Neurosurgery Update

REVIEW ARTICLE
Neuroanesthesiology Update
Jerey J. Pasternak, MD and William L. Lanier, MD
Abstract: We provide a synopsis of innovative research, recurring themes, and novel experimental ndings pertinent to the
care of neurosurgical patients and critically ill patients with
neurological diseases. The following broad topics are covered:
general neurosurgery, spine surgery, stroke, traumatic brain
injury, anesthetic neurotoxicity, perioperative cognitive dysfunction, and monitoring.
Key Words: neuroanesthesia, spine surgery, traumatic brain injury, neurological monitoring, anesthetic neurotoxicity, postoperative cognitive dysfunction, stroke, intracranial hemorrhage,
subarachnoid hemorrhage
(J Neurosurg Anesthesiol 2016;28:93122)
GENERAL NEUROANESTHESIOLOGY
Improved operating room eciency decreases cost
and may reduce patient anxiety by reducing waiting times
before surgery. In addition, ecient time management
may also reduce work-day length and improve employee
satisfaction. Mathews et al1 reported the eect of a performance improvement project at a single institution with
a high-volume neurosurgical practice on the rate of ontime room starts. The work group: (1) streamlined the
admission process to reduce paperwork, (2) set expectations that admission by nursing services would be completed within 30 minutes, (3) assumed that the operating
room was ready on time unless a reason for delay was
communicated, (4) instituted a huddle by nursing (ie, to
communicate patient status and planned activities) 30 to
45 minutes before the expected start time, and (5) provided daily feedback to the team about rates of on-time
starts from the prior day. A room start was considered
delayed if the patient was brought into the room
>5 minutes after the expected start time. During the
study period, 2328 elective neurosurgical cases and 22,985
non-neurosurgery cases were performed. Initially the rate
of on-time starts for neurosurgical procedures was 33%.
Following implementation of the performance improvement project, the rate of on-time starts increased to 68%
Received for publication December 31, 2015; accepted January 6, 2016.
From the Department of Anesthesiology, Mayo Clinic College of
Medicine, Rochester, MN.
The authors have no conicts of interest to disclose.
Reprints: Jerey J. Pasternak, MD, Department of Anesthesiology,
Mayo Clinic College of Medicine, 200 First Avenue SW, Rochester,
MN 55905 (e-mail: Pasternak.jerey@mayo.edu).
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Neurosurg Anesthesiol
(P-value not reported). In non-neurosurgical operating

rooms that served as a comparative group during the
study period, the rate of on-time starts remained stable at
approximately 29%. Factors associated with delayed
room starts were: (1) female patients, (2) a nurse anesthetist as the in-room provider, (3) cases performed on
Friday, and (4) American Society of Anesthesiologists
(ASA) physical status classication score of 4.
Pulmonary and airway complications in neurosurgical patients can increase the length of hospital stay
and are associated with long-term morbidity.26 Neurosurgical patients may require replacement of a tracheal
tube following surgery for a variety of reasons including
neurological deterioration or respiratory complications.
Shalev and Kamel7 determined the rate of reintubation
within 48 hours of elective and emergent neurosurgical
procedure performed with general anesthesia in 17,483
patients enrolled in the National Surgical Quality Improvement Program (NSQIP) database. Overall, 0.42%
(95% condence interval [CI], 0.33%-0.52%) of this cohort required replacement of a tracheal tube following
surgery. Factors associated with increased odds for reintubation were: (1) age above 65 years (odds ratio
[OR] = 2.1; 95% CI, 1.3-3.4), (2) presence of chronic
obstructive pulmonary disease (OR = 2.1; 95% CI, 1.04.3), (3) higher ASA physical status classication score
(OR = 2.1 per point vs. score = 1; 95% CI, 1.4-3.1), (4)
operative time >3 hours (OR = 2.9; 95% CI, 1.8-4.8), (5)
preoperative renal failure (OR = 2.9; 95% CI, 1.0-8.5),
and (6) quadriplegia (OR = 8.2; 95% CI, 3.3-20.3).
Compared with intracranial neurosurgical procedures
and carotid endarterectomy, spine surgery was associated
with reduced odds for reintubation (OR = 0.3; 95% CI,
0.2-0.5). Unfortunately, indication for craniotomy and
location of craniotomy were not evaluated because those
data were not recorded in the NSQIP database. On the
basis of other data, posterior fossa procedures are associated with increased risk for respiratory complication
compared with supratentorial craniotomy.4 Also, outcome data for patients requiring reintubation, such as
other postoperative complications and mortality rate,
were not evaluated in the Shalev and Kamel7 research.
Hypertension is common in craniotomy patients
during emergence from general anesthesia. This increase
in blood pressure can increase cerebral blood ow (CBF)
and predispose patients to increased risk for surgical-site
hemorrhage. Often antihypertensive and anesthetic drugs
are used to attenuate this response.810 A laryngeal mask
airway (LMA) is associated with less noxious stimulation
and hypertension than a standard tracheal tube.11
Volume 28, Number 2, April 2016
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93
Pasternak and Lanier
Perello-Cerda et al12 prospectively compared hemodynamic and stress responses during emergence from general anesthesia following craniotomy between patients
with a tracheal tube in place and those in whom the
tracheal tube was changed to an LMA before emergence
from anesthesia. Patients were excluded if there was difculty with initial tracheal tube placement, increased risk
for aspiration, or poorly controlled preoperative hypertension. Forty-two patients were randomized to either
having their tracheal tube left in place or removed and
replaced with a ProSeal LMA (Laryngeal Mask Ltd, Le
Rocher, Victoria, Mahe Seychelles) immediately after the
Mayeld head holder was removed. All patients underwent a standardized anesthetic that consisted of propofol
and remifentanil infusions, and propofol dose was adjusted to maintain a bispectral index (BIS) of 40 to 60.
Muscle paralysis was achieved with a rocuronium infusion. All infusions were terminated after the Mayeld
head holder was removed, and sugammadex was then
administered to reverse neuromuscular block. The tracheal tube or LMA was removed when eective spontaneous ventilation was present and the patient was able to
follow commands. Patients who had a tracheal tube left in
place had a higher average mean arterial pressure (MAP)
(11.9 mm Hg; 95% CI, 2.1-21.8 mm Hg; P = 0.017),
higher average systolic blood pressure (SBP) (35.6 mm
Hg; 95% CI, 8.9-62.3 mm Hg; P = 0.009), and higher
average heart rate (HR) (7.2 beats per minute; 95% CI,
0.7-13.7 beats per minute; P = 0.03) compared with the
group with an LMA in place during the rst 60 minutes
following Mayeld removal. Nine (42%) patients with a
tracheal tube in place required treatment with antihypertensive medications during emergence compared
with only 3 (14%) patients with an LMA in place
(P = 0.04). Although there were no dierences in middle
cerebral artery blood ow velocity between groups, those
with a tracheal tube in place had signicantly higher regional cerebral oxygen saturation (rSO2) (mean dierence
in regional oxygen saturation = 26.1%; 95% CI, 9.1%43.2%; P = 0.002). Although the authors stated that the
tracheal tube or LMA was removed, they did not report
the median and range of the time to airway device removal. This may have confounded the results because a
tracheal tube left in place longer may have contributed to
the longer duration of more extensive hypertension and
tachycardia. Coughing during emergence was much more
common in patients with a tracheal tube in place (88%)
than in those with an LMA (10%, P < 0.001). There were
no intracranial hemorrhagic (ICH) complications in any
patient. Although exchange of a tracheal tube to an LMA
decreased hemodynamic responses and coughing, this
technique can only be applied to select patients. Further,
if adverse airway issues arise during airway exchange, this
can result in signicant hemodynamic perturbations and
hypoxia that can potentially have adverse consequences.
The additional cost of an LMA must also be considered.
The LMA-Supreme (Teleex, San Diego, CA) is an
inatable LMA that also allows for advancement of
a suction catheter into the esophagus. The I-gel LMA
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(Intersurgical Inc, Jiangsu, China) also allows for a suction catheter to be advanced into the esophagus but is
composed of a solid thermoplastic polymer and changes
contour to adjust to t into the supraglottic region; it does
not require ination. The LMA has been used in patients
having procedures performed in the prone position.13
Kang et al14 reported on the use of an LMA during prone
lumbar spine surgery and compared the ecacy and
safety of the LMA-Supreme and I-gel LMA. A total of
264 patients having elective simple lumbar spine surgery
were randomized to have an LMA-Supreme or I-gel
LMA placed following induction of anesthesia and before
turning the patient to the prone position. Patients were
not included if they were obese (body mass index
[BMI] > 30 kg/m2), had high risk for airway management
diculty, or were at risk for gastric aspiration. Mechanical ventilation was used in all patients with a tidal
volume of 8 mL/kg and a respiratory rate adjusted to
maintain normocarbia. Patients with an I-gel LMA more
frequently required >1 attempt to position the device
(18% vs. 3% in the LMA-Supreme group, P < 0.001).
No patient had to be rotated back to supine for airway
management after being placed prone. There were no
episodes of aspiration, laryngospasm, or hiccoughs.
However, in this small study, despite no signicant
complications, there are still potential dangers to performing prone procedures with a supraglottic airway device in place. These can include diculty maintaining a
seal and loss of tidal volume, aspiration, and risk for
emergent airway management in the prone position with
limited, if any, airway access.
Klug et al15 reported a novel technique for airway
management in patients undergoing thermal ablation of
the gasserian ganglion to treat trigeminal neuralgia. The
technique was designed to allow simultaneous mechanical ventilation and communication with the patient
without encroaching on the surgical location. Following
induction of general anesthesia and conrmation of
mask ventilation, a 5.0 mm internal diameter tube was
advanced through the nose to a distance of 16 to 17 cm
(measured at the nare) and the cu tube was inated.
This depth likely placed the tip of the tube at or immediately above the vocal cords, as mean distance from the
nare to the glottic opening is reported to be 18.3 and
16.3 cm in adult males and females, respectively.16 Patients airways were then insuated with 100% oxygen
at 18 L/minute to compensate for gas volume loss
through the mouth. Anesthesia was maintained with
intermittent boluses of propofol and fentanyl. The patient was allowed to emerge from anesthesia following
puncture of the ganglion to conrm painful stimuli to
the surgeon. After that, general anesthesia was induced
again to facilitate thermal destruction of the ganglion.
The authors reported no episodes of oxygen desaturation, hypercapnia (venous blood samples were obtained
at intervals during the procedure), or other adverse
events. This technique is likely only suitable for select
patients such as those without obesity, without prior
airway or nasal surgery, and at low risk for gastric
Copyright
2016 Wolters Kluwer Health, Inc. All rights reserved.
aspiration. We also question whether adequacy of ventilation can be assessed by venous blood gas data.
Ablative procedures performed on the trigeminal
ganglion can be associated with signicant cardiovascular
perturbation due to the trigeminocardiac reex. Not only
are increases in vagal outow common (resulting in
bradycardia and hypotension), but hypertension can
also occur in the setting of both bradycardia and tachycardia.17,18 Wang et al19 reported that, during balloonfacilitated ablation of the trigeminal ganglion, SBP
increased from a baseline of 112 28 to 168 21 mm Hg
(P < 0.001), diastolic blood pressure (DBP) increased
from 66 18 to 99 21 mm Hg (P < 0.001), and HR
decreased from 66 11 to 52 14 bpm (P < 0.001), despite the administration of atropine 0.5 mg intravenously,
before balloon ination. The SBP and DBP responses to
balloon ination were both attenuated (leading to no
signicant change from baseline) by instituting an infusion of sodium nitroprusside at 0.5 mg/kg/minute before
balloon ination. Heart rate still decreased in those who
received sodium nitroprusside along with 0.5 mg atropine
(from 62 9 to 50 13 bpm, P < 0.001). We refer interested authors to a recent review of the trigeminocardiac reex where Chowdhury et al20 discuss its
epidemiology, pathophysiology, and management.
Theoretically, shorter-acting anesthetic drugs should
allow for faster recovery from general anesthesia, although
this is not consistently supported in the literature.21 Ghoneim et al22 prospectively compared the rapidity of emergence from anesthesia in pediatric patients who underwent
supratentorial tumor resection during either isourane,
sevourane, or desurane general anesthesia. Sixty patients
ages 7 to 18 years were randomly allocated to receive one of
the 3 inhaled anesthetics in addition to fentanyl through
continuous infusion (0.5 mg/kg/h). Inhaled anesthetic dose
was begun at 1 minimum alveolar equivalent (MAC) and
adjusted to maintain MAP within 20% of baseline values.
Inhaled anesthetic drugs were discontinued upon removal
of the Mayeld head holder, but there were no reductions
in concentrations before this. Emergence characteristics
were more favorable in patients who received desurane
and sevourane as shown in Table 1. There were no differences among groups in neurosurgeon-assessed brain
volume, systemic hemodynamics, postoperative nausea and
vomiting (PONV), or shivering. We feel that a limitation of
this investigation was that it did not reect standard
practice. Specically, anesthesiologists are likely to reduce
the concentrations of longer-acting medications earlier before emergence from anesthesia. Therefore, it was not surprising that emergence from anesthesia required a longer
duration in patients who received a longer-acting inhaled
anesthetic. As such, it is unclear how these data can be
applied to clinical practice.
Cerebral arterioles will regulate their diameter in
response to systemic blood pressure and the tension of
oxygen and carbon dioxide in blood. We refer the reader
to a review of the responsiveness of the cerebral vasculature to carbon dioxide tension published in 2015.23 Some
drugs also impact cerebrovascular resistance. This can
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TABLE 1. Emergence Characteristics

