Use of Amiodarone in Atrial Fibrillation Associated With Severe Sepsis or Septic Shock

Step-by-Step Methods:

Population: The study will be conducted at University Hospital, the 716-bed county hospital
for Bexar County and serves a varied population, including patients from medically
underserved areas. The patient population will come from the medical intensive care unit and
the cardiac intensive care unit, a 20 and 26-bed unit, respectively, at University Hospital
that is the clinical practice and teaching site for one study investigator.

Screening: Consecutive patients admitted to the medical or cardiac intensive care unit at
University Hospital with new onset atrial fibrillation in the setting of severe sepsis or
septic shock will be screened for study inclusion. Participants will be 18 years or older.
Patients who develop new-onset atrial fibrillation in the setting of severe sepsis or septic
shock will be considered for study inclusion. Exclusion criteria apply to those younger than
18 years of age, those with a history of atrial flutter, baseline QTc (a measurement made on
a electrocardiogram which measures the start of the Q wave to the end of the T wave) > 500
msec, atrial fibrillation during the index admission or in their past medical history, second
or third degree atrioventricular (AV) block, those recovering from cardiac surgery done
during the same hospital admission, those who have received amiodarone or other Vaughan
Williams class I or III antiarrhythmic drugs in the last 6 months, untreated/poorly
controlled hypothyroidism, hyperthyroidism, acute or chronic hepatic failure, other
requirements of antiarrhythmic drug therapy, recent cardiac surgery in the preceding 30 days,
and those who are pregnant.

Intervention: Patients aged 18 years or older who develop new-onset atrial fibrillation in
the setting of severe sepsis or septic shock and in whom the medical team deems appropriate
to initiate amiodarone therapy in will be considered for study inclusion. All patients will
receive a 150 mg IV bolus dose of amiodarone, followed immediately by a continuous infusion
of 1 mg/min for the first six hours, with a recommended reduction to 0.5 mg/min subsequently.
Conversion from IV to PO amiodarone will occur based on patient hemodynamic stability and
physician/pharmacist discretion. Patients will be randomized to receive amiodarone at a full
loading dose (≥ 5g IV or ≥10g PO +/- 20%) or a partial loading dose (<4g IV or < 8g PO). The
assigned total loading dose will include all IV and PO amiodarone administered within 7 days
from initiation of amiodarone. All doses will be compared in total PO amount (accounting for
50% bioavailability of PO versus IV amiodarone). The primary attending or fellow physician
may over-ride randomization if the patient's amiodarone dose if the patient's severity of
illness warrants a duration that differs from that assigned during randomization. In the full
loading dose group, discontinuation of amiodarone will be at the discretion of the
physician/pharmacists, after the pre-determined randomization loading dose has been provided.

Management Components: Facilities to be used throughout the project include the University
Hospital and The University of Texas Health Science Center at San Antonio. Equipment use for
direct patient care will be in keeping with standards-of-care, without any additional
equipment being required for the clinical research study.

Data Collection: Data collection will include age, race, gender, body mass index (BMI), data
for calculating an Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential
Organ Failure Assessment (SOFA) scores, suspected source of infection, identified pathogens,
pre-existing conditions that may predispose the patient to AF and the severity/classification
of such illness (coronary artery disease, heart failure, chronic kidney disease, chronic
obstructive pulmonary disease, diabetes mellitus); vital signs at the onset of AF (mean
arterial pressure, systolic blood pressure, heart rate), lactate, pH (scale of acidity), and
serum bicarbonate at the time of AF onset; fluid resuscitation volume for the 24 hours prior
to AF, vasopressor use (including drug, dose, duration) in the preceding 24 hours; other
medications used to stabilize hemodynamic status in AF (e.g. β-blockers, calcium channel
blockers, digoxin), other attempted methods of cardioversion attempted prior to amiodarone
use (e.g. direct current cardioversion, other antiarrhythmic drug therapy); amiodarone
loading dose, cumulative study amiodarone dose; the duration of time spent in AF before
conversion to normal sinus rhythm (NSR), the incidence of AF recurrence; and hemodynamic
variables to be assessed at various time points after the initiation of amiodarone (-6 hours,
at onset of AF, 2 hours, 6 hours, 12 hours, and every 6 hours thereafter until day 7 or
death) including mean arterial pressure, central venous pressure, systolic blood pressure,
heart rate, pH, serum bicarbonate, and serum lactate.

