Download Amiodarone role in ventricular arrhythmias in aortic Stenosis

Evaluation of Early Intraoperative Intravenous Amiodarone as Prophylaxis
Against Ventricular Arrhythmias for Patients with Aortic Stenosis Undergoing
Aortic Valve Replacement
Hisham Hosny Abdelwahab, MD1, Ahmed Fikry Attaallah, MD, PhD1, Mohamed Abuldahab
Mahmoud, MD2, Tarek Salah Abdallah, MD2
1- Department of Anesthesia and Critical Care, Cairo University
2- Department of Cardiothoracic Surgery, Cairo University
Abstract
Background and Goal of Study:
A high prevalence of ventricular arrhythmias is well documented in patients with severe aortic stenosis.
Ventricular fibrillation accounts for up to 20% of early mortality after aortic valve replacement and
remains the second most common cause of postoperative death in this population.
Several studies have shown significant reduction in the incidence of atrial fibrillation with prophylactic
amiodarone after open heart surgery. We designed this study to evaluate the role of amiodarone
prophylaxis against ventricular arrhythmias in patients with aortic stenosis undergoing valve
replacement surgery.
Methods
Thirty patients undergoing aortic valve replacement were randomly assigned to two groups; patients in
the first group received a 2.5 mg/kg bolus of amiodarone intravenously after induction of anesthesia
and patients in the other group served as control.
The incidence of ventricular arrhythmias, the number of shocks and the total energy dose needed for
cardioversion, and the length of intensive care unit (ICU) stay were recorded and compared between the
two groups.
Results
11 patients (73.3%) in the amiodarone group experienced ventricular arrhythmias during separation
from the cardiopulmonary bypass. On the other hand, 14 patients (93.3%) in the control group
experienced ventricular arrhythmias. Although the incidence of ventricular arrhythmias in the patients
who received a prophylactic dose of amiodarone was less than controls, 20% difference, yet
establishment of statistical significance was not achieved (p = 0.165). Moreover, the patients in the
amiodarone group responded to a lesser number of direct-current cardioversion shocks when compared
to controls (1.36 vs 2.36, p = 0.033) and needed less total dose of energy (21.33 vs 51.33 joules, p =
0.013).
All patients in the amiodarone group had a less eventful ICU course and did not experience any
ventricular arrhythmias during the postoperative ICU period, while 5 patients (33.3%) in the control
group experienced ventricular arrhythmias (p = 0.021). Patients in the amiodarone group had an almost
statistically significant shorter ICU stay when compared to controls (2.8 vs 4.13, p = 0.05).
Conclusion
Early intraoperative low doses of intravenous amiodarone seem to improve the ventricular arrhythmias
response to direct-current cardioversion therapy, when given to patients with aortic stenosis undergoing
aortic valve replacement. In addition, amiodarone decreased the incidence of ventricular arrhythmias in
the immediate postoperative period
Although a trend was shown in this study, future larger scale studies are needed to establish its role in
decreasing intraoperative ventricular arrhythmias during separation from the cardiopulmonary bypass
and in decreasing ICU length of stay.
Introduction:
Pathophysiology of AS & LVH
Chronic systolic pressure overload, of arterial hypertension and AS, results in increased ventricular
wall stress. As consequence of the hemodynamic abnormality, myocardial hypertrophy is thought to be
a compensatory process that leads to normalization in wall stress. Structural remodeling of the main
myocardial components (myocytes, collagen, and microvessels) is initially adaptive, but may have
deleterious consequences at a later stage [1].
Adverse effects of long-term hypertrophy include depressed myocardial contractility and altered
diastolic function, an increased collagen content, abnormal electrophysiologic properties, and
decreased myocardial perfusion due to a reduction in coronary vasodilator reserve [2,3]
Electrophysiologic abnormalities in LVH
The cardiac muscle is basically anisotropic; that is the direction of myocardial syncytium dictates its
electrophysiologic properties with different axial resistance along and perpendicular to the fiber axis.
During conduction of the impulse, axial current flows from one myocardial cell to an adjacent cell
through the gap junctions of the intercalated disks. The anisotropic properties involved are determined
by the alignment of cardiac myocytes, the distribution of gap junctions, and the geometry of
