
positive in 9.4%;
significant: 1.2%

Yesd

PCD
Yes

No

In 355 p (59%) any
air:25.6%
significant: 4.8%

a

No

TEE

Yes/ECG
ND

Yes/ND

ND

¨
Schafer
Ammirati
&&
et al. [13] et al. [4 ]

Aspiration of air

Ganslandt
&&
et al. [10 ]

CVL /tip in right atrium Yes/-

Lindroos
&&
et al. [8 ]

Table 2. Venous air embolism intraoperative monitoring, diagnosis, complications and treatment in sitting position neurosurgical studies

Craniotomy in sitting position Gracia and Fabregas

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www.co-anesthesiology.com
Yes
Sevoflurane if
hypertensionb
Remifentanyl
200 ml over
2.4 min. New
bolus until
increase
> 10%SVV
6% HES/Ringer
acetate

Propofol
maintenance

Halogenate
maintenance

Opioid
maintenance

‘preloading’
(presitting)

Colloids/crystalloids

ND

No

500/3500 ml
VAE: 500/4500 ml
NoVAE:500/3000 ml

ND

ND

ND

ND

500 ml colloid

Fentanyl

ND

Sevoflurane1 MAC
in some patients
Fentanyl or
Remifentanyl

Yes

ND

Propofol þ
Fentanyl

In some patients

Rocuronium

Propofol or
Etomidate þ
Fentanyl

ND

Not N2O

ND

Scha¨fer
et al. [13]

ND

ND

ND

ND

ND

ND

ND

ND

ND

7–10

Efedrine

No

ND

ND

Remifentanyl

No

Yes

Rocuronium

Propofol þ
Remifentanyl

6–7

0.5

30–35

35–40a
ND

Hervias
&
et al. [12 ]

Ammirati
&&
et al. [4 ]

ND

ND

ND

ND

Remifentanyl

ND

Yes

ND

Propofol þ
Sufentanyl þ
Remifentanyl

except in PFO
patients

ND

Arterial blood
once per hour

Feigl
&&
et al. [3 ]

CVP, central venous pressure; HES, 6% hydroxyethyl starch; ND, no data; NoVAE, without air embolism; PFO, patent foramen ovale; SVV, stroke volume variation; VAE, venous air embolism.
a
(Mild hypercapnia).
b
(Used in three patients of each group).

Efedrine or
Phenylephrenine
boluses

Rocuronium

RNMB

Vasopressors

Thiopental
Propofol þ
Fentanyl

Induction

Yes

No

Stroke volume direct
fluid administration

0.4–0.5

0.5–1

FiO2

PEEP (cmH2O)

ND

30–40

Ganslandt
&&
et al. [10 ]

33.75–37.5

ETCO2(mmHg)
maintenance

Lindroos
&&
et al. [8 ]

Table 3. Anesthesia management in neurosurgical sitting procedures studies

ND

Yes, to 5–12 cmH2O
CVP

ND

ND

ND

ND

ND

5–10

ND

Avoid hyperventilation

Jadik
et al. [7]

Neuroanesthesia

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Craniotomy in sitting position Gracia and Fabregas

anesthesia induction) until SV did not increase more
than 10%. During craniotomy new fluid boluses
were given with the same target. The intraoperative
fluid balance was more positive in the RAC than in
the HES group. CI and SVI increased in the HES
group (P < 0.05). Neither coagulation profile nor
blood loss differed between the groups. The authors
suggested that the 34% smaller volume of HES than
crystalloid and less positive fluid balance in the HES
group might be important in craniotomy patients
with decreased brain compliance. The target for
MAP was 60 mmHg or higher at the brain level.
Boluses of phenylephrine (0.05–0.1 mg) or ephedrine (5–10 mg) were given if needed. A phenylephrine infusion was started whenever MAP
remained below 60 mmHg for more than 5 min.
Targeting an MAP during sitting position is
something scarcely defined in the reported clinical
studies, Lindroos et al. [8 ] being one of the exceptions. Moore et al. [21], in a retrospective study,
analyzed the electronic intraoperative records of
neurosurgical patients with intracranial and arterial
pressure monitoring devices and calculated CPP. It is
interesting to remark that the median minutes of
CPP < 60 mmHg was 39, probably greater than
expected.
Ephedrine [8 ,12 ] and phenylephrine [8 ,18 ]
are the vasopressors more frequently used to treat
intraoperative hypotension in the reviewed studies.
Meng et al. [22], in a randomized cross-over design,
administered one bolus dose of phenylephrine
(100–200 mg) or ephedrine (5–20 mg) to American
Society of Anesthesiology I–III patients anesthetized
with propofol and remifentanil. Frontal near infrared
spectroscopy (NIRS), MAP and cardiac output (CO)
were recorded before and after treatments. The CO
decreased significantly after phenylephrine treatment, but was preserved after ephedrine treatment.
NIRS was significantly decreased after phenylephrine
treatment but preserved after ephedrine treatment.
CO was identified to have the most significant association with a decrease in cerebral tissue oxygen saturation (SctO2) (P < 0.001). Concordant with changes
in CO, cerebral oxygenation significantly decreased
after phenylephrine bolus treatment and remained
unchanged after ephedrine bolus treatment, even
though MAP was significantly increased by both
agents.
In Joshi et al. study [23] patients undergoing
cardiac surgery with cardio pulmonary bypass
(CPB) underwent TCD monitoring of the middle
cerebral arteries and NIRS monitoring. A continuous, correlation coefficient was calculated between
MAP and CBF velocity and between MAP and NIRS
data to generate mean velocity index and cerebral
oximeter index (COx). When MAP is below the
&&

&&

&

&&

&

lower limit of autoregulation (LLA), mean velocity
index and COx approach 1. They found that there
is a wide range of MAP at the LLA [66 mmHg (95%
prediction interval, 43–90 mmHg)] in patients
during CPB, making estimation of this target difficult. Ono et al. [24], using an equivalent study
design, found impaired CBF-autoregulation in
20% of patients during CPB. Perioperative stroke
occurred in six of 47 (12.8%) patients with
impaired autoregulation compared with five of
187 (2.7%) patients with preserved autoregulation
(P¼0.011).
The most widely proposed mechanism of a postoperative stroke is arterial embolism; nevertheless,
the role of intraoperative hypotension in the occurrence and evolution of postoperative stroke is
largely unknown. A case-control study was conducted among 48 241 patients who underwent noncardiac and non-neurosurgical procedures by Bijker
et al. [25]. A total of 42 stroke cases (0.09%) were
matched on age and type of surgery to 252 control
patients. They found seven (17%) strokes in watershed areas and concluded that intraoperative hypotension, especially for mean blood pressure values
decreasing more than 30% from baseline blood
pressure, might play a role in the development of
postoperative ischemic stroke. All these results need
to be kept in mind when dealing with neurosurgical
patients under sitting position, probably a ‘targeted’
MAP is not enough. In the near future, neurosurgical
patients will probably undergo standardized perioperative autoregulation study test, easily assessed at
the bedside without further patient manipulation,
to continuously adjust the ‘better MAP’ to maintain
CBF and brain oxygenation without increasing
cerebral blood volume (CBV). Furthermore, a goaldirected fluid administration for CO and SV variation optimization is needed [8 ].
&&

RESPIRATORY MANAGEMENT
Mechanical ventilation during sitting position
procedures is set to maintain normocapnia
[7,8 ,10 ,14] or mild hypercapnia [4 ]. Meng
et al. [26] found in normal healthy individuals that
the impacts of head-up tilt (HUT) and hyperventilation on cerebral hemodynamics are mechanistically different. In their study, changes in brain
oxygenation and CBF do not correlate with changes
in MAP and CO during HUT at 30o; however,
changes in both SctO2 and CBV correlate with
changes in end-tidal CO2 (ETCO2) during hyperventilation. Alexander et al. [27 ] compared, in
non-neurosurgical patients, the effects of propofol-remifentanil and sevoflurane anesthesia
over cerebral tissue oxygen saturation response to

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&&

&&

&&

&&

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Neuroanesthesia

stepwise hyperventilation. The main mechanism
responsible for hyperventilation-induced decrease
in SctO2 is hypocapnia in both groups.
The use of positive end expiratory pressure
(PEEP) to decrease the incidence of VAE may facilitate the incidence of a paradoxical (arterial) air
embolism (PAE) if an air embolus occurs. It is used
from 6 to 10 cmH2O in some groups [7,4 ,12 ], not
applied in one of the recently published studies [8 ]
and not mentioned in others [10 ,13]. Ammirati
et al. [4 ] used a PEEP of 7–10 cmH2O for all
patients. In cases of proven PFO, they established
biphasic PEEP to increase the intrathoracic pressure.
In the Schramn et al. [28 ] study, increasing the
PEEP in patients with acute respiratory distress
syndrome had no clinically relevant effects on
cerebrovascular autoregulation, independently of
pre-existing autoregulation impairment.
&&

&

&&

&&

&&

&&

VENOUS AIR EMBOLISM
In recent literature, the reported incidence of VAE
ranges from 1.6 [7] to 50% [8 ] (Table 2), depending
on the diagnostic method used. However, most
detected VAE are reported not to be clinically
relevant. With the increased use of continuous
intraoperative TEE the risks of false positive
increase. Different VAE grading scales [3 ,13,29]
have been used to classify the severity of VAE,
interestingly most of the referred episodes are
accompanied by minimal clinical alterations
(Table 4). Early detection is crucial to stop the
endovascular air entrance. ETCO2 fall is one of
the clinical signs of VAE severity, with different
thresholds being used (Table 2).
Hemodynamic instability due to VAE occurs in
a few cases (Tables 2 and 4), no death has been
reported in the reviewed literature. Only in the
largest study [10 ] including 600 patients was
necessary to stop surgery by persistent VAE in three
patients (0.5%), they were operated on uneventfully afterwards. There was no difference between
the VAE and no-VAE groups with respect to administered colloids, estimated blood loss, transfusion
volume, duration of postoperative ventilation,
length of ICU and hospital stay, reoperation
(defined as hematoma evacuation) and inhospital
mortality.
A series of common maneuvers are used by all
teams to stop venous air entrance (Table 2).
Hypoxemia with VAE is referred from 0.5 [7] to
18% [12 ] of the reviewed literature.
Scha¨fer et al. [13] found in their retrospective
study that VAE (Table 4) was associated with a significant decrease in platelet count, in their opinion
following VAE reassessing blood coagulation and
&&

&&

&&

&

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platelet count intraoperatively is mandatory. Thrombelastometry and aggregometry will allow an
immediate analysis of platelet function and whole
blood coagulation [30].
Particulate venous bone embolism has been
recently reported during neurosurgery in sitting
position, with a good outcome [31].
The major risk of a VAE is the occurrence of
paradoxical arterial embolism (PAE), but this risk
seems to be more theoretical than real, if a standardized management protocol is followed. A confirmation of that is the Feigl et al. [3 ] study, in which
all included patients had a PFO previously diagnosed. A strict protocol, including the modified
sitting position [7] and a meticulous specific
monitoring (TEE with intermittent jugular compression to detect any bleeding, and evoked potentials), was followed.
We have found only one recent published
case of PAE in a patient operated on in a sitting
position [14], TEE inserted after induction did
not evidence any intracardiac shunt, contrastenhanced ultrasound with Gelafundin 4% microbubbles was injected during a simulated Valsalva
maneuver (25–30 cmH2O) focusing on the release
phase, and was negative. Four episodes of VAE
were intraoperative detected, third and fourth
with respiratory and hemodynamic repercussion.
Norepinephrine was started and aspiration through
a CVL was attempted. Manual compression of
jugular veins was done. Surgical wound was closed
temporarily and patient transferred to supine
position. When repositioned they detected a
significant crossover of air bubbles into the left
heart deriving from the left pulmonary vein.
Bilateral postoperative perivascular interstitial
edema appeared on chest radiograph. The patient
had a good outcome, but a persistent left superior
cava vein blood flow into the coronary sinus and to
the right heart was diagnosed.
&&

