Keywords
phenytoin - fosphenytoin - propofol - sevoflurane - cardiovascular effects - arrhythmias
- QT interval
Introduction
Seizure is one of the frequent complications in patients undergoing craniotomy; the
reported incidence is approximately 7 to 18%.[1]
[2]
[3] Phenytoin is the most frequently used prophylactic antiepileptic drug (AED).[1] A dose of 15 mg/kg is recommended to prevent seizures.[4] Intravenous phenytoin is reported to be safe at therapeutic levels of 10 to 25 µg/mL
when administered slowly at 50 mg/min.[5] The therapeutic safety is altered by intraoperative conditions such as changes in
the intravascular volume, hemodilution, and hypothermia.[6] There are several intraoperative serious adverse cardiac events such as hypotension,
arrhythmia, and sometimes even cardiac arrest with phenytoin.[6]
[7]
[8] The cardiovascular interactions between anesthetic agents and phenytoin may contribute
to the adverse cardiac effects, but it has not been evaluated.
Fosphenytoin, a prodrug of phenytoin, has been introduced as a safer alternative to
phenytoin with minimal adverse effects, including cardiovascular adverse effects.[9] However, adverse cardiovascular reactions such as severe hypotension and cardiac
arrhythmias like bradycardia, heart block, QT interval prolongation, ventricular tachycardia,
ventricular fibrillation, asystole, cardiac arrest, and death[10]
[11] have been described in elderly, debilitated, children especially infants,[12] critically ill, those with pre-existing hypotension and severe myocardial insufficiency.
There are no reports of its safety in the intraoperative period. Metabolism of fosphenytoin
yields equimolar concentrations of phenytoin and inorganic phosphate. Although many
cardiovascular effects of fosphenytoin are directly attributed to the blood phenytoin
concentrations, it has been shown to cause less hypotension than phenytoin.[13] The electrocardiogram (ECG) changes, however, are not solely related to phenytoin
accumulation. It causes QT prolongation, which is attributed to indirect toxicity
from inorganic phosphate and hypocalcemia. Anesthetic agents such as propofol[14] and inhalational agents also influence the QT interval.[15] The interaction of fosphenytoin and anesthetic agents has not been evaluated. We
hypothesized that fosphenytoin does not offer a hemodynamic benefit over phenytoin
during nonemergent administration of phenytoin and fosphenytoin under anesthesia,
and there would be a possible additive effect on the heart rate corrected QT interval
(QTc) changes during sevoflurane anesthesia. The trial's primary objective was to
compare the changes in hemodynamic parameters and QTc with phenytoin and fosphenytoin
in the intraoperative period during propofol and sevoflurane anesthesia. The secondary
objectives were to compare the need for cardioactive drugs and the incidence of arrhythmia.
Materials and Methods
After ethical committee approval, informed consent was obtained from 80 American Society
of Anesthesiologist grade I and II patients aged between 20 and 60 years, with body
mass index between 20 and 30 kg/m2, belonging to either gender, undergoing elective supratentorial surgery, and requiring
intraoperative intravenous loading dose of phenytoin for seizure prophylaxis who were
recruited for the study. Patients with baseline QTc more than 420 ms; patients who
received AED preoperatively; patients with previous adverse effects to phenytoin,
with significant cardiac disease; patients on antihypertensive and other drugs causing
QT changes; patients with electrolyte disturbances like hypokalemia, hypocalcemia,
patients undergoing surgery for neurovascular conditions; patients with large meningiomas;
patients requiring surgery in positions other than supine position; and patients requiring
induced hypo or hypertension and induced hypothermia were excluded from the study.
Withdrawal criteria were patients with significant blood loss during the study period,
patients requiring a change in the anesthetic drug concentration and depth of anesthesia
during the study period; patients with significant brain bulge requiring an additional
dose of mannitol or frusemide, hyperventilation, or intravenous thiopentone or propofol
for control of intracranial hypertension; patients with intraoperative temperature
drift to less than 35°C, intraoperative acid-base and electrolyte derangements; patients
developing hemodynamic changes due to neurosurgical causes; patients requiring cardioactive
drugs such as vasopressors, inotropes, vasodilators, atropine, and β-blockers.