Isourane Sevourane Desurane
N
20
20
20
Extubation time (min)
21.3 0.7 14.1 0.8* 11.6 0.8*
Emergence time (min)
15.5 0.9 11.7 0.7* 9.7 0.5*
Time to Aldrete score Z9 (min) 35.6 1.0 29.3 1.2* 26.5 0.9*
No. patients with extubation time
0
11 (55)
13 (65)
<15 min
Extubation time: interval between cessation of anesthesia and removal of the
tracheal tube.
Emergence time: interval between cessation of anesthesia and eye opening.
Data represented as mean SE of mean or n (%).
*P < 0.05 versus isourane group.
Modied from Ghoneim et al,22 with permission.
occur either directly by inducing vasodilation or vasoconstriction or indirectly by causing changes in cerebral
metabolism that aect cerebrovascular resistance through
ow-metabolism coupling. For example, midazolam decreases CBF through ow-metabolism coupling.24 One
would expect that administration of umazenil will reverse
this eect. In 16 healthy male subjects, Ogawa et al25
studied the eect of midazolam followed by umazenil on
CBF velocity and cerebral autoregulatory capacity. Midazolam was administered intravenously in 0.5 mg aliquots
every 2 minutes until the patient achieved a modied
Observers Assessment of Alertness/Sedation (OAA/S)
Score of 3 (ie, responds to name if called repeatedly or
loudly). Flumazenil was administered 30 minutes following the last dose of midazolam in 0.1 mg aliquots until an
OAA/S score of 5 (ie, responds to name on rst attempt if
spoken in normal tone) was achieved. Vital signs (including arterial blood pressure waveform obtained with a
noninvasive monitor [JENTOW 7700; Colin, Aichi, Japan]), and middle CBF velocity, were recorded at 6-minute intervals before administration of midazolam, after
midazolam but before umazenil, and then again after
umazenil. A transfer function analysis was conducted
from these data, allowing quantication of the ability of
the distal cerebral arterioles to buer changes in systemic
blood pressure. The mean doses of midazolam and umazenil were 2.4 0.5 and 0.24 0.07 mg, respectively.
Midazolam caused decreases in MAP, CBF velocity, and
transfer function gain (indicating improved autoregulatory capacity). Although umazenil antagonized the
sedative eect and eect on blood pressure induced by
midazolam, it led to a further decrease in middle CBF
velocity and transfer function gain (indicating an even
greater improvement in autoregulatory capacity). Although there were statistically signicant changes in endexpired carbon dioxide tension, the extent of changes may
be clinically inconsequential. However, the authors did
not measure arterial blood carbon dioxide tension. Arterial values may have provided a more accurate estimate of
changes in ventilatory status that, in turn, could impact
middle CBF velocity and the integrity of autoregulation.
Dexmedetomidine is commonly used for sedation during neurosurgical procedures, for example, awake craniotomy and during deep brain stimulatorlead implantation.26,27
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The effect of dexmedetomidine on cerebral hemodynamics

has been controversial, with some data from animal models
suggesting that the drug induces a decrease in CBF without
significantly affecting cerebral metabolism.28 In humans,
dexmedetomidine decreases CBF and cerebral metabolic rate
and does not reduce brain tissue partial pressure of oxygen
(PbtO2).29,30 In 15 subjects with unilateral supratentorial brain
tumors supplied (at least in part) by the middle cerebral artery, and in 15 patients without central nervous system
pathology, Arulvelan et al26 measured the differential effect of
dexmedetomidine on middle CBF velocity and cerebral autoregulatory capacity. Cerebral autoregulatory capacity was
estimated by the transient hyperemic response method,31
whereby changes in middle cerebral artery blood flow velocity
are assessed following temporary unilateral carotid manual
compression and then abrupt release. Intact autoregulation
will be associated with a lesser increase in blood flow velocity
upon release of compression. Baseline measurements were
obtained, followed by the administration of dexmedetomidine
1 mg/kg IV over 10 minutes, and thereafter measurements
were repeated. During the dexmedetomidine infusion, blood
pressure and HR were kept constant by the incremental administration of mephentermine and glycopyrrolate, respectively. Middle cerebral artery blood flow velocity was
similar between normal hemispheres and those with tumor.
Dexmedetomidine resulted in a decrease in CBF velocity (of
approximately 27%, P < 0.001) in normal hemispheres,
whereas no significant change was observed in the hemisphere
containing a tumor (P = 0.071). Dexmedetomidine caused
attenuation of cerebral autoregulatory capacity in healthy
hemispheres and no significant change in autoregulation in
the hemisphere containing tumor. By comparison, dexmedetomidine causes cerebral arteriolar constriction in vitro.32 The
authors hypothesize that this lack of an effect of dexmedetomidine in the hemisphere containing tumor may be due to
tumor-induced alterations in vascular collagen, smooth muscle innervation, or expression of receptors for dexmedetomidine. Of note, Banik et al33 report that when used in patients
receiving sevoflurane anesthesia and having lumbar spine
surgery, dexmedetomidine does not attenuate cerebral autoregulation.
Pituitary tumors are commonly resected through
the transsphenoidal route. However, this procedure is
associated with hemodynamic aberrations and requires a
smooth emergence from anesthesia to minimize risk of
disruption of the operative site and risk for bleeding.34
Various drugs can be used to attenuate hypertension that
can occur during emergence.35 Gopalakrishna et al36
randomized 46 patients having transsphenoidal resection
of a pituitary tumor during isourane anesthesia to additionally receive either placebo or supplemental dexmedetomidine. Isourane was titrated to a processed
electroencephalogram (EEG) endpoint, and there were
predetermined algorithms to adjust other drug doses
(including fentanyl) in response to aberrations in hemodynamics. The dexmedetomidine-treated group received a
1 mg/kg loading dose over 10 minutes followed by a
continuous infusion of 0.7 mg/kg/h. Patients who received
dexmedetomidine required less fentanyl and had lower
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TABLE 2. Mean Arterial Pressure Comparison at Prespecified

Perioperative Time Points
Dexmedetomidine
Perioperative Time Point Group (n = 22)
Before induction of
anesthesia
Before intubation
Immediately following
intubation
Before nasal speculum
insertion
insertion of nasal
speculum
During sphenoid
dissection
During sellar dissection
extubation
15 min following
extubation
30 min following
extubation
60 min following
extubation
97.2 4.9
95.3 11.8
95.1 7.7
Control
Group
(n = 22)
96.6 7.4
P
0.776
88.5 11.5
0.061
106.1 8.5 < 0.01
84.6 1.2
92.2 6.4
< 0.01
92.5 11.4
114.5 9.3
< 0.01
87.6 8.8
104 8.9
< 0.01
82.3 9.2
84.9 9.3
103.5 6.9
115.7 7.0
< 0.01
< 0.01
81.2 0.0
106.8 7.0
< 0.01
83.1 7.6
104.7 4.6
< 0.01
85.1 0.9
101.5 4.3
< 0.01
Data expressed as mean SD.

From Gopalakrishna et al,36 with permission.
isourane requirements intraoperatively. Patients who

received dexmedetomidine consistently had lower MAPs at
prespecied times points during surgery (as shown
in Table 2) and less intraoperative estimated blood loss
(135 94 vs. 225 129 mL in control patients, P < 0.01).
Time to eye opening to command (7.6 4.0 vs. 11.8 4.9,
P < 0.01), time to extubation (8.7 4.2 vs. 13.5 5.3 min,
P < 0.01), and rates of PONV (5% vs. 41%, P < 0.01)
were less in the dexmedetomidine group.
PONV are common following neurosurgical procedures, and, in neurosurgical patients, drugs used to treat
PONV can have meaningful adverse eects.37,38 Nonpharmacologic methods to decrease PONV, such as
acupressure, can possibly decrease the need for medications. Nilsson et al39 prospectively randomized adult
patients having supratentorial or infratentorial craniotomy to receive a wrist band (Sea Band; Sea-Band Ltd,
Hinckley, Leicestershire, England) that either did
(n = 42) or did not (n = 52) provide pressure at the P6
acupuncture pressure point. The location of the P6 acupressure point is illustrated in Figure 1. The sham band
did not contain a plastic button that is placed over the P6
point. Bands were placed at the end of surgery, unilaterally on the side that did not have an arterial catheter,
and were covered to maintain blinding. Bands were removed in 48 hours. General anesthesia was standardized
and consisted of sevourane and remifentanil. All patients received ondansetron with or without droperidol,
and droperidol use was similar between groups. PONV
was assessed at multiple prespecied time points for 48
hours after surgery. Groups were well matched for demographics, surgery location, risk factors for PONV, and
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FIGURE 1. The P6 pressure point is located 3 finger breaths

proximal to the wrist joint in between the tendons of the
flexor carpi radialis and flexor digitorum superficialis.
periprocedural opioid requirement. Overall, 67% of

subjects had PONV during the rst 24 hours. There was
no dierence between study groups in the rates of PONV
or the need for rescue antiemetics at any time point
during the study period. Patients having infratentorial
surgery required more rescue antiemetics during the study
interval.
Cerebral edema can contribute to a reduction in
cerebral perfusion and a corresponding increased risk for
ischemic injury. Intraoperatively, cerebral edema can
hinder surgical access by limiting space within the intracranial vault. Administration of large-protein colloid
solution intravenously has not been eective at decreasing
cerebral edema.40 However, administration of smaller
molecule solutions that allow an osmotic gradient across
an intact blood brain barrierfor example, intravenous
administration of mannitol or sodium chloride can
decrease brain edema. Many prospective trials that
compared the efficacy of mannitol and hypertonic saline
did not standardize drug volume or osmolarity. Dostal
et al41 randomized 74 patients undergoing elective supratentorial craniotomy for tumor resection to receive a
3.75 mL/kg infusion of either 3.2% sodium chloride or
20% mannitol over 30 minutes, starting at the time of
skin incision. Both solutions had an osmolarity of
1099 mOsm/L. Patients underwent a standard anesthetic
consisting of inhaled isoflurane and sufentanil boluses.
End-expired carbon dioxide was maintained between 35
and 38 mm Hg. Fluid administration and hemodynamic
management were also standardized. Surgeons, blinded to
group assignment, judged the degree of brain relaxation
at the time of dural opening on a scale of 1 (excellent
relaxation) to 4 (bulging brain). Patients were well
matched for demographics and tumor characteristics.
Patients in the hypertonic saline group had better brain
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relaxation (percent with score = 1: 28% vs. 8%,

P = 0.02). Patients in the hypertonic saline group also
had a lower intraoperative urine output (656 496 vs.
1395 825 mL, P < 0.001), received less crystalloids
during surgery (2093 1190 vs. 2971 1390 mL,
P < 0.01), and had a higher central venous pressure at
the end of surgery (10.4 4.8 vs. 8.1 4.3 mm Hg,
P = 0.04). There were no differences between groups in
the rates of complications following surgery. Mannitol
use, when compared with hypertonic saline, correlated
with a prolonged left ventricular ejection time, a finding
that has previously been reported by others.42 This finding may be due to relative intravascular volume depletion
that results from mannitol, causing a prolonged duration
of left ventricular ejection.
Perioperative management of pregnant patients
with signicant neurological disease can be challenging.4347 Although it would be expected that mannitol
administered intravenously to pregnant women would
aect fetal uid status, this has not been previously
quantied. Handlogten et al48 estimated maternal intrauterine volume through ultrasound before and following
the administration of 0.25 g/kg mannitol in a patient who
was at 20 weeks gestation and having surgical resection of
a left temporal lobe mass. The procedure was performed
during dexmedetomidine-facilitated sedation to allow for
functional mapping of the cerebral cortex. Baseline intrauterine volume was estimated at 1092 cm3, and 9 hours
following mannitol administration intrauterine volume
was 770 cm3 (a 30% decrease in volume). At 47 hours
following mannitol administration, intrauterine volume
was 953 cm3 (a 13% decrease from premannitol values).
Intermittent fetal monitoring was conducted during and
following the procedure. Fetal HR was always within
normal limits, no fetal HR decelerations were noted, and
there were no uterine contractions detected. The patient
later delivered a healthy child after a full-term pregnancy,
and both mother and child appeared in good health when
last assessed at 30 months after surgery.
Patients with intracranial diseases may be at increased risk for seizures.49 For example, new-onset seizures are the presenting sign of brain tumors in up to 60%
of patients.50 However, recent guidelines (from the
American Academy of Neurology and others) recommend against prophylactic antiseizure medications in
patients with brain tumors, andin patients who may
have already been placed on such medications for seizure
prophylaxistapering off the antiseizure medications in
the week following surgical resection.50,51 Kong et al52
performed a meta-analysis of prospective randomized
trials that evaluated the efficacy of antiepileptic drugs to
reduce the incidence of seizure in patients with brain
tumors. They identified 6 trials that included 547 patients
randomized to treatment (n = 272) and control (n = 275)
groups. In 5 trials, patients in the treatment group received phenytoin (n = 235), and sodium valproate was
the treatment drug in the remaining trial (n = 37). Seizure
rates in the treatment and control groups were 18.4% and
19.6%, respectively (P = NS). Patients randomized to
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treatment did not have a reduced odds of seizures

(OR = 0.939; 95% CI, 0.609-1.448; P = 0.775). Further
analysis demonstrated no publication bias (through Begg
and Egger test) and no individual study affected the
pooled OR. Limitations of this research include: (1) the
inability to assess the impact of newer antiepileptic drugs,
such as levetiracetam, and (2) the results were generalized
to brain tumors collectively. As such, there may be utility
in studying different antiseizure drugs, and more specific
tumor types or locations, in future research. As this was a
meta-analysis, the criteria for diagnosis of seizures and
distribution of seizure phenotypes were both not reported.
For readers with an interest in seizures and EEG
monitoring in critically ill patients, we refer you to consensus statements by the Critical Care Continuous EEG
Task Force of the American Clinical Neurophysiology
Society.53,54 The authors discuss indications for continuous monitoring. They describe characteristic EEG
patterns that can be used to assess ecacy of pharmacologic seizure control, the diagnosis of cerebral ischemia,
monitoring of sedation, and assessment of severity of
encephalopathy. They also discuss dierent technical
specications that can be used for given clinical settings.
5-aminolevulinic acid (5-ALA) is an intermediate in
the biosynthesis of heme. Specically, 5-ALA is converted
to protoporphyrin IX, and this biomarker accumulates in
high-grade gliomas. Protoporphyrin IX will uoresce by
absorbing light in the blue region of the electromagnetic
spectrum and emitting light in the red region. Thus, if 5ALA is administered orally 2 to 4 hours before surgery,
the uorescent properties of its metabolite can be used
intraoperatively to delineate tumor boundaries, because
the tumor will uoresce more than the normal brain parenchyma. 5-ALA has a variety of associated adverse
eects such as hypotension, dermal photosensitivity,
anemia, thrombocytopenia, and transient increases in
liver function tests. Honorato-Cia et al55 reported on
complications associated with the use of 5-ALA in 207
patients having glioma resection. Perioperative data were
compared with 57 patients who had glioma resection
without 5-ALA. Patients who received 5-ALA had routine postoperative blood testing to monitor for anemia
and thrombocytopenia, and they were restricted from
exposure to sunlight for 24 hours. Glioblastoma multiforme was more common in the group that received 5ALA (81%) compared with the rate in the control group
(19%). The authors reported a decrease in serum hemoglobin concentration postoperatively following the use of
5-ALA, although it is unclear whether this dierence was
statistically signicant. There were no dierences between
groups in the rates of transfusion of packed red blood
cells; rates of transfusion of nonred blood cell products
were too infrequent to compare. Most patients had
postoperative magnetic resonance imaging (MRI) of the
brain. Complete resection of tumor was obtained in 137
of 204 (67%) patients who received 5-ALA and 28 of 47
(60%) patients in the control group (P = 0.3). Note that
not all patients in the study cohort had MRI where tumor
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resection was quantified. Patients who received 5-ALA

