Recurrent Seizures Following Cardiac Surgery: Risk Factors and Outcomes
in a Historical Cohort Study
Rizwan A. Manji, MD, PhD, MBA, FRCSC,*†‡ Hilary P. Grocott, MD, FRCPC,*†‡ Jacqueline S. Manji, PhD,*
Alan H. Menkis, DDS, MD, FRCSC,*‡ and Eric Jacobsohn, MBChB, MHPE, FRCPC*†
Objectives: To determine the risk factors for and out-
comes after recurrent seizures (RS) in patients following
cardiac surgery.
Design: A historical cohort study.
Setting: A single-center university teaching hospital.
Participants: Cardiac surgery patients from April 2003 to
September 2010 experiencing postoperative seizures.
Interventions: None.
Measurements and Main Results: Patients were divided
into an isolated seizure group and an RS group. Risk factors
for RS were determined using logistic regression. Intermedi-
ate-term follow-up was conducted by phone. Of 7,280
consecutive patients undergoing cardiac surgery, 61 (0.8%)
experienced postoperative seizure and 36 (59%) of those
experienced at least 1 recurrence. Of these, 32 (89%)
experienced RS within 24 hours of the first seizure, and 29
(81%) had grand mal seizures. Preoperative creatinine Z120
μmol/L (p ¼ 0.02), time until first seizure occurred (r4
P OSTOPERATIVE SEIZURES, although relatively uncom-
mon, are a well-documented complication of cardiac
surgery. The incidence of seizures after cardiac surgery varies
between 0.5 and 7.6%.1 When seizures occur, recurrence rates
of 40% to 66% have been reported.2–5 Seizures may be caused
by thromboembolic ischemic stroke, cerebral air embolism,
medication toxicity related to antibiotics, or other perioperative
drugs such as tranexamic acid (TXA).6–8 The authors previ-
ously reported that administration of TXA, preoperative cardiac
arrest, Acute Physiology and Chronic Health Evaluation
(APACHE) II scores 420, previous cardiac surgery, open-
chamber procedure, cardiopulmonary bypass (CPB)
time 4150 minutes, and preoperative neurologic disease are
all independent risk factors for seizures after cardiac surgery.4
Importantly, approximately 60% of patients in that study had
more than 1 seizure during their postcardiac surgery hospital
stay, thereby defining recurrent seizure (RS).
In the general non-surgical population, RS often is related to
factors such as a history of epilepsy, subtherapeutic anticon-
vulsant levels, alcohol withdrawal, and structural brain abnor-
malities.9,10 However, associated risk factors and outcomes for
RS after cardiac surgery are not known. Knowing these risk
factors could influence in-hospital clinical decision making and
From the *Cardiac Sciences Program, Winnipeg Regional Health
Authority and St. Boniface Hospital, †Department of Anesthesia and
Perioperative Medicine; and ‡Department of Surgery, University of
Manitoba, Winnipeg, Manitoba, Canada.
Address reprint requests to Rizwan A. Manji, University of Mani-
toba, St. Boniface Hospital, CR3014 - 369 Tache Avenue, Winnipeg,
Manitoba, Canada R2H 2A6. E-mail: rmanji@sbgh.mb.ca
© 2015 Elsevier Inc. All rights reserved.
1053-0770/2601-0001$36.00/0
http://dx.doi.org/10.1053/j.jvca.2015.03.020
1206 Journal of Cardiothoracic and Vascular Anesthesia, Vol 29, No 5 (October), 2015: pp 1206–1211
hours; p ¼ 0.01), and procedures involving the thoracic
aorta were associated with RS (R2 ¼ 0.53, p o 0.05).
Patients with RS had longer intensive care unit stays (5.3 v
2.9 days, p ¼ 0.03) and longer mechanical ventilation
duration (53.3 v 15.0 hours, p ¼ 0.01). At a median follow-
up of 21 months for the RS group and 16 months for the
isolated seizure group, restrictions, anticonvulsant use,
morbidity, and mortality were similar between patients with
isolated versus recurrent seizures.
Conclusions: Higher preoperative creatinine, thoracic
aortic surgery, and early seizure onset were associated with
RS after cardiac surgery. When compared to isolated seiz-
ures, recurrence per se was not associated with significantly
increased long-term morbidity or mortality.
& 2015 Elsevier Inc. All rights reserved.
KEY WORDS: recurrent seizures, cardiac surgery, follow-up,
anticonvulsants, tranexamic acid
impact a patient’s quality of life regarding return-to-normal
activity and the possibility of long-term anticonvulsant therapy.
The purpose of this historical cohort study was to create an
exploratory predictive model for seizure recurrence after
cardiac surgery as well as to compare the outcomes for these
patients compared to those with isolated seizure.
METHODS
The local Research Ethics Board approved this study
(January 2010) and waived the requirement for patient consent
for the historical cohort component of the study. For follow-up,
informed consent was obtained from patients prior to the
telephone interview.
This report represents a subset of patients from a previously
published single-center historical cohort study performed on all
