REVIEW

CURRENT
OPINION Neuroanesthesia and outcomes: evidence, opinions,
and speculations on clinically relevant topics
Alana M. Flexman a, Tianlong Wang b, and Lingzhong Meng c

Purpose of review
The objective of this review is to identify outstanding topics most relevant to neuroanesthesia practice and
patient outcomes. We discuss the role of awake craniotomy, choice of general anesthetic agents,
monitoring of anesthetic ‘depth’, mannitol-induced diuresis, neurophysiological monitoring,
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hyperventilation, and cerebral hypoperfusion.

Recent findings
Awake craniotomy, although a technique likely underused, is associated with enhanced recovery after
surgery and prolonged survival after brain tumor resection compared with surgery under general
anesthesia. The choice of general anesthetic must balance patient and surgical factors. Although propofol
may be associated with favorable oncologic outcomes, currently available retrospective evidence does not
specifically address neurosurgical patients. Both the definition and monitoring of anesthetic ‘depth’ remains
elusive. Neuroanesthesiologists need to recognize and manage intraoperative light anesthesia in a timely
fashion. Further evidence related to the optimal management of mannitol-induced diuresis and
hyperventilation in neurosurgical patients is needed. Contemporary neurophysiological monitoring can
reasonably detect intraoperative neurologic injury; however, its effect on patient outcome is unclear.
Finally, cerebral hypoperfusion without stroke may be common; however, the clinical significance requires
further investigation.
Summary
We provide an overview of several topics that are relevant to neuroanesthesia practice and patient
outcomes based on evidence, opinions, and speculations. Our review highlights the need for further
outcome-oriented studies to specifically address these clinically relevant issues.
Keywords
evidence, neuroanesthesia, outcomes, topics

INTRODUCTION outcomes [1]. We have emphasized high-quality

The practice of neuroanesthesia encompasses the
anesthetic care provided to patients undergoing a
neurosurgical procedure or the maintenance of
brain health in patients having any surgery. Neuro-
anesthesia practice requires knowledge, skill, flexi-
bility, agility, and dedication to adapt to the needs
of each individual patient. As specific evidence to
guide particular aspects of clinical care is often
lacking, neuroanesthesiologists often rely on their
own experience, preferences, and intuitions in
decision-making. We have identified seven key out-
come-based questions pertaining to neuroanesthe-
sia practice and provided an overview of the
evidence related to each question. As the fundamen-
tal goal of healthcare is to offer patients the most
favorable outcomes within the capacity of modern
medicine, our review focuses on patient-centered
evidence when available; however, where there is
a lack of evidence, opinions and speculations
are discussed.
a
Department of Anesthesiology, Pharmacology and Therapeutics, Van-
couver General Hospital, University of British Columbia, Vancouver,
British Columbia, Canada, bDepartment of Anesthesiology, Xuanwu
Hospital, Capital Medical University, Beijing, China and cDepartment
of Anesthesiology, Yale University School of Medicine, New Haven,
Connecticut, USA
Correspondence to Lingzhong Meng, MD, Professor and Division Chief,
Department of Anesthesiology, Yale University School of Medicine, 333
Cedar Street, TMP 3, PO Box 208051, New Haven, CT 06520, USA.
Tel: +1 203 785 2802; e-mail: lingzhong.meng@yale.edu
Curr Opin Anesthesiol 2019, 32:539–545
DOI:10.1097/ACO.0000000000000747