had a lower prevalence of surgical-site bleeding (17.9%)
than patients who did not receive 5-ALA (22.7%,
P = 0.04). The authors did not compare long-term outcome between groups. In a separate study, Bhatia et al56
reported increased need for vasopressors for blood pressure support in patients who received 5-ALA.
Mebel et al57 reported on the use of tranexamic acid to
reduce the risk of bleeding in patients having complex skull
base procedures. Patients were identied retrospectively. Of
519 patients having complex skull base procedures, 245 received tranexamic acid intraoperatively, administered as an
intravenous bolus dose of 10 to 25 mg/kg followed by an
infusion of 5 to 10 mg/kg/h. Rates of perioperative transfusion were lower in those who received tranexamic acid (7%
vs. 13% in the control group, P = 0.04) despite larger mean
tumor diameter (3.5 vs. 2.9 cm diameter, P < 0.001) and
longer mean procedure duration (7.2 vs. 6.2 h, P < 0.001).
Thrombotic complications (5 in the tranexamic acid group
and 14 in the control group, P = 0.06) and postoperative
seizures (8 vs. 6, respectively, P = 0.45) were similar between
groups. Hooda et al58 demonstrated a 27% reduction in estimated intraoperative blood loss, without an increased rate
of complications, when tranexamic acid was used in patients
having meningioma resection.
Patients taking oral anticoagulant drugs may require
rapid reversal of the anticoagulant eect before emergency
surgery. Prothrombin complex concentrate contains vitamin
K-dependent factors (ie, factors II, VII, IX, and X) that can
be used to urgently reverse vitamin K-associated oral anticoagulants, such as warfarin.59 Beynon et al60 reported on the
use of prothrombin complex concentrate to urgently reverse
phenprocoumon, taken to prevent embolic phenomena in 5
patients who had chronic atrial brillation and who later required emergent intracranial surgery. Phenprocoumon is a
derivative a Coumadin and is commonly used in Germany.
Prothrombin complex concentrate (Beriplex P/N 500; CSL
Behring GmbH, Marburg, Germany) was administered intravenously at a dose of 25 to 50 IU/kg. Pretreatment International Normalized Ratio (INR) values were 1.43, 1.76, 4.98,
5.04, and 5.55. Following administration of drug, the INR
values were decreased to 1.10, 1.12, 1.23, 1.21, and 1.27, respectively, after 1.4 to 5.2 hours. All patients also received
10 mg vitamin K intravenously upon hospital admission to
increase the intrinsic synthesis of vitamin K-related clotting
factors and prevent a rebound increase in INR that might
occur as a result of phenprocoumons long duration (halflife = 5 to 6 d). No other therapy was administered to reverse
the coagulopathy, and it was assumed that the early reversal
of anticoagulation was the result of the prothrombin complex,
not vitamin K, due to the known time courses of the various
treatments. Further studies will be needed to characterize the
safety of prothrombin complex concentrate in the neurosurgical population.
SPINE
Traumatic spinal cord injury presents a considerable
burden to society in terms of disability and health care cost.
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Management of patients with acute spinal cord injury requires

coordinated eort from a multidisciplinary team that includes
neurologists, neurosurgeons, intensivists, anesthesiologists,
physiatrists, and nurses.61 Prior comprehensive reports of the
epidemiology of acute traumatic spinal cord injury are more
than a decade old. To provide an update, Jain et al62 published data from 63,109 spinal cord injury patients registered
in the Nationwide Inpatient Sample database from 1993 to
2012. The overall incidence of traumatic spinal cord injury
was 53 cases per million in 1993 and 54 cases per million in
2012. There was decrease in the rate of spinal cord injury
among young patients during the 1993 to 2012 study interval,
and rates of acute spinal cord injury decreased in both males
and females 44 years of age and below. However, this was
oset by an increase in the rates of spinal cord injuries in both
males and females above 44 years of age. The highest rates of
new spinal cord injury were among patients 85 years of age
and above. Rates in males 85 years of age and above increased from 204 per million in 1993 to 234 per million in
2012, and rates in females 85 years of age and above increased
from 107 per million in 1993 to 134 per million in 2012. Rates
of injuries due to motor vehicle crashes and rearm injuries
remained stable during the study period at 29.8% to 38.6%
and 4.1% to 7.0%, respectively. However, the rates of spinal
cord injuries due to falls steadily increased during the study
period from 19.3% to 40.4% in 1993 and 2012, respectively.
Acute inpatient mortality was 6.6% in 1993 and 7.5% in
2012, and this was likely due to the increased prevalence of
spinal cord injury among older patients.
For readers interested in an update on recent advances in the treatment of spinal cord injury, we refer you
to the September 4, 2015, issue of Brain Research. This
issue contained a series of review articles that address
recent advances in our understanding of spinal cord injury and its treatment. Gensel and Zhang63 reviewed the
role of macrophage activation in the pathophysiology and
repair of injury following spinal cord trauma. Nardone
et al64 reviewed the utility of transcranial magnetic stimulation of descending pathways for delineation of the
extent of neurological injury. Sandrow-Feinberg and
Houle65 discussed the basic science evidence for exercise
in the rehabilitation of patients. Ohtake and Li66 addressed axonal growth inhibitors derived from the glial
scar and their impairment of regeneration. Harvey et al67
reviewed the eect of neuronal growth factors on spinal
cord injury. Their manuscript contains a table that
summarizes the ndings of animal-based studies that
evaluated the eect of growth factors on injured neurons.
Falnikar et al68 and Deng et al69 discussed astrocytes and
Schwann cells, respectively, as potential targets in the
pathophysiology and treatment of spinal cord injury.
Bonner and Steward70 discussed the use of fetal grafts and
neural stem cells to provide neural connections to bypass
the injury site. Nielson et al71 reported on work from the
California Spinal Cord Consortium and described how
bioinformatics can be used to assess the plasticity and
repair of spinal cord injury. Smith and Krynska72 reviewed advances in the prevention and treatment of
myelomeningocele.
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Surgery on the spine can involve diverse procedures

that, in turn, are performed in patients of all ages who have
elective or emergent procedures that range from simple
operations often performed as an outpatient to complex
procedures staged over multiple days. Spine surgery is also
associated with a variety of complications including
bleeding, blindness, infection, medical complications, and a
requirement for prolonged tracheal intubation.7377 Preoperative disclosure of these risks by the care team is an
important part of the informed consent process. Saigal
et al78 prospectively measured recall of complications disclosed to patients before having spine surgery. Fifty-six
adult patients undergoing scoliosis correction surgery, and
family members if present, received a standard verbal
consent discussion and were required to watch a 20-minute
video describing surgical risks and complications. Patients
were then asked to rate the importance of the preoperative
disclosure of the consent process on a scale of 0 (not important) to 10 (extremely important). Patients and family
members were asked independently to immediately recall
the complications of surgery, and recall assessment was
repeated at discharge and at 6 to 8 weeks, 3 months, 6
months, and 1 year following surgery. The median importance score for the consent process was 9 (range not
provided). This implies that patients generally felt that
consent and disclosure of risks is very important. Immediately following the informed consent process, correct recollection of 45% and 55% of complications was recorded
among patients and family members, respectively
(P = 0.06), and this value decreased during the study period as shown in Figure 2. There was a tendency for greater
recall of complications by female patients preoperatively
(55%) than male patients (36%, P = 0.09), but this tendency declined at the later time points.
Spinal hematoma is a rare but potentially catastrophic complication of major spine surgery. Yamada
et al79 retrospectively identied 32 (0.39%) cases of postoperative spinal hematoma following 8250 spine procedures performed at a single institution. Compared with
procedures performed on the cervical spine, spinal hematoma was 1.9- and 11.4-fold times more common following procedures performed on the lumbar and thoracic
spine, respectively. Two factors that were independently
associated with increased odds for spinal hematoma
were a >50 mm Hg increase in SBP immediately following
tracheal extubation (adjusted OR = 3.22; 95% CI, 1.228.51; P < 0.05) and high BMI (adjusted OR = 1.15; 95%
CI, 1.01-1.31; P < 0.05). It is unclear whether the data
analysis included the location of surgery (ie, cervical,
thoracic, or lumbar). Further, the authors did not dene
the comparison groups for the analysis of BMI. Age,
preoperative hypertension, previous spine surgery, and
preoperative INR > 1.15 were not associated with increased risk for hematoma formation. Patients who experienced neurological decits attributed to a hematoma
had a signicantly better outcome if the hematoma was
evacuated within 24 hours of diagnosis.
Signicant blood loss is also a major complication
of spine surgery. Factors associated with increased risk
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99
FIGURE 2. Recall of preoperatively disclosed complications of

scoliosis surgery among adult patients and family members.
From Saigal et al,78 with permission.
for bleeding include long surgical duration, increased

number of levels requiring instrumentation, increased
surgical complexity, and lower preoperative hemoglobin.80 Further, estimated blood loss likely underestimates
the actual amount of bleeding in patients having major
spine surgery.81,82 Pharmacologic preventative strategies,
such as the use of antibrinolytics, are reported to decrease transfusion requirements in patients having major
spine surgery, and without evidence for increased
thrombotic complications.83 Dosing of tranexamic acid is
commonly 10 mg/kg as an intravenous bolus followed by
1 mg/kg/h as a continuous infusion during surgery.
However, some have suggested that higher dosing may be
equally safe and have greater ecacy.84,85 Xie et al86
retrospectively identied 26 patients who had major spine
surgery and received tranexamic acid 100 mg/kg intravenous bolus followed by a continuous infusion of 10 mg/
kg/h during surgery. Thirty-three patients having similar
procedures without antibrinolytics were used as a control group. Age range within the entire study cohort was 7
to 46 years. Estimated intraoperative blood loss was signicantly less in those who received tranexamic acid
(2441 1666 mL) compared with those in the control
group (4789 4719 mL, P < 0.05). Patients in the tranexamic group also received fewer allogenic red blood cell
transfusions. The benet of tranexamic acid was even
more pronounced in those having posterior vertebral
column resection. The investigators reported no cases of
thrombotic complications in either study group. However, the safety of high-dose tranexamic acid cannot be
established by these data, given the small cohort.
Preoperative autologous blood donation has been
proposed as a strategy to reduce allogenic blood transfusion during major spine surgery. However, 1 major
limitation is that patients who predonate blood may start
surgery with a lower hemoglobin concentration, thus
osetting some of the benet of blood donation. Use of
human recombinant erythropoietin may help attenuate
the decrease in hemoglobin concentration that can occur
100 | www.jnsa.com
with blood donation. Ikegami et al87 retrospectively

identied 56 patients below 20 years of age who underwent weekly preoperative blood donation (for later autologous transfusion), for up to 6 weeks, and also received
subcutaneous human recombinant erythropoietin
(24,000 U) following each donation, unless hemoglobin
was >14 g/dL. Median blood collected per donation
session was 200 mL (range, 40 to 400 mL), and median
amount of blood available at the time of surgery was
700 mL (range, 160 to 1350 mL). Median estimated blood
loss was 1015 mL (range, 10 to 2940 mL). Only 3 patients
in this series required transfusion with allogenic blood in
the perioperative period. Unfortunately, the authors did
not report 2 important variables of interest. First, they
did not report hemoglobin concentrations at the intervals
during the donation period or immediately before surgery. These data would help provide an appreciation for
the ecacy of erythropoietin to renormalize hemoglobin
concentration before the next donation. Also, the authors
did not report the amount of autologous blood that was
transfused back in the perioperative period and there was
no control group in this research.
STROKE
Stroke remains a major source of morbidity and
mortality. It is now the second leading cause of death
worldwide, and survivors of stroke represent the third
leading cause of disability.88,89 Ischemic strokes account
for approximately 87% of all strokes, thus contributing
greatly to the worldwide stroke burden.90 We refer the
reader to 2 consensus statements endorsed by the Society
for Neuroscience in Anesthesiology and Critical Care on
perioperative management of patients at high risk for
stroke and care of patients having endovascular treatment
of acute stroke.91,92 Also, because current management of
ischemic stroke begins with prevention through risk-factor reduction, we refer the reader to a review article that
addresses recent advances in stroke prevention.93
In those who suer an ischemic stroke, acute treatment focuses on reestablishing blood ow to injured yet
viable brain tissue (ie, the ischemic penumbra). This treatment may include intravenous administration of thrombolytic drugs, intra-arterial administration of thrombolytic
drugs, or mechanical thrombectomy. Although some
early research suggested a benet from mechanical
thrombectomy in patients with anterior circulation stroke, 3
more recent studiesall published in the New England
Journal of Medicine in 2013found no benefit in this scenario.9496
We identied 5 additional articles,97101 all published in the New England Journal of Medicine in 2015,
that described prospective randomized trials in patients
who had acute ischemic stroke and in whom treatment
consisted of medical therapy with or without mechanical
thrombectomy. We will discuss these articles individually.
In the Multicenter Randomized Clinical Trial of
Endovascular Treatment for Acute Ischemic Stroke in the
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Netherlands (MR CLEAN),97 patients who presented to

16 medical centers with anterior circulation stroke with
symptom onset <6 hours received usual care with
(n = 233) or without (n = 267) mechanical thrombectomy. Although usual care was not clearly dened in
the manuscript, it did allow for intravenous thrombolytic
drugs in both groups. Tissue plasminogen activator was
used in 87% and 91%, respectively, of those that did and
did not have mechanical thrombectomy. General anesthesia was used in 38% of patients to facilitate mechanical
thrombectomy. The actual method of mechanical
thrombectomy was left to the discretion of the interventionalist. The primary outcome measure was the rate
of functional independence at 90 days following
randomization (dened as a modied Rankin Scale [mRS]
score of 0 to 2). This was achieved in 32.6% and 19.1% in
those who did and did not receive mechanical thrombectomy, respectively (P < 0.05). Also, National Institutes of Health Stroke Scale score and infarct volume at
3 months (determined by computerized tomography [CT]
scan) also signicantly favored mechanical thrombectomy. There was no dierence between groups in the rates
of ICH or mortality at 3 months.
The Solitaire with the Intention for Thrombectomy as
Primary Endovascular Treatment (SWIFT PRIME) Trial100 halted enrollment prematurely in response to the
ndings of MR CLEAN. (Solitaire is a proprietary mechanical device used for thrombectomy; it is manufactured by
Covidien.) SWIFT PRIME was also a prospective trial
where patients with acute ischemic stroke of <6 hours since
symptom onset and conrmed absence of large ischemic
core lesions were randomized to usual care with or without
mechanical thrombectomy. All patients in SWIFT PRIME
had occlusion of the intracranial internal carotid artery, the
rst segment of the middle cerebral artery, or both. Intravenous tissue plasminogen activator was administered to all
patients in both groups. Mechanical thrombectomy was
performed with either a Solitaire Flow Restoration or
Solitaire 2 device, and the study was funded by Covidien. A
total of 196 patients were enrolled with 98 per group. Rates
of functional independence (mRS score of 0 to 2) at 3
months following randomization were 60% and 35% in the
thrombectomy plus intravenous thrombolytic versus intravenous thrombolytic-only groups, respectively (P < 0.001).
Rate of successful reperfusion at 27 hours after randomization, dened as reperfusion of Z90% of the initial lesion
volume, assessed by CT or MRI, occurred in 83% and 40%
in those with and without mechanical thrombectomy, respectively (P < 0.001). Rates of death at 90 days (9% vs.
12% in those with and without mechanical thrombectomy,
respectively; P = 0.5) and rates of symptomatic ICH (0%
and 3% in those with and without mechanical thrombectomy, respectively; P = 0.12) were similar between groups.
The Endovascular Treatment for Small Core and
Anterior Circulation Proximal Occlusion with Emphasis
on Minimizing CT to Recanalization Times (ESCAPE)
Trial,99 also funded by Covidien, enrolled patients with
anterior circulation stroke with a small ischemic core,
proximal occlusion, and evidence of moderate-to-good
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collateral circulation for up to 12 hours following onset of