patients who underwent cardiac surgery at the authors’
institution between April 1, 2003 and September 30, 2010
who had postoperative seizures.4 In the original study, the
impact of TXA and other risk factors were compared between
patients who did and did not experience postoperative seizure.
For this present study, patients from the previous cohort who
experienced post–cardiac surgery seizures were divided into 2
groups: those who had one postoperative isolated seizure and
those who experienced RS (ie, more than one postoperative
seizure while in the hospital). The reason for this division was
to specifically explore the significance of recurrent seizures as
compared to isolated seizures.
Data collected from the authors’ cardiac surgery, perfusion
service, and intensive care unit (ICU) databases included
information on all consecutive cardiac surgery cases performed
at their institution. The perfusion service database collects
intraoperative variables, and the cardiac surgery and ICU
databases collect demographic and comorbidity variables
(including postoperative complications), ventilation time, and
lengths of ICU and hospital stays. A concurrent pharmacy
database maintains information related to the inventory of
RECURRENT SEIZURES
drugs dispensed to various clinical services, including anes-
thesia for cardiac surgery.4
A seizure was defined as a physician-documented event
such as rhythmic tonic-clonic motion of localized body parts
consistent with a focal seizure, or of all four limbs with a
decreased level of consciousness consistent with a grand mal
seizure that required prescribed intervention. Nonconvulsive
seizures were diagnosed in patients with a persistent decrease
in the level of consciousness and confirmed seizure activity on
serial electroencephalography (EEG).
A telephone interview was conducted more than a year after
discharge to ascertain if there had been any hospital readmis-
sion, new neurologic diagnoses (eg, RS and stroke), the need
for long-term anticonvulsant therapy, and/or any activity
restrictions (such as driving) instituted that were related to
seizures.
Statistical Analysis
All statistical analyses were performed using SPSS 17.0
software (SPSS Inc., Chicago, IL). Univariate analysis was
performed with a Student’s 2-sample t-test (for normally
distributed data), the Mann–Whitney U test (for non-normally
distributed data) and Pearson’s chi-square test (for categoric
data) in which potential recurrent seizure risk factors and
outcomes were compared between groups. Due to a relatively
small sample size, the authors opted to create an exploratory
(ie, hypothesis-generating) model for risk factors for RS that
could serve as a basis for future studies. As such, multivariable
logistic regression was performed using clinically relevant
variables (that had a univariate p value o0.1) to create a
Fig 1. Flow diagram of the historical cohort observed in this study comparing patients with isolated seizures to patients with recurrent
seizures (RS). The median follow-up period was 21 (6-30) months for the recurrent seizure group and 16 (11-28) months for the isolated
seizure group.
1207
model with the highest R2 value and largest area under the
receiver operating curve (ROC). A 2-tailed p value r 0.05 was
considered statistically significant.
RESULTS
Sixty-one (0.8%) of 7,280 consecutive patients experienced
a postoperative seizure (Fig 1). Of these 61 patients, 36 (59%)
had at least 1 RS, 17 patients (28%) experienced more than 1
recurrence, and 3 (8%) had non-convulsive status epilepticus.
Of the 36 patients with RS, 32 (89%) experienced RS within 24
hours of the first seizure, and 4 patients (11%) experienced
RS 424 hours after the first seizure. Grand mal seizures
accounted for the majority of patients with RS (29/36; 81%),
and each seizure (except for the 3 patients with nonconvulsive
status epilepticus) lasted less than 5 minutes.
A comparative univariate analysis between patients with RS
and patients with isolated seizure is outlined in Table 1.
Importantly, patients with RS had higher preoperative crea-
tinine levels, higher APACHE II scores, more thoracic aortic
and deep hypothermic circulatory arrest (DHCA), more post-
operative cerebrovascular accidents (CVA), and a shorter
period of time from the end of surgery until the first seizure
occurrence (ie, early onset of the first seizure). Of note, patients
with isolated seizures and patients with RS had similar doses of
TXA given, although the authors did not know the serum (or
cerebrospinal fluid levels11) of TXA.
Variables associated with RS that were considered bio-
logically plausible and that had a p value o 0.1 were further
examined in the authors’ multivariate model. These variables
included preoperative creatinine, APACHE II score, open-
1208 MANJI ET AL