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Neuroanesthesia
KEY POINTS
 Awake craniotomy is associated with enhanced
recovery after surgery and prolonged survival after
brain tumor resection, but likely underused. Propofol
may be related to favorable oncological outcomes after
surgery. Neuroanesthesiologists need to be prepared to
recognize and manage intraoperative
‘light’ anesthesia.
 Hyperventilation likely provides improved operating
conditions during neurosurgery, but must be balanced
with reduced cerebral blood flow. Further evidence is
needed to determine the optimal strategy for
hyperventilation during craniotomy.
 Neurophysiological monitoring can accurately detect
intraoperative neurologic injury, but its role in
improving patient outcomes requires
further investigation.
 Cerebral hypoperfusion without stroke may be a much
more common mishap than stroke; however, its clinical
significance is the focus of further study.
 Where clear evidence to guide management is not
available, neuroanesthesia practice must be informed
by patient goals and preferences, clinical experience,
and institutional practices.
AWAKE CRANIOTOMY: AN
UNDERUTILIZED TECHNIQUE?
Awake craniotomy refers to an intracranial proce-
dure performed with the patient awake and respon-
sive intermittently during or throughout the surgery
[2]. It is often used for patients with a brain lesion in
close proximity to eloquent centers of the brain [3].
Compared with surgery under general anesthesia,
awake craniotomy is associated with several advan-
tages, including shorter length of stay, fewer com-
plications, and longer survival after brain tumor
resection [4,5]. Although the benefits associated
with awake craniotomy are intriguing [4], the evi-
dence supporting the use of this technique is largely
based on cohort data, rather than randomized con-
trolled trials (RCTs). Although randomized trials
comparing awake vs. asleep craniotomy are chal-
lenging to conduct, mostly for ethical concerns, the
results could inform clinical practice.
Despite evidence supporting the benefits of
awake craniotomy, this technique remains underu-
tilized. Previous publications have demonstrated
that awake craniotomies can be performed on a
routine basis [6] and that patients tolerate awake
craniotomy very well in experienced centers [3,6].
What are the barriers to awake craniotomy? Multi-
ple factors likely contribute to this reluctance,
540 www.co-anesthesiology.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
including a lack of familiarity with the process
and the potential for complications such as airway
loss and intraoperative seizure [7]. Moreover, awake
craniotomy requires advance intraoperative moni-
toring techniques such as language and motor map-
ping which may not be available at all sites. All
members of the perioperative team must embrace
this technique, including anesthesiologists, sur-
geons, nurses, and intraoperative neuromonitoring
specialists. Furthermore, hospital policy makers and
insurance payers need to value the benefits associ-
ated with this unique surgical approach to support
the multidisciplinary implementation of this tech-
nique, particularly as awake craniotomy can be
lengthier and require additional resources compared
with surgery under general anesthesia.
WHAT IS THE IDEAL CHOICE OF GENERAL
ANESTHETIC FOR CRANIOTOMY?
The concept of balanced anesthesia emphasizes the
inclusion of unconsciousness, analgesia, and amne-
sia. General anesthetic renders unconsciousness.
There is a long-standing debate on the choice of
general anesthetic agents in patients undergoing a
neurosurgical procedure, that is, a propofol-based
intravenous regimen vs. a volatile-based regimen.
Which general anesthetics to choose is not always a
straightforward decision. Different stakeholders,
including patients, anesthesiologists, neurophysiol-
ogists, and surgeons, develop different preferences
for general anesthetic agents based on evidence, and
frequently, opinions (Table 1). Different consider-
ations and perspectives must be balanced and prior-
itized, focusing on the desired patient outcomes for
a particular procedure.
In principle, a general anesthetic chosen for a
neurosurgical procedure should optimize operating
conditions, facilitate neurophysiological monitor-
ing, and emerge patients smoothly and timely to
allow for early neurological assessments. At the
same time, it is ideal to use a general anesthetic that
has a rapid on/off profile, is neuroprotective not
neurotoxic, does not adversely affect organ system
function (such as the cardiovascular system) and
lead to unwanted consequences, and has minimal
residual effects after termination. Regarding out-
comes, the choice of anesthetic should contribute
towards the therapeutic goal of permanent cure
with no complications, and help the patient rapidly
return to function and quality of life.
The concept discussed is well illustrated by
examining the impact of a propofol-based intrave-
nous regimen vs. a regimen with a volatile anes-
thetic on oncological outcomes after tumor surgery.
Evidence suggests that propofol may be associated
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 Neuroanesthesia and outcomes Flexman et al.