The patients were randomly assigned to one of the four groups using computer-based
randomization using the function “Randbetween” on Excel; The group concealment was
performed using closed envelopes, and all the investigators were blinded to the group
assignment for the AED used. The AED was diluted to 100 mL 0.9% normal saline by a
technician not involved in anesthetic management or data entry. Patients in group
PP received propofol for the maintenance of anesthesia and intravenous phenytoin as
AED; group SP received sevoflurane for the maintenance of anesthesia and intravenous
phenytoin as AED, group PF received propofol for the maintenance of anesthesia and
intravenous fosphenytoin as AED and group SF received sevoflurane for maintenance
of anesthesia and intravenous fosphenytoin as AED. A baseline blood pressure, heart
rate, and ECG in the lead II were recorded. To facilitate intubation, patients were
induced with propofol 1.5 to 2 mg/kg fentanyl 2 mcg/kg, and muscle relaxant atracurium
0.5 mg/kg, intravenously. Patients were ventilated to maintain an oxygen saturation
of 100% and end-tidal carbon dioxide between 34 and 36 mm Hg. Maintenance of anesthesia
was based on randomization to propofol or sevoflurane. In the propofol groups, an
infusion of propofol, 2 mg/kg/hr, was administered along with fentanyl, 0.5 mcg/kg/hr,
and atracurium, 0.05mcg/kg/hr. In the sevoflurane groups, anesthesia was maintained
with end-tidal sevoflurane of 1MAC and fentanyl, 0.5 mcg/kg/hr, and atracurium, 0.05mg/kg/hr,
to maintain bispectral Index between 50 and 60. Invasive blood pressure, heart rate,
and ECG in the lead II were monitored during the maintenance of anesthesia. Blood
gas analysis was performed, and serum electrolytes were measured at the dural opening.
Patients were excluded if there was any derangement. Patients with significant brain
bulges requiring intervention were excluded from the study. An intravenous loading
dose of phenytoin 15 mg per kg or phenytoin equivalent to fosphenytoin (50 mg of phenytoin = 75mg
of fosphenytoin) was infused at the rate of 50mg/min after craniotomy and dural opening.
Patients were excluded from the study if the core temperature was less than 34°C.
Patients with significant blood loss (>500 mL) or hemodynamic disturbance (requiring
volume administration of >1,000 mL or use of cardioactive drugs) were excluded from
the study. Systolic, diastolic, and mean arterial pressure and heart rate were noted
and ECG in the lead II was recorded at the following measurement time points—1. baseline,
2. maintenance of anesthesia after intubation, infusion of phenytoin/fosphenytoin
at 25, 50, 75, and 100% completion of infusion (time points 3, 4, 5, 6, respectively)
after 5, 15, 30, and 60 minutes after completion of the infusion (time points 7, 8,
9, 10, respectively). Mild dysrhythmia such as bradycardia, defined as heart rate
less than 50 beats/min was treated with inj. atropine 0.6 mg. Hypotension, defined
as a reduction in systolic blood pressure by 20% of the baseline, was treated initially
with a fluid loading of 200 mL; if there was no response, mephentermine 6 mg bolus
was given and repeated after 10 minutes if the hypotension persisted. An infusion
of dopamine was started for persistent hypotension. Occurrence of arrhythmias and
significant hemodynamic changes during and after phenytoin/fosphenytoin infusion were
noted. Phenytoin/fosphenytoin was discontinued and administered at a slower rate in
patients with significant hemodynamic disturbances, and these patients were excluded
from the analysis of hemodynamics and QTc. QTc was calculated using Bazett's Eq.[16]
The hemodynamics and measured QT interval and the heart rate-adjusted QT interval
(QTc interval) during infusion of phenytoin and fosphenytoin were compared between
the groups.
Statistical Analysis
The sample size was determined using GPower, based on the prior probability of the
proportion of patients developing hemodynamic changes. The required sample size was
calculated for χ2 tests—goodness-of-fit tests, with an effect size of 0.45 with df of 5, the α error
probability of 0.05, and the power of 0.8 was 64. Eighty patients were recruited for
the study.