Table 1. Univariate Comparison Between Patients With Isolated or Recurrent Seizure After Cardiac Surgery

Variable Isolated Seizure Recurrent Seizure p Values

Number of patients per group 25 36
Age (years) 68.7 (13.0) 70.6 (10.6) 0.53
Female 8/25 (32%) 10/36 (28%) 0.78
Preoperative seizure disorder 0/25 (0%) 2/36 (6%) 0.51
Preoperative alcohol abuse 2/25 (8%) 1/36 (3%) 0.56
Preoperative cerebrovascular disease 5/25 (20%) 8/36 (22%) 1.00
Ejection fraction (%) 55.0 (55.0-60.0) 55.0 (45.0-60.0) 0.64
Preoperative hemoglobin (g/L) 125 (17) 121 (22) 0.54
Preoperative creatinine (μmol/L) 92.0 (73.0-103.0) 103.0 (93.5-136.5) 0.01
APACHE II score 17.7 (6.6) 22.3 (5.8) 0.01
Preoperative cardiac arrest 0/25 (0%) 3/36 (8%) 0.07
Preanesthetic use of benzodiazepine 2/20 (10%) 6/36 (17%) 0.70
Intraoperative use of benzodiazepine 1/20 (5%) 2/36 (6%) 1.00
Intraoperative use of propofol 17/20 (85%) 27/36 (75%) 0.51
TXA dose (mg/kg) 68.4 (36.1) 74.9 (34.3) 0.51
CABG only (including redo CABG) 9/25 (36%) 7/36 (19%) 0.24
Open-chamber procedure (valve procedure, aortic procedure, intracardiac procedure) 15/25 (60%) 29/36 (81%) 0.08
Procedure involving aortic valve 6/25 (24%) 16/36 (44%) 0.10
Procedure involving thoracic aorta 1/25 (4%) 11/36 (31%) 0.02
Deep hypothermic circulatory arrest during surgery 0/25 (0%) 8/36 (22%) 0.02
Cross-clamp time (min) 75.0 (51.5-134.0) 77.0 (50.5-130.0) 0.96
Cardiopulmonary bypass time (min) 124.0 (85.0-200) 165.0 (92.3-218.3) 0.23
Lowest mean arterial pressure (mmHg) during OR 51.6 (6.9) 49.9 (10.9) 0.53
Duration of lowest mean arterial pressure (min) 10.0 (10.0-20.0) 10.0 (10.0-15.0) 0.95
Postoperative cerebrovascular accident 1/25 (4%) 8/36 (22%) 0.05
Postoperative cardiac arrest 2/25 (8%) 0/36 (0%) 0.16
New postoperative renal dysfunction 6/25 (24%) 5/36 (14%) 0.33
Time from end of surgery until first seizure (hours) 10.5 (4.8-17.5) 4.1 (1.8-10.6) 0.03

NOTE. Continuous variables reported as mean (SD) for normally distributed data or median (IQR) for non-normally distributed data. Categoric
data are reported as n/range.
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II score; CABG, coronary artery bypass graft; OR, operating room;
TXA, tranexamic acid.