POSTOPERATIVE COMPLICATIONS
Despite the theoretical risk of airway complications,
mainly in the form of edema of the airway, anyone
of the last published studies has reported this
sort of comorbidity. Peripheral neuropathy, quadriplegia, facial edema or tongue edema have not
been reported. Supratentorial pneumocephalus is
a known complication of neurosurgical procedures
when conducted in the sitting position [32], but it is
mentioned in only two of the recent published
studies. In both studies, pneumocephalus provoked
transient postoperative lethargy with a 3.7% incidence in one study [12 ] and a 31% in the other [7],
one patient required a subdural drain.
&

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Positive PCD signal without
hemodynamic alterations

18 (34.6%)

Girard scale [29]

Scha
¨ fer et al. [13]

0952-7907 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

2 (66.6%)

1 (33.3%),

Moderate clinical
VAE: positive TEE
with ABP decrease
or HR increase

2 (6.9%)

Air bubbles on TEE þ
decrease ETCO2
3 mmHg

20 (38.4%)

Positive PCD signal
þ increase SPAP
> 5 mmHg and/or
a decrease ETCO2
> 3 mmHg

Grade 2

0

Severe clinical VAE,
positive TEE and
decrease ABP > 40%
or HR increase > 40%;
including situations CPR

4 (13.8%)

Air bubbles on TEE
þ decrease of ETCO2
> 3 mmHg

11 (21.2%)

Positive PCD signal
þ increase SPAP
> 5 mmHg and/or
a decrease ETCO2
> 3 mmHg

Grade 3

NA

NA

1 (3.4%)

Air bubbles on TEE þ decrease
ETCO2 > 3 mmHg þ decrease
MAP 20% or increase
HR 40% (or both)

3 (5.7%)

Sudden ABP decrease of at
least 40% or a 40% increase
in HR in the presence of at
least one positive ‘grade 2’
criterion

Grade 4

NA

NA

0

VAE causing arrhythmia with
hemodynamic instability requiring
cardiopulmonary resuscitation

0

Cardio circulatory collapse in the
presence of at least one positive
‘grade 2’ criterion

Grade 5

ABP, arterial blood pressure; CPR, cardiopulmonary resuscitation; ETCO2, end-tidal CO2; HR, heart rate; NA, not applicable; PCD, precordial Doppler signal; SPAP, systolic pulmonary artery pressure; TEE,
transesophageal echocardiography; VAE, venous air embolism.

patients (percentage)
in different grades

Jadik et al. [7]

Jadik scale [7]

patients (percentage)
in different grades

Minor clinical VAE: positive
TEE accompanied
by an ETCO2 decrease
> 3 mmHg

22 (75.8%)

Feigl et al. [3 ]

&&

Air bubbles on TEE

&&

Tu¨bingen scale [3 ]

patients (percentage)
in different grades

Grade 1

VAE Classification

Table 4. Grading scales for venous air embolism. Results in different published studies in neurosurgical patients operated on in sitting position

Craniotomy in sitting position Gracia and Fabregas

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Neuroanesthesia

CONCLUSION
Sitting position is still used among neurosurgeons,
with clear differences between countries [2]. It lowers intracranial pressure, reduces bleeding and
allows better anatomic orientation. Modified sitting
position aiming at achieving a positive venous pressure at the operation site increases the safety of the
procedure. This, together with specific monitoring
for VAE detection and strict anesthetic and neurosurgical protocol, seems to minimize VAE incidence
and intraoperative complications. Noninvasive
monitoring of CBF and cerebral oxygenation should
be incorporated into these procedures. We want to
highlight that no death related to VAE has been
reported and that no PAE episodes were detected in
patients with known PFO operated on in a sitting
position.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
1. Nozaki K. Selection of semisitting position in neurosurgery: essential or
reference? World Neurosurg 2014; 81:62–63.
2. Ju¨rgens S, Basu S. The sitting position in anaesthesia. Eur J Anaesthesiol
2013; 30:1–3.
3. Feigl GC, Decker K, Wurms M, et al. Neurosurgical procedures in the
&&
semisitting position: evaluation of the risk of paradoxical venous air embolism
in patients with a patent foramen ovale. World Neurosurg 2014; 81:159–
164.
It is the first prospective study performed in patient with known PFO and operated
on sitting position. Fifty-two patients were included. A strict standardized protocol
was followed: electrophysiological monitoring, transesophageal echocardiography and scheduled jugular compression to early detect any bleeding that could
imply venous air entrance. Their results confirm the safety of the procedure; no
episodes of paradoxical air embolism were reported.
4. Ammirati M, Lamki TT, Shaw AB, et al. A streamlined protocol for the use of the
&&
semi-sitting position in neurosurgery: a report on 48 consecutive procedures.
J Clin Neurosci 2013; 20:32–34.
A retrospective study including 41 patients operated on sitting position. Their
protocol includes a postinduction transesophageal echocardiography to detect
PFO and an intraoperative VAE detection with precordial Doppler. Four patients
with PFO were operated on semisitting position. Clinically relevant VAE was
detected in 4.9% of the total series. Good outcome and absence of complications
are reported.
5. Leslie K, Kaye AH. The sitting position and the patent foramen ovale.
Commentary: ‘‘a streamlined protocol for the use of the semi-sitting position
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Prospective study in 26 neurosurgical procedures. Ventilation was adjusted
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patients with acute respiratory distress syndrome autoregulation was impaired.
Increasing PEEP form 9 to 14 cmH2O had no further clinical relevant effect on
autoregulation.

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Craniotomy in sitting position Gracia and Fabregas
29. Girard F, Ruel M, McKenty S, et al. Incidences of venous air embolism and
patent among patients undergoing selective peripheral denervation in the
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REVIEW
URRENT
C
OPINION

Anesthesia management for endovascular treatment
Chanhung Z. Lee and Adrian W. Gelb

Purpose of review
The review highlights recent data regarding the safety and efficacy of endovascular treatment of
cerebrovascular disease and concerns in anesthesia management.
Recent findings
Ongoing trials, including the Barrow Ruptured Aneurysm Trial and the International Subarachnoid
Aneurysm Trial II, are aimed at improving understanding of the applicability of the International
Subarachnoid Aneurysm Trial data and the roles of surgical clipping and endovascular treatment
in the broad general patient population of ruptured aneurysms. Two recent studies in unruptured brain
arteriovenous malformation management – ARUBA (a multicenter, randomized clinical trial) and the
Scottish population-based cohort study – concluded that conservative medical management is superior to
interventional therapy (including endovascular embolization) in preventing death or stroke. Three
randomized clinical trials failed to prove the superiority of endovascular therapy to standard care
for acute ischemic stroke, but pointed out to the need and direction of future trials. Studies of
anesthesia for acute ischemic stroke suggested that inadequate brain perfusion may contribute to
poorer outcome.
Summary
Recent data further support the role of endovascular coiling for ruptured aneurysm in broader patient
populations. Further studies are needed to investigate the proper management of unruptured arteriovenous
malformations, and the key factors in endovascular therapy and anesthesia management associated with
stroke outcome.
Keywords
acute ischemic stroke, anesthesia, endovascular treatment, ruptured intracranial aneurysm, unruptured
brain arteriovenus malformation

INTRODUCTION
‘Endovascular treatment’ in this article refers to the
endovascular procedures to treat vascular diseases of
the central nervous system, also termed ‘endovascular neurosurgery’, or ‘interventional neuroradiology’ (INR) therapy.
With the rapid advancement and expansion of
INR procedures in treating cerebral vascular diseases, anesthesiologists have been widely involved
in perioperative care of patients for these interventions. Updating our understanding of this rapidly
evolving therapeutic practice is imperative because
anesthetic and perioperative management plans are
predicated on the goals of therapeutic intervention
and anticipation of potential problems.
The review will provide information on recent
advances in the ongoing research on: aneurysm
coiling; brain arteriovenous malformation (AVM)
management choices; and endovascular therapy
of acute stroke and anesthesia considerations.
www.co-anesthesiology.com

TREATMENT OPTIONS FOR
INTRACRANIAL ANEURYSM
Rupture of intracranial aneurysm is life-threatening
and causes long-term disabilities in many survivors.
The incidence of rebleeding from a ruptured aneurysm is around 30% in the first month following
subarachnoid hemorrhage (SAH), and peaking in
the first 7 days. Recurrence of aneurysm rupture is
a catastrophic event with 60% mortality. Early treatment of the aneurysm reduces the risk of rebleeding
[1].
Department of Anesthesia and Perioperative Care, University of
California, San Francisco, San Francisco, California, USA
Correspondence to Chanhung Z. Lee, MD, PhD, Department of Anesthesia and Perioperative Care, University of California, San Francisco,
1001 Potrero Avenue, Box 1363. Tel: +415 206 8906; fax: +415 206
8907; e-mail: clee4@anesthesia.ucsf.edu
Curr Opin Anesthesiol 2014, 27:484–488
DOI:10.1097/ACO.0000000000000103
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Anesthesia management for endovascular treatment Lee and Gelb

KEY POINTS
Endovascular coiling shows better outcome compared
with surgical clipping in ruptured intracranial
aneurysms at short-term and mid-term follow-up.
Newer devices need to be included in evaluating
endovascular therapy of acute ischemic stroke.
Supporting adequate cerebral perfusion is crucial in
anesthesia management for stroke patients.

of the patients who received aneurysm clipping and
in 23.2% of the patients who received coil embolization [odds ratio (OR) 1.68, 95% confidence interval
(CI) 1.08–2.61, P ¼ 0.02], that is, coil embolization
resulted in significantly fewer poor outcomes than
clip occlusion. On the basis of the mRS scores at year
3, the outcomes of all patients assigned to coil embolization showed a favorable 5.8% (P ¼ 0.25) absolute
difference compared with outcomes of those
assigned to clip occlusion, which had decreased since
the observation at year 1 [8 ]. Patients in the clip
group, on the contrary, had a significantly higher
degree of aneurysm obliteration and a lower rate of
recurrence and retreatment, suggesting that clipping
may provide superior protection from rebleeding and
may not require frequent follow-up, as noted in the
ISAT follow-up [9] and other series [10].
The ISAT II is designed as a pragmatic, multicenter, randomized trial (clinicaltrials.gov: NCT016
68563), comparing clinical outcomes for non-ISAT
patients with SAH allocated to coiling or clipping
[11 ]. Similar to BRAT, it aims to provide evidence to
support coiling in the wide spectrum of non-ISAT
patients who are currently treated endovascularly.
The trial, like the previous ISAT, requires ‘equipoise’
before randomization so that a patient is only considered eligible for inclusion if both treatment
options are acceptable. Analysis will be by intention
to treat. This ongoing trial will involve at least
50 international centers, and will take approximately
12 years to complete.
&

To prevent rebleeding from the aneurysm, surgical clipping has traditionally been the treatment
until endovascular coiling became an alternative
option in the past 20 years [2]. However, for a long
time, there was a lack of comparative data on the
safety and efficacy of these two treatment choices to
guide clinical decisions.
Ground-breaking results of the International
Subarachnoid Aneurysm Trial (ISAT) [3,4] demonstrated superior clinical outcomes in patients who
received endovascular coiling in comparison with
patients who underwent surgical clipping. Applicability of ISAT to the general patient population of
ruptured aneurysms, however, has been questioned
based on the potential selection bias of including
only the small and low-grade ruptured aneurysms
in the anterior circulation, which excluded almost
80% of eligible aneurysms in the study population.
Further, although appropriately an intention-to-treat
paradigm, more patients randomized to surgery died
before treatment. If one compares the outcomes
based on actual treatment, then there are no differences between modalities [5]. In addition, clinical
practices vary tremendously, with different centers
coiling from 20 to 70% of ruptured aneurysms [6].

