Treatment of Ventricular Tachyarrhythmias Refractory To Shock With Beta Blockers: The SHOCK and BLOCK Trial

Sudden cardiac death (SCD) is a catastrophic event and most commonly results from acute
ventricular tachyarrhythmias (abnormal and lethal heart rhythms). It is often triggered by
acute coronary events, which may occur in persons without known cardiac disease or in
association with structural heart disease. Advanced therapies such as thrombolytic agents,
percutaneous coronary intervention, and implantable cardioverter defibrillators are of no
value to thousands of victims who do not survive. Many instances of SCD cannot be predicted
and any intervention directed toward the general population would have to be applied to an
estimated 1000 persons for every 1 person in whom SCD might be prevented. Thus, it would be
reasonable to develop new treatment strategies to improve response to resuscitative efforts.

Prompt electrical defibrillation (electrical shocks) is the treatment of choice in persons
who develop SCD due to ventricular fibrillation (VF) or pulseless ventricular tachycardia
(pVT). However, in up to 25% of all cardiac arrests, patients develop shock resistant VF,
defined as VF persisting beyond three defibrillation attempts, and 87-97% of these patients
die. Medical therapy, including antiarrhythmic agents, sympathomimetic agents (i.e.
stimulants), and buffers have been relegated to a secondary role since there is little
evidence that they are of benefit and there use is considered indeterminate or class IIB.
Furthermore, the "Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care" of the American Heart Association and the International Liaison
Committee on Resuscitation recommend antiarrhythmic drugs as "acceptable" and "probably
helpful" in the treatment of VF that persists after three or more external defibrillation
shocks. It has been previously reported that the survival rate of hospital patients
suffering a cardiac arrest in which epinephrine was required was only 6%. Furthermore,
Dorian et al reported a survival to hospital admission of 22.8% in patients suffering an out
of hospital cardiac arrest and receiving amiodarone. It is believed that the acute effects
of amiodarone are due to the class II or beta blocking effects of the drug.

Resuscitation can only be considered successful if the survivor has no disabling cognitive
function. The American Heart Association/International Liaison Committee on Resuscitation
guidelines state that with a duration of cardiac arrest of > 8 to 10 minutes, the frequency
of significant, permanent neurologic damage becomes unacceptably high. Newer treatment
modalities are needed to improve patient outcomes.

Epinephrine has been used during cardiopulmonary resuscitation for more than 100 years yet
its use has become controversial because it is associated with increased myocardial