chamber procedure, procedure involving the thoracic aorta, and
time duration from the end of surgery until the first seizure
occurred. Preoperative cardiac arrest was not included in this
analysis as the event rate was too low; only 3 patients with RS
experienced this variable. “Deep hypothermic circulatory arrest
during surgery” was the same as “procedures involving the
thoracic aorta.” Thus, only the thoracic aortic procedure
variable (with the larger event rate) was examined. Post-
operative CVA also was the same as the thoracic aortic
procedure variable and, thus, was not examined separately.
The multivariate model (Table 2) demonstrated that elevated
preoperative creatinine (Z120 μmol/L), procedure involving
the thoracic aorta and early seizure onset (r4 h from the end of
surgery until the first seizure) were associated with RS [R2 ¼
0.53, p o 0.05, area under the ROC curve 0.859 (95%
confidence intervals, 0.756-0.963)].
The median (IQR) duration of anticonvulsant therapy was
significantly longer in the RS group (4.0 [3.0-5.8]) days) versus
the isolated seizure group (0.3 [0.1-1.0] days; p o 0.001).
However, at the discretion of the attending physicians, 29
(81%) of the 36 patients in the RS group and 19 (76%) of the
25 in the isolated seizure group had their anticonvulsant
therapy discontinued during their hospitalization (p ¼ 0.69).
Patients underwent extended periods of in-hospital observation
(see below). No seizure occurred in-hospital after discontinua-
tion of anticonvulsant therapy in either group.
Patients in the RS group had significantly longer median
(IQR) mechanical ventilation times than in the isolated seizure
group (53.3 h [18.5 to 154.0] v 15.0 h [2.2 to 48.0] group; p ¼
0.01), as well as significantly longer median (IQR) ICU stay
(5.3 days [3.0 to 10.3] v 2.9 days [1.9 to 6.0]; p ¼ 0.03).
However, the median (IQR) length of hospital stay was similar

Table 2. Logistic Regression of Potential Predictors of Recurrent Seizures After Cardiac Surgery

Variable Unadjusted Odds Ratio 95% CI Adjusted Odds Ratio 95% CI

Preoperative creatinine (Z120 μmol/L) 2.6 0.7-9.6 11.3 1.6-81.8
Procedure involving thoracic aorta 10.6 1.3-88.2 Undefined† Undefined†
Time from end of surgery until first seizure r4 h 4.6 1.1-19.2 11.0 1.9-65.5

NOTE. R2 ¼ 53%; Area under the ROC Curve ¼ 0.859 (0.756 – 0.963).
†Undefined since odds ratio approaches infinity as almost all events occurred within the recurrent seizure group.
RECURRENT SEIZURES 1209

Table 3. In-Hospital Mortality and Live Discharge for All Patients Experiencing Seizure Post–Cardiac Surgery (Includes Patients With Isolated and
Recurrent Seizures)

Variable In-hospital Mortality Live Discharge p Value

Total no. of patients 13 48
Age (years) 72.3 (8.2) 69.2 (12.3) 0.41
Female 2/12 (17%) 16/48 (33%) 0.48
COPD 4/12 (33%) 4/48 (8%) 0.04
Ejection fraction (%) 42.5 (32.5-55.0) 55.0 (53.860) 0.02
APACHE II score 26.7 (7.0) 18.9 (5.4) o0.001
Preoperative creatinine (μmol/L) 122.0 (100.8-161.5) 96.5 (80.3-109.9) 0.02
Major stroke (watershed or large vessel) on CT head 4/8 (50%) 5/40 (13%) 0.03
New stroke on CT head 4/8 (50%) 5/40 (13%) 0.03
New postoperative renal dysfunction 7/13 (54%) 5/48 (10%) 0.01
Focal seizure 2/13 (15%) 10/48 (21%) 1.00
Grand mal seizure 6/13 (46%) 30/48 (63%) 1.00
Nonconvulsive seizure 1/13 (8%) 2/48 (4%) 0.57
Recurrent seizure 6/13 (46%) 30/48 (63%) 0.53