ONGOING CLINICAL TRIALS TO INCLUDE
ALL RUPTURED ANEURYSMS
To minimize the problem of selection bias
from ISAT, the Barrow Ruptured Aneurysm Trial
(BRAT) – a prospective, randomized controlled
study (ClinicalTrials.gov: NCT01593267) – was
designed as an intent-to-treat study to include all
eligible patients presenting with SAH [7]. One of
BRAT’s aims is to improve understanding of the
applicability of the ISAT data and the roles of surgical and endovascular treatment. BRAT is a current
ongoing trial with a 10-year follow-up plan after
completion of enrollment. To date, the 1-year and
3-year follow-up reports have been published. At
1 year after treatment, a poor outcome of modified
Rankins scale (mRS) above 2 was observed in 33.7%

&

CLINICAL TRIALS TO COMPARE THE RISK
OF MEDICAL MANAGEMENT AND
INTERVENTIONAL TREATMENT IN BRAIN
ARTERIOVENOUS MALFORMATIONS
Brain AVMs represent a relatively infrequent but
important source of neurological morbidity in relatively young patients [12]. The primary focus in
brain AVM management is to prevent initial and
recurrent rupture that can result in life-threatening
intracranial hemorrhage. Interventional therapy
may help obliterate the lesion, but entails risk for
many patients. With recent advances in modern
imaging technology, more AVMs are being diagnosed before they become symptomatic.
A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) aims to compare the
risk of death and symptomatic stroke in patients with
an unruptured brain AVM, who are allocated to either
medical management alone or medical management
with interventional therapy, including neurosurgery,
embolization, or stereotactic radiotherapy, alone or
in combination [13]. Among 223 patients (mean
follow-up 33.3 months), 114 were assigned to

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Neuroanesthesia

interventional therapy and 109 to medical management [14 ]. The primary endpoint was reached after
follow-up of the first 46 patients – 11 (10.1%) in the
medical management group compared with 35
(30.7%) in the interventional therapy group. The
data and safety monitoring board recommended
halting randomization because of the superiority of
the medical management group (log-rank Z 4.10,
exceeding the prespecified stopping boundary value
of 2.87). The ARUBA trial suggests that medical management alone is superior to medical management
with interventional therapy for the prevention of
death or stroke in patients with unruptured brain
AVMs, during a 33-month follow-up period.
For long-term comparative data, Al-Shahi et al.
[15 ] published the population-based inception
cohort study of 204 residents of Scotland, aged
16 years or older, who were first diagnosed as having
an unruptured brain AVM and followed up prospectively for 12 years. Of the 204 patients, 103
underwent intervention. Those who underwent
intervention were younger, more likely to have presented with seizure, and less likely to have large AVMs
than patients managed conservatively. During a
median follow-up of 6.9 years (94% completeness),
the rate of progression to the primary outcome was
lower with conservative management during the first
4 years of follow-up (36 versus 39 events; 9.5 versus
9.8 per 100 person-years; adjusted hazard ratio 0.59,
95% CI 0.35–0.99), but rates were similar thereafter.
They concluded that conservative management was
associated with better clinical outcomes compared
with intervention for up to 12 years.
&

&

ACUTE ISCHEMIC STROKE TREATMENT
Stroke is a leading cause of death and long-term
disability worldwide. The primary aim of treatment
in acute stroke is to re-establish blood flow through
the occluded cerebral artery (recanalization) so as to
perfuse the ischemic brain area. Intravenous (i.v.)
fibrinolysis with tissue plasminogen activator (tPA)
remains the only US Food and Drug Administration
(FDA)-approved treatment for stroke patients presenting within 3–4.5 h of symptom onset in selected
patients [16,17]. However, the significant limitations of i.v. tPA have also been long recognized
and include a limited eligibility time window,
time-consuming treatment, and ineffectiveness in
recanalizing of large cerebral arteries [18].

CLINICAL TRIALS OF ENDOVASCULAR
TREATMENT VERSUS INTRAVENOUS
TISSUE PLASMINOGEN ACTIVATOR
In recent years, endovascular therapy has emerged
as a new treatment option for acute ischemic stroke
486

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(AIS) [19]. Endovascular approaches using intraarterial thrombolysis and mechanical devices have
been shown to significantly increase the chance of
revascularization in large arteries [20,21], therefore
showing promise as a supplementary and/or alternative treatment option to i.v. tPA. Endovascular treatment for patients with AIS is currently an area of
intense investigation to establish its efficacy and
safety.
The study by Broderick et al. [22 ] was terminated
after a futility analysis of 656 participants who had
undergone randomization (434 patients to endovascular therapy and 222 to i.v. tPA alone). The proportion of participants with a mRS 2 or less at 90 days
did not differ significantly according to treatment
(40.8% with endovascular therapy and 38.7% with
i.v. tPA). Likewise, no significant difference was
noted in mortality at 90 days and the proportion
of patients with symptomatic intracerebral hemorrhage within 30 h after tPA initiation. Hence, continuing randomization was deemed to be futile.
Ciccone et al. [23 ] randomly assigned 181
patients to receive endovascular therapy (intraarterial thrombolysis with tPA, mechanical clot
disruption or retrieval, or a combination of these
approaches), and 181 intravenous tPA, within 4.5 h
after symptom onset. The median time from stroke
onset to the start of treatment was 3.75 h for endovascular therapy and 2.75 h for intravenous tPA
(P < 0.001). At 3 months, 55 patients in the endovascular therapy group (30.4%) and 63 in the intravenous tPA group (34.8%) were alive without
disability (adjusted odds ratio 0.71, 95% CI 0.44–
1.14, P ¼ 0.16), indicating that endovascular therapy
is not superior to standard treatment with i.v. tPA.
Another study randomly assigned patients
within 8 h after the onset of large-vessel, anteriorcirculation strokes to undergo mechanical embolectomy or receive standard care [24 ]. Randomization
was stratified according to whether the patient had a
favorable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core, small or absent penumbra).
Among all patients, mean scores on the mRS did
not differ between embolectomy and standard care
(3.9 versus 3.9; P ¼ 0.99). Embolectomy was not
superior to standard care in patients with either a
favorable penumbral pattern (mean score 3.9 versus
3.4; P ¼ 0.23) or a nonpenumbral pattern (mean score
4.0 versus 4.4; P ¼ 0.32). This suggested that a favorable penumbral pattern on neuroimaging did not
identify patients who would differentially benefit
from endovascular therapy for AIS, nor was embolectomy shown to be superior to standard care.
Much of the criticism of the above studies
pointed to the lack of application of newer
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&

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Anesthesia management for endovascular treatment Lee and Gelb

mechanical devices that could potentially provide
much quicker and more effective recanalization,
and the delayed time to endovascular treatment.
Although all three long-awaited randomized trials
failed to show the superiority of endovascular
therapy to i.v tPA, they have highlighted the potential value of optimizing medical care of AIS patients,
including the time urgency of stroke treatment and
considerations of the dynamic pathological changes
of the disease, which are important in addition to
achieving recanalization and restoration of blood
flow to the ischemic brain.

ANESTHESIA MANAGEMENT FOR
ENDOVASCULAR TREATMENT
As a result of the rapidly expanding endovascular
treatment of cerebral vascular occlusions, anesthesiologists have been increasingly involved in the
management of patients with AIS [25]. The potential
risk from anesthesia has subsequently become a
concern and center of debate.
The choice of anesthesia type has been mainly
based on institution experience and the preference
of individual anesthesia providers. A survey of
neurointerventionalists showed that there was a
preference for general anesthesia because of eliminating patient movement, perceived procedural
safety and improved procedural efficacy. Cited
limitations to general anesthesia include risk of time
delay, propagating cerebral ischemia due to hypoperfusion, and a lack of adequate anesthesia workforce [26]. However, retrospective analyses reported
that general anesthesia was an independent predictor of poor outcome and mortality after endovascular treatment for AIS [27,28]. It was noted that
patients in the general anesthesia group were
‘sicker,’ including more carotid terminus occlusions
and higher National Institute of Health Stroke Scale
scores. Another caveat in these studies was that it
did not report any specific anesthetic factors or
parameters that could be responsible for the difference in outcome.
A more recent study by Davis et al. [29] concluded that independent predictors for good neurologic outcome were local anesthesia, SBP greater
than 140 mmHg, and low baseline stroke scores.
Lowest SBP and general anesthesia were correlated
(r ¼ 0.7, P < 0.001). These results implied that
hypotension induced by general anesthesia may
enhance the ischemic insult and that maintenance
of blood pressure until restoration of flow may result
in improved outcomes. Previous large stroke trials
had noted that poor outcome increased when SBP
was allowed to fall below 140 mmHg [30] and the
parameter seems to apply to anesthesia as well.

Ventilation control is another key part in anesthesia management. Takahashi et al. [31 ] reported
that low end-tidal CO2, but not the decreases in
blood pressure under general anesthesia, could be
associated with poorer outcome in stroke patients.
Mean ETCO2 in patients with favorable outcomes
(mRS 0–3) was higher than in those with unfavorable outcomes (mRS 4–6): 35.2 mmHg versus 32.2
(p 0.03) at 60 min and 34.9 versus 31.9 (P ¼ 0.04) at
90 min after induction of anesthesia. Hyperventilation has been known to decrease cerebral blood flow
[32]. Short-time hypocarbia-hyperventilation can
help decrease acute intracranial hypertension, but
there is no proof of any benefit from prolonged
hypocarbia in pathological brain conditions. This
study demonstrated the importance of maintaining
adequate perfusion to the ischemic brain by properly managing ventilation in anesthesia.
A task force, on behalf of the Society for
Neuroscience in Anesthesiology and Critical Care
(SNACC), has recently produced recommendations
regarding the perioperative care of patients undergoing endovascular treatment for AIS [33 ]. This
consensus document will be helpful at many critical
decision points in anesthesia perioperative stroke
care. Given the limited availability of high-quality
studies to guide anesthesia practice in acute stroke
care, however, these SNACC guidelines are based
largely on expert experience and opinions.
&&

&&

CONCLUSION
The use of endovascular treatments has advanced
rapidly in recent years and has demonstrated great
promise for the treatment of select cerebrovascular
diseases. Current data support better outcomes with
endovascular coiling for many aneurysms, but
with a need for ongoing follow-up and further treatment. Although study results show superiority of
medical management in unruptured AVMs, there
are ongoing debates about the applicability to all
patients, given the heterogeneity of the disease and
the small sample sizes, short follow-up, and poor
participation of American centers in the projects.
The value of optimal medical care of acute stroke
patients cannot be overemphasized, including
the use, when appropriate, of intravenous tPA to
achieve recanalization and restoration of blood flow
to the ischemic brain. Evaluation of the role of
newer endovascular devices to foster recanalization
will be needed, given that older devices are not
better than standard medical care. It is crucial for
anesthesiologists to focus on how to best manage
anesthesia, recognizing the essence of time and the
importance of maintaining adequate cerebral perfusion when caring for patients suffering from AIS.

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Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

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(ARUBA): a multicentre, nonblinded, randomised trial. Lancet 2014; 383:
614–621.
This is the first international, multicenter, randomized trial to assess the outcome of
two management strategies of unruptured brain arteriovenous malformations:
medical management and interventional therapy.
15. Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative
&
management or intervention for unruptured brain arteriovenous malformations. J Am Med Assoc 2014; 311:1661–1669.
This is a population-based cohort study addressing the management option of
unruptured brain arteriovenous malformations with follow-up time of up to 12 years.

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16. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study
Group. Tissue plasminogen activator for acute ischemic stroke National
Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
N Engl J Med 1995; 333:1581–1587.
17. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 h
after acute ischemic stroke. N Engl J Med 2008; 359:1317–1329.
18. Lee M, Hong KS, Saver JL. Efficacy of intra-arterial fibrinolysis for acute
ischemic stroke: meta-analysis of randomized controlled trials. Stroke 2010;
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19. Meyers PM, Schumacher HC, Connolly ES Jr, et al. Current status of
endovascular stroke treatment. Circulation 2011; 123:2591–2601.
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21. Nogueira RG, Liebeskind DS, Sung G, et al. Predictors of good clinical
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&
ischemic stroke. N Engl J Med 2013; 368:904–913.
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&
endovascular treatment for ischemic stroke. N Engl J Med 2013; 368:914–
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19.
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41:1175–1179.
28. Jumaa MA, Zhang F, Ruiz-Ares G, et al. Comparison of safety and clinical and
radiographic outcomes in endovascular acute stroke therapy for proximal
middle cerebral artery occlusion with intubation and general anesthesia
versus the nonintubated state. Stroke 2010; 41:1180–1184.
29. Davis MJ, Menon BK, Baghirzada LB, et al. Anesthetic management and
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outcomes in the International Stroke Trial. Stroke 2002; 33:1315–1320.
31. Takahashi CE, Brambrink AM, Aziz MF, et al. Association of intraprocedural
&&
blood pressure and end tidal carbon dioxide with outcome after acute stroke
intervention. Neurocrit Care 2014; 20:202–208.
This is the latest study of anesthesia management for endovascular treatment of
acute ischemic stroke that highlights the importance of supporting cerebral
perfusion through management of ventilation in anesthesia care for acute ischemic
stroke patients.
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3:566–575.
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siology and Critical Care Expert Consensus Statement: Anesthetic management of endovascular treatment for acute ischemic stroke: Endorsed by
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This recent article is the first published practice guidelines regarding periprocedural anesthesia management for endovascular treatment of acute
ischemic stroke. The recommendations are largely based on expert opinions
and experience, indicating the need for future studies to provide evidence
to guide clinical practice for better and safer perioperative care of stroke
patients.