Table 1. The choice between a propofol-based intravenous regimen and a regimen based on a volatile anesthetic per
different factors in patients undergoing a neurosurgical procedure
Factors Preference LOEa Comments

Patient’s factors
High risk of PONV Intravenous [8,9] A Direct evidence [8]; indirect evidence [9]
Preoperative cognitive impairment Intravenous C-EO Lack of direct evidence
High risk of intraoperative awareness Volatile C-EO Lack of direct evidence
Brain tumor surgery Intravenous [10,11]; B-NR Colon cancer [10]; any cancer [11]; breast cancer [12 ]
&

equivocal [12 ]
&

Elevated ICP Intravenous [8,13] A Also advantageous for brain relaxation

Patient satisfaction Intravenous [9] C-EO Indirect evidence in ambulatory and in-patient surgery [9]
Anesthesiologist’s factors
Organ protection Equivocal [14,15] C-EO Cardiac protection in noncardiac surgery [14,15]
Stable hemodynamics Equivocal C-EO Lack of direct evidence
Rapid emergence Equivocal [16–19] B-R The titration of anesthetics toward the end of surgery may
be more important
Smooth emergence Intravenous [20] C-EO Indirect evidence [20]; TIVA with remifentanil may reduce
confusion, agitation, shivering, and hypertension during
emergence
Reduced POD and POCD Equivocal [16,21] C-LD Propofol may reduce POCD in noncardiac surgery [21]
Reduced postoperative pain Intravenous [9] C-EO Indirect evidence [9]
Reduced PACU length of stay Intravenous [9] C-EO Indirect evidence [9]
Neurophysiologist’s factors
EEG monitoring Equivocal C-EO Dose-dependent suppression
ECoG monitoring Equivocal C-EO Opioid-based and/or dexmedetomidine-based ‘light’
anesthesia preferred [22]
SSEP monitoring Equivocal C-EO Dose-dependent suppression
MEP monitoring Intravenous C-EO Dose-dependent suppression
Cranial nerve monitoring Equivocal C-EO Least sensitive to anesthesia
EMG monitoring Equivocal C-EO Avoid muscle relaxation
Surgeon’s factors
Awake craniotomy Intravenous C-EO Smooth emergence

Cortical and subcortical mapping Equivocal C-EO Opioid-based and/or dexmedetomidine-based ‘light’
anesthesia preferred
Brain relaxation Equivocal [8] C-LD Intravenous agent may be more advantageous
Quality of recovery Equivocal [8] C-LD ‘Light’ anesthesia may be better based on the experience
of awake craniotomy [4,5]
Favorable oncological outcomes Intravenous [10,11]; C-EO Colon cancer [10]; any cancer [11]; breast cancer [12 ]
&

equivocal [12 ]
&

Reduced postoperative complications Equivocal [8] C-LD PONV is less with propofol-based regimen. Effects on
other complications are less clear
Reduced mortality Equivocal [23] C-EO Indirect evidence [23]

The priority of citation goes to randomized controlled trials conducted in neurosurgical patients. ECoG, electrocorticography; EEG, electroencephalography;
EMG, electromyography; ICP, intracranial pressure; MEP, motor evoked potential; PACU, postanesthesia care unit; POCD, postoperative cognitive decline; POD,
postoperative delirium; PONV, postoperative nausea and vomiting; SSEP, somatosensory evoked potential; TIVA, total intravenous anesthesia.
a
Level of evidence (LOE): Level A ¼ high-quality evidence from more than one randomized controlled trial, meta-analyses of high-quality randomized controlled
trials, one or more randomized controlled trials corroborated by high-quality registry studies; Level B-R ¼ moderate-quality evidence from one or more randomized
controlled trials, meta-analyses of moderate-quality randomized controlled trials; Level B-NR ¼ moderate-quality evidence from one or more well designed, well
executed nonrandomized studies, observational studies, or registry studies; meta-analyses of such studies; Level C-LD ¼ randomized or nonrandomized
observational or registry studies with limitations of design or execution, meta-analyses of such studies, physiological, or mechanistic studies in humans; Level C-
EO ¼ consensus of expert opinions based on clinical experience (based on the American Heart Association/American Stroke Association guideline [24]).