NOTE. Continuous variables are expressed as mean (standard deviation) for normally distributed variables and median (IQR) for non-normally
distributed variables. Categoric variables are reported as n/range.
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II score; CABG, coronary artery bypass graft; COPD, chronic
obstructive pulmonary disease; CT, computed tomography; ICU, intensive care unit; OR, operating room.

between groups (17.0 days [12.0 to 34.5] in the RS group v
12.5 days [6.3 to 28.3] in the isolated seizure group; p ¼ 0.09).
To investigate what factors, including RS, were associated
with survival, the authors performed a comparative analysis of
patients who died while in-hospital or were discharged alive
after surgery (Table 3). All patients who experienced one or
more seizures after cardiac surgery were included in this
analysis (n ¼ 61). Patients who died were more likely to have
chronic obstructive pulmonary disease, lower ejection fraction,
higher APACHE II scores, elevated preoperative creatinine,
postoperative CVA, and have postoperative renal dysfunction.
Interestingly, RS was not associated with in-hospital mortality
(p ¼ 0.53).
As seen in Figure 1, 83% of patients in the RS group and
76% of patients in the isolated seizure group were discharged
from the hospital. At a median (IQR) follow-up period of 21
(6-30) months for the RS group and 16 (11-28) months for the
isolated seizure group (p ¼ 0.79), a similar percentage of
patients died during the follow-up period, and a similar
percentage were restricted from driving at follow-up. One
person suffered a stroke in the RS group during follow-up
whereas one person experienced a seizure in the isolated
seizure group. Twenty-three percent of patients in the RS
group were readmitted to the hospital during the follow-up
period as compared to 16% in the isolated seizure group, and
17% of patients in the RS group were still on anticonvulsants at
the time of follow-up compared to 11% in the isolated
seizure group.
DISCUSSION
The risk factors and outcomes for patients who experience
RS after cardiac surgery have not yet been defined. With this
study, the authors examined the differences between patients
who experienced isolated seizure or RS after cardiac surgery.
They observed an RS rate of 59% in patients who had a
primary seizure (0.6% of all cardiac surgery patients in their
cohort). Patients with higher preoperative creatinine, patients
who undergo a procedure involving the thoracic aorta, and
patients who experience an initial seizure onset fewer than 4
hours postoperatively were more likely to have RS. In addition,
most patients with RS had grand mal seizures (81%), and the
majority occurred within 24 hours of surgery.
Mechanisms underlying postoperative seizures are not well
understood. One possible mechanistic explanation that links RS
to the risk factors identified in this study and previously
published data4 is higher levels of proconvulsant drugs in the
cerebrospinal fluid (CSF) in combination with pre-existing
brain abnormalities. For instance, TXA is a renally cleared,
proconvulsant antifibrinolytic drug that is an independent risk
factor for post–cardiac surgery seizures.1,2,4,5,12–14 In addition,
TXA-associated seizures occur in a dose-dependent manner
and have a higher incidence in patients with a previous history
of renal dysfunction.3,4 It is possible (although not proven in
this study) that patients with pre-existing brain abnormalities
and a disrupted blood-brain barrier (secondary to stroke or
other cerebral embolic phenomena from thoracic aortic surgery)
with high CSF levels of TXA and renal dysfunction are more
susceptible to seizure, particularly as sedation is decreased
postoperatively. In addition, when these patients have a seizure
and are resedated, it may be that circulating TXA levels are still
high when attempts to wean sedation are undertaken a second
time, thus provoking another seizure. Eventually, patients
eliminate TXA from their CSF, and the blood-brain barrier is
restored; this may explain why there is no further seizure in-
hospital or even postdischarge in most patients. It is noted that
the hospital length of stay for the RS and isolated seizure
groups was similar despite ICU and mechanical ventilation
time (likely related to sedation to prevent recurrent seizures)
being different. Although TXA levels were not statistically
significantly different between the isolated seizure and RS
groups in the authors’ study, they do not know what the CSF
TXA concentrations were. As dosing of TXA is an easily
modifiable variable, clinicians should consider using the lowest
dose of TXA that is optimal for the patient, especially if the
1210
patient has renal dysfunction and is going to have thoracic
aortic surgery. Obviously, TXA dosage must be balanced with
the risks of bleeding and need for transfusions. As mentioned
earlier, the authors’ study did not “prove” that there are indeed