The categorical data were compared using χ2 tests—the goodness-of-fit test. The continuous data were compared between the groups
using analysis of variance (ANOVA), and posthoc analysis was done using the Bonferroni
test. The within-group comparison was made using ANOVA for repeated measures, and
posthoc analysis was performed using the Dunnett test with baseline and postanesthesia
values as control. A two-tailed p-value of 0.05 was considered significant to reject the null hypothesis that there
is no difference between the groups.
Results
Eighty patients were recruited for the study. Twenty-three patients were excluded
from the study after initial inclusion ([Fig. 1]). Eighteen patients were further excluded from the analysis of hemodynamic data
and QTc analysis as they developed significant hemodynamic changes requiring slowing
of administration of AED causing deviation from protocol. The study included 10 patients
in group PP, 9 in group SP, 12 in group PF, and 8 in group SF.
Fig. 1 CONSORT flow diagram. AED, antiepileptic drug.
There was no statistically significant difference in the demographic data between
the groups. The proportion of patients developing hypotension was higher with phenytoin
during propofol (11 [64.7%]) and sevoflurane anesthesia (11 [68%]), but there was
no statistically significant difference between phenytoin and fosphenytoin (p = 0.09 i.e., (6 [40%]) in group PF and (4 [44.4%]) in group SF depicted in [Table 1]. There was no statistically significant difference in the need for volume or mephentermine
to treat hypotension. Fourteen patients responded to volume alone. Seventeen patients
required mephentermine to manage hypotension; these patients were excluded from the
analysis of QT interval. Ten patients developed bradycardia with hypotension that
responded to mephentermine and did not require atropine.
Table 1
Comparison of demographic data and hemodynamic changes between the groups
|
Group
|
Group PP
(n = 17)
|
Group SP
(n = 16)
|
Group PF
(n = 15)
|
Group SF
(n = 9)
|
p-Value
|
|
Age (y)
|
43.2 (SD: 14.7)
|
39.2 (SD: 8.3)
|
38.9 (SD: 12.1)
|
35.9 (SD: 12.6)
|
0.62
|
|
Weight (kg)
|
59.0 (SD: 10.2)
|
53.3 (SD: 7.7)
|
61.1 (SD: 6.5)
|
57.3 (SD: 9.1)
|
0.30
|
|
Gender
|
|
|
|
|
0.29
|
|
Male
|
9(52.9%)
|
6 (37.5%)
|
8 (53.3%)
|
7 (77.8%)
|
|
|
Female
|
8 (47.1%)
|
10 (62.5%)
|
7 (46.7%)
|
2 (22.2%)
|
|
|
Bradycardia
|
2 (11.8%)
|
1 (6.2%)
|
3 (20.0%)
|
4 (44.4%)
|
0.09
|
|
Hypotension
|
11 (64.7%)
|
11(68%)
|
6(40%)
|
4 (44.4%)
|
0.34
|
|
Mephentermine
|
|
|
|
|
|
|
6 mg
|
5 (29.4%)
|
7 (43%)
|
2(13.3%)
|
1(11.1%)
|
0.34
|
|
12 mg
|
2(11.8%)
|
|
|
|
|
|
Volume resuscitation
|
4 (23.5%)
|
4(25%)
|
4(26.7%)
|
2(22.2%)
|
0.94
|
|
QTc > 450ms[a]
|
2/10 (20%)
|
6/9 (60%)
|
12/12 (100%)
|
8/8 (100%)
|
<0.001
|
Abbreviation: SD, standard deviation.
a Analysis of patients after the postinclusion exclusion.
There was no statistically significant difference in the baseline hemodynamic parameters
like heart rate, systolic, diastolic, or mean arterial blood pressure. The hemodynamic
changes following anesthesia were comparable between the four groups. The heart rate
changes during infusion of phenytoin, from baseline, and during anesthesia were not
statistically significant. There was a significant reduction in systolic, diastolic,
and mean arterial pressure from baseline toward the completion of phenytoin infusion
in both PP and SP groups. The fall of blood pressure with propofol was significantly
greater than with sevoflurane anesthesia. There was a fall in the systolic and mean
arterial pressure compared with baseline at 75% completion of infusion but returned
to baseline in group PF and at 25, 50, and 75% completion in the group SF, but these
changes were comparable during both propofol and sevoflurane anesthesia ([Figs. 2],[3],[4],[5]).