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Neuroanesthesia
with favorable oncological outcomes after surgery
&
[10,11,12 ]. However, the existing reports are con-
flicting and do not specifically target patients with
brain tumors.
CAN WE MEASURE DEPTH OF
ANESTHESIA AND AVOID LIGHT
ANESTHESIA?
Significant efforts have been devoted to investigat-
ing anesthetic depth. Let us first consider this anal-
ogy: Can we reliably measure the ‘depth’ of natural
sleep? Different stages of natural sleep, that is, stages
1, 2, 3, and rapid eye movement, are qualitative
rather than quantitative. Similarly, measuring the
‘depth’ of anesthesia based on electroencephalogra-
phy (EEG) is intrinsically complex, and unlikely to
be reliably simplified to a scale from 0 to 100. Just
because we can give patients different doses of gen-
eral anesthetics, can we easily alter the ‘depth’ of
anesthesia? The first step in solving this puzzle is to
define anesthetic ‘depth’.
As the concept of balanced anesthesia suggests,
analgesia is an essential component of general anes-
thesia. If a painful pinch can wake a human from a
natural sleep, what effect would a knife cutting into
the skin have on two nonparalyzed patients: one
anesthetized with an average dose of propofol only
and the other anesthetized with the same dose of
propofol and 3-mg/kg fentanyl? Most of us would say
that the first, not the second, patient may move; the
question is whether the movement is a consequence
of ‘light’ anesthesia or inadequate analgesia. This
example stresses the need to separate unconscious-
ness and analgesia when attempting to define the
‘depth’ of anesthesia. If we use the level of uncon-
sciousness to define anesthetic ‘depth’, we should
give patients adequate analgesics (i.e., no pain) or
have the pain controlled at a constant predetermined
level. This scenario also demonstrates that the ‘depth’
of anesthesia cannot be sufficiently quantified by
patient movement because the movement may be
caused by inadequate analgesia not general anes-
thetics and it is an all-or-none phenomenon, not a
quantification based on a continuous scale.
On the contrary, the use of processed EEG mon-
itor, such as the bispectral index, to measure the
‘depth’ of anesthesia has been unsatisfactory. The
outcome research showed that it neither prevents
intraoperative awareness [25,26] nor reduces post-
&&
operative delirium [27 ]. Although processed EEG
monitors correlate with clinical assessments of seda-
tion and anesthesia, we must consider whether or
not processed EEG monitors accurately measure
anesthetic ‘depth.’ More recent literature has
described the dynamic changes in cortical
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connectivity which may ultimately lead to
improved assessment of consciousness using EEG
analysis [28]. Given the lack of a unanimous defini-
tion and a gold standard measure of anesthetic
‘depth’, it is premature to call currently available
processed EEG monitors sufficient to measure
‘depth’ of anesthesia reliably.
Nonetheless, a challenge in neuroanesthesia is
the timely identification of anesthesia that is too
‘light’, implying that the patient may be waking up,
having intraoperative awareness, or moving. Intra-
operative movement during neurosurgical proce-
dures can be disastrous given the delicate nature
of operations such as aneurysm clipping, and the
fact that the patient’s head is fixed in pins. As
anesthesiologists must facilitate intraoperative
neurophysiological monitoring, this can require a
decrease in anesthetic administration in a nonpar-
alyzed patient. Neuroanesthesiologists must, there-
fore, be prepared to recognize and manage light
anesthesia during neurosurgical procedures. We
suggest the following strategies when ‘light’ anes-
thesia is anticipated during the procedure: first,
communicate with and thoroughly reassure the
patient in the preoperative area and ask the patient
to wave his or her hands or wiggle his or her toes if
he or she wakes up, but try not to move the head and
shoulders; second, perform an effective scalp infil-
tration or nerve blocks and give adequate analgesics,
such as fentanyl bolus and remifentanil infusion, to
ease pain-related, positioning-related, and endotra-
cheal tube-related discomfort; third, closely watch
for changes in EEG, hemodynamics, operating con-
dition (e.g., a bulging brain), and patient movement
for early signs of light anesthesia (although nonspe-
cific); and fourth, routinely confirm the appropriate
delivery of intravenous and volatile anesthetic
agents throughout the procedure, particularly if
total intravenous anesthesia is used.
In summary, further elucidation of the defini-
tion and quantification of anesthetic ‘depth’ and
the ideal ‘depth’ of anesthesia in neurosurgical
patients is needed. Anesthesiologists should be
prepared to titrate down the delivery of general
anesthetics to facilitate intraoperative neurophysio-
logical monitoring and at the same time, to recog-
nize and promptly treat potential ‘light’ anesthesia.
HOW DO WE TREAT OSMOTIC DIURESIS
FROM MANNITOL DURING CRANIOTOMY?
Mannitol is commonly used during craniotomy for
brain relaxation [29]. It is a drug that has been used
for more than 50 years [30]. Although it is regarded
as relatively safe [30], mannitol may cause massive
diuresis in some patients. The relevant questions
Volume 32  Number 5  October 2019