high TXA levels in CSF,11 but their study puts forward a
possible hypothesis for future studies. Other factors of impor-
tance also include cerebral emboli from thoracic aortic surgery
as well as inadequate cerebral protection during DHCA. Hence,
care must be taken to minimize chances of cerebral emboli
from thoracic aortic surgery and to ensure adequate hypo-
thermia and consider selective cerebral perfusion during
DHCA.15
Risk of RS after cardiac surgery and the need to continue
antiseizure drugs (with side effects and drug interaction risks)
are a complication that may restrict resumption of normal
activity and may affect a patient’s quality of life. Intuitively,
clinicians might equate an RS with a poor outcome and risk of
further RS, thus compelling them to keep a patient on
anticonvulsants for a prolonged period. In the authors’ study,
however, most patients in the RS group were able to
discontinue anticonvulsant therapy within days of their first
seizure with no recurrence while in the hospital or at follow-up.
This lends support to the hypothesis that RS are due to transient
perioperative factors such as higher TXA levels in abnormal
brains, and, thus, long-term treatment with anticonvulsants may
not be warranted. Long-term follow-up showed no major
significant differences in outcomes between patients with
recurrent seizure and those with isolated seizure, suggesting
that having an RS does not necessarily predict a poor
prognosis.
Lastly, upon comparative analysis of patients who died
while in-hospital versus those who were discharged, the authors
observed that patients having RS were not more likely to die.
Factors important for death involved other comorbidities and
complications such as poor ventricular function, severe respi-
ratory disease, high APACHE II score, and stroke. It is
important to note that in the postdischarge follow-up, patients
with RS had mortality rates, readmission rates, requirements for
anticonvulsant therapy, and driving restriction rates that gen-
erally were comparable to patients with isolated seizures,
suggesting that RS do not increase morbidity or mortality.
These data could influence in-hospital management of patients
with RS.
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MANJI ET AL
As with any historical cohort study, there are limitations
related to retrospectively analyzed data. However, the information
in the authors’ databases is collected prospectively, and these
databases undergo periodic audits to ensure validity. Additionally,
the authors’ follow-up was by phone interview, and a small
percentage of patients were lost to follow-up. Thus, it is possible
that there were more patients who had RS postdischarge.
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of the authors’ study was to develop an exploratory model and to
suggest a possible mechanism that could identify important
factors worth investigating in future studies. As such, the authors
felt the best approach to the regression analysis was not using a
stepwise approach but rather choosing variables that appeared
clinically relevant and that had a p value o 0.1. Variables that
were collinear (eg, DHCA with thoracic aortic surgery) were
tested in the model and did not change the R2 value significantly;
thus, the authors kept the variables with the larger event rates in
the analysis. They obtained an R2 value of 0.53 and an area under
the ROC curve of 0.859 suggesting that their model has some
value in predicting seizure recurrence. Lastly, the treatment
decisions for seizures were dependent on the individual physician
caring for the patient at the time the seizure occurred and, as a
result, were not standardized. Hence, it is possible that the RS rate
may have been different if all patients with isolated seizure had
been similarly treated. However, the authors’ data, analysis, and
synthesis may provide clinicians with some additional informa-
tion for clinical decision-making and long-term management as
well as expanding on data currently available in the literature.
In conclusion, the authors’ data suggest that several risk
factors for recurrent postoperative seizure should be considered
when caring for this patient subset. For patients who are
administered anticonvulsant therapy, discontinuation of these
medications might be considered for most patients while in the
hospital followed by a period of observation. This may
minimize accompanying side effects and resulting restrictions
on activities.
ACKNOWLEDGMENTS
The authors would like to acknowledge Brett M. Hiebert
BSc (Statistics), MSc (Community Health Sciences) who
provided assistance with statistical analyses.
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system injury associated with cardiac surgery. Lancet 368:
694-703, 2006
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RECURRENT SEIZURES
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