symptoms. Of note, patients received an intravenous
thrombolytic if not contraindicated and if onset of stroke
was <4.5 hours. As such, 73% and 79% in the intervention and nonintervention groups received intravenous
thrombolytics, respectively. The study did not specify a
particular mechanical thrombectomy device but recommended retrievable stents. The study was stopped early
due to ecacy with 120 and 118 patients in the intervention and nonintervention groups, respectively. The
rate of functional independence at 90 days after
randomization (dened as a mRS score of 0 to 2) was
53% and 29% in mechanical thrombectomy and nonintervention groups, respectively (P < 0.001). General
anesthesia was used in 9.1% of patients who received
mechanical thrombectomy. Rate of deaths within 90 days
were 10% and 19% (P = 0.04), but there was no dierence in the rates of symptomatic ICH (3.6% and 2.7%,
P > 0.05) in the intervention and nonintervention groups,
respectively.
The Extending the Time for Thrombolysis in
Emergency Neurologic DecitsIntra-Arterial (EXTEND-IA) Trial98 compared outcome following intravenous thrombolytics with (n = 35) and without (n = 35)
mechanical thrombectomy performed with a Solitaire
stent retriever. This investigation was funded by Covidien. Patients were eligible if they were receiving intravenous tissue plasminogen activator within 4.5 hours of
anterior circulation stroke onset and had a small ischemic
core (< 70 cm3 in volume, determined by CT). In those
randomized to mechanical thrombectomy, the procedure
had to be instituted no later than 6 hours following onset
of symptoms, and it had to be completed within 8 hours
of symptoms onset. Coprimary endpoints were: (1) percent reperfusion at 24 hours after randomization (defined
as percentage decrease in hypoperfusion lesion volume)
and (2) >8-point reduction (improvement) in National
Institutes of Health Stroke Scale Score or a score of 0 to 1
at 3 days after randomizationdefined as early neurological improvement. This investigation was also stopped before completion of planned subject recruitment. All
subjects in the mechanical thrombectomy group had
100% reperfusion, whereas the median reperfusion in the
intravenous therapy-only groups was 37% (range,
0.5% to +96%) (P < 0.001). Rates of early neurological improvement were 80% and 37% in those with
and without mechanical thrombectomy (P < 0.001).
Rates of functional independence at 90 days (mRS
score = 0 to 2) were 71% and 40% in those with and
without mechanical thrombectomy (P = 0.009). There
was no difference in rates of death at 90 days (9% vs.
20% in those with and without mechanical thrombectomy, P = 0.18) or rates of symptomatic ICH (0% vs. 6%
in those with and without mechanical thrombectomy,
P = 0.49).
The Randomized Trial of Revascularization with
Solitaire FR Device Versus Best Medical Therapy in the
Treatment of Acute Stroke Due to Anterior Circulation
Large Vessel Occlusion Presenting Within Eight Hours of
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101
Symptom Onset (REVASCAT)101 was conducted in

Spain and enrolled patients with acute anterior circulation stroke who did not have evidence of large infarct
on imaging and who could undergo randomization within
8 hours of symptom onset. The study was funded by
Covidien. Patients could be included in the study if onset
of stroke symptoms had occurred <8 hours earlier. Patients were also eligible if they had a proximal vessel occlusion and did not have a large infarct zone before
randomization. A large infarct zone was dened as a
score of <7 on the Alberta Stroke Program Early
Computed Tomography Score (ASPECTS) based on CT,
or a score of <6 if based on MRI. An ASPECTS score
ranges from 0 to 10 with larger values indicating lower
ischemic burden. All patients were eligible for intravenous
thrombolytics if they did not meet typical exclusion criteria and onset of stroke symptoms was <4.5 hours. All
patients received best medical therapy but were randomized to treatment with or without mechanical thrombectomy. The study was stopped after enrollment of 206
patients (25% of planned enrollment, with 103 receiving
mechanical thrombectomy) because of the ndings of MR
CLEAN and ESCAPE. The primary outcome measure
was the odds of improvement in mRS score by 1 point
measured at 90 days following randomization. Mechanical thrombectomy resulted in a greater odds of the
primary outcome compared with patients who did not
receive intervention (OR = 1.7; 95% CI, 1.05-2.8;
P < 0.05). Mechanical thrombectomy also resulted in
greater rates of functional independence (mRS score = 0
to 2) at 90 days (44% vs. 28% in those who did not
receive mechanical thrombectomy, P < 0.05). Rates of
symptomatic ICH (1.9% vs. 1.9%, P > 0.05) and death
rate at 90 days (18% and 16%, P > 0.05) were similar
between those with and without mechanical thrombectomy, respectively.
Badhiwala et al102 reported a meta-analysis of trials
that compared best medical management with or without
mechanical thrombectomy. Eight trials were included in
this analysis, including the 5 trials published in 2015 and
discussed above.94101 The entire analysis included data
from 2423 patients (with 53% of the patients obtained
from the 5 trials discussed individually above97101).
Functional independence (dened as a mRS score of 0
to 2) was greater in those who received mechanical
thrombectomy (44.6% of patients vs. 31.8% of patients
who received medical therapy alone, P = 0.005). The rate
of revascularization was also greater in those who received thrombectomy (75.8% vs. 34.1%, P < 0.001).
Rates of symptomatic ICH (5.7% vs. 5.1%, P = 0.56)
and death (15.8% vs. 17.8%, P = 0.27) at 90 days were
similar (rates are reported for the thrombectomy vs.
medical management-alone groups, respectively). The
reader should be aware that this meta-analysis only included multicenter trials where patients were randomized
to groups that either included or did not include mechanical thrombectomy. Studies were included in the metaanalysis if they allowed for intravenous tissue plasminogen
activator in all groups and allowed for intra-arterial
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thrombotic drugs in the mechanical thrombectomy

groups. Finally, only studies that assessed outcome based
on the mRS were included. Therefore, given the: (1) highly
specic research-inclusion criteria, (2) premature stoppage
of some protocols, and (3) the large number of patients
associated with research funding and devices linked to a
single industry source, we question whether the results are
generalizable to other patient populations, other approaches to mechanical thrombectomy, and nonproprietary research funding.
The patient inclusion criteria, along with premature
stoppage of some of the protocols, deserve further consideration. First, all investigations discussed above included only patients with anterior circulation strokes and
small infarct regions, and a few investigations also required demonstration of good collateral ow. Therefore,
these ndings can only be applied to a subset of stroke
patients and may not include those with large stroke,
posterior circulation stroke, or signicant disease aecting collateral ow. Also, stoppage of some of the investigations prematurely may give the appearance of
magnication of eect resulting from a small sample
size.103105 Finally, 3 reports from 2013 discovered
equivalent outcomes from intravenous thrombolytics
with and without mechanical thrombectomy in patients
who had anterior circulation strokes.9496 As such, there
may be subpopulations of patients with anterior circulation stroke that may not benet from mechanical
thrombectomy. For example, Daniere et al106 recently
reported that in the setting of anterior ischemic strokes
and major vessel occlusion: (1) younger patients may
benet from mechanical thrombectomy independent of
the size of the ischemic core; however, (2) older patients
tend to benet from mechanical thrombectomy only if the
ischemic core is relatively small.
Patients with intracranial arterial stenosis are at increased risk for ischemic stroke. Recently, the ndings of
the Stenting and Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial107 showed that patients who underwent stenting
of an intracranial stenosis concomitant with optimal medical therapy were at greater risk for recurrent stroke and
ICH than those who received optimal medical therapy
alone. In 2015, the ndings of the Vitesse Stent Ischemic
Therapy Trial108 conrmed these ndings. Similar to
SAMMPRIS, patients with stenosis in the anterior and
posterior circulation were eligible. Patients were randomized to receive best medical therapy (ie, antiplatelet medications and risk factorreducing strategies including
antilipid medications) with or without stenting with a balloon expandible stent. The study was stopped early in response to the findings of the SAMMPRIS trial after
enrollment of 112 of 250 planned patients. The 30-day
primary safety endpoint of the combined rate of stroke,
transient ischemic attack, death, or ICH was greater in the
group that received stenting plus medical therapy (24%)
compared with medical therapy only (9%, P < 0.05). The
rate of stroke or transient ischemic attack in the territory of
the stenotic vessel at 1 year was significantly greater in
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those who received stenting plus medical therapy (36%)

versus medical therapy only (15%, P = 0.02). Rate of death
at 1 year and rate of symptomatic ICH had a tendency to
higher rates in the stenting group, but neither achieved
statistical significance.
Unlike the Vitesse Stent Ischemic Therapy Trial and
SAMMPRIS Trial, the Vertebral Artery Stenting Trial
(VAST)109 enrolled only patients with symptomatic intracranial or extracranial vertebral artery stenosis of
Z50%. Patients received best medical therapy with or
without stenting. The study planned to enroll 180 patients
but stopped after enrollment of 115 because of death of a
single patient in the stent group; this prompted external
safety monitoring. Three of 57 patients (5%) in the
stenting group had a stroke, vascular-related death, or
myocardial infarction within 30 days compared with 1 of
58 (2%) in the medical therapy group (P = 0.36). During
the 3-year follow-up, 7 of 57 (12%) and 4 of 58 (7%) had
a stroke in the territory of the stenosis (P = 0.36). The
study was never reactivated due to logistical problems.
Although this study possibly lacked statistical power to
detect dierences, the authors concluded that stenting of
intracranial or extracranial vertebral artery stenosis is not
warranted.
General anesthesia to facilitate stroke treatment has
been associated with an increased risk for poor outcome
when compared with sedation. Specically, use of general
anesthesia has been associated with lower odds of favorable
outcome, longer time to treatment, decreased odds of revascularization, increased mortality, and increased rates of
respiratory complications during hospitalization.110112 It is
likely that there is selection bias in the studies related to
patients with more severe stroke requiring general anesthetics more often to facilitate airway management or to
render the patients motionless during a radiologic procedure.
However, research has determined that after correction for
factors known to inuence poststroke outcome, the association between general anesthesia and worse outcome is lost
because patients with less severe stroke tend to have a better
outcome.113,114 One other factor that might aect outcome is
blood pressure dierences between patients having general
anesthesia or conscious sedation. Jagani et al115 retrospectively assessed intraprocedural blood pressure in patients
having neuroradiologic treatment of ischemic stroke, and
compared data from patients having general anesthesia to
those having conscious sedation. The medical records from
99 patients were reviewed; 38 received general anesthesia and
the remainder had conscious sedation. There was a signicantly greater rate of posterior circulation stroke in the
general anesthesia group (34%) compared with the conscious sedation group (2%, P < 0.0001). General anesthesia
was associated with signicantly lower intraprocedural blood
pressure. Although conscious sedation was associated with
better overall outcome, odds of better outcome was also
associated with less intraprocedural blood pressure variability. Specically, in this investigation, blood pressure variability was determined as the absolute dierence between
maximum and minimum blood pressures occurring during
the case. Clinicians should be aware of a decrease in blood
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pressure that can occur with general anesthesia in patients

who have preexisting stroke or are experiencing stroke in
evolution.116 In this scenario, treatment of hypotension can
theoretically modulate neurological outcome. Of note, Somal and Farag117 reported in abstract form that dexmedetomidine, when used for sedation for intravascular treatment
of acute stroke, was associated with greater hemodynamic
instability and a trend toward increased in-hospital mortality
compared with propofol sedation.
Magnesium is a vasodilator, attenuates glutamate
excitotoxicity, and is reported to have neuroprotective
benets in animal models.118 In humans, intravenous
magnesium use during pregnancy has been associated with
subsequent reduced rates of cerebral palsy in newborns119
but has not been associated with improved outcome in
adult patients with subarachnoid hemorrhage (SAH).120,121
Earlier research discovered no overall benet from magnesium supplementation in patients with stroke (median
time from onset of symptoms to treatment was 7.4 h) but
subgroup analysis suggested a benet if magnesium therapy
was initiated within 3 hours.122 Saver et al123 reported the
ndings of the Field Administration of Stroke TherapyMagnesium (FAST-MAG) Trial. Seventeen hundred patients with stroke signs and symptoms were randomized to
receive either magnesium sulfate intravenously (4 g over
15 min then 16 g over 24 h) or saline placebo, started by
paramedics in the eld. Overall, 73% and 23% of patients
had ischemic and hemorrhagic stroke, respectively, and 4%
had stroke-mimicking conditions. Median time to treatment following onset of symptoms was 45 minutes (interquartile range, 35 to 60 min). There were no dierences
between magnesium-treated or placebo-treated groups in:
(1) distribution of mRS scores, (2) rates of death, (3)
hemorrhagic transformation in those with ischemic stroke,
or (4) rates of serious events. Although magnesium did not
increase risk, it did not improve functional outcome. Other
earlier data support the notion that increased serum magnesium may have a detrimental impact on overall outcome,
possibly related to calcium antagonism.124126
Infection, especially pneumonia or urinary tract
infection, can be a major complication following
stroke.127 Westendorp et al128 reported the ndings of the
Preventative Antibiotics in Stroke Study (PASS), where
2550 patients with either ischemic or hemorrhagic stroke
in the Netherlands were randomized to receive either
placebo or ceftriaxone, 2 g intravenously every 24 hours
for 4 days. Although prophylactic ceftriaxone decreased
the rate of urinary tract infections during hospitalization
(5% in placebo group and 1% in treatment group,
P < 0.001), there was no dierence in the rates of pneumonia during hospitalization (2% in the placebo group
and 3% in the treatment group, P = 0.18). Further,
prophylactic ceftriaxone did not signicantly impact the
distribution of mRS scores at 90 days, rate of death at 90
days, or hospital length of stay. Increased stroke severity
was associated with increased risk for infection.
Blood pressure management in the setting of acute
stroke can have a signicant impact on functional outcome. In the Ecacy of Nitric Oxide in Stroke (ENOS)
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Trial,129 4011 patients with ischemic or hemorrhagic stroke