are, what are the potential clinical sequelae, and
should the intravascular volume be replaced? On
the one hand, mannitol-induced tissue dehydration
may facilitate tissue perfusion via a reduction in
blood flow resistance, so treatment is not needed
as long as the organ blood flow is not significantly
decreased. On the other hand, severely depleted
circulating volume secondary to mannitol-induced
diuresis may jeopardize tissue perfusion and thus
lead to hypoperfusion-related organ injury or dys-
function. This is an area that lacks evidence-based
consensus for management. Ideally, mannitol
administration should be individualized (e.g. based
on tumor size and location), rather than routinely
given during all craniotomy. In addition, mannitol
should be administered at the minimal effective
dose, rather than a ‘standard’ dose. A recent study
suggested that a dose of 0.5 g/kg provides effective
brain relaxation for supratentorial craniotomy with
minimal side effects [31]. Future research is needed
to identify the optimal strategy to replace intravas-
cular volume once diuresis occurs, although a recent
RCT has suggested that goal-direct therapy may be
beneficial [32]. The evolution of flow-centered
hemodynamic monitoring may facilitate the reso-
&&
lution of this issue [33,34 ].
WHAT IS THE ROLE OF
NEUROPHYSIOLOGICAL MONITORING IN
NEUROSURGICAL PROCEDURES?
Intraoperative neuromonitoring is commonly used
for neurosurgical procedures, to preserve the integrity
of the brain, spinal cord, and nerves during surgery,
and includes evoked potential monitoring, EEG, elec-
tromyography, and cerebral oximetry. A high level of
evidence supports the accuracy of neurophysiological
monitoring for detecting intraoperative neurologic
injury [35,36]. In contrast, the evidence supporting
the use of neuromonitoring to prevent injury and
change outcomes is far less robust.
Despite the absence of competent evidence
showing outcome benefits [36], intraoperative
neurophysiological monitoring is commonly used
for patients having craniotomy, spine surgery, or
procedures that may injure peripheral nerves. These
monitoring techniques are used to inform the sur-
geon about potential neurologic injury during the
procedure, and to identify critical structures. These
monitors are used routinely in some centers, even
though limited evidence exists to support their role
in preventing neurologic injury. This phenomenon
is similar to the implementation of pulse oximetry.
Although there is no evidence showing its impact on
anesthesia-related morbidity and mortality, it is a
standard monitor in perioperative care [37]. Due to
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Neuroanesthesia and outcomes Flexman et al.
widespread clinical adoption of certain monitors in
certain regions, RCTs are difficult to conduct for
ethical and pragmatic considerations although fur-
ther investigation is needed.
HYPERVENTILATION FOR BRAIN
RELAXATION: FRIEND OR FOE?
Carbon dioxide is a powerful modulator of cerebral
hemodynamics [38]. Hyperventilation is commonly
used during craniotomy to improve operating con-
ditions via a better brain relaxation [29]. Some pro-
viders habitually set a threshold below which the
carbon dioxide is maintained. In patients with trau-
matic brain injury, short-term, moderate hyperven-
tilation does not significantly change the metabolic
profiles of glucose, lactate, and pyruvate in cerebral
extracellular fluid and it does not decrease brain
tissue oxygen tension below the normal range [39].
On the contrary, hyperventilation has negative
consequences, the most prominent being the reduc-
tion of cerebral blood flow (CBF) [40]. In spontaneously
breathing awake humans, hyperventilation can lead to
symptoms such as dizziness or syncope [41–43]. In