Monitoring for Efficacy and Safety:

Efficacy: Patients will be stratified based on response to therapy into one of three groups:
conversion to NSR, non-converting AF that is hemodynamically stable or non-converting AF that
is hemodynamically unstable. The primary efficacy outcome is the mean heart rate every 6
hours after initiation of the amiodarone infusion to day 7 or death. Secondary efficacy
endpoints will include the percentage of time spent hemodynamically unstable in the first 7
days following amiodarone initiation, ICU LOS, hospital LOS and 28-day mortality along with
comparisons of the individual portions of the hemodynamic endpoints [mean arterial pressure
(MAP), heart rate (HR), systolic blood pressure(SBP)], cumulative vasopressor doses of
norepinephrine and vasopressin, central venous pressure (CPR), conversion to NSR, maintenance
of NSR, proportion of time spent in NSR after the start of the infusion to day 7 or death,
pH, standard bicarbonate, serum lactate, and central venous oxygen saturation.

Safety: Safety outcomes include worsening of hypotension (largely related to the rate of
infusion and the polysorbate 80 diluent), bradycardia, acute elevations of liver function
tests ≥ 3 times the upper limit of normal, phlebitis, QTc prolongation, skin reactions,
neuropathy, and pulmonary toxicity. We will also collect premature study discontinuation due
to any adverse event. Because the experimental group of this study is a partial load of
amiodarone, rather than a full load, it is likely that the experimental group will experience
fewer amiodarone related adverse effects than those receiving the current practice. In the
setting of worsening hemodynamic stability during amiodarone infusion (i.e. SBP <90 mmHg OR
MAP < 70 mmHg, despite HR control of < 120 bpm; need for fluid boluses ± vasopressors or
dobutamine), which the medical team believes to be caused by IV amiodarone therapy:

1. the amiodarone infusion rate should be decreased by 50%, with efforts to increase back
to the standard infusion rate after the patient is hemodynamically stable, or

2. switch from IV amiodarone to PO amiodarone therapy at a dose of 400 mg PO three times
daily (TID), or

3. emergent electro-cardioversion at the discretion of the medical team (as is the standard
of care)

Data Analysis Plan: Data will be collected and stored using Microsoft Excel or Access. After
data organization and cleaning, data will be imported into JMP 12.0 or SPSS. Data will be
analyzed using both descriptive and comparative statistics. The primary outcome will be
analyzed using repeated measures ANOVA. Nominal and ordinal variables will be compared using
Chi-square test or Fisher's Exact test, as appropriate. Continuous variables will be tested
for normality using the Shapiro-Wilk W goodness of fit test. Continuous variables with normal
distributions will be compared using the student's t-test, while non-parametric variables
will be compared using the Wilcoxon rank sum test. Statistical significance will be defined
as an alpha level less than 0.05.

All baseline demographics, including patient comorbidities, amount of fluid resuscitation,
previous vasoactive therapies, and use of other interventions such as direct current
cardioversion, will be entered into a multivariate regression model if the p value is less
than 0.20 on univariate comparison between treatment groups. The multivariate regression
model will be used to assess if baseline factors or previous treatment other than the
intervention affected the study outcomes.

Based on extrapolation from available literature assessing HR control at 24 hours, we
estimate that the full loading dose group will have a mean HR of 110 bpm over the course of 7
days, while the partial loading dose group will have a mean HR of 130 bpm over the course of
7 days. 7 day mean HR that is 20 bpm lower than the partial loading dose group. Therefore, we
estimate that 250 patients will be necessary in each group to have an 85% power to detect a
difference, assuming a 15% drop-out rate.

Inclusion Criteria:

- New onset atrial fibrillation

- Severe sepsis or septic shock (defined by ≥2 systemic inflammatory response syndrome
criteria + infection)

Exclusion Criteria:

- Age < 18 years

- History of atrial flutter

- History of atrial fibrillation

- QTc >500 msec at baseline

- 2nd or 3rd degree AV block

- Currently receiving anti-arrhythmic therapy

- Untreated thyroid dysfunction

- Acute or chronic hepatic failure

- Other indication for antiarrhythmic therapy

- Recent cardiac surgery in last 30 days

- Pregnancy