Fig. 2 Comparison of changes in the heart rate (HR). Times of measurement. 1: Baseline;
2: Anesthesia; 3: 25% completion of antiepileptic drug (AED); 4: 50% completion of
AED; 5: 75%completion of AED; 6: 100% completion of AED; 7: 5 minutes after completion
of AED; 8: 15 minutes after completion of AED; 9: 30 minutes after completion of AED;
10: 1 hour after completion of AED.
Fig. 3 Comparison of changes in systolic blood pressure (SBP). Times of measurement. 1:
Baseline; 2: Anesthesia; 3: 25% completion of antiepileptic drug (AED); 4: 50% completion
of AED; 5: 75%completion of AED; 6: 100% completion of AED; 7: 5 minutes after completion
of AED; 8: 15 minutes after completion of AED; 9: 30 minutes after completion of AED;
10: 1 hour after completion of AED.
Fig. 4 Comparison of changes in diastolic blood pressure (DBP). Times of measurement. 1:
Baseline; 2: Anesthesia; 3: 25% completion of antiepileptic drug (AED); 4: 50% completion
of AED; 5: 75%completion of AED; 6: 100% completion of AED; 7: 5 minutes after completion
of AED; 8: 15 minutes after completion of AED; 9: 30 minutes after completion of AED;
10: 1 hour after completion of AED.
Fig. 5 Comparison of changes in mean arterial blood pressure (MAP). Time of measurement.
1: Baseline; 2: Anesthesia; 3: 25% completion of antiepileptic drug (AED); 4: 50%
completion of AED; 5: 75%completion of AED; 6: 100% completion of AED; 7: 5 minutes
after completion of AED; 8: 15 minutes after completion of AED; 9: 30 minutes after
completion of AED; 10: 1 hour after completion of AED.
Prior to the administration of AEDs at measurement point 2, there was no significant
change in the QTc from baseline during propofol infusion (in groups PP and PF) and
QTc was significantly prolonged during sevoflurane anesthesia compared with the baseline
(in SP and SF groups). The infusion of phenytoin during propofol anesthesia did not
result in changes in QTc. There was no further significant change in the QTc with
phenytoin infusion during sevoflurane anesthesia. During fosphenytoin infusion in
group PF, there was a substantial prolongation of QTc compared with baseline and propofol
anesthesia at 50% completion of infusion and remained prolonged even at 30 min after
completion of fosphenytoin infusion. There was a significant prolongation of QTc in
the group SF compared with the other three groups. The prolongation was significant
as compared with baseline and sevoflurane anesthesia ([Fig. 6]). All patients in groups PF and SF had QTc more than 450 ms; 60% of patients in
group SP and 20% in group PP had long QT during the study period. There was one case
of significant nodal bradycardia followed by ventricular tachycardia and significant
hypotension in the group SF, which was resuscitated with inj. lignocaine, inj. adrenaline,
and inj calcium, and administration of AED was discontinued. This case was excluded
from analysis due to deviation from protocol, but the ECG showed significant prolongation
of PR and QT intervals before developing dysrhythmia.
Fig. 6 Comparison of changes in QTc. Times of measurement. 1: Baseline; 2: Anesthesia; 3:
25% completion of antiepileptic drug (AED); 4: 50% completion of AED; 5: 75%completion
of AED; 6: 100% completion of AED; 7: 5 minutes after completion of AED; 8: 15 minutes
after completion of AED; 9: 30 minutes after completion of AED; 10: 1 hour after completion
of AED.
Discussion
The results of this hypothesis generating pilot study indicate that phenytoin and
fosphenytoin produce significant hypotension, which was more pronounced during propofol
anesthesia than sevoflurane anesthesia. However, the study failed to show any statistically
significant difference in the proportion of patients developing hemodynamic changes
and needing volume or mephentermine between phenytoin and fosphenytoin during anesthesia.
There was a significantly greater prolongation of QTc in the group SF compared with
the other three groups. All patients in groups PF and SF had QTc more than 450ms.