extracellular space. This architecture is reflected in a lower axial resistivity and a higher conduction
velocity in the longitudinal direction of myocardial fibers rather than crosswise [4, 5]
In an experimental model of LVH, Kowey et al confirmed the presence of prolonged monophasic
action potential duration in the hypertrophic myocardium, and also showed that hypertrophic myocytes
had a larger dispersion of refractoriness and a lower ventricular fibrillation threshold, both of which
could be responsible for development of functional reentry in LVH [6]
Stretch-induced arrhythmias may appear in LVH when the length of the fibers exceeds their optimal
point [7]. The mechanism suggested to cause arrhythmias under these conditions is the development of
electrophysiologic changes during or after changes in mechanical loading conditions (during sudden
changes in volume or pressure load), a mechanism known as mechanoelectrical feedback [8, 9].
Increased Risk of Ventricular Arrhythmias in LVH
In patients with essential hypertension, programmed ventricular stimulation induced intraventricular
reentry beats in 92% of the subjects with Left Ventricular Hypertrophy (LVH) and 17% of the subjects
without LVH, indicating that the increase in myocardial mass may represent an anatomic substrate for
ventricular arrhythmias [10]. Vester and coauthors also performed programmed ventricular stimulation
In 40 hypertensive patients with history of syncope, complex ventricular arrhythmias, and/or aborted
sudden death. Ventricular tachycardia or ventricular fibrillation were induced in 30% in the patients
with LVH, and it was shown that ventricular arrhythmias were closely related to ventricular
hypertrophy [11]
AS and Ventricular Arrhythmias
Premature ventricular contractions, documented by Holter monitoring, are frequent in patients with
aortic valvular disease. [12]
Also, a high prevalence of ventricular arrhythmias in patients with aortic valve disease, without
significant coronary artery disease, was documented by Santiga et al [13]. The frequency and
complexity of the ventricular arrhythmias were closely related to myocardial function and thus were
more common in patients with higher left ventricular systolic stress and reduced systolic function. On
the contrary, the severity of arrhythmias was not related to the etiology of valve stenosis, the severity of
aortic valve disease, or the transvalvular gradient [14]
Consequences of Ventricular Arrhythmias in AS
Compared with normal hearts, the hypertrophic myocardium in AS has normal or increased blood flow,
and normal myocardial oxygen consumption at rest. During increased load an impairment of the ability
to mobilize the coronary vascular reserve may be attributed to both structural (fewer capillary
vessels/volume) and functional (vascular tone) disturbances [15,16]
This causes an increase in the minimum coronary vascular reserve value. A redistribution of blood flow
from the endocardium to the epicardium is demonstrated by an endo/epicardial blood flow ratio below
1.0 [17, 18]. The redistribution is augmented with increasing heart rate and muscle tension [19]
Despite sufficient coronary perfusion and unchanged global myocardial oxygen consumption, VF in
AS patients rapidly led to myocardial ischemia, acidosis and a transient increase in the myocardial
noradrenalin release. Simultaneously, VF also instantly induced equilibration of left ventricular and
aortic pressure[20, 21]
Due to these severe metabolic derangements, ventricular arrhythmias account for up to 20% of early
mortality after aortic valve replacement and remain the second most common cause of postoperative
death in this population [22, 23].
Amiodarone prophylaxis and atrial fibrillation after open heart surgery
The concept of pharmacologic prophylaxis against atrial arrhythmias after cardiac surgery has been
well studied.
Amiodarone has been shown to significantly reduce in the incidence of atrial fibrillation after open
heart surgery in small case series, often combining the oral and intravenous formulation.
Butler et al. administered 15 mg/kg of amiodarone immediately after releasing the aortic cross clamp
followed by 600 mg/day for three days. “Clinically significant” supraventricular arrhythmias occurred
in Eight percent of the amiodarone-treated group as compared with 20% in the placebo control group
[24].
Hohnloser and colleagues] administered a loading intravenous bolus of 300 mg of amiodarone
postoperatively followed by 1200 mg/day for two days and 900 mg/day for two days. Twenty one