were assigned to one of 4 data analysis groups based on: (1)
whether or not prestroke antihypertensive medications were
continued or discontinued during hospitalization and (2)
whether or not transdermal nitroglycerin (5 g/d for 7 d) was
instituted during hospitalization. Overall, 83% of patients
had ischemic stroke. The primary outcome measure was the
distribution of mRS scores at 90 days. Although neither use
of nitroglycerin nor management of prestroke antihypertensives had an eect on the distribution of mRS
scores, patients who continued their prestroke antihypertensive medications were more likely to die while in
the hospital or be discharged to a special care institution
(vs. home) than patients who discontinued their antihypertensive medications while in the hospital. No adverse
events were attributed to the use of nitroglycerin.
Ruptured cerebral aneurysms account for the majority of SAH in the world. Although cigarette smoking
has been associated with an increased risk for aneurysmal
SAH, the nature of this association is unclear. Ho et al130
compared aneurysm morphologic characteristics between
102 patients who never smoked and 97 smokers. Smoking
was independently associated with patients having: (1)
multiple aneurysms (OR = 2.15; 95% CI, 1.07-4.42;
P = 0.03), (2) a basilar tip aneurysm (OR = 6.26; 95%
CI, 1.46-29.53; P = 0.02), and (3) a large size ratio
(OR = 1.78; 95% CI, 1.16-2.77; P = 0.01). The authors
dened the size ratio as the ratio of the maximal height
of the aneurysm (dened as the maximum distance between the dome of the aneurysm and the plane dened by
the lowest portion of the neck of the aneurysm) and the
average diameter of all vessels associated with the
aneurysm. A larger value of the size ratio indicates a
larger dome corrected for the size of feeding vessels.
Treatment of both ruptured and unruptured cerebral
aneurysms typically involve clipping, coil embolization, or
stenting (ie, approaches intended to isolate the aneurysms
anatomy from the arterial circulation). Anesthetic management of patients undergoing, or who have undergone,
treatment of cerebral aneurysm can be quite challenging, and
anesthetic technique may inuence outcome.131 In patients
with an unruptured aneurysm, perioperative risk is generally
very low. Thus, in patients with unruptured aneurysms who
had successful surgical or invasive radiologic treatment and
an uneventful periprocedural course, bypassing admission to
an intensive care unit or even outpatient aneurysm clipping
have been advocated by some.132,133 Management of patients with aneurysmal SAH can be more complicated and is
associated with greater mortality and both short-term and
long-term morbidity among survivors. In recent years,
multiple sets of guidelines have been published for the
management of patients with aneurysmal SAH, and conicting recommendations have emerged.134136 In response,
the European Neuroanesthesia and Critical Care Interest
Group conducted a survey of neuroanesthesiologists in Europe to assess current practice patterns related to the management of aneurysmal SAH.137 Although the authors did
not report the number of recipients of the survey, there were
268 respondents from 172 distinct institutions representing
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12 European countries. Seventy-two percent of centers admitted all patients with aneurysmal SAH to the intensive
care unit, but this rate varied with the highest rate in Germany (98%) and lowest in Italy (47%). Eighty-two percent
of centers treated aneurysms within 24 hours of admission.
Coiling was more commonly used than clipping, but 19% of
centers still had a high-volume clipping practice (dened as
>60% of aneurysms are clipped). Most centers used total
intravenous anesthesia for either clipping or coiling, <4%
utilized induced hypothermia, and 34% used pharmacologically induced burst suppression during surgical or interventional procedures. Nimodipine, statins, and magnesium
sulfate were given to all patients in 97%, 21%, and 20% of
practices, respectively. For patients with cerebral vasospasm,
44% utilized triple H therapy (ie, hypertension, hemodilution, and hypervolemia), whereas 22% used just hypertension and induced hypervolemia without specic serum
hemoglobin concentration targets.
Treatment of ruptured aneurysms is generally performed within 72 hours of rupture.138,139 The decision to
perform clipping or coiling of ruptured aneurysms depends on multiple factors including institutional practice
pattern, aneurysm morphology, and patient comorbidities. Perioperative management of patients having these 2
procedures can be very dierent due to dierences in
surgical stress and risk for various complications. Mutoh
et al140 measured various hemodynamic variables in the
postoperative period following either clipping or coiling
of intracranial aneurysms. The study design was a post
hoc analysis of prospectively collected data from other
trials conducted by the authors. All patients underwent
aneurysm treatment within 24 hours of rupture. All patients received a standardized general anesthetic and
standardized uid management that consisted of a crystalloid solution administered at 1 to 2 mL/kg/h to maintain euvolemia. Postoperatively, uid was administered to
maintain hemodynamic stability and guided by the
PiCCO monitor (Pulsion Medical, Munich, Germany)
that allows for real-time estimation of cardiac output
from contour analysis of the arterial waveform and both
global end-diastolic volume (GEDV) and extravascular
lung water content (EVLW) through thermodilution.
Hemodynamic stability was dened as a cardiac index
Z3L/min/m2, GEDV Index Z680 mL/m2, and EVLW
Index r14 mL/kg. An established protocol was used to
manage uids to achieve these target values, and we refer
the reader to the manuscript for specic details. Of note,
the protocol included increased uid administration for
patients who developed vasospasm. Overall, 38 and 35
patients who underwent, respectively, clipping and coiling
were included in the study. Groups were well matched for
demographics, aneurysm location, and SAH severity.
Compared with coiling, clipping was associated with
greater intraoperative uid administration, greater intraoperative blood loss, and a longer procedural duration.
Postoperatively, compared with coiling, clipping was associated with a higher cardiac index and hypovolemia (ie,
GEDV Index <680 mL/m2), but only immediately postoperatively. Greater uid administration was required
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during days 7 to 9 in patients who had clipping, and those

who had clipping had greater EVLW during days 7 to 9.
Overall, 3 patients (8%) developed pulmonary edema in
the clipping group compared with 2 (5%) in the coiling
group (P > 0.05). These ndings may have been related to
volume expansion used for the treatment of cerebral
vasospasm.
High-quality data supporting the use of hypertension and hypervolemia in the management of cerebral
vasospasm are lacking. Currently only observational and
small randomized trials exist in support of improved
neurological function following induced hypertension and
hypervolemia in vasospastic patients.141,142 Togashi
et al143 conducted a pilot investigation to assess the feasibility of a large randomized trial to assess the eect of
induced hypertension and hypervolemia for the prophylaxis against or treatment of vasospasm. Twenty patients
with acute SAH were randomized into 4 groups, based on
2 parameters: (1) uid management (normovolemia or
hypervolemia) and (2) blood pressure management (conventional or induced hypertension). The investigators set
specic uid and blood pressure management parameters
that diered based on the presence or absence of vasospasm. Although this pilot investigation lacked power to
draw any conclusions, the authors reported that the
management protocol was feasible and no major complications were directly attributed to the protocol. As an
aside, recent results from a small retrospective investigation suggest that patients with elevated serum calcium
may be at greater risk for developing vasospasm.144
Cardiac complications are common in patients with
SAH.145,146 This can manifest in a variety of ways including
electrocardiographic abnormalities, arrhythmias, decreased
myocardial function, and increased serum myocardial enzyme concentrations. Decreased myocardial function (eg,
new regional wall motion abnormalities) occurs in about
15% of patients with SAH.147,148 However, in most circumstances, the decrease in myocardial function is transient.
Van der Bilt et al149 prospectively obtained serial electrocardiograms and echocardiograms in 301 patients following
SAH. The 3 most common ndings on the electrocardiogram were: prominent U waves (33% on admission, 27% on
day 8), inverted T waves (19% on admission, 27% on day 8),
and evidence of left ventricular hypertrophy (14% on admission, 17% on day 8). Regional wall motion abnormalities
were present in 21% and 16% of patients on admission and
day 8, respectively, whereas elevated troponin T concentrations were found in 37% and 15% of patients, respectively. The authors reported that 9% of patients had
evidence of Takotsubo cardiomyopathy but did not state at
which time point during their hospitalization. Signicant
independent predictors of regional wall motion abnormalities on admission were: poor neurological status, presence of
sinus tachycardia, ST-segment depression, and elevated serum troponin T concentration. Signicant independent
predicators of regional wall motion abnormalities occurring
later during hospitalization (ie, days 4 to 8) were the presence
of a myocardial infarct pattern on the electrocardiogram (ie,
ST-segment or T-wave changes occurring in leads consistent
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with a coronary artery distribution) and increased serum

troponin T concentration. Unfortunately, the authors did
not report serum electrolyte concentrations. Therefore, it is
unclear whether electrolyte abnormalities contributed to
these observed electrocardiographic changes or whether
these ndings were the result of SAH, likely mediated
through changes in autonomic function.
Kilbourn et al150 prospectively obtained serial
echocardiograms on 63 patients admitted to the hospital
for management of aneurysmal SAH, and echocardiographic measurements were taken at 48 hours and 21 days
following SAH. The authors reported that neurogenic
stress-induced cardiomyopathy (NSICM; dened as a
decrease in left ventricular ejection fraction to r55%)
was present in 17% of patients at 48 hours. In-hospital
mortality rate was greater in patients with NSICM (36%
vs. 10% in those without NSICM, P = 0.003). A higher
Hunt Hess Score, increased Fisher grade, elevated serum
brain natriuretic peptide and troponin T concentrations,
or the presence of ST-segment abnormalities were signicantly associated with the development of NSICM.
Oddly, smokers had a lower risk for NSICM (9%) compared with nonsmokers (42%, P = 0.038). Echocardiograms were obtained in only 8 patients at 21 days and, of
those, 5 had persistent wall motion abnormalities. At 3
months following hemorrhage, the rate of poor outcome
(as assessed by the mRS score and modied Barthels
Index) was higher in the group with NSICM. Stress-induced cardiomyopathy is not specic to patients with
SAH. Belcour et al151 reported that stress-induced cardiomyopathy occurred in 56% of patients following an
episode of convulsive status epilepticus.
For readers interested in learning more about SAH,
we refer you to a review article by DSouza.152 The author
reviews epidemiology, risk factors, management strategies, complications, and management of complications.
We also refer readers to a brief review article that addresses neuroprotective strategies for neurosurgical procedures and in patients who have either ischemic or
hemorrhagic stroke.153
TRAUMATIC BRAIN INJURY (TBI)

In the United States, approximately 1.4 million
people sustain TBI annually, resulting in 50,000 deaths per
year andin survivorsa leading cause of disability.154
Current management of acute TBI focuses on minimizing
risk for secondary injury by improving cerebral perfusion
and oxygenation. Exploratory research in animal models
is also evaluating the use of stem cells and progenitor cells,
in an attempt to improve outcomes, as reviewed by Gennai et al.155 Intermediate among these therapeutic approaches are new innovations in pharmacotherapy and
physiological manipulation, as we will discuss below.
Hypothermia has been evaluated as a potential
neuroprotectant in a variety of experimental models and
in human trials. Although therapeutic hypothermia has
promise in improving outcome after global cerebral ischemia in adult humans (as can occur following cardiac
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105
arrest) and in the setting of neonatal encephalopathy,

induced hypothermia is not consistently benecial in
other clinical scenarios.156158 For example, in patients
who have focal cerebral ischemia associated with SAH, or
who have TBI, therapeutic hypothermia is of questionable or no benet.159,160
In the European Study of Therapeutic Hypothermia
for Intracranial Pressure Reduction after Traumatic
Brain Injury (Eurotherm 3235) trial, Andrews et al161
randomized 387 patients with severe TBI requiring ICP
monitoring, and emanating from 47 centers in Europe, to
receive either normothermic or hypothermic management. Patients were included only if ICP was >20 mm Hg
for at least 5 minutes despite conservative treatment, and
if TBI had occurred within 10 days previously. Patients
unlikely to survive 24 hours were excluded. In patients
randomized to receive hypothermia, core temperature
was decreased by the minimum amount required to
maintain ICP < 20 mm Hg, and within the range of 32 to
351C. Hypothermia was maintained for at least 48 hours
and rewarming was conducted at a rate of 0.251C/h, but
adjusted to maintain the ICP < 20 mm Hg during rewarming. Patients in both groups received other additional treatments for elevated ICP. The study was
terminated after recruitment of 387 of 600 patients due to
evidence of harm in the treatment group. Mean ICP
during treatment was similar, but barbiturate infusions
were required in more patients in the normothermic
group (21%) than in the hypothermic group (10%,
P < 0.05). Favorable outcome, dened as an Extended
Glasgow Outcome Scale score of 5 to 8 at 6 months,
occurred in 37% and 26% of patients in the normothermic and hypothermic groups, respectively (P = 0.03).
Serious adverse events were less common in the normothermic group (5.2%) than in the hypothermic group
(16.9%, P < 0.05).
It is possible that a lack of benet in patients with
TBI may be due, in part, to: (1) limitations in the study
protocol that include application to a very broad population of patients with TBI, (2) a delay in instituting hypothermia after TBI, or (3) titration of rewarming. Of 764
consecutive children admitted to a pediatric intensive care
unit with severe TBI, Beca et al162 randomized 26 to normothermia (goal temperature = 36 to 371C) and 24 to induced hypothermia (goal temperature = 32 to 331C) for 72
hours. Many prior investigations induced hypothermia for
48 hours and rewarming was conducted at a set rate,
whereas rewarming was titrated in this trial to maintain a
stable ICP and cerebral perfusion pressure (CPP). Patients
were also all randomized within 6 hours of injury. Hypothermia was maintained for a minimum of 72 hours, and
rewarming was conducted no faster than 0.51C every 3
hours. Further, rewarming was adjusted to maintain a CPP
of: (1) 40 to 50 mm Hg for age below 2 years, (2) >50 mm
Hg for age 2 to 11 years, and (3) >60 mm Hg for age 11
years and above. Primary outcomes were score on the Pediatric Cerebral Performance Category Scale (PCPCS) at
12 months, and rates of major adverse events were determined. The PCPCS quanties gross neurological out-
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come in children on a scale of 1 = normal to 6 = brain

death. Poor outcome was dened as a PCPCS score of 4 to
6. At 12 months following randomization, the rates of poor
outcome were 17% and 12% in the hypothermic and
normothermic groups, respectively (P = 0.70). Mortality
rates were also similar at 12 months (13% and 4%, respectively; P = 0.34). There was no dierence between
groups in the rates of adverse events during hospitalization,
including infectious complications. These data support
earlier research that therapeutic hypothermia should not be
used routinely in children with severe TBI.
Release of the excitatory neurotransmitter glutamate in the setting of brain ischemia and injury can be an
important cause of secondary brain injury. Xenon gas can
be used as a general anesthetic. Not only does it have
minimal eect on cardiovascular function, but it is also an
antagonist of the N-methyl-D-aspartate subgroup of glutamate receptors. Thus, xenon may attenuate excitotoxic
injury from excessive glutamate release. Campos-Pires
et al163 used a TBI model in mice anesthetized with sevourane and varied exposure to xenon. Specically, xenon was administered either: (1) both before and after
TBI or (2) only following TBI. Delay of exposure following TBI was varied and concentration of xenon was
also varied. Functional outcome was assessed through the
Neuroscore,164 where gross neurological function is
quantied on a score of 0 = no neurological impairment
to 15 = severe neurological impairment. Xenon, administered for 2 hours both before and following a
percussive insult, resulted in a signicant improved neurological function, and it decreased contusion volume by
43% 7% (P < 0.01). Xenon administration, starting at
15 minutes after insult and continuing for 3 hours, also
resulted in improved neurological function and a
19% 7% decrease in contusion volume (P < 0.05).
Improvement in functional outcome and decreased contusion volume were only observed if xenon was instituted
within 1 hour, but not at 3 or 6 hours, following insult.
Treatment with 30%, 50%, and 75% xenon all resulted in
reduced contusion volume. Doses of 30% and 75% were
associated with improved neurological function; there
was a trend for improved function in the group that received 50% xenon, but it did not reach statistical signicance. Improved function was only observed when
animals were assessed within 4 days of treatment; on day
5, there was a trend for improved neurological function,
but it did not reach statistical signicance. After 1 month,
animals that received xenon had faster locomotor speed
compared with animals that did not receive xenon, suggesting a persistent neurological benet.
Brain monitoring, including use of the neurological
examination, is an important part of care for patients
with acute TBI and has utility for following the eectiveness of therapies and for prognostication of outcome.165167 A recent survey of neurological intensive
care units in the United Kingdom discovered that, in
patients with TBI, ICP monitoring is commonly used,
especially as a tool to optimize CPP. However, other
types of brain monitoring, such as cerebral microdialysis,
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jugular bulb oximetry, and cerebral oxygen partial pressure measurements, were not as commonly used.168 In
China, Yuan et al169 retrospectively evaluated outcome
from 1443 patients with TBI in whom ICP monitoring
was either used or not used while receiving care in one of
22 hospitals. ICP monitoring was instituted in 838 patients and consisted of either intraventricular (51%), intraparenchymal (30%), or subdural (18%) monitoring.
Patients who received monitoring were more likely to
have: (1) a decrease in GCS over the rst 24 hours after
injury, (2) a Marshall CT score of III-IV (denoting diuse
injury with no focal lesion of >25 cm3 in volume present),
(3) major extracranial trauma, (4) the presence of subdural hematoma, (5) major intraparenchymal pathology,
(6) received care at a major trauma center, or (7) received
care at a hospital where ICP monitoring is common. An
ICP > 20 mm Hg was observed in 69% of patients during
monitoring. Overall, management was guided by Brain
Trauma Foundation Guidelines. Data analysis determine
that patients who received ICP monitoring were generally
sicker, and the use of ICP monitoring was not associated with an increased mortality or unfavorable outcome at 6 months following injury. This was also true
when only comparing those patients with a GCS of 3 to 5
on admission. Use of ICP monitoring was independently
associated with signicantly reduced mortality in those
who had: (1) a GCS of 3 to 5 on admission, (2) worsened
neurologically during the rst 24 hours, and (3) expected
high mortality. These data suggest that ICP monitoring
may improve outcome following TBI; however, data
interpretation was confounded by the fact that ICP
monitoring was more commonly used at major trauma
centers where one would expect better resources and
greater experience in dealing with TBI. Regardless of the
outcomes, results of this original research study appear in
agreement with results from a recent meta-analysis by
Yuan et al.170 Analysis of data on the utility of ICP
monitoring in TBI in 24,792 patients discovered no improvement in mortality. However, when only studies
published in 2012 or later were analyzed, patients having
ICP monitoring had signicantly lower odds of death.
The authors attributed this benet to greater compliance
with brain trauma management guidelines. However,
Banik et al171 found no dierence in outcome when
comparing children below 12 years old who did or did not
have ICP monitoring following severe TBI.
Although guidelines serve to provide management targets, patients dier in their baseline extent of injury and impairment. As such, there may be some utility in individualizing
the management of TBI by using treatment modalities targeted to the individual patient. One of the most commonly
used means of individualized management of patients with
TBI involves determining the extent of impairment of cerebral
autoregulatory capacity and optimizing of cerebral perfusion
pressure. Such an approach may determine the pressure reactivity index (PRx), a correlation coecient between MAP
and ICP. PRx ranges in values from 1 to +1, where a
negative values indicate intact autoregulation (ie, as MAP increases, cerebral vasoconstriction produces a decrease in ICP)
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and a positive value (especially a values between 0.3 and 1.0)