There is no consensus on the efficacy of seizure prophylaxis in patients undergoing
craniotomy for nontraumatic conditions.[2] However, most neurosurgeons prefer to use intraoperative prophylactic AEDs. Even
patients taking AEDs preoperatively require additional loading intraoperatively as
the plasma levels may fall below the therapeutic levels due to factors such as blood
loss.[4]
[17] The incidence of intraoperative seizures was 2.3%.[3] The incidence of postoperative seizures in patients who did not have seizures preoperatively
was 17.7%.[1] Phenytoin, fosphenytoin, and levetiracetam are commonly used intraoperatively for
protection against postoperative seizure. It has been shown that phenytoin and fosphenytoin
are more protective than levetiracetam.[3]
Phenytoin is an established AED in treating acute repetitive seizures and status epilepticus
and is the most commonly used prophylactic anticonvulsant agent for postoperative
seizures.[1] However, cardiovascular adverse effects are frequently reported with intravenous
use of phenytoin. Phenytoin can cause a lowering in blood pressure as a result of
peripheral vasodilatation and a negative inotropic effect. It is also known that propylene
is found in phenytoin preparations to increase water solubility and may cause bradycardia
and asystole in toxic dosages. The incidence of hypotension reported with phenytoin
administered for seizure prophylaxis is approximately 25%. The infusion rate was the
most critical factor in determining the incidence of cardiovascular adverse effects.
Most of the reported deaths were in patients who received phenytoin at higher rates
(50–100 mg/min) than currently recommended rates.[5] Phenytoin has a narrow therapeutic margin (therapeutic range of [10–20 mg/L]). A
rapid infusion may cause temporary high levels of the drug because the distribution
of phenytoin in human tissues takes approximately 2 hours. A rate of lower than 50mg
per minute resulted in lower cardiovascular changes. The risk factors for adverse
cardiac events were age and comorbid cardiac and metabolic disorders.[5] The pre-existent cardiac disease made the patients more vulnerable to the infusion
of phenytoin. Metabolic disorders and advanced age may also have changed the elimination
and distribution of phenytoin and may have facilitated the adverse effects of hypotension
and arrhythmia. The interaction of phenytoin with neuromuscular blocking drugs and
its impact on the bispectral index have been studied. There are no reports of cardiovascular
changes with intravenous phenytoin administered intraoperatively.
The study population's incidence of hypotension during a 15 mg/kg loading dose of
phenytoin administered at 50mg/min was 65% during propofol anesthesia and 67% during
sevoflurane anesthesia. Significant hypotension requiring an inotropic agent was noted
in more than 40% of the patients. The intraoperative phenytoin may have resulted in
a higher incidence of hypotension due to its interaction with the anesthetic agents,
propofol and sevoflurane, which also influence cardiovascular function. This study
was conducted on patients screened for cardiac comorbidities and other concomitant
diseases such as hepatic or renal disease, hypoalbuminemia, malnutrition, and metabolic
disorders. The inclusion was restricted to selected patients with no risk for phenytoin
toxicity undergoing supratentorial craniotomy. Patients with significant intracranial
hypertension, blood loss, and electrolyte disturbances, which are not uncommon in
neurosurgical patients, were excluded from the study. It is possible that the incidence
and magnitude of hypotension would be more significant in these patients.[18] The unfavorable reports on the usage of intravenous phenytoin resulted in the new
AEDs with less adverse cardiac effects replacing phenytoin. Still, they are not more
effective than phenytoin.[2]
Fosphenytoin is a water-soluble, disodium phosphate ester of phenytoin. It does not
contain propylene glycol vehicle, which causes hypotension and cardiac arrhythmias.
Hence, it is considered safer to administer parenterally and rapidly with fewer significant
adverse cardiovascular effects than phenytoin.[9] The incidence of hypotension with fosphenytoin was 40% during propofol anesthesia
and 44% during sevoflurane anesthesia. Though the incidence was lower with fosphenytoin,
the study failed to show a statistically significant difference in the incidence of
hypotension between phenytoin and fosphenytoin as it was not adequately powered. A
similar incidence was seen in other reports too. Intravenous administration of fosphenytoin
has shown to be associated with hypotension in 39% and also atrioventricular block
in a retrospective case–control study.[19] Studies comparing adverse effects of phenytoin and fosphenytoin in the emergency
department did not find a difference between the two.[20] The current study failed to show a significant difference in the incidence of hypotension,
but the incidence was higher when phenytoin and fosphenytoin were coadministered with
propofol than sevoflurane. Hypotension was associated with bradycardia in ten patients
(17.5%), which improved with mephentermine and did not require additional atropine.