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REVIEW
URRENT
C
OPINION

Postoperative ICU management of patients after
subarachnoid hemorrhage
Shaun E. Gruenbaum a and Fedrico Bilotta b

Purpose of review
This article reviews recent advances in the postoperative ICU management of patients after subarachnoid
hemorrhage (SAH), especially with regards to hemodynamic management, methods of improving
neurological outcomes, and management of cardiac and pulmonary complications.
Recent findings
Several hemodynamic monitors and parameters may be useful for guiding volume therapy, including cardiac
output, stroke volume variation monitoring, and global end-diastolic volume index. Early goal-directed
hemodynamic therapy after SAH has recently been shown to improve clinical outcomes in patients with a
poor clinical grade or coexisting cardiopulmonary complications. Recent laboratory and imaging modalities
are being developed to identify patients at risk for developing vasospasm after SAH. Evidence for the use of
various prophylactic adjuvant therapies to prevent vasospasm, including magnesium, phosphodiesterase 3
inhibitors, and therapeutic hypothermia, is emerging. Intrathecal administration of vasodilators or fibrinolytics
may have offered advantages over systemic drug administration in the treatment of vasospasm. Pulmonary
and cardiac complications are common after SAH, and are associated with an increased risk of mortality.
Summary
The postoperative ICU period after SAH is associated with a significant morbidity and mortality risk, and
recent studies have greatly contributed to our understanding of how to optimally manage these patients.
Keywords
cerebral vasospasm, delayed cerebral ischemia, ICU management, subarachnoid hemorrhage

INTRODUCTION
The diagnosis and management of acute subarachnoid hemorrhage (SAH) represents a major challenge for practitioners. Although SAH accounts for
only 5% of strokes, the disease often presents in
patients younger than 55 and is often fatal [1]. Up
to 15% of patients with SAH die before reaching the
hospital, and the overall mortality rate of SAH
approaches 50%. After initial treatment with endovascular coiling or direct surgical clipping, patients
are typically managed in the ICU.
Cerebral vasospasm and delayed cerebral ischemia (DCI) are major complications of SAH, and early
postoperative care includes the administration of
oral nimodipine and maintenance of cerebral blood
flow (CBF). The course of acute SAH is often complicated by pulmonary and cardiac dysfunction.
Although great strides have been made in the last
decade in decreasing mortality and improving
neurological outcomes after SAH, postoperative
management remains a challenge.
In recent years, there has been much interest in
postoperative hemodynamic management, methods

of improving neurological outcomes, and identifying
and treating other non-neurological complications
of SAH. In this article, we will highlight some of the
recent studies that have contributed to our understanding of how to best manage patients in the early
period after SAH.

HEMODYNAMIC MANAGEMENT
Optimal hemodynamic management is essential
in the early period after SAH. Patients with SAH
are prone to hemodynamic instability that may
result from impairment of cerebral blood flow
a
Department of Anesthesiology, Yale University School of Medicine, New
Haven, Connecticut, USA and bDepartment of Anesthesiology, Critical
Care and Pain Medicine, ‘Sapienza’ University of Rome, Rome, Italy

Correspondence to Fedrico Bilotta, MD, PhD, Department of Anesthesiology, Critical Care and Pain Medicine, ‘Sapienza’ University of Rome,
Rome, Italy. Tel: +39 06 8608273; fax: +39 06 8608273; e-mail:
bilotta@tiscal.it
Curr Opin Anesthesiol 2014, 27:489–493
DOI:10.1097/ACO.0000000000000111

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Neuroanesthesia

KEY POINTS
After SAH, brain tissue oxygen response and cardiac
response to fluid resuscitation, as well as global enddiastolic volume index, may be useful for guiding
volume therapy.
Low plasma levels of Arg-vasopressin and oxytocin,
and elevated levels of visfatin may have prognostic
utility for predicting poor clinical outcomes after SAH.
Recent evidence suggests that phosphodiesterase 3
inhibitors cilostazol and milrinone, magnesium therapy,
and therapeutic hypothermia may be useful adjuncts in
the treatment of cerebral vasospasm.
Intrathecal administration of vasodilators and
fibrinolytics has been successful in lysing subarachnoid
clots, attenuating cerebral vasospasm, and improving
clinical outcomes with minimal side-effects.
Pulmonary disease and cardiogenic shock are common
after SAH, are difficult to treat, and are significant risk
factors for mortality.

autoregulation and cardiac dysfunction. Volume
resuscitation should be aimed to provide adequate
preload to maintain cardiac stability and optimal
CBF and oxygenation. Hemodynamic insufficiency
related to hypovolemia or low cardiac output is an
important cause of secondary brain injury and DCI,
which are associated with an increased risk of death
and poor neurological outcomes. Avoiding volume
overload and pulmonary edema is equally important, and may be particularly challenging in patients
with a poor grade SAH in whom hypovolemia and
cardiac dysfunction are common. These patients
may initially require aggressive resuscitation to
avoid hypovolemia and hypotension, but are also
especially vulnerable to fluid overload.
A recent study compared functional outcomes
in 160 patients after receiving either early goaldirected therapy guided by preload volume and
cardiac output or monitoring with standard therapy
[2 ]. In SAH patients with a poor clinical grade or
coexisting cardiopulmonary complications, early
goal-directed therapy reduced the likelihood of
developing DCI and improved clinical outcomes.
For patients with a good clinical grade, there was
no benefit demonstrated to early goal-directed
therapy over standard, less-invasive hemodynamic
therapy.
Many recent studies have aimed at identifying
optimal hemodynamic monitors and parameters
that may be useful for guiding volume therapy.
One study demonstrated a strong correlation
between brain tissue oxygen response and cardiac
response to fluid resuscitation in patients with SAH
&&

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[3]. The authors suggested that cardiac output and
stroke volume variation (SVV) be incorporated in
the hemodynamic monitoring of patients after SAH.
They further asserted that the decision to administer
a fluid challenge should reflect the baseline SVV and
brain tissue oxygen pressure response to the fluid
challenge. Another study demonstrated that mean
global end-diastolic volume index (normal range
680–800 ml/m2) was an independent risk factor
for the development of DCI (when less than
820 ml/m2) and pulmonary edema (when greater
than 921 ml/m2) [4 ]. The authors concluded that
global end-diastolic volume index should be maintained slightly above normal during fluid management of patients with SAH.
Interestingly, recent evidence suggests that the
method of SAH treatment (surgical clipping or endovascular coiling) may greatly impact the patient’s
postoperative hemodynamic profile. Postoperative
volume status and hemodynamics were compared
in 73 patients treated with either surgical clipping or
coiling, and patients who underwent clipping had a
higher cardiac output and hypovolemia in the early
postoperative period and a poorer preload responsiveness to volume [5 ]. As such, after surgical clipping, patients required more intravenous volume to
maintain normovolemia. These findings, which the
authors attribute to increased surgical invasiveness
and postoperative stress related to surgical clipping,
have important implications for volume management in patients after SAH. Compared with endovascular coiling, patients after clipping may benefit
from invasive hemodynamic monitoring to help
guide volume resuscitation and achieve euvolemia.
This is especially important during the period when
patients are at risk for vasospasm and DCI.
&&

&

IMPROVING NEUROLOGICAL OUTCOMES
AFTER SUBARACHNOID HEMORRHAGE
The prevalence of cerebral vasospasm in patients
with SAH ranges from 30 to 70%, and permanent
morbidity or morality results in up to 30% of
these patients [6]. Although cerebral hypoperfusion
may occur in the absence of cerebral vasospasm,
cerebral vasospasm is an important cause of critically reduced cerebral perfusion [7]. Prevention of
cerebral vasospasm is an important cornerstone of
management after SAH. The risk of developing DCI
is highest between days 4 and 10, and calcium
channel antagonists are administered to decrease
the risk.
A great deal of recent literature has aimed at
determining etiologic factors that predict outcomes
in patients after SAH. One study demonstrated that
neuropeptides Arg-vasopressin and oxytocin are
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Postoperative ICU management of SAH Gruenbaum and Bilotta

lower in patients with a poor outcome after SAH,
possibly reflecting hypothalamic damage after SAH
[8]. Furthermore, plasma levels of visfatin, an adipokine linked with inflammation, have been shown
to predict the severity of SAH and have prognostic
utility for clinical outcomes [9 ].
Recent evidence has also suggested that cerebral
vasospasm may be, in part, due to an acute endothelial dysfunction that results from an imbalance
in the Arg and asymmetric dimethylarginine
(ADMA) pathway [10 ]. Interestingly, the ratio of
plasma Arg:ADMA ratio has even been shown to
predict mortality after SAH [11 ]. Similarly, a recent
study demonstrated that low levels of adiponectin
from days 3 to 14 after SAH, which affects nitric
oxide production and endothelium-dependent vasorelaxation, might be associated with the development of DCI [12].
Currently, there are efforts being made to
develop techniques to clinical diagnostic tools to
determine endothelial dysfunction. A few promising modalities include ultrasonographic imaging of
endothelial-dependent flow-mediated dilation of
the brachial artery and peripheral arterial tonometry
[13]. Other models that attempt to predict cerebral
vasospasm include various grading scales, and more
recently, the application of a neural network model
that will be examined in future studies [14]. One
recent study identified younger age and early onset
of vasospasm on transcranial Doppler as important
predictors of severe vasospasm, and the authors
recommend early and aggressive therapy in these
patients [15].
It is unclear whether the choice of treatment
modality for a ruptured aneurysm (surgical clipping
or endovascular treatment) impacts the risk of developing vasospasm, although one recent retrospective
study demonstrated that surgical clipping may be
associated with an increased risk of vasospasm and
delayed radiographic infarction [16 ]. These findings have generated some discussion and debate
in the literature, and future prospective studies will
be needed to confirm or rule out this assertion
[17,18].
A great deal of research has focused on treatments that may reduce secondary brain injury and
DCI after SAH in an effort to improve neurological
outcomes and reduce mortality. Nimodipine is the
only prophylactic drug that is known to reduce the
risk of cerebral ischemia and improve neurological
outcomes after SAH. The evidence for other calciumblocking agents is inconclusive. Many recent studies
attempt to identify other agents that may reduce the
risk of cerebral vasospasm and improve neurological
outcomes after SAH. Selective phophodiesterase 3
inhibitors, such as cilostazol and milrinone, offer
&

&

&

&

promise in the prevention of cerebral vasospasm
after SAH because of their direct vasodilation and
anti-inflammatory effects. Results of a recent metaanalysis demonstrated that cilostazol is effective in
decreasing the incidence of symptomatic cerebral
vasospasm, severe cerebral vasospasm, and cerebral
vasospasm-related new cerebral infarctions after
SAH [19 ]. Similarly, continuous infusion of milrinone significantly improved global cerebral oxygenation, and reduced the incidence of cerebral
vasospasm during the critical 4 to 11 day postoperative period following cerebral aneurysm clipping
surgery [20].
Magnesium is known to result in cerebral arterial dilation, and is a noncompetitive antagonist of
calcium channels. Magnesium has therefore been
suggested to be a potentially useful adjuvant to
decrease the risk of vasospasm and improve neurological outcomes. A large randomized controlled
trail however failed to demonstrate an improvement
in clinical outcome with administration of magnesium after SAH, and the authors therefore recommended against the routine administration of
magnesium [21]. Following this study, a metaanalysis demonstrated a decreased incidence of
DCI in patients treated with magnesium after
SAH, but failed to demonstrate any benefit with
regards to neurological outcome, risk of cerebral
vasospasm, or mortality [22]. The authors of the
meta-analysis also advised against the routine use
of magnesium in SAH. Other authors have pointed
out, however, that every trial that failed to demonstrate an improvement in neurological outcomes
or mortality did not compare magnesium-treated
patients to a true placebo group [23]. Nimodipine,
a calcium channel blocker, was administered to
patients in both the treatment and nontreatment
groups. Therefore, it should not be surprising that a
combination of two calcium channel antagonists
failed to confer any additional benefit over nimodipine alone. The authors concluded that nimodipine might simply be the wrong partner for
combination therapy with magnesium. Although
current evidence suggests that nimodipine is the
standard of care in SAH, a definitive clinical trial
of nimodipine that examines neurological outcomes and mortality is needed [24].
The use of therapeutic hypothermia in the treatment of SAH has also been debated in the literature.
Despite evidence from animal studies that therapeutic hypothermia may reduce secondary brain
injury and the risk of cerebral vasospasm, hypothermia during aneurysm surgery has failed to
demonstrate a clinical benefit [25]. One recent
study examined Doppler middle cerebral artery
(MCA) blood flow after induction of therapeutic