indicates a pressure-dependent increase in ICP.
PRx may have some limitations. For example, correlation of low frequency oscillations in ICP (ie, 0.0008 to
0.008 Hz) with blood pressure do not predict optimal
cerebral perfusion pressure.172 Also, techniques serving as
a surrogate for ICP (ie, middle cerebral artery CBF velocity, regional cerebral oximetry) may also have limited
utility for predicting the status of autoregulation.173 Another major issue associated with the use of PRx is that in
some patients, optimal CPP cannot be obtained. Optimal
CPP is obtained from a plot of PRx (on the y-axis) versus
CPP (on the x-axis), often resulting in a U-shaped curve in
which the minimum value of PRx is interpreted as the
optimal CPP. Weersink et al174 analyzed PRx data obtained from 48 patients with severe TBI. PRx data were
divided into 4-hour epochs, and data from 1561 epochs
were included in the analysis. Optimal CPP was not evident in 28% of epochs, although the authors did not state
the number of patients in whom an optimal CPP was never
attainable. Epochs without an optimal CPP were compared with those that had an optimal CPP. Factors independently associated with a lack of an optimal CPP per
epoch were: (1) absent arterial pressure variability or slow
waves, (2) higher values of PRx (indicating impaired
autoregulation), (3) lower amounts of sedation drugs administered during that epoch, (4) higher vasoactive medication doses during that epoch, (5) lack of use of muscle
relaxants, and (6) therapeutic decompressive craniectomy.
This last correlation may be due to alterations in cerebral
hemodynamics immediately following decompressive craniectomy.
Another individualizable variable that can be determined through monitoring in patients with TBI is the CPP
threshold below which hypoperfusion (ie, inadequate delivery
of blood ow and oxygen) results. The measurement of
PbtO2 and cerebral microdialysis have been evaluated as
possible techniques to assess the adequacy of blood and
oxygen delivery to the injured brain. These techniques have
limitations including confounding physiological factors that
can inuence measurements and the dependency on location
of measurement. In 27 patients with severe TBI, Bouzat
et al175 prospectively determined the utility of individual and
combined monitoring techniques to detect cerebral hypoperfusion. Patients were managed according the Brain
Trauma Foundation Guidelines, as appropriate. Patients had
an ICP monitor, a PbtO2 monitor, and a microdialysis probe
placed into the subcortical white matter of the right frontal
lobe. Global and regional CBF were determined through
perfusion CT, and oligemia was dened as a CBF < 35 mL/
100 g/minute or 2 SDs below normal CBF. Regional CBF
near the monitoring probes was well correlated with global
CBF. Cerebral hypoxia was dened as a PbtO2 < 20 mm Hg,
intracranial hypertension as ICP > 20 mm Hg, and low CPP
as <60 mm Hg. Inadequate substrate delivery was dened as
a microdialysate glucose concentration <1 mmol/L or a
lactate-to-pyruvate ratio of >40 mmol/mmoL. Area under
the receiver-operating characteristic curve (AUC) relating
oligemia and monitoring thresholds was slightly greater with
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multimodal monitoring of ICP, PbtO2, and microdialysis

(AUC = 0.88; 95% CI, 0.79-0.96) compared with
ICP+PbtO2 (AUC = 0.84; 95% CI, 0.74-0.93), ICP+
microdialysis (AUC = 0.79; 95% CI, 0.69-0.90), or ICP
alone (AUC = 0.74; 95% CI, 0.61-0.87). These ndings may
suggest the utility of using multiple thresholds with multiple
monitoring techniques to improve the detection of cerebral
hypoperfusion.
In patients with low PbtO2, the most straightforward
treatment is generally increasing inspired oxygen fraction
(FiO2). Recent research discovered worse neurological
outcome when hyperoxia was used following an ischemic
insult to the brain.176,177 Quintard et al178 retrospectively
compared 1130 microdialysate glutamate concentrations
from 36 patients with severe TBI, stratied by FiO2 (ie,
<40%, 41% to 60%, 61% to 80%, and >80%). The
microdialysis probe was placed along with a beroptic ICP
monitor and a PbtO2 monitor in the subcortical white
matter of the frontal lobe in apparently normal brain.
Patients were managed according to the Brain Trauma
Foundation Guidelines, when appropriate. FiO2 was adjusted to maintain an arterial oxygen tension of 90 to
100 mm Hg, unless PbtO2 was <20 mm Hg. If a low PbtO2
occurred, ICP was rst controlled. If ICP was not elevated
or brain oxygen changes were persistent, the FiO2 was increased. Acute respiratory distress syndrome was diagnosed
in 6 of 36 patients (17%) during monitoring. Compared
with patients with an FiO2 < 40%, those with FiO2 Z40 %
had signicantly increased microdialysate glutamate concentrations (Fig. 3A). Increased brain glutamate was found
in patients with normal and decreased PbtO2 (Figs. 3B, C).
However, microdialysate glutamate concentration only increased if the arterial partial pressure of oxygen was
>150 mm Hg. Although increasing FiO2 is a common
strategy for treating PbtO2 desaturations, these ndings
suggest that hyperoxia leads to increased glutamate release
and the potential for exacerbation of excitotoxic secondary
brain injury. Unfortunately, other variables such as lactate,
pyruvate, and glycerol concentrations were not reported in
this investigation. These additional variables may have
provided a more complete picture of the eect of hyperoxia
on cerebral metabolism and well-being in brain-injured
patients.
Hyperglycemia is common following TBI and is
well known to exacerbate brain injury.179,180 Recently,
Donnelly et al181 reported that hyperglycemia is associated with impairment of cerebral autoregulatory capacity, an eect that was probably related to injury
severity. However, in the setting of TBI, glucose metabolism by the brain may increase leading to increased
glucose requirements.182 Therefore, following TBI, one
must balance appropriate glucose delivery with avoidance
of excessive brain glycemic load. Shijo et al183 administered 4 mL/kg of either 50% glucose in sodium
chloride or sodium chloride solution without glucose at 0,
1, 3, and 6 hours following controlled cortical impact in
rats. Animals that received glucose performed similarly to
those that received only sodium chloride on tests of motor
function and spatial memory, except those that received
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glucose had signicantly faster rates of hind paw retraction following limb extension. Also, rats that received
glucose exhibited a 30% attenuation of cortical injury
volume at 15 days following brain injury. Unfortunately,
serum glucose concentrations were not measured in this
investigation, an issue that has importance because 2 mL/
kg of 50% glucose represents a large glucose load. It is
unclear whether serum glucose concentrations in the animals resulted in mild, moderate, or severe hyperglycemia.
Sedation is frequently required in patients with brain
injury. In addition to providing patient comfort, sedation
medications can also decrease cerebral oxygen consumption, cerebral glucose consumption, and ICP. However, use of sedatives has not led to improved outcomes,
although a potential bias may confound these ndings
because there may be an association of dierential requirement of sedations in patients who have greater brain
injury.184 Hertle et al185 compared retrospectively acquired
cerebral microdialysis glucose concentrations between
patients who did and did not receive sedation. Sedation
medications included midazolam, fentanyl, sufentanil,
propofol, and ketamine. In patients with normal microdialysate glucose concentrations (ie, Z1 mmol/L), only
midazolam had a signicant dose-dependent relationship
with glucose measurements. Specically, as midazolam
dose increased, glucose concentration increased, probably
as a result of diminished glucose utilization by the brain
after drug-induced metabolic depression. However, in
patients with critically low microdialysate glucose concentrations (ie, <1 mmol/L), glucose concentration was
independent of drug dose for all 5 sedative drugs. This may
occur because of increased metabolism following brain
injury, leading to increased glucose utilization and lower
microdialysate glucose concentrations that cannot be
suppressed by sedative medications.
Cognitive dysfunction is common following TBI
and can be a major factor that can impair return to
preinjury lifestyle in patients who suered TBI.186 Following TBI, neuronal apoptosis in the hippocampus may
occur in concert with cognitive dysfunction, and proliferation of neuronal progenitor cells in this region may
play a role in post-TBI repair.187189 Peptide-6 is a neurotrophic peptide that is reported to increase neurogenesis
in the dentate nucleus in normal mice and transgenic
murine models of Down syndrome and Alzheimer disease.190192 Chohan et al193 administered either peptide-6
or placebo to mice each day for 30 days following controlled cortical impact. Animals that received peptide-6
exhibited an 80% increase in the number of progenitor
cells that dierentiated into mature neurons and an 18%
decrease in neuronal apoptosis in the dentate gyrus of the
hippocampus. In peptide-6-treated animals, there was
also increased expression of microtubule-associated protein-2 (a marker of dendrites) and synaptophysin (a
marker of synaptic density) in the dentate gyrus. Peptide6 did not aect the concentration of hyperphosphorylated
tau protein. Tau protein is an important structural
component of neuronal microtubules. Hyperphosphorylated tau protein is unable to support microtubule
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FIGURE 3. Influence of inspired oxygen fraction on cerebral microdialysate glutamate concentration. Data illustrated for all 1130
samples (A), those obtained only when the PbtO2 Z20 mm Hg (B), and those where PbtO2 < 20 mm Hg (C). Mean value and 95%
confidence intervals are illustrated. *P < 0.05 and **P < 0.01 compared with those with FiO2 < 40 with correction for multiple
comparisons. CMD indicates cerebral microdialysis; FiO2, fraction inspired oxygen (%); PbtO2, brain tissue oxygen partial pressure
(mm Hg). From Quintard et al,178 with permission.
structure and leads to neuronal dysfunction, presumably

because microtubules are an important intracellular
transport system within neurons. Finally, peptide-6treated animals had evidence of improved memory
function on behavioral testing. Thus, drugs that stimulate
neurogenesis may hold promise for preventing or reversing cognitive dysfunction after TBI.
We would also like to refer readers to 2 brief review
articles. Wijayatilake et al194 addressed systemic complications of TBI including cardiovascular, pulmonary,
hematologic, immunologic, and endocrine disorders. In
another review, Wijayatilake et al195 discussed physiological targets in patients with TBI.
ANESTHETIC NEUROTOXICITY AND

PERIOPERATIVE COGNITIVE DYSFUNCTION
Many in vitro and animal model studies have demonstrated neuronal degeneration and apoptosis in immature
and developing brains following exposure to clinically used
general anesthetics. Further, general anesthetic drugs were
also reported to have other potentially adverse eects on the
brain such as attenuating intermediaries in cellular energetics,196 impairing cellular signaling mechanisms,197,198
impairing synapse formation,199201 inducing changes in
gene expression,202 and altering mitochondrial function.203
This causes ultrastructural changes within neurons and can
lead to functional decits.204207 Cheng et al208 recently
discovered that similar anesthetic-associated apoptosis
occurs in the retina of young mice. This aords a unique
Copyright
opportunity to study anesthetic neurotoxicity because: (1)