The incidence of bradycardia was greater in patients who received fosphenytoin, but
the difference was not statistically significant. There was no significant change
in heart rate during phenytoin or fosphenytoin infusion of a loading dose in patients
who did not have significant hypotension.
Prolonged QTc is frequently observed after brain surgery.[21] Hypokalemia, hypocalcemia, and hypothermia can also prolong the QTc. The anesthetic
drugs can also influence QT interval. There have been conflicting reports on whether
propofol prolongs,[14] shortens,[22] or does not change the QT interval.[23] Sevoflurane has been shown to prolong QTc.[23] Coadministration of drugs that prolong QT has shown to have an additive effect.[24]
[25] Fosphenytoin can theoretically alter the ECG by two mechanisms: the direct effects
of phenytoin on cardiac conduction and phosphate binding of calcium, which could indirectly
alter cardiac conduction as a result of hypocalcemia. Its interaction with anesthetic
agents has not been studied. Patients receiving sevoflurane 1 MAC for maintenance
of anesthesia had significant prolongation of QTc from the baseline, whereas the change
in QTc with propofol was not significant. Coadministration of intravenous phenytoin
did not result in further changes in QTc. Intravenous fosphenytoin resulted in significant
prolongation of QTc. Fosphenytoin coadministered with sevoflurane resulted in a more
substantial prolongation of QTc than propofol. However, the sample size was insufficient
to demonstrate statistical significance or the nature of interaction with sevoflurane.
One patient in group SF had significant bradycardia atrioventricular conduction delay
and QT prolongation with subsequent ventricular tachycardia. The remaining patients
with long QT had an unremarkable postoperative course. The perioperative period presents
several conditions that may prolong QT and increase the patient's risk of developing
complications of prolonged QT, such as polymorphic ventricular tachycardia or torsades
de pointes. The fosphenytoin-induced QT prolongation may be clinically relevant in
the presence of additional risk factors such as electrolyte abnormalities, hypothermia,
intracranial hypertension, and massive blood loss, which were excluded from QTc analysis
in this study. Even in the low-risk group, long QT (QTc > 450ms) at some point during
the study period was seen in all patients who were administered fosphenytoin, in 60%
of patients in group SP and the incidence was significantly lower in group PP.
Limitations
The major limitation of this study is the small number of patients included in the
analysis. About 225 were screened for possible inclusion to obtain eighty eligible
subjects. An interim analysis was performed after 80 cases. The withdrawal was high
in this study. The sample size of this study for analysis was small, but the findings
were significant and had implications for practice. We did not recruit further after
the interim analysis due to the high incidence of serious adverse event. A few changes
have been introduced into the practice of prophylactic anticonvulsant administration
since. Phenytoin was administered at a rate lower than recommended to reduce the cardiovascular
adverse effects. The recommendation by Meek et al for the use of phenytoin in nonemergency
situations in patients with a severe concomitant disease such as sepsis, hemodynamic
instability, peripheral vascular disease, and hyponatremia was 10 to 20 mg/min[18] that was followed. Subsequently, levetiracetam has become widely accepted as a safer
AED for intraoperative use,[26] but its efficacy is not yet established. The other limitation is that the study
did not evaluate the serum phenytoin levels or serum ionized calcium levels. The pilot
study is hypothesis-generating and needs further studies to validate the results of
this proof-of-concept study.
Conclusion
Loading dose of phenytoin and fosphenytoin administered intraoperatively produces
significant hemodynamic changes such as hypotension and bradycardia. There was no
significant difference in cardiovascular adverse effects between the two drugs. Fosphenytoin,
in nonemergent situations, did not offer any hemodynamic advantage. Fosphenytoin,
in addition, produced significant prolongation of QTc, and the prolongation was greater
during sevoflurane anesthesia. These agents must be administered cautiously in the
intraoperative period with monitoring for hemodynamics and changes in the ECG.