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Neuroanesthesia

hypothermia (338, on average 5 days after SAH) in
patients with increased intracranial pressure or DCI
[25]. The authors demonstrated that therapeutic
hypothermia resulted in decreased MCA blood flow,
suggesting that therapeutic hypothermia may be
useful for select patients. At present, more clinical
data are needed before routine use of therapeutic
hypothermia can be advocated.
Currently, the primary treatment of vasospasm
is local injection of antispasmodic drugs. One study
described their experience with 116 patients who
underwent endovascular management for cerebral
vasospasm [6]. The authors demonstrated that endovascular therapy is both well tolerated and effective
in treating vasospasm and improving neurological
outcomes. Both balloon angioplasty and nicardipine were shown to be equally effective, although
nicardipine was less durable. Poor Hunt and Hess
grades, preprocedure hypodensities, posterior circulation aneurysms, and the absence of neurological
improvements after therapy were independent predictors of poor outcomes.
A recent review examined several clinical trials
in which cerebral vasospasm was treated with
intrathecal drug administration [26 ]. The trials
demonstrated that intrathecal administration of
vasodilators or fibrinolytics was successful in lysing
subarachnoid clots, attenuating cerebral vasospasm,
and improving clinical outcomes. Furthermore, compared with systemic drug administration, intrathecal
drug administration was associated with the delivery
of higher concentrations of drug to the vessels in
cerebral vasospasm with minimal systemic sideeffects. Although intrathecal drug administration
has not yet been widely adopted to treat cerebral
vasospasm, it appears to be a promising alternative
approach in the treatment of cerebral vasospasm.
There is evidence that some ICU interventions,
such as early ambulation after SAH, improve clinical
outcomes in elderly patients [27]. Other interventions used in patients after SAH, such as the intravenous administration of albumin, are commonly
used among practitioners despite a lack of clinical
trials that confirm its efficacy or safety [28]. Lastly,
early preclinical data demonstrate that estrogen
therapy can promote vasodilation by activating
endothelial nitric oxide synthase, and may be neuroprotective after SAH [29]. However, at this time
there is no clinical evidence supporting its routine
use.
&&

PULMONARY AND CARDIAC
COMPLICATIONS
The clinical course for patients admitted to the ICU
after SAH are often complicated by multisystem
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organ dysfunction, which may significantly worsen
outcomes. A great deal of recent literature has
focused on identifying and treating patients at risk
for developing non-neurological complications.
Pulmonary complications are the most common
non-neurological, medical cause of comorbidity
after SAH. The incidence of acute respiratory distress
syndrome (ARDS) in SAH may be as high as 37.6%,
with a mortality rate in these patients exceeding
60% [30]. Neurogenic pulmonary edema is a lifethreatening cause of ARDS, and should be considered in patients who develop ARDS after SAH
[31]. Another recent study identified that more than
25% of patients after SAH develop postoperative
aspiration pneumonia, which was associated with
a significant (9.7%) risk of mortality [32].
Cardiac injury and left ventricular dysfunction
are also common after SAH. The initiation of hypertension and hypervolemia to treat acute cerebral
vasospasm may be especially problematic in these
patients, and may result in significant morbidity. A
recent prospective, multicenter cohort study determined that wall motion abnormalities on echocardiogram were independent risk factors for a
poor outcome after SAH, explained in part by a higher
risk of DCI [33]. The results of that trial mirrored prior
retrospective studies, in which neurogenic stress
cardiomyopathy after SAH was associated with a
higher mortality and worsened functional outcomes
[34]. Although it is unclear which patients are at
increased risk for developing cardiogenic shock after
SAH, a recent study [35 ] demonstrated that prehospital use of b-blockers might decrease the risk.
There is new evidence that in some patients,
namely young women with poor grade SAH, intraaortic balloon pump placement may be a useful
adjunct to ameliorate severe cardiogenic shock
[36]. Future studies will need to better define the
exact indication for this intervention, to confirm its
efficacy, and to better define which patients might
benefit from it. A ventricular assist device was also
recently utilized to successfully facilitate myocardial
and neurological recovery after SAH-related cardiogenic shock [37]. Other methods that may increase
CBF, such as the NeuroFlo device, also show great
promise but need to be studied further [38].
&&

CONCLUSION
In recent years, there have been great advances in
the postoperative ICU management of patients after
SAH. Recent clinical studies have greatly focused
on identifying prognostic indicators of poor outcomes and on establishing optimal hemodynamic
monitors and parameters to guide volume therapy.
Importantly, there are promising new treatment
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Postoperative ICU management of SAH Gruenbaum and Bilotta

modalities aimed at improving neurological outcomes and treating non-neurological complications
of SAH. As we improve our understanding of the
pathophysiology and management of SAH and its
clinical sequela, the next decade will hopefully see
significant improvements in outcomes.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED
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&
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REVIEW
URRENT
C
OPINION

Diagnosis, mechanisms and treatment of complex
regional pain syndrome
Mark Rockett

Purpose of review
The incidence and disease course of complex regional pain syndrome (CRPS) has been unclear until
recently. This was due to inconsistent diagnostic criteria used in previous studies and a lack of large-scale
prospective datasets. Multiple mechanisms of CRPS have been suggested, and recent research has begun
to explain how inflammation, the immune system and the autonomic nervous system may interact with
aberrant central neuroplasticity to produce the clinical picture. This review summarizes progress in these
fields.
Recent findings
National registries of patients with CRPS have provided us with an invaluable insight into the epidemiology
of the disorder. We now have a better understanding of the disease course and expected outcome.
Widespread sensory abnormalities, not limited to the CRPS limb, have been found suggesting that systemic
changes may occur. Parietal lobe dysfunction and problems with sensory-motor integration have also been
revealed. Abnormalities in the immune system in CRPS have also been demonstrated.
Summary
Recent findings in diverse research fields suggest novel treatment options for CRPS: from targeting
autoimmunity to correcting abnormal body image. Many of the advances in our understanding of CRPS
have arisen from the development of collaborative research efforts, such as the TREND group in the
Netherlands.
Keywords
autoimmunity, autonomic nervous system, complex regional pain syndrome, inflammation

INTRODUCTION
Complex regional pain syndrome (CRPS) is a peripherally limited pain syndrome. It is characterized
by intense pain, inflammation, altered autonomic
function, abnormal motor function and trophic
changes. Although most individuals recover rapidly
from mild to moderate injury to the distal limbs, a
small proportion will develop CRPS, and in some it
may occur spontaneously [1]. The disorder was first
described by Mitchell [2] following battlefield injuries. Numerous terms have been used to describe
the condition, from causalgia to reflex sympathetic
dystrophy and algodystrophy. Currently, CRPS is
the accepted terminology, and is divided into two
subtypes: CRPS type I occurs without nerve injury
and CRPS II in which significant nerve injury can be
demonstrated. Although the majority of individuals
recover within 12 months, CRPS may result in severe
long-term pain, and sufferers report a very low quality of life [3,4]. As there is no gold-standard test for
CRPS, clinical diagnostic criteria have been developed. The most often accepted diagnostic criteria
www.co-anesthesiology.com

are based on the Bruehl and Harden 1999 criteria,
modified at a consensus meeting in 2003 and subsequently validated and termed the Budapest
Criteria in 2010 [5]. The Budapest clinical criteria
are as follows:
(1) continuing pain disproportionate to any inciting event;
(2) must report at least one symptom in three of the
four following categories:
(a) sensory: hyperalgesia and/or allodynia,
(b) vasomotor: temperature asymmetry and/or
skin colour changes and/or skin colour
asymmetry,

Plymouth Hospitals NHS Trust, Plymouth, Devon, UK
Correspondence to Mark Rockett, MB ChB, PhD, Department of Anaesthesia, Level 9, Derriford Hospital, Plymouth, PL68DH, UK. Tel: +44
1752 439203; e-mail: mark.rockett@nhs.net
Curr Opin Anesthesiol 2014, 27:494–500
DOI:10.1097/ACO.0000000000000114
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Complex regional pain syndrome Rockett

KEY POINTS
Recent population-based studies have, for the first
time, established the incidence of CRPS (about
20/100 000), and distinct risk factors for CRPS.
CRPS is associated with abnormal peripheral sensory
and autonomic nerve function, immune activation, and
peculiar and distressing changes in central
signal processing.
Although comprehensive treatment guidelines rely
largely on expert consensus, clinical research in this
field has taken off, promising the emergence of novel,
evidence-based treatment approaches.

(c) sudomotor or oedema: oedema and/or
sweating asymmetry,
(d) motor or trophic: decreased range of
motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic
changes (nail, hair, skin);
(3) must display at least one sign at time of evaluation in two or more of the following categories:
(a) sensory: hyperalgesia (to pin-prick) and/or
allodynia (to light touch, deep somatic pressure, joint movement),
(b) vasomotor: temperature asymmetry and/or
skin colour changes and/or skin colour
asymmetry,
(c) sudomotor or oedema: oedema and/or
sweating changes and/or sweating asymmetry,
(d) motor or trophic: decreased range of motion
and/or motor dysfunction (weakness,
tremor, dystonia) and/or trophic changes
(nail, hair, skin);
(4) there is no other diagnosis that better explains
the signs and symptoms.

An additional problem is defining recovery from
CRPS, as some symptoms commonly resolve with
time, but the individual cannot be said to have
recovered their quality of life. The term CRPS not
otherwise specified has been suggested for patients
in this group. Differential diagnoses for CRPS are
listed as follows:
(1) common conditions:
(a) arterial insufficiency,
(b) arthritis or arthrosis,
(c) bony or soft tissue injury,
(d) compartment syndrome,
(e) complications of orthopaedic surgery,
(f) infection (bony, soft tissue, joint),
(g) lymphatic or venous obstruction,
(h) Raynaud’s disease;
(2) rare conditions:
(a) erythromelalgia (may include all limbs),
(b) Gardner–Diamond syndrome,
(c) self harm,
(d) thoracic outlet syndrome.

Sensory findings
Altered skin sensitivity to noxious and innocuous
stimulation is commonly found in a CRPS limb.
Both hyperalgesia (an increased response to a painful stimulus) and allodynia (a painful response to an
innocuous stimulus) occur. Using quantitative sensory testing, both sensory gain and sensory loss have
been demonstrated in CRPS I and II, with sensory
loss more common in the latter [8,9 ]. Interestingly, recent studies have demonstrated bilateral
sensory abnormalities in patients with unilateral
CRPS, including increased pain response to capsaicin and widespread muscle sensitivity [10,11]. This
suggests a generalized disturbance of pain processing, which may reflect a process of central sensitization within the spinal cord and brain.
&&

CLINICAL FINDINGS AND DIAGNOSIS
In the acute phase of CRPS (<6 months), there are
marked inflammatory changes; the limb is painful,
discoloured, often sweaty, hot, swollen and held
immobile, reflecting both autonomic dysfunction,
and inflammation or neurogenic inflammation.
Bone metabolism is abnormal leading to patchy
osteoporosis in up to 50%. The diagnostic utility
of X-rays or bone-scanning for CRPS appears limited
[6].
Utilizing a criterion-based diagnostic model has
led to difficulties in defining CRPS for clinical and
research purposes [7 ]. Features suggestive of CRPS
may be present following recent trauma, even if the
inflammatory response to injury is entirely normal.
&

Motor function findings
Weakness and a limited range of movement develop
in 80% of cases. There are also impairments in
voluntary control, sense of force production and
proprioception. Dystonia occurs in 25–30% and
there is emerging evidence that this may have a
genetic basis in some cases [12].