the retina is the only component of the central nervous
system that can be visualized noninvasively, and (2) novel
optical techniques allow for single cell apoptosis detection in
the retina.209
Animals exposed to general anesthesia at a young
age later exhibited an increased rate of behavioral disorders.210 For example, monkeys exposed to general anesthesia at a young age were found to later have increased
anxiety.211 Interestingly, some recent research has discovered an attenuation of this eect by environmental
enrichment.212215 Many recent studies have reported an
association between exposure to multiple general anesthetics in young children and learning and behavioral
decits later in life.216218 Related to this research in humans, and to complementary laboratory studies, the potential methods of anesthetic neurotoxicity have been
summarized in the proceedings of the fourth Pediatric
Anesthesia and Neurodevelopment Assessment (PANDA)
Symposium, held on April 12, 2014.219228 Subsequently,
the initial results of the General Anesthesia Compared to
Spinal Anesthesia (GAS) Trial were published ahead of
print in The Lancet on October 23, 2015.229 Infants
younger than 60 weeks postmenstrual age, born at >26
weeks gestation, and having inguinal hernia repair were
randomized to receive either spinal anesthesia without
sedation or general anesthesia. Patients having general
anesthesia received sevourane, without nitrous oxide or
an opioid, and either caudal or ilioinguinal-iliohypogastric
nerve blocks were used for postoperative pain control.
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109
Exposure to sevourane was <1 hour. The primary outcome measure was performance on the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, at
5 years after randomization. Although primary outcome
data from this trial have not yet been released, the authors
reported the secondary outcome measurethat is, the
composite cognitive score of the Bayley Scales of Infant
and Toddler Development (ie, the Bayley III)230at 2
years after randomization. Briefly, the Bayley III assesses
infant and toddler development based on 5 major axes:
cognitive skills, communication skills, motor skills, social/
emotional behavior, and adaptive behavior. Scores from
each axis are compiled into a composite score that is
scaled such that the mean of a large random sample is 100
with a SD of 15. Outcome data were available from 238 of
363 children in the regional anesthesia group and 294 of
359 children in the general anesthesia group; missing data
were imputed. Overall, the composite scores at 2 years
were 98.6 14.2 and 98.2 14.7 in the regional
and general anesthesia groups, respectively (P not significant). Although additional outcome results from this
trial are still pending, these data preliminarily suggest that
sevoflurane does not result in overt neurotoxicity in young
children. However, because these data are limited to the
use of only 1 volatile anesthetic drug (ie, sevoflurane), and
children were exposed to that anesthetic for <1 hour, the
results of this research, though encouraging, may not be
generalizable to other anesthetic agents, multiple exposures to general anesthetics, or longer individual or
combined durations of general anesthesia and surgery.
Young children exposed to multiple general anesthetics at an early age were more likely to subsequently
manifest attention-decit hyperactivity syndrome.231 Using the National Health Insurance Research Database of
Taiwan, Ko et al232 assessed the relationship between
early exposure to general anesthesia and subsequent risk
for autism. The database used in this project contains
information from approximately 99% of the population
of Taiwan. Of the 114,435 children born in Taiwan between January 1, 2001 and December 31, 2007, and whose
data were in the database, 5197 received general anesthesia before the age of 2 years. Each study subject was
matched with 4 control subjects (those who did not receive general anesthesia before the age of 2 y) based on
sex, birth year, and birth month. The index date in the
control group was dened as the date that their matched
study subject received general anesthesia. No study subject had been diagnosed with autism before receiving
anesthesia, and control subjects were not diagnosed with
autism before their index date. The mean age of diagnosis
of autism was 4.04 1.80 years. Rates of autism were
0.96% and 0.89% in the study and control groups, respectively (P = 0.62). Although the rates of perinatal
medical complications, congenital anomalies, neurological diseases, and endocrine diseases were more common in the study cohort, and these factors were
associated with the diagnosis of autism, anesthesia exposure was still not associated with increased risk for
subsequent diagnosis of autism. Age at the time of rst
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exposure was not associated with increased risk for autism. Further, the number of anesthetics was not associated with risk for autism.
It has been reported that up to 50% of children who
undergo anesthesia and surgery suer from negative behavioral changes afterward.233 These changes can involve increased anxiety, changes in eating or sleeping patterns, or
unusual fears. Stipic et al234 randomized 64 children having
tonsillectomy to receive general anesthesia with either sevourane and nitrous oxide or a propofol infusion. Sevourane
and propofol were titrated to maintain a BIS of 40 to 60
during the procedure. Patients in the propofol group received
an intravenous induction with propofol, whereas those in the
sevourane group received an inhalational induction with
sevourane. Postoperative behavior assessment was conducted with the Post-Hospitalization Behavior Questionnaire
before surgery, on postoperative days 1, 3, 7, and 14, and
again at 6 months following surgery. This questionnaire
quantied parental assessment of 6 axes: general anxiety,
separation anxiety, sleep patterns, eating disturbances, aggression, and apathy/withdrawal. Scores following surgery
were compared with presurgical scores. A score indicating
worsening of any axis was dened as a negative postoperative
behavioral change. As illustrated in Table 3, negative postoperative behavioral changes were common following surgery and anesthesia but were more common following
sevourane than propofol at every time point of assessment.
Further, simultaneous changes in all 6 axes were more
common in patients who received sevourane at all postoperative time points. The greatest dierence between groups
was noted in the separation anxiety axis, although this may
have been related to inhalation induction of anesthesia with
sevourane. Specically, it was implied in the methods that
all children had intravenous access obtained and intravenous
midazolam (a drug with anxiolytic properties) administered
(0.05 mg/kg) before induction of anesthesia. Inhalational induction of anesthesia without adequate amnesia may have
confounded the results.
Older patients having anesthesia and surgery are
at increased risk for postoperative delirium and cognitive dysfunction. Delirium refers to an acute confusional state that temporally uctuates. Hesse et al235
reported that prolonged procedures and preexisting
neurological comorbidities were risk factors for delirium in the recovery room. Kichloo et al236 found that
increased age, higher ASA physical status classication,
and preoperative depression were independent risk
factors for delirium. Punjasawadwong and Punjasawadwong237 reported a meta-analysis that discovered
that the use of BIS monitoring is associated with reduced delirium in elderly patients. It is unclear how
postoperative delirium contributes to long-term outcome. For example, Gottschalk et al238 recently reported that postoperative delirium following repair of
hip fracture in the elderly did not predict an increased
long-term risk of death.
Postoperative cognitive dysfunction refers to a decrease in cognitive abilities following anesthesia and surgery. It is a more static condition that appears to slowly
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TABLE 3. Prevalence of Negative Postoperative Behavioral

Changes
Assessment
Point
POD 1
POD 3
POD 7
POD 14
6 mo
postoperatively
49
48
41
29
26
Propofol
Group (n [%])
23
21
16
9
5
(72)
(66)
(52)
(28)
(16)
Sevourane Group
(n [%])
28
29
26
20
22
(88)
(91)
(84)
(65)
(69)
P
NS
0.016
0.007
0.004
< 0.001
64 subjects were included on the investigation.

Assessment data from each subject in the cohort was not available at each time
point.
POD indicates postoperative day.
From Stipic et al,234 with permission.
improve; however, approximately 10% of elderly patients

demonstrate persistent cognitive decits at 3 months following anesthesia and surgery.239,240 Patients having
surgery may dier from the general population of patients
of a similar age and may have a dierent rate of preoperative cognitive decits. Diering factors may include
rates of chronic diseases and comorbidities, increased
need for medications including pain medications, or disruption in environment or daily routine. Silbert et al241
performed a battery of 7 neuropsychometric tests preoperatively to quantify cognitive function in 300 patients
above 60 years of age having rst-time total hip arthroplasty for osteoarthritis. Similar tests were also performed
in a control group of 51 age-matched and sex-matched
persons not having surgery. Preoperative cognitive dysfunction was dened as a score <2 SDs below the control
populations score on at least 2 of the 7 tests. Preoperative
cognitive dysfunction was identied in 96 of the 300 patients (32%; 95% CI, 23%-43%); the rate of baseline
cognitive dysfunction was not reported in the control
group. All study subjects underwent postoperative testing, similar to preoperative testing, at 7 days, 3 months,
and 12 months following surgery. Subjects in the control
group underwent testing at similar time points as study
subjects to correct for learning eect. Postoperative cognitive dysfunction was dened by the reliable change index as illustrated in Figure 4.242 A combined score was
then obtained by adding the reliable change index scores
from all tests for a specic patient at the assessment time
point. Postoperative cognitive dysfunction was dened as
a reliable change index score of < 1.96 on at least 2
tests or a combined score of < 1.96. Postoperative
cognitive dysfunction was identied in 17%, 10%, and
3%, at 7 days, 3 months, and 12 months following surgery, respectively. As illustrated in Table 4, postoperative
cognitive dysfunction was more common in patients with
cognitive dysfunction existing before surgery. Of note, the
incidence of cognitive dysfunction lasting 12 months following surgery was low, that is, only 3%.
Lifestyle modications, such as regular exercise and
cognitive stimulation, are associated with reduced odds of
cognitive impairment in the elderly.243 The Finnish
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Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)244 randomized 1260
persons 60 to 77 years of age to either an accountable
lifestyle modication program (ie, improved diet, regular
exercise, cognitive training, and vascular risk factor
modication) or just general health advice. Subjects in the
treatment group had signicantly better postintervention
executive functioning skills and processing speed than
those who received general health advice at 24 months
after randomization. Recently, various animal models
have demonstrated an attenuation of anesthetic neurotoxicity (ie, decreased apoptosis, improved cognitive
function) by environmental enrichment.245,246 However,
the mechanism for this eect is unclear. Kawano et al212
assigned rats to one of 4 groups based on a 2 2 design:
(1) an environment with or without enrichment items and
(2) anesthesia with or without surgery. Environmental
enrichment items consisted of a maze that was changed
daily and an exercise wheel, and assignment to the environments was for 14 days before anesthesia exposure.
Surgery consisted of a standardized laparotomy followed
by small bowel manipulation for 3 minutes and closure of
the incision. Anesthesia consisted of 1.5% to 2% inspired
isourane, with ropivacaine inltration of the incision
restricted to the surgical group. Cognitive function was
assessed with the Novel Object Recognition Test that
assesses memory at 7 days following anesthesia (ie, normal rats spend more time exploring a novel object). The
experimental protocol was conducted with a group of
young (age 2 to 3 mo) and old (age 24 to 25 mo) rats,
separately. Additional sets of young and old rats underwent microglial harvesting from the hippocampus for
quantication of inammatory cytokine concentrations
(ie, tumor necrosis factor-a and interleukin-1-b). Cytokine harvesting was conducted 2 weeks before anesthesia
exposure, and rats were then placed into either enriched
or unenriched environments. A subset underwent microglial harvesting before anesthesia and surgery, with the
remaining animals having microglial harvesting at 7 days
following anesthesia and surgery. In young rats, neither
surgery nor environmental enrichment impacted memory
function or expression of inammatory cytokines in the
hippocampus. In older rats assigned to an unenriched
environment for 14 days followed by anesthesia and surgery, memory decits and increased expression of both
)
(
(
(
)]
)]
FIGURE 4. Calculation of the reliable change index (RCI) (s, A,

t): RCI by subject (s) on test (A) at assessment time point (t).
x(s, A, t) = score by subject (s) on test (A) at assessment time
point (t). x(s, A, 0) = score by subject (s) on test A before surgery. m(A, t) = mean score of control group on test (A) at assessment point (t). m(A, 0) = mean score of control group on
test (A) obtained at baseline assessment. s[m(A, t) m(A,
0)] = SD of the difference between m(A, t) and m(A, 0). Equation
developed by author (J.J.P.) from text description of RCI in
Rasmussen et al.242
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111
TABLE 4. Preoperative Cognitive Deficits are a Risk Factor for

Short- term and Long-term Postoperative Cognitive
Dysfunction
Day 7
POCD
95% CI (%)
3 mo
POCD
95% CI (%)
12 mo
POCD
95% CI (%)
PreCI (n = 96)
No PreCI (n = 204)
23/91 (25.3)
16.7-35.5
26/195 (13.3)
8.9-18.9
0.012
13/87 (14.9)
8.2-24.2
14/197 (7.1)
3.9-11.6
0.039
5/83 (9.4)
2.0-13.5
2/188 (1.1)
0.1-3.8
< 0.001
Data are presented as: number with POCD/number of subjects tested (%).
CI indicates condence interval; POCD, postoperative cognitive dysfunction;
PreCI, preexisting cognitive impairment.
From Silbert et al,241 with permission.
tumor necrosis factor-a and interleukin-1-b occurred in

animals that had surgery. In contrast, in rats with exposure to environmental enrichment, the eect of anesthesia and surgery on memory and cytokine expression
was attenuated. Recently, Tamura et al247 reported that
erythropoietin can also attenuate cytokine release
by microglia in cell culture and in intact mice following
microglial stimulation by lipopolysaccharide.248 Ikeda and
Koener249 reported that depletion of microglia attenuated
histologic manifestations of brain injury following global
cerebral ischemia. Although microglia may play a role in
exacerbating ischemic brain injury, astrocytes may attenuate injury by buering probrain-derived neurotrophic factor.250
Inammation may not be the only factor responsible
for postoperative cognitive dysfunction, as evidenced by
the fact that administration of the corticosteroid dexamethasone increases the risk for postoperative cognitive
dysfunction in humans.251 Other factors that may contribute to postoperative cognitive dysfunction include increased sensitivity of the aged brain to the hypnotic eects
of general anesthetics252 or anesthetic-induced increased
blood-brain barrier permeability.253
MONITORING
Recent reports of new neurological decits following
surgical procedures performed in the sitting position have
been attributed, in part, to cerebral hypoperfusion.254 This
hypoperfusion can result from inadequate systemic blood
pressure, possibly related to failure to correct for hydrostatic gradients between the brain and the site of blood
pressure measurement. In theory, ischemic brain injury
would be most likely when cerebral perfusion pressure falls
below the brains lower limit of autoregulation. Recently,
Laam et al255 hypothesized that cerebral autoregulation
may be impaired in patients having surgery in the sitting
position, further contributing to increased risk for hypoperfusion. A total of 218 patients having shoulder surgery
in the beach chair (n = 109) and lateral decubitus (n = 109)
positions underwent a standard set of neuropsychometric
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tests both before surgery and at specied intervals following

surgery (ie, 7 to 10 d and again 4 to 6 wk following surgery).
Position was not randomized but was selected based on the
indication for surgery and surgeon preference. All patients
had regional cerebral oximetry monitoring and continuous
systemic blood pressure measured with a nger plethysmographic monitor (Finometer Pro; Finapres Medical
Systems, Amsterdam, The Netherlands) that was intermittently calibrated to pressures measured with a blood
pressure cu on the upper arm. Blood pressure measured
with the plethysmographic monitor was used as a study
variable to estimate cerebral autoregulatory capacity and
not for the direct conduct of the anesthetic. The anesthesia
provider measured blood pressure in the leg in all but 11
patients. Cerebral autoregulatory capacity was assessed by
calculating a moving Pearson correlation coecient between
MAP determined by plethysmography and rSO2. This correlation variable was termed the cerebral oximetry index
(COx). Values of COx > 0.3 were interpreted as impaired
cerebral autoregulation. Serum concentrations of neuronspecic enolase (a marker of neuronal injury), glial brillary
acidic protein (a marker of astrocyte injury), and S100 b
(also a marker of astrocyte injury) were measured before
surgery, while the patient was in the recovery room, and on
the day following surgery. All patients received an interscalene block and general anesthesia maintained with a potent volatile anesthetic titrated to a BIS of 40 to 50.
Estimated average MAP at the tragus, corrected for the
hydrostatic gradient, was signicantly lower in the beach
chair group (50 16 mm Hg) compared with the lateral
group (76 13 mm Hg, P < 0.0001). Mean COx was also
signicantly higher in the beach chair group (0.15 0.13)
compared with the lateral group (0.09 0.12, P = 0.035).
However, a similar number of patients in both groups achieved a COx > 0.3 (ie, impaired autoregulation) during
surgery (75% in beach chair and 65% in lateral position,
P = 0.367). The lower limit of cerebral autoregulation was
dened as the MAP where the COx = 0.3. The median
lower limit of cerebral autoregulation was 65 mm Hg (interquartile range, 55 to 75 mm Hg) in the lateral decubitus
group and 70 mm Hg (interquartile range, 55 to 80 mm Hg)
in the beach chair group (P = 0.620). After adjusting for
baseline dierences in performance on neurocognitive tests,
there was no dierence between positioning groups at 7 to 10
days or at 4 to 6 weeks after surgery in overall cognitive
function. Further, there was no dierence in any serum biomarker concentration at any time point following surgery
between groups. It is unclear how measurement of leg blood
pressure in this researchthat is, a practice that is not universal in this patient population and may introduce systematic errors in estimating central blood pressuremay
have affected the results.
rSo2 (ie, regional cerebral oxygen saturation) decreases upon position change from supine to beach
chair.256,257 Picton et al258 prospectively randomized 56
patients having surgery in the beach chair position to
have anesthesia maintained with either propofol or desurane titrated to a BIS of 40 to 60. rSo2 was determined
on each patient: (1) before induction of anesthesia, (2)
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TABLE 5. Regional Cerebral Oxygen Saturation of Hemoglobin

Supine
Combined
(n = 56)
Propofol
(n = 29)
Desurane
(n = 27)
Beach Chair
FiO2 = 0.3,
EECO2 = 30 mm Hg
FiO2 = 0.3,
EECO2 = 30 mm Hg
FiO2 = 1.0,
EECO2 = 30 mm Hg
FiO2 = 1.0,
EECO2 = 45 mm Hg
FiO2 = 0.3,
ETEO2 = 45 mm Hg
68 12
61 12*
66 12*
75 12*
65 13*
67 13
59 13*
64 14*
74 12*
64 14*
69 11
62 10*
67 11*
76 11*
67 12*
Data expressed as percent saturation of hemoglobin.