percent (8 of 38 control of patients) experienced atrial fibrillation while only 5% (2 of 39) of patients
treated with amiodarone had atrial fibrillation [25].
Daoud preoperatively gave patients an oral dose of 600 mg / day for seven days preoperatively,
followed by 200 mg/day until discharge. In the control group, 32 of 64 (50%) experienced atrial
fibrillation, whereas only 16 of 64 (25%) treated with amiodarone had atrial fibrillation. The degree of
benefit appears to be greatest in the Daoud study, possibly because of the large preoperative dose [26].
Two meta-analyses had a consistent finding; that antiarrhythmic agents with beta-blocking properties
(i.e., class II beta-blockers, sotalol, and amiodarone) have shown to be the most promising for
successful atrial fibrillation prophylaxis [27, 28].
The ARCH study was specifically designed to analyze the effects of the intravenous formulation of
amiodarone only, given in the immediate postoperative period, and showed a decrease in the incidence
of atrial fibrillation after open heart surgery by 26% [29].
Goal of Study:
We designed this open-label randomized prospective study to evaluate the role of intravenous
amiodarone prophylaxis against ventricular arrhythmias, during the intraoperative and immediate
postoperative periods, in patients with aortic stenosis undergoing valve replacement surgery.
Patients and methods:
Patient Population
After the approval of the Ethics and Research Committee of the Department of Anesthesiology in Kasr
El-Aini Hospital, Cairo University; thirty consecutive patients undergoing elective aortic valve
replacement were included in the study.
After obtaining written informed consents, patients were randomly assigned to two groups. Patients in
the first group received a 2.5 mg/kg bolus of amiodarone intravenously after induction of anesthesia
and central venous line insertion, and the patients in the other group served as control.
Preoperative evaluation included a detailed medical history with documentation of preoperative
medication, physical examination, 12-lead electrocardiogram, chest X-ray, pulmonary function tests (if
lung disease was suspected), and thyroid function tests.
Patients with contraindications to amiodarone (sick sinus syndrome, atrioventricular conduction
abnormalities, thyroid disease, interstitial lung disorders, and renal or liver disease) were excluded. We
also excluded patients who needed a concomitant cardiac surgical procedure or an emergency
operation, and patients with history of chronic or intermittent arrhythmias, and the ones pretreated with
amiodarone or other antiarrhythmics.
Anesthesia
After premedication with midazolam 1-3 mg, general anesthesia was induced with propofol 1-2 mg/kg,
fentanyl 2 mcg/kg, and pancuronium 0.1 mg/kg. Patients were intubated and mechanically ventilated
with an inspiratory mixture of 50% air and 50% oxygen. Anesthesia was maintained with isoflurane,
fentanyl, and pancuronium. Electrolytes, acid-base status, and temperature were monitored and kept
within normal levels till reaching the ICU
Surgical Procedure
All operations were performed with cardiopulmonary bypass, cardioplegic arrest (HTK solution, 4°C,
15 mL/kg), and moderate hypothermia (28°C). Venous cannulation was done by a single common
atrial cannula through the right atrium and the arterial cannula was placed into the ascending aorta.
Debubbling was done through cannulation of the right superior pulmonary vein and the cardioplegia
cannula in the ascending aorta. Valve replacement was performed using ethibond 2/0 in transverse
mattress sutures and closure of aortotomy was performed using prolene 4/0 in two layers. All patients
received ventricular temporary bipolar pacing wires.
Recovery
At the end of surgery, the patients were transferred to the surgical ICU and mechanical ventilation was
continued. All patients who were hemodynamically stable and had normal ventilatory mechanics, acid-base
status, PaO2, and PaCO2 at an inspired FiO2 of 0.4, were weaned from sedation and extubated when they
were able to respond comprehensibly to simple verbal commands.
Monitoring
Continuous electrocardiographic monitoring was performed intraopertively and for the length of ICU
stay with two leads display of Lead II and V5, in addition to ST segment analysis. Ventricular arrhythmia
was defined as any episode of ventricular tachycardia or fibrillation. If judged clinically necessary,
additional therapy including the administration of more/other antiarrhythmic drugs, direct-current
cardioversion, or temporary pacing for bradycardia of less than 50 beats per minute was instituted.
Data Collection