elective neurosurgical patients, severe hyperventila-
tion can significantly reduce jugular venous oxygen
saturation and should be applied judiciously [44]. Sig-
nificantly, a recent study did not demonstrate an
association with the degree of hyperventilation (as
assessed by end-tidal carbon dioxide level) in aneurysm
clipping, although the retrospective, observational
nature of this study is a limitation [45].
Although the application of hyperventilation in
neurosurgical procedures improves operating con-
ditions, the role of this practice in optimizing
patient outcomes is not available. Investigations
are needed to identify optimal strategies for ventila-
tion and carbon dioxide management. At this time,
it is prudent to use hyperventilation carefully and
deliberately when required, rather than routinely.
CEREBRAL HYPOPERFUSION:
THEORETICAL CONCEPT OR CLINICAL
PROBLEM?
Cerebral perfusion is robustly regulated by multiple
factors, including but not limited to systemic blood
pressure, arterial carbon dioxide, and cerebral met-
&&
abolic rate [38,46,47 ]. The maintenance of an opti-
mal CBF is one of the goals of perioperative care for
any surgical patient. The most devastating conse-
quence of cerebral ischemia is perioperative stroke
defined as a brain infarction arising during surgery
or within 30 days after surgery [48]. Perioperative
ischemic stroke can be either overt [49] or covert [50]
depending on the existence of clinically diagnosable
www.co-anesthesiology.com 543
Neuroanesthesia
neurologic deficits. Overt stroke is associated with
increased morbidity and mortality [51], while the
long-term outcomes after covert stroke remain to be
determined [50].
Clinically, not every episode of cerebral hypo-
perfusion leads to stroke. On the contrary, a patient
waking up from anesthesia without a stroke does not
necessarily mean they have not experienced cere-
bral hypoperfusion. Cerebral hypoperfusion is dis-
tinct from, and likely more common than stroke.
This speculation is corroborated by a study which
showed that cerebral injury, diagnosed with diffu-
sion-weighted MRI, occurred in more than 50% of
patients undergoing cardiac surgery with cardiopul-
&&
monary bypass [52 ], an incidence that is much
higher than that of overt ischemic stroke (1–
2%) in the same patient population [53].
It is thus likely that cerebral hypoperfusion is a
real issue in anesthetized surgical patients. The ensu-
ing questions are how to monitor cerebral perfusion
and what are the consequences, if not a stroke, of
cerebral hypoperfusion? At this time, it is difficult to
monitor cerebral perfusion practically and continu-
ously at patient bedside. The effect of cerebral tissue
oxygen saturation monitored using near-infrared
spectroscopy on perioperative neurological compli-
cations remains inconclusive but is a promising area
of ongoing research [54,55]. The consequences of
cerebral hypoperfusion are poorly understood and
should be studied.
CONCLUSION
It is essential to continuously improve the quality of
neuroanesthetic care by identifying the key issues
that matter to patient outcomes. We discussed seven
topics in neuroanesthesia, with a focus on their
clinical relevance, current evidence, opinions, and
areas for future research. The incremental additions
to the literature have advanced our understanding
of these issues although several areas need further
investigation. The care of neurologically at-risk
patients relies on the currently available evidence
base, patient goals and expectations, clinical expe-
rience, and local institutional practices.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
L.M. is a consultant for CAS Medical Systems, Inc. The
other authors declare no competing interests.
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