EPIDEMIOLOGY
The absence of a gold-standard diagnostic test has
resulted in slow progress in researching the epidemiology of the disorder. However, retrospective cohort
studies, longitudinal observational studies, and

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Pain medicine

recently national registries of patients with CRPS,
such as the Dutch TREND (trauma related neuronal
dysfunction) consortium, have rapidly increased our
knowledge base (http://www.trend-consortium.nl).
The incidence of CRPS varies with diagnostic
criteria and has been quoted as 18.1–26.2 per
100 000 person years in Europe. The first large-scale
retrospective cohort study was based on primary
care data in the Netherlands and revealed that the
disorder occurs most commonly in women (sex ratio
3–4 : 1), between 50 and 70 years of age. Most cases
involve trauma (45% fracture, 18% ligamentous
injury and 12% surgery) [13].

Risk factors for onset and persistence of
complex regional pain syndrome
The frequency of CRPS following fracture is approximately 7%. CRPS occurred more frequently after
intra-articular fractures and was more common in
patients with rheumatoid arthritis or other musculoskeletal conditions, such as chronic back pain
[14 ]. Additionally, a pain score of 5 or above on
a 0–10 verbal rating scale in the first week following
wrist fracture was predictive of the development of
CRPS at 4 months [15 ]. Immobility may be an
independent risk factor. In fact, immobilizing the
limbs of healthy volunteers produces sensory abnormalities similar to CRPS (although not pain) [16].
The small proportion of spontaneous cases of CRPS
(< 10%) occur mostly in women at a younger age
and more commonly follow a chronic course (12 : 1
F : M) [1]. CRPS tends to run a more chronic course in
younger adults. Further risk factors include asthma,
migraine, osteoporosis and the use of angiotensinconverting enzyme (ACE) inhibitor drugs (but not
other antihypertensives) [13,17]. ACE inhibitors
prevent the breakdown of the peptide neurotransmitters – potentially leading to increased inflammation. The co-occurrence of migraine and asthma
with CRPS may reflect a common neuroinflammatory mechanism of these disorders.
It is likely that genetic factors play a role in the
development of CRPS, as there is an increased incidence in siblings with an odds ratio varying between
1.5 and 9.8 [18,19]. CRPS is also associated with
specific human leukocyte antigen (HLA) system
haplotypes. HLA-DQ8 was associated with CRPS in
general, whereas HLA-B62 was associated with CRPS
with dystonia [20]. This suggests that the dystonia
associated with CRPS in 25–30% of cases may have a
separate mechanism to CRPS without dystonia.
Psychological factors play a role in determining
the impact of any chronic painful condition on
patients’ functioning and quality of life. However,
there is currently little evidence for the involvement
&&

&&

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of psychological factors in the onset of CRPS other
than perhaps the number of life events, and no clear
evidence for such factors playing a role in the maintenance of the disorder [21,22].

MECHANISMS
Explanatory models of CRPS must account for
abnormal inflammation, nociceptive sensitization,
autonomic dysfunction and maladaptive neuroplasticity. It has been debated as to whether CRPS
I can be defined as a neuropathic pain syndrome, on
the basis of the most recent diagnostic criteria for
neuropathic pain [23,24]. Symptoms and signs suggestive of neuropathic pain are present in CRPS I
[25]. Some studies have demonstrated a mild loss of
small nerve fibres, providing support for a neuropathic mechanism [26,27].

Inflammation
There is evidence for abnormal immune activation
in CRPS [28], but most proinflammatory cytokine
markers found in blood and blister fluid return to
normal levels after 6 months [29].
Nociceptors release peptide neurotransmitters
including substance P and calcitonin gene-related
peptide (CGRP), which may activate immune cells
in peripheral tissues. Levels of substance P and its
receptor neurokinin-1 are elevated following fracture
in a rat model of CRPS, and mast cell degranulation
may consequently be triggered via a substance P
pathway [30]. Numerous substances are released from
mast cells, including tryptase, histamine and cytokines. Binding of histamine, substance P and CGRP to
receptors on small blood vessels results in oedema,
vasodilation and pain – characteristic of both early
CRPS and neurogenic inflammation.
In early CRPS, keratinocyte proliferation occurs,
resulting in epidermal thickening. Increased numbers of mast cells were found in the skin and there
was upregulation of interleukin-6 and tumor
necrosis factors. Later, keratinocytes were reduced,
leading to epidermal thinning [31]. This suggests
that early CRPS involves activation of the cutaneous
immune system, resulting in increased production
of inflammatory mediators. Interestingly, similar
changes in inflammatory mediators were found in
the skin biopsied from the operated arm of patients
who did not develop CRPS following hand surgery.
This suggests that such inflammatory changes do
not exclusively occur in CRPS and may be part of a
normal response to injury [32].
Oxidative stress is also a potential contributor to
the abnormal inflammatory state seen in CRPS. As
part of the chronic inflammatory process, activated
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Complex regional pain syndrome Rockett

immune cells produce reactive oxygen species (ROS),
which may cause oxidative damage to cells. In the
healthy individual, ROS are inactivated by antioxidant pathways. However, it has been suggested
that excessive production of ROS in CRPS results in an
imbalance in the redox pathway, affecting cell function and resulting in pain, ongoing inflammation
and cell damage [33].
Finally, macrovascular changes suggestive of
ongoing inflammation have been found in patients
with chronic CRPS [34].

Autoimmunity
It has recently been suggested that autoantibodies
may play a role in CRPS. Autoantibodies found in
the plasma of patients with CRPS are active at the
muscarinic cholinergic receptor and the b2 adrenoceptor [35]. An autoimmune mechanism for CRPS is
also suggested by the finding that transfer of serum
IgG from patients to mice elicits signs similar to
CRPS in the recipient animals [36 ].
&&

Autonomic dysregulation
Autonomic dysregulation is a key clinical feature of
CRPS. The sympathetic outflow to skin vasoconstrictors is inhibited, resulting in the warm, swollen
limb seen in the acute phase. The cold limbs seen in
chronic CRPS may reflect increased sympathetic
nervous system (SNS) receptor sensitivity rather
than an increase in sympathetic outflow [37]. In
addition to marked peripheral abnormalities in
autonomic function, there are also mild abnormalities in systemic autonomic function in CRPS;
haemodynamic instability increased with CRPS
duration but not pain severity [38].
Animal studies support a role for the SNS in CRPS.
In a rat tibial fracture model, noradrenaline released
from sympathetic nerve terminals triggers the production of inflammatory mediators (interleukin-6)
by epidermal keratinocytes, via noradrenaline binding to b2-adrenoreceptors [39]. Independently,
a1-adrenoreceptors are upregulated in the skin of
CRPS II-affected limbs in humans, potentially
increasing the effects of sympathetic activation [40].
Interestingly, some autonomic features of CRPS
(skin temperature) seem to be under marked cortical
control as they change with the perceived position
of the limb related to the body, rather than its actual
position or anatomical location [41].

motor abnormalities. Imbalanced reflex sensitivity
in agonist and antagonist muscles has been implicated in generating the flexion deformities seen in
CRPS with dystonia [42]. Abnormal processing of
proprioceptive information results in impairment in
arm position sense [43]. Perceptual changes in body
shape and position also involve sensory cortex processing abnormalities, but meta-analysis of available
studies has revealed limited consistent findings.
The spatial representation of the CRPS limb in the
primary somatosensory cortex is reduced [44 ].
There is limited evidence for bilateral disinhibition
within the motor cortex, but no change in spatial
representation, reactivity or glucose metabolism
[45]. [The first sentence refers to the somatosensory
cortex (reduced representation), and the second to
the motor cortex (no reduction in representation
area)].
There may also be altered functional connectivity between brain regions in CRPS. In the resting
state patients with CRPS had decreased functional
connectivity within sensory and motor regions of
the cortex and greater diffuse connectivity with
other brain regions [46].
These functional abnormalities are mirrored by
structural changes in grey matter volumes of several
brain areas. MRI scanning of the brains of patients
with right upper limb CRPS revealed altered
morphology within not only sensory and affective
regions, but also motor and autonomic centres [47].
&

PREVENTION AND TREATMENT
Longstanding CRPS is difficult to manage, and
therefore prevention of progression to chronic disease is a priority. Acute CRPS presents relatively
commonly to the anesthetist, potentially providing
an opportunity to influence disease progression
within his or her practice [4]. Originally, CRPS
was thought to pass through predictable clinical
stages, but this has not been substantiated by cluster
analysis studies [48 ]. Nonetheless, the management
of CRPS may be usefully divided into prevention,
early CRPS (< 6 months) and established CRPS.
Recently, a Cochrane review [49] of interventional treatment for CRPS reached limited conclusions based on a lack of good quality evidence.
Practical guidelines based partly on expert opinion
have been produced in the UK, USA and the
Netherlands [48 ,50,51].
&

&

Prevention
Maladaptive neuroplasticity
Maladaptive neuroplastic changes occur throughout the neuraxis in CRPS, resulting in sensory and

No specific technique has been shown to prevent
CRPS following surgery, but avoidance of prolonged
immobilization may be important [32]; the latter

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Pain medicine

constitutes a key argument for initiating early
physiotherapy after operations, where possible.
There is limited evidence for vitamin C reducing
the incidence of CRPS following lower limb injury
and wrist fracture [52,53]. However there is no evidence that vitamin C is useful for the treatment
of CRPS.

Early complex regional pain syndrome
The key to management of early CRPS is the return of
normal limb function, which may be facilitated by
adequate analgesia. Physiotherapy or occupational
therapy should be instituted and immobilization
avoided. Although multidisciplinary management
is usually considered in the context of long-term
CRPS, it is nevertheless important to consider aspects
of this approach (such as patient education) early in
the disease process.
Analgesia should be provided following the
WHO analgesic ladder. Given the large number of
proposed mechanisms for CRPS, it is not surprising
that numerous pharmacological treatments have
been proposed. Pain with neuropathic characteristics is treated following guidelines developed for
neuropathic pain such as the National Institute for
Health and Care Excellence guidelines (guidance.
nice.org.uk/cg173). However, there is no strong evidence to support the use of one antineuropathic
drug over another. First-line medications for neuropathic pain (and by extension CRPS) include
tricyclic antidepressants, such as amitriptyline, nortriptyline or imipramine. Gabapentin and pregabalin are also listed as first line. However, there have
been negative trials of gabapentin in CRPS. Selective
serotonin and norepinephrine reuptake inhibitors,
such as duloxetine and venlafaxine, are also
included in this group [54].
Early CRPS often involves marked inflammation. Corticosteroids, given orally as a short
tapering course, could be considered in early CRPS,
in which inflammation is prominent, but may be
associated with significant side-effects [55]. The use
of cyclooxygenase inhibitors has also been studied,
with generally negative or weakly positive outcomes
[56]. Bisphosphonates, acting to inhibit osteoclastic
bone resorption, have shown some promise [57].
Guidelines for the interventional management
of neuropathic pain have been produced [58]. SNS
blockade with local anesthetic has short-term analgesic effects in CRPS. Intravenous regional anesthesia (IVRA) with guanethidine is no longer
recommended and recent reviews emphasize the
risk of significant adverse effects [49]. Most controlled trials are confounded in that the control
arm usually involves IVRA with lidocaine or the
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application of a tourniquet. It is, therefore, possible
that positive effects of IVRA found in these studies
may be due to lidocaine or tourniquet pressure.

Established complex regional pain syndrome
Approximately 15% of patients will continue to
suffer from significant symptoms beyond 12 months.
Multidisciplinary management, addressing the four
pillars of treatment, includes patient education, pain
relief, physical rehabilitation and psychological
intervention [59].

Education
Education plays an important role in developing
concordance between the patient and therapists
[60].