Data expressed as mean SD.
*P < 0.001 compared with data in box to immediate left.
EECO2 indicates end-expired carbon dioxide tension; FiO2, fraction inspired oxygen.
From Picton et al,258 with permission.
following induction of anesthesia with FiO2 = 0.3 and

end-expired carbon dioxide tension = 30 mm Hg, and (3)
after being placed in the beach chair position with
FiO2 = 0.3 and end-expired carbon dioxide tension = 30
mm Hg. While in the beach chair position, 2 2 permutations were produced in FiO2 (either 0.3 or 1.0) and endexpired carbon dioxide tension (either 30 or 45 mm Hg),
with rSo2 recorded for each permutation. In the entire
cohort, there was a signicant decrease in rSo2 when
changing from supine position (68% 12%) to beach
chair position (61% 12%, P < 0.001). As illustrated
in Table 5, anesthetic choice did not inuence the decrease
in rSo2 with position change. This independence of rSo2
on anesthetic drug was conrmed by others.259,260 Further, the decrease in rSo2 was oset by an increase in FiO2
and end-expired carbon dioxide tension. Other data by
Meng et al261 showed that blood pressure can also impact
rSo2.
Closhen et al262 measured changes in rSO2 in patients placed in the prone position during general anesthesia and compared ndings to those obtained in awake
volunteers in the prone position. Oximetry was measured
for 120 minutes in the patients having general anesthesia
and 10 minutes in the awake volunteers. Regional cerebral oximetry was measured simultaneously with both an
INVOS oximeter (type not specied, Somanetics, Troy,
MI) and a FORE-SIGHT oximeter (Cas Medical System,
Branfort, CT). In patients having surgery, general anesthesia was maintained with sevourane (0.7 to 1.0 MAC)
and an infusion of sufentanil. The head was positioned
with a neutral spine in a Disposa-View device (Vital Signs
Inc., Totowa, NJ). With the INVOS device, rSO2 of hemoglobin initially decreased from 75% 8% in supine
position to 72% 8% (P-value not reported in manuscript) immediately following placement in the prone
position, and then increased at a rate of 0.0321% per
minute thereafter. No patient had a >5% decrease in
rSO2 in the prone position compared with the value obtained before instituting the prone position. In awake
volunteers, baseline, supine INVOS oxygen saturation
was 75% 8%. There was no change following placement in the prone position. Thereafter, rSO2 increased at
Copyright
a rate of 0.082%/minute. In anesthetized patients monitored with the FORE-SIGHT device, rSO2 of hemoglobin
decreased from 74% 5% in the supine position to
72% 4% (P-value not reported in manuscript) immediately following placement in the prone position, but
thereafter increased at a rate of 0.0314%/minute. No
anesthetized patient had a saturation decrease of >5% of
the supine value. In awake volunteers, the INVOS rSO2
of hemoglobin was 70% 3% at baseline, and there was
no change following placement in the prone position.
Thereafter, saturation increased by 0.179%/minute.
Indocyanine green is a uorescent dye commonly
used during intracranial vascular surgery and can cause a
false decrease in traditional pulse oximetry readings, but
its eects on cerebral oximetry are unknown.263 Yoo
et al264 conrmed a 0% to 4% decrease in hemoglobin
oxygen saturation by traditional pulse oximetry following
intravenous administration of indocyanine green, and
values returned to baseline in 2.9 1.4 minutes. However, there was a 6% to 20% increase in rSO2 of hemoglobin measured with an INVOS 5100B oximeter
(INVOS; Somanetics), and 12.1 3.8 minutes were required before values returned to baseline. These dierences are likely due to dierences in the wavelengths of
light and the algorithms used to determine oxygen saturation of hemoglobin between the standard pulse oximeter and the cerebral oximeter. Also of note, Sun et al265
reported that skin pigment coloration correlates with
rSO2 values when measured with an INVOS 5100C (Somanetics) device. Specically, presurgical baseline regional oximetry values were 53% 13% in African
Americans and 65% 12% in whites (P < 0.01).
Robot-assisted prostatectomy is generally performed
with the patient in the steep Trendelenburg position and
requires insuation of the abdominal cavity with carbon
dioxide gas. These 2 factors (ie, Trendelenburg position
and increased systemic carbon dioxide tension) can potentially increase intracranial pressure. Whiteley et al266
measured optic nerve sheath diameter with ultrasonography in 25 patients having robotic prostatectomy.
Optic nerve sheath diameter can be used as a surrogate
metric of ICP and is responsive to physiological changes
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113
that are known to aect ICP.267269 Measurements were

obtained immediately following induction of general anesthesia and again following release of the pneumoperitoneum just before placing the patient into the supine
position. A nerve sheath diameter of Z5.2 mm has a 93%
sensitivity and 74% specicity to predict an ICP > 20 mm
Hg.270 Patients with ocular disorders or a history of increased ICP were excluded from the study. All patients
received inhaled isourane along with intermittent vecuronium and fentanyl intravenously. Ventilation was
adjusted to maintain an end-expired carbon dioxide tension of 30 to 40 mm Hg. Optic nerve sheath diameter was
4.5 0.5 mm (range, 3.3 to 5.5 mm) following induction
of anesthesia and before placement in the Trendelenburg
position for surgery. Optic nerve sheath diameter increased to 5.5 0.5 mm (range, 3.8 to 6.5 mm; P < 0.001)
after the robotic portion of the surgical procedure and
release of the pneumoperitoneum while the patient was
still in the Trendelenburg position. When controlling for
presurgical optic nerve sheath diameter, postprocedural
optic nerve sheath diameter was independently and positively correlated with MAP. However, postprocedural
optic nerve sheath diameter did not correlate with patient
age, race, BMI, ASA physical status, surgical duration,
intravenous uids and volume, mean expired isourane
concentration, or end-expired carbon dioxide tension.
Had hypercarbia not been attenuated by increasing ventilation, it is likely that end-expired carbon dioxide tension
may have also been independently associated with postprocedural optic nerve sheath diameter. It is possible that
the increase in MAP compensated for an increase in ICP,
and thus cerebral perfusion pressure was not diminished.
Unfortunately, the authors did not report the fraction of
patients that met criteria for increased ICP in this cohort.
Also, optic nerve sheath diameters reported in the primary
table in this manuscript were probably reported in cm
(and not mm as labeled in the table). Therefore, it was
dicult to determine whether changes that were reported
in nerve sheath diameter as a function of expired carbon
dioxide tension were correct or incorrect by an order of
magnitude.
Evoked potential monitoring is commonly used
during surgical procedures to assess the integrity of the
nervous system.271273 Evoked potential monitoring has
also demonstrated some utility at identifying position-related nerve injuries.274277 Plata Bello et al278 report on the
utility of evoked potential monitoring to detect cervical
cord compromise during positioning in patients having
cervical spine surgery. Electrophysiological monitoring
with motor evoked potential (MEPs), somatosensory
evoked potentials (SSEPs), and free running electromyography were monitored in 75 patients having cervical
spine surgery. Fifty-one percent of cases were performed
for myelopathy due to degenerative disease, 24% for disk
herniation, 23% for fracture, and 3% for tumor. Anesthesia was maintained with infusions of propofol and remifentanil. In 5 cases, there were changes in waveforms in
at least 1 modality during neck positioning. All 5 cases
involved complete loss of MEP waveforms and 2 cases
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also had complete loss of SSEP waveforms. In 4 patients,

there was recovery of signals upon repositioning of the
neck. In the remaining patient, there was no improvement
in signals following neck repositioning and, following
emergent decompression, the patient manifested a new
tetraplegia with recovery after 2 weeks.
Many factors such as anesthetic drugs, blood pressure, patient temperature, and age can have an impact on
neuroelectrophysiology waveforms.279282 Also, nonanesthesia drugs, such as the anticonvulsant drug levetiracetam (Keppra), can signicantly impact recording of
intraoperative evoked potential waveforms.283 Sevourane has a greater suppressant eect than either desurane or propofol on transcranial electrical-stimulation
MEPs.284,285 It is unclear whether desurane or propofol
leads to greater suppression of MEP waveforms.
Malcharek et al286 prospectively studied 21 patients
without preexisting neurological decits having carotid
endarterectomy with transcranial electrical MEP monitoring. Anesthetic depth was titrated to a BIS value of 30
to 45, and waveforms were recorded at 35 and 70 minutes
after institution of desurane. All patients also received
remifentanil 0.2 to 0.6 mg/kg/minute intravenously. After
recordings were obtained in all patients during desurane
anesthesia, their anesthetic was switched to propofol and
the recordings were obtained at 35 and 70 minutes following the change. At 35 minutes, MEP waveform amplitude in the upper extremity (specic nerve not
indicated) was signicantly less when patients received
desurane (359 74 mV) than propofol (840 50 mV,
P = 0.0006). Waveform amplitudes were similar between
anesthetics at 70 minutes (902 150 vs. 793 43 mV for
desurane and propofol, respectively; P > 0.05).
Dexmedetomidine is an agonist of the a2 adrenergic receptor and provides sedation and analgesia
without signicant respiratory depression. Dexmedetomidine is used in the perioperative period for sedation and as part of a balanced anesthetic. Contradictory
eects of dexmedetomidine on MEPs have been reported.287,288 Commonly used general anesthetic drugs
are also known to signicantly suppress visual evoked
potential waveforms, making this monitoring technique
dicult in patients who are receiving general anesthesia.289,290 Rozet et al291 systematically characterized
the eect of dexmedetomidine on MEPs, SSEPs, and
visual evoked potentials during balanced total intravenous anesthesia in adult patients having elective spine
surgery. All patients received infusions of propofol,
titrated to a BIS value of 30 to 55, and remifentanil.
Following recording of baseline evoked potential data,
patients were randomized to receive either dexmedetomidine (4 mg/mL) or saline administered as 0.9 mL/kg/h
for 10 minutes, then 0.15 mL/kg/h during the study
period. Study personnel were blinded to group assignment. In the dexmedetomidine group, this corresponded to a bolus dose of 0.6 mg/kg over 10 minutes,
then a 0.6 mg/kg/h infusion rate. Evoked potential
waveforms were then generated at 60 30 and
150 30 minutes. SSEPs were stimulated in the
Copyright
distribution of the median and tibial nerves and recorded from the scalp. MEPs were induced by electrical
stimulation of the scalp and measured in the belly of the
thenar and abductor halluces muscles. At no point was
there a dierence in MEP, SSEP, or visual evoked potential waveform amplitude or latency between groups
during the study. Therefore, dexmedetomidine was
found to have minimal, if any, eect on evoked potential waveforms during propofol and remifentanil
anesthesia. These ndings may not be directly applicable to children or those with preexisting neurological
decits.
Some patients, such as children or those with developmental delay, may not be able to tolerate having a diagnostic EEG awake and require sedation. Unfortunately,
many drugs that are commonly used for sedation, such as
barbiturates, propofol, and benzodiazepines, can profoundly aect not only the frequency and amplitude
properties of the EEG but can also attenuate epileptiform
and epileptic activity. Chloral hydrate is a commonly used
sedative in this setting because it is reported to have less of
a suppressant eect on epileptiform activity than other
anesthetic drugs.292,293 Fernandes et al294 compared EEGs
obtained in patients age 12 to 40 years who initially received an EEG during chloral hydrate sedation followed
by a second EEG at a dierent time during dexmedetomidine sedation. Patients received chloral hydrate (50 mg/
kg) orally with an additional 25 mg/kg given for
inadequate sedation. Dexmedetomidine was administered
as an intravenous bolus of 1 mg/kg over 10 minutes followed by an infusion of 0.2 to 0.7 mg/kg/h. Sedation was
titrated to have the patient either very sleepy with a tendency to go to sleep if not stimulated versus continually
sleeping with minimal, if any, response to stimulation. The
frequency and characteristics of sleep spindles were similar
between groups. Compared with the EEG during chloral
hydrate, dexmedetomidine was associated with increased
power in the d and y ranges and less power in the a and b
ranges. The authors commented that dexmedetomidine did
not grossly change the presence and properties of epileptiform activity, but they did not quantify this eect.
Further study will be required to determine whether use of
dexmedetomidine for sedation to obtain EEGs impairs the
diagnostic ability of this test for epilepsy.
For readers interested in additional information on
central nervous system monitoring, we refer you to a review by Hiles et al.295 The review focuses on noninvasive
technologies and emphasizes technologies that can be used
in remote environments including mainstream aviation,
high-altitude ascension, and spaceight. The authors also
discuss ultrasound-based techniques such as time-of-ight
ultrasonography, transcranial Doppler sonography, and
ocular ultrasound. Spectroscopic techniques including
near-infrared spectroscopy and diuse-correlation spectroscopy are discussed. Finally, they include ocular and
otic techniques such as pupillometry, visual evoked potentials, ophthalmodynamometry, tympanic membrane
displacement, and distortion-product otoacoustic emissions.
Copyright
CONCLUSIONS
Our synopsis and speculative synthesis of the 2015
literature is intended to provide an overview for anyone
involved in the care of neurosurgical patients or involved
in basic or translational neuroscience research. For interested readers, we refer you to some of our more recent
annual reviews of the neuroanesthesia literature from
prior years.296,297
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REVIEW ARTICLE

(P-value not reported). In non-neurosurgical operating

Volume 28, Number 2, April 2016

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Pasternak and Lanier

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TABLE 1. Emergence Characteristics

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Pasternak and Lanier

The effect of dexmedetomidine on cerebral hemodynamics

Volume 28, Number 2, April 2016

TABLE 2. Mean Arterial Pressure Comparison at Prespecified

Data expressed as mean SD.

isourane requirements intraoperatively. Patients who

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Volume 28, Number 2, April 2016

FIGURE 1. The P6 pressure point is located 3 finger breaths

periprocedural opioid requirement. Overall, 67% of

relaxation (percent with score = 1: 28% vs. 8%,

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Pasternak and Lanier

treatment did not have a reduced odds of seizures

Volume 28, Number 2, April 2016

resection was quantified. Patients who received 5-ALA

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Volume 28, Number 2, April 2016

Management of patients with acute spinal cord injury requires

Surgery on the spine can involve diverse procedures

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Pasternak and Lanier

FIGURE 2. Recall of preoperatively disclosed complications of

for bleeding include long surgical duration, increased

Volume 28, Number 2, April 2016

with blood donation. Ikegami et al87 retrospectively

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Volume 28, Number 2, April 2016

Netherlands (MR CLEAN),97 patients who presented to

collateral circulation for up to 12 hours following onset of

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Pasternak and Lanier

Symptom Onset (REVASCAT)101 was conducted in

Volume 28, Number 2, April 2016

thrombotic drugs in the mechanical thrombectomy

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Volume 28, Number 2, April 2016

those who received stenting plus medical therapy (36%)

pressure that can occur with general anesthesia in patients

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Pasternak and Lanier

Trial,129 4011 patients with ischemic or hemorrhagic stroke

Volume 28, Number 2, April 2016

2016 Wolters Kluwer Health, Inc. All rights reserved.