Demographic data

Aortic cross-clamp time

Cardio-pulmonary bypass time

The incidence of ventricular arrhythmias in the intraoperative period

Number of direct-current shocks

The total energy needed (J)

The length of ICU stay

The incidence of ventricular arrhythmias in the postoperative ICU period
Sample size calculation
We planned to study independent cases and controls, with 1 control(s) per case. Prior data indicate that
the occurrence rate of ventricular arrhytmias among controls is 92% [10].
If we expect that amiodarone use will decrease the incidence to half (45%), we will need to study 15
experimental subjects and 15 control subjects to be able to reject the null hypothesis; that the
occurrence rates of ventricular arrhythmias for experimental and control subjects are equal with a
power of 80%. Type I error probability associated with this test was adjusted at 0.05.
Statistical analysis
Data were statistically described in terms of range, mean  standard deviation ( SD), median,
frequencies (number of cases) and percentages when appropriate. Since all data were not normally
distributed, comparison of quantitative variables was done using Mann Whitney U test for independent
samples. For comparing categorical data, uncorrected Chi square (2) test was performed. Exact test
was used instead when the expected frequency is less than 5. A probability value (p value) less than
0.05 was considered statistically significant. All statistical calculations were done using Microsoft
Excel 2003 (Microsoft Corporation, NY, USA) and SPSS (Statistical Package for the Social Science;
SPSS Inc., Chicago, IL, USA) version 15 for Microsoft Windows.
Results
There were no significant preoperative differences regarding age (p = 0.902), sex (p = 0.132), or
ventricular function (p = 0.367) between the two groups. Also, there were no significant intraoperative
differences regarding cross-clamp time (p = 0.744) or bypass time (p = 0.902). [Table 1]
Group I (Amiodarone)
Group II (Control)
p value
53.60 (±16.8)
57.47 (±10.3)
0.902
4:11
8:7
0.132
26.7% male
53.3% male
EF
62.67 (±8.5)
62.13 (±4.6)
0.367
AXC time
59.93 (±18.8)
58.53 (±11.9)
0.744
CPB time
86.93 (±26.7)
77.93 (±12.9)
0.902
Age
Sex (M:F)
Amiodarone infusion was terminated prematurely in one patient because of hemodynamic instability
but that patient was included in the statistical analysis as an intention to treat subject.
Four patients (26.7%) in the amiodarone group returned to spontaneous sinus rhythm during separation
from the cardiopulmonary bypass, while the other 11 patients (73.3%) in that group experienced
ventricular arrhythmias. On the other hand, only 1 patient (6.7%) in the control group returned to
spontaneous sinus rhythm while the other 14 patients (93.3%) experienced ventricular arrhythmias.
Although the incidence of ventricular arrhythmias in the patients who received a prophylactic dose of
amiodarone was less than controls, 20% difference, yet establishment of statistical significance was not
achieved (p = 0.165).
Moreover, the patients in the amiodarone group responded to a lesser number of direct-current
cardioversion shocks when compared to controls (1.36 vs 2.36, p = 0.033) and needed less total dose of
energy (21.33 vs 51.33 joules, p = 0.013).
All patients in the amiodarone group had a less eventful ICU course and did not experience any
ventricular arrhythmias during the postoperative ICU period, while 5 patients (33.3%) in the control
group experienced ventricular arrhythmias (p = 0.021). Patients in the amiodarone group had an almost
statistically significant shorter ICU stay when compared to controls (2.8 vs 4.13, p = 0.05). [Table 2 –
Figure 1]
Group I (Amiodarone)
Group II (Control)
4
1
26.7%
6.7%
11
14
73.3%
93.3%
Number of shocks
1.36 (±0.7)
2.36 (±1.4)
0.033
Total energy dose
21.33 (±19.6)
51.33 (±42.6)
0.013
Ventricular
arrhythmias in ICU
0
5
0.021
0%
33.3%
2.80 (±1.6)
4.13 (±3.1)
Spontaneous SR after
CPB
Ventricular
arrhythmias in OR
ICU LOS
Group I (Amiodarone)
p value
0.165
0.165
0.050
Group II (Control)
60
50
40
30
20
10
0
Spontaneous SR after Ventricular arrhythmias
CPB
in OR
Number of shocks
Total energy dose
Ventricular arrhythmias
in ICU
ICU LOS
Discussion
Pharmacologic prophylaxis against atrial arrhythmias after cardiac surgery has received lot of attention
and has been well studied. Different drugs for atrial arrhythmias prophylaxis have shown a significant
benefit with a reduction in their incidence [27, 28].
On the contrary, no previous studies have investigated the concept of prophylaxis against ventricular
arrhythmias in these patients. While ventricular arrhythmias are considered more serious and a
common cause of mortality after open heart surgery, to the best of our knowledge, amiodarone is only
used for treatment of such arrhythmias.
We chose to use amiodarone in our study because it is a unique antiarrhythmic agent that inhibits
multiple ion channels (i.e., potassium and calcium) and adrenergic receptors, and it can be utilized as a
prophylactic therapy in patients with structural heart disease because of its low risk of proarrhythmia
[27].
In our study, intravenous amiodarone was the chosen route of administration. Unlike the oral
compound, which has an onset of action of at least several days, intravenous amiodarone appears to act
within a few hours as judged by the treatment of refractory ventricular tachycardia [29, 30].
This shorter onset of action would provide a more accurate timing for the drug effect in these patients
as they separate from cardiopulmonary bypass.
The concept of administering the prebypass prophylactic dose was both attractive and practical for the
purpose of our preliminary study. It allowed us to examine the cause-effect relation for amiodarone
during the peak of the ventricular arrhythmias risk in the.intraoperative and immediate postoperative
periods in a simplified manner.
We chose to study AS patients, as a subset group undergoing open heart surgery, because ventricular
arrhythmias happen with high prevalence in these patients. [13]
We assumed that studying this subset group would allow us to conduct this preliminary study in a
smaller number of subjects undergoing cardiac surgery.
Limitations of study
The current study was specifically designed to test the effect of low doses of intravenous amiodarone in
preventing ventricular arrhythmias when given in the prebypass period intraoperatively.
The lack of previous data on the proper dosage, the time of administration, and the small study size
dictate the need for further larger studies to investigate different dosing regimens.
Given the results of the Daoud report [26], it is possible that a higher prophylactic doses of amiodarone
might have a more pronounced beneficial effect.
Further future study are also needed to examine the value of extending amiodarone therapy,
intravenous or oral, in the postoperative period and its effects on long-term outcomes.
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