Pain relief
Putative neuroplastic changes in CRPS have led to
the use of ketamine as a potential treatment at both
high and low doses. In two trials, low dose ketamine
infusion over several days resulted in improvements
in pain but not function. In one study (n ¼ 19),
ketamine was infused at 0.35 mg/kg/hr with clonidine for 4 h daily for 10 days. Pain scores averaged
over 2 weeks reduced from 7.51 þ/ 0.4 to 6.01 þ/
0.6 (P < 0.01) after treatment in the active group. No
such change in scores was seen in the placebo group,
who received clonidine and a saline infusion
[61,62].
Spinal cord stimulation, a neuromodulation
technique, has a moderate quality evidence base.
Long-term reduction in pain has been demonstrated
in CRPS I, but the effect reduces with time, disease
progression is unaffected and reoperation rates for
complications are high [49].
In general, evidence for pharmacological and
interventional treatment in chronic CRPS is weak,
and nonpharmacological options predominate.

Physical rehabilitation
General physiotherapy or occupational therapy
with gradual desensitization of hyperalgesic skin
encourages normalization of function [63]. Physical
therapies and psychological therapies often overlap
in CRPS treatment, as aberrant neuroplasticity may
respond to both approaches.

Psychological intervention
Specific treatments for CRPS, including mirror
visual feedback and graded motor imagery, may
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Complex regional pain syndrome Rockett
&

be offered in more specialist settings [64,65,66 ]. It
may also be helpful to assess and treat disturbed
body perception [67]. These treatments may be
combined and tailored to the individual in specialist
CRPS pain management programmes [68–70].

CONCLUSION
Our knowledge of the epidemiology and mechanisms of CRPS has advanced significantly in recent
years. National registries and well designed studies
show promise for assessing the effects of potential
new treatments for CRPS. Prospective studies may
point to strategies, which may be delivered by
anesthetists to prevent the progression of CRPS to
a chronic disease. In the absence of a strong evidence base, recent guidelines for the management
of CRPS in various settings provide a valuable
resource for clinicians involved in managing this
multifaceted condition. As a multidisciplinary
approach would seem to be optimal, the effects of
combining pharmacological or interventional
treatment with CRPS-specific pain management
programmes should be one target for future
research.
Acknowledgements
Mark Rockett has received honoraria from Pfizer, Grunenthal and Astellas Pharma.
Thanks to Dr Andreas Goebel for advice and peer review
of the manuscript.
Conflicts of interest
There are no conflicts of interest.

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REVIEW
URRENT
C
OPINION

Regional analgesia techniques for total knee
replacement
Martin C.R. Bauer a, Esther M. Pogatzki-Zahn b, and Peter K. Zahn a

Purpose of review
Pain following total knee arthroplasty is a challenging task for healthcare providers. Concurrently, fast
recovery and early ambulation are required to regain function and to prevent postoperative complications.
Ideal postoperative analgesia provides sufficient pain relief with minimal opioid consumption and
preservation of motor strength. Regional analgesia techniques are broadly used to answer these
expectations. Femoral nerve blocks are performed frequently but have suggested disadvantages, such as
motor weakness. The use of lumbar epidurals is questioned because of the risk of epidural hematoma.
Relatively new techniques, such as local infiltration analgesia or adductor canal blocks, are increasingly
discussed. The present review discusses new findings and weight between known benefits and risks of all
of these techniques for total knee arthroplasty.
Recent findings
Femoral nerve blocks are the gold standard for total knee arthroplasty. The standard use of additional
sciatic nerve blocks remains controversial. Lumbar epidurals possess an unfavourable risk/benefit ratio
because of increased rate of epidural hematoma in orthopaedic patients and should be reserved for lower
limb amputation; peripheral regional techniques provide comparable pain control, greater satisfaction and
less risk than epidural analgesia. Although motor weakness might be greater with femoral nerve blocks
compared with no regional analgesia, new data point towards a similar risk of falls after total knee
arthroplasty with or without peripheral nerve blocks. Local infiltration analgesia and adductor canal
blockade are promising recent techniques to gain adequate pain control with a minimum of undesired
side-effects.
Summary
Femoral nerve blocks are still the gold standard for an effective analgesia approach in knee arthroplasty
and should be supplemented (if needed) by oral opioids. An additional sciatic nerve blockade is still
controversial and should be an individual decision. Large-scale studies are needed to reinforce the
promising results of newer regional techniques, such as local infiltration analgesia and adductor canal
block.
Keywords
analgesia, arthroplasty, peripheral nerve blocks

INTRODUCTION
Joint surgery of the knee belongs to the most painful
procedures with a need for fast recovery to gain
function and prevent complications such as thromboembolic incidents. Additionally, the increasing
financial pressure in healthcare systems requires a
short hospital stay, early ambulation and rehabilitation. Regional anesthesia techniques seem to be an
ideal method to deliver intraoperative analgesia and
to minimize postoperative pain, if catheters are used.
With the ongoing evolution of regional anesthesia
and the development of ultrasound guidance, success
rates increased, complications were minimized and
the various techniques became more popular.

Nevertheless, the optimal nerve block, combination of blocks and/or combination of catheter and
single-shot techniques, is still a matter of debate

a

Clinic for Anesthesiology, Intensive Care Medicine, Palliative Medicine
and Pain Medicine, University Hospital Bergmannsheil, Bochum and
b
Department of Anesthesiology, Intensive Care and Pain Medicine,
University Hospital Muenster, Muenster, Germany
Correspondence to Martin C.R. Bauer, Clinic for Anesthesiology, Intensive Care Medicine, Palliative Medicine and Pain Medicine, University
Hospital Bergmannsheil, Bu¨rkle-de-la-Camp-Platz 1, 44789 Bochum,
Germany. Tel: +49 234 302 6825; e-mail: mcrbauer@gmail.com
Curr Opin Anesthesiol 2014, 27:501–506
DOI:10.1097/ACO.0000000000000115

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Pain medicine

KEY POINTS
Regional analgesia techniques are cornerstones of
multimodal analgesia in hip and knee replacement
surgery. Patients are profiting from reduced pain scores
and lesser opioid consumption.
Femoral nerve blocks can be viewed as the gold
standard for pain management after TKA. The
advantage of routinely used sciatic nerve blocks has
not been adequately clarified.
Lumbar epidurals have an unfavourable risk/benefit
ratio and regional techniques provide comparable
pain control.
The standard application of catheter techniques remains
controversial. Single-shot techniques often provide
sufficient analgesia for the first 24 h and early
ambulation is most often not delayed.
LIA and adductor canal blocks may initiate the change
away from femoral nerve blocks to the desired ‘pure
analgesic’ blocks in total knee replacement surgery;
however, the exact advantages need to be determined.

increase pain relief and satisfaction as patients
with postoperative nausea and vomiting may avoid
opioids in the early postoperative period [6].
Patients older than 65 years undergoing
total knee arthroplasty (TKA) have a better chance
for a fast postoperative recovery, if they received
lumbar plexus and sciatic nerve blocks than those
patients receiving general anesthesia [7]. However,
there is no clear evidence that the length of hospital
stay in TKA can be shortened by regional and local
anesthetic techniques [8]. Choi et al. [9] demonstrated in a recent Cochrane Review, that beneficial
effects of epidural analgesia in knee (and hip)
replacement are limited to the first 4–6 postoperative hours. No positive impact on hospital
length of stay or morbidity could be shown [9].
The role of regional anesthesia for the improvement of long-term functional outcome after a large
joint replacement is therefore not determined
but will be investigated by Atchabahian for the
Cochrane Collaboration.

EPIDURAL ANESTHESIA
&&

[1 ]. Furthermore, the use of peripheral nerve
blocks has been questioned by some authors for
knee surgery because of side-effects, such as impairment of motor function and risk of falls, risk of
infection and neurological complications. Finally,
the possibility of newer techniques, such as local
infiltration analgesia (LIA), challenges the value of
nerve blocks in hip and knee surgery. Here, we will
review the most recent literature on this topic and
discuss advantages and disadvantages of different
analgesic techniques for knee surgery.

REGIONAL ANALGESIA AND OUTCOME
AFTER KNEE ARTHROPLASTY
In general, nerve blocks with local anesthetics
appear to have better analgesic efficacy compared
with placebo or patient-controlled analgesia (PCA)
[2]. The opioid-sparing effect of regional anesthesia
techniques reduces opioid-related side-effects,
such as postoperative nausea, vomiting, pruritus,
sedation and – possibly – respiratory depression.
In general, neuraxial blockade may reduce the
0–30-day mortality if compared with general anesthesia [3]. A recent analysis by Memtsoudis et al. [4]
similarly showed that morbidity and mortality in
patients undergoing knee arthroplasty was significantly lower when receiving neuraxial anesthesia.
Furthermore, the growing number of patients with
sleep apnea may benefit from reduced opioid consumption in the postoperative period [5]. Reduced
postoperative nausea and vomiting may in turn
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For many years epidural analgesia played a major
role in orthopaedic anesthesia because analgesic
efficacy is very high. However, risks associated with
lumbar epidural analgesia and recent advances in
the use of ultrasound-guided catheter techniques
are questioning the superiority of epidural analgesia
in lower limb surgery. Most important, the risk of
epidural catheters in patients receiving orthopaedic
surgery has been underestimated. Incidence rates
vary in different cohort studies but seem to be much
higher for lumbar epidurals undergoing orthopaedic
surgery (1 : 4000) compared with epidurals for other
types of surgical procedures (1 : 10 000–20 000) or
for labour (1 : 200 000) [10]. Hypotension, urinary
retention and specific opioid-related side-effects are
less serious but more frequent side-effects. Given an
approximate risk of 40–80% for deep vein thrombosis in patients undergoing hip or knee arthroplasty, thromboprophylaxis is mandatory in the
early postoperative stage, which at the same time
may increase the risk of hemorrhagic complications
with neurologic dysfunction, especially in the light
of new oral anticoagulants [11]. Furthermore, a
systematic review by Fowler et al. [12] compared
femoral nerve blocks (FNB) with epidurals for TKA
and demonstrated that FNB provide similar analgesia but less hypotension than epidural analgesia. In
conclusion, high-risk patients undergoing thoracic
or abdominal surgery may benefit from thoracic
epidural analgesia [13]. However, there is no such
proven advantage of lumbar epidurals in hip or
knee replacement surgery. The risk/benefit ratio of
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Regional analgesia for total knee replacement Bauer et al.

epidural analgesia compared with peripheral nerve
blocks is less favourable [14].

FEMORAL NERVE BLOCK
FNB are frequently used for postoperative pain control after TKA. According to a currently published
Cochrane analysis, FNB with or without concomitant
intravenous PCA provide better analgesia than PCA
alone [15]. Opioid consumption, pain scores and
opioid-related side-effects, such as nausea and vomiting, were lower; knee flexion was greater and
patients’ satisfaction was higher in patients with
any FNB compared with opioid-based analgesia.
Compared with epidural analgesia, FNB provide
similar analgesia but less nausea/vomiting and
better patient’s satisfaction.

CONTINUOUS VERSUS SINGLE-SHOT
FEMORAL NERVE BLOCK
One question is the superiority of a continuous
FNB compared with single shot FNB. One analysis
published in 2010 indicated no advantages of continuous FNB over single-shot techniques [16] with
regard to pain scores and opioid consumption. However, this meta-analysis has been criticized because
of inconsistent study inclusion/exclusion and the
type of analysis [17]. In a more recent Cochrane
meta-analysis by Chan et al. [15], continuous nerve
blockade provided improved pain scores and
reduced opioid consumption at 24 and 48 h after
TKA compared with single-shot FNB. In addition,
improvement in functional outcome has been
shown with continuous FNB. This is in accordance
with clinical experiences demonstrating very sufficient pain management over days after surgery by
using a continuous FNB after TKA. Thus, for knee
surgery with significant pain for several days after
surgery and requirement of extensive physiotherapy, a continuous catheter infusion might be the
primary choice. Nevertheless, our knowledge about
infusion rates, dosing and delivery strategies is
thoroughly limited. Too many variables, such as
catheter location, catheter type or surgical technique, make the comparison of scientific findings
difficult [18].

RISK OF MUSCLE WEAKNESS AND FALLS
Multiple investigations [19,20] and the abovementioned meta-analysis by Paul et al. [16] suggest
that continuous blockade of the femoral nerve induces weakness of the quadriceps muscle, and therefore rises the risk for falls during early ambulation.
However, as suggested by the accompanied editorial

[17], only two studies included in the meta-analysis
directly compared continuous with single-shot
FNB. A very recent cohort study analyzed data from
191 570 patients in more than 400 acute care hospitals and indicated that peripheral nerve blocks
do not necessarily increase the likelihood for falls
in the postoperative setting [21 ]. This study questioned the increased fall hypothesis due to nerve
blocks and identified other factors associated with
increased fall risk, such as age and comorbidities.
Adjustment of continuous infusion with rather
low-dose regimes may effectively enable minimizing catheter-associated quadriceps weakness. The
amount of motor side-effects in continuous nerve
blocks seems to be dosage-dependent and not concentration-dependent [22]. Injection of repeated
boluses of local anesthetic seems to be similar to
continuous infusion with respect to motor weakness
[23]. Ultrasound-guided approaches to perform peripheral nerve blocks, in general, may be associated
with a higher success rate (insertion of the catheter,
faster onset and longer duration of single-shot
injection) and a lower risk for accidental vascular
puncture [24]. However, advantages in peripheral
catheter placement might only result in a minor
reduction of postoperative pain scores [25].
&&

SCIATIC NERVE BLOCK
Insufficient pain control after TKA despite an FNB is
frequently seen in clinical practice. Therefore, the
combination of an FNB with a sciatic nerve block
appeals to be a suitable option to optimize pain
management for TKA. Wegener et al. [26] demonstrated that an additional sciatic nerve block can
reduce the pain scores and opioid consumption,
both with single shot and continuous infusion.
However, there were not enough data to draw a
final conclusion about possible superiority of sciatic
nerve catheter and FNB versus FNB alone in the
meta-analysis performed by Chan et al. [15]. Ilfeld
and Madison [27 ] discussed the pro and cons of
recommending dual femoral or sciatic continuous
nerve blocks for all TKA procedures in an editorial
accompanied the Wegener study, 2010. Major concerns for performing an additional sciatic block are
risk of neuronal injury and increased motor weakness after surgery, which hinders control of nerve
function early after surgery. Similarly, a systematic
review by Abdallah and Brull [28] in the same year is
questioning the advantage of sciatic nerve blocks
when combined with femoral blocks. The use of an
additional sciatic nerve block (single shot or
catheter) should be to date an individual decision
by considering advantages (improved analgesia and
reduction of opioids/opioid-related side-effects) and

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Pain medicine

disadvantages (risk of nerve injury and possible
motor weakness).

ADDITIONAL DRUGS TO LOCAL
ANESTHESIA IN FEMORAL NERVE BLOCK
Additive drugs, such as opioids, clonidine or dexamethasone, to prolong the effect of local anesthetics in continuous or single-shot nerve blocks
did not show convincing clinical benefits [29,30].
One study on volunteers indicates that perineural
dexmedetomidine as an adjuvant to ropivacaine
prolongs peripheral nerve block [31]. Administration of liposomal bupivacaine and other formulas
may challenge catheter-based techniques or will
eventually abandon certain ones in the future
[32 ].
&

LOCAL INFILTRATION ANALGESIA
LIA of the knee (and hip) is gaining increasing
popularity as an alternative method of providing
pain control after joint replacement surgery. As
introduced by Kerr and Kohan [33], a mixture of
ropivacaine 2 mg/ml, ketorolac 30 mg and adrenaline 10 mg/ml is infiltrated in different layers of
the joint in volumes of 150–170 ml for TKA and
150–200 ml for total hip arthroplasty. Different
mixtures, containing among others opioids and
steroids, have been used in subsequent years [34].
However, there are no direct dose-finding (and
drug-finding) studies to support a certain mixture.
Some authors claim that LIA provides well tolerated
and efficient pain relief without the disadvantage of
motor impairment [35,36]. Kehlet and Andersen
[37] reviewed the efficacy of infiltration in joint
replacement surgery and concluded that recent data
supports the intraoperative use in TKA. The authors
found only little evidence to encourage the use in
hip surgery and limited data to maintain the use of
NSAID and adrenalin in the solution. Two recently
published studies are presenting yet again contrasting results [38,39]. The chosen infiltration volume
and study setup are hardly to compare, and therefore the results are somewhat conflicting. Sideeffects are surprisingly rare considering the usage
of high volume. Even the administration of 360 mg
of bupivacaine in a high-dose solution did not
increase the plasma levels of elderly patients above
a toxic threshold [40]. To date there is no clear
evidence that intra-articular high-volume infusion
provides better analgesia than soft tissue administration [41]. In a direct comparison between a continuous FNB and LIA after TKA, LIA produced
lower pain scores and lesser consumption of opioids
in the early postoperative period [42]. However,
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a FNB might be advantageous for the complete
postoperative period after TKA to mobilize the knee
adequately for days after surgery. Although LIA seems
to be promising for the earliest 1–2 days after TKA,
the studies supporting this are small, heterogeneous
and do not support long-term benefits.

ADDUCTOR CANAL BLOCK
The idea of performing a conduction block on the
sensory branches of the femoral nerve and to avoid
the disadvantage of motor impairment for knee
surgery seems tempting. However, clinical studies
are only recently available and still sparse. A recent
randomized controlled trial investigated the effect
of ACB on quadriceps strength in healthy volunteers
[43]. The loss of muscle strength was significantly
lower when compared with placebo or FNB. These
findings suggest a preserved ability to ambulate and
a lower risk for falls after surgery with an ACB
compared with FNB. However, whether this provides similar analgesia in patients is unclear from
that investigation. Kim et al. [44] published quite
recently a prospective study comparing ACB with
FNB for TKA. Opioid consumption and pain scores
were comparable in both groups; patients with ACB
had less motor impairment of the quadriceps but
only for the first 6–8 h postoperatively. However, in
both groups, regional analgesia (FNB or ACB) was
accompanied with lumbar epidural analgesia until
day 2 after surgery. Thus, the validity of similar
pain scores and opioid use in the FNB and ACB
group is limited and does not represent maximal
possible effects of both techniques (and therefore
not representative motor weakness) if used without
an epidural analgesia. The addition of a peripheral
nerve block together with an epidural analgesia is,
in our point of view, inadequate because of higher
risks without major advantages (except singleshot spinal anesthesia for intraoperative and continuous FNB for postoperative analgesia). A study
presented by Jaeger et al. [45], comparing ACB with
FNB in patients undergoing TKA [45], demonstrated
that both groups showed preserved quadriceps
strength, similar pain scores and opioid consumption. A recent study comparing continuous ACB
with placebo infusion following TKA demonstrated
reduced opioid consumption in the first 48 h with
ACB [46].
Thus, ACB might be similarly effective to FNB
but with only very few randomized controlled trials;
it is too early to recommend this technique for pain
management after TKA. However, if more studies
support these findings, ACB with similar analgesia
and minor motor impairment may have the potency
to replace the femoral nerve as a gold standard of
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Regional analgesia for total knee replacement Bauer et al.

pain management for joint replacement surgery of
the lower extremities [47 ].
&&

CONCLUSION
Regional analgesia techniques are an important part
of a multimodal pain management concept. For
TKA, FNB are the preferred method of choice, but
pain may not be completely under control. An
additional sciatic ‘rescue’ nerve block seems to be
a reasonable choice if pain scores are intense; however, the advantage of routinely used sciatic nerve
blocks has not been adequately clarified. Single-shot
techniques often provide sufficient analgesia for the
first 24 h; continuous FNB seems beneficial for prolonged analgesia to improve functional outcome.
Control for motor weakness by adjusting infusion
rate and local anesthetic dose should provide preserved motor function and does not increase the risk
of falls.
There is no advantage of epidurals in knee surgery
compared with regional analgesia like FNB. Lumbar
epidurals posses an unfavourable risk/benefit ratio
and peripheral regional analgesia techniques provide
comparable pain control. LIA with high-volume
solution might be a promising technique for TKA
with a lower incidence for adverse events. However,
there is no agreement regarding composition and
volume of the analgesic agents. LIA has the potential
to enhance early functional recovery after TKA, however, further research is required in this field, for
example if it is superior to femoral nerve blockade.
ACB may initiate the change away from FNB, but
again, further clinical trials to reinforce the recent
promising study results so far are strongly needed.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

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17. Hadzic A, Houle TT, Capdevila X, Ilfeld BM. Femoral nerve block for analgesia
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&&
arthroplasty: the role of anesthesia type and peripheral nerve blocks.
Anesthesiology 2014; 120:551–563.
Original article disproving a preconception.
22. Ilfeld BM, Moeller LK, Mariano ER, et al. Continuous peripheral nerve blocks:
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27. Ilfeld BM, Madison SJ. The sciatic nerve and knee arthroplasty: to block, or not
&&
to block–that is the question. Reg Anesth Pain Med 2011; 36:421–423.
An outstanding editorial discussing the role of the sciatic block in TKA under
general considerations.
28. Abdallah FW, Brull R. Is sciatic nerve block advantageous when combined with
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30. Brummett CM, Williams BA. Additives to local anesthetics for peripheral nerve
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2013; 110:438–442.

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Pain medicine
32. Ilfeld BM, Malhotra N, Furnish TJ, et al. Liposomal bupivacaine as a singleinjection peripheral nerve block: a dose-response study. Anesth Analg 2013;
117:1248–1256.
This original article gives an outlook on pharmacological options of regional
analgesia.
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total knee replacement: a review of current literature. J Bone Joint Surg Br
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36. Ganapathy S. Wound/intra-articular infiltration or peripheral nerve blocks for
orthopedic joint surgery: efficacy and safety issues. Curr Opin Anaesthesiol
2012; 25:615–620.
37. Kehlet H, Andersen LØ. Local infiltration analgesia in joint replacement: the
evidence and recommendations for clinical practice. Acta Anaesthesiol
Scand 2011; 55:778–784.
38. Solovyova O, Lewis CG, Abrams JH, et al. Local infiltration analgesia followed
by continuous infusion of local anesthetic solution for total hip arthroplasty: a
prospective, randomized, double-blind, placebo-controlled study. J Bone Joint
Surg Am 2013; 95:1935–1941.
39. Kucha´lik J, Granath B, Ljunggren A, et al. Postoperative pain relief after total
hip arthroplasty: a randomized, double-blind comparison between intrathecal
morphine and local infiltration analgesia. Br J Anaesth 2013; 111:793–799.

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40. Gill AM, Scott NB, Abbas M, et al. Ropivacaine plasma levels following local
infiltration analgesia for primary total hip arthroplasty. Anaesthesia 2014;
69:368–373.
41. Dobrydnjov I, Anderberg C, Olsson C, et al. Intraarticular vs. extraarticular
ropivacaine infusion following high-dose local infiltration analgesia after total
knee arthroplasty: a randomized double-blind study. Acta Orthop 2011;
82:692–698.
42. Toftdahl K, Nikolajsen L, Haraldsted V, et al. Comparison of peri- and
intraarticular analgesia with femoral nerve block after total knee arthroplasty:
a randomized clinical trial. Acta Orthop 2007; 78:172–179.
43. Jaeger P, Nielsen ZJ, Henningsen MH, et al. Adductor canal block versus
femoral nerve block and quadriceps strength: a randomized, double-blind,
placebo-controlled, crossover study in healthy volunteers. Anesthesiology
2013; 118:409–415.
44. Kim DH, Lin Y, Goytizolo EA, et al. Adductor canal block versus femoral nerve
block for total knee arthroplasty: a prospective randomized controlled trial.
Anesthesiology 2014; 120:540–550.
45. Jæger P, Zaric D, Fomsgaard JS, et al. Adductor canal block versus femoral
nerve block for analgesia after total knee arthroplasty: a randomized, doubleblind study. Reg Anesth Pain Med 2013; 38:526–532.
46. Hanson NA, Allen CJ, Hostetter LS, et al. Continuous ultrasound-guided
adductor canal block for total knee arthroplasty: a randomized, double-blind
trial. Anesth Analg 2014; 118:1370–1377.
47. Mariano ER, Perlas A. Adductor canal block for total knee arthroplasty: the
&&
perfect recipe or just one ingredient? Anesthesiology 2014; 120:530–
532.
Outstanding editorial discussing the potential of adductor canal blockades.

Volume 27 Number 5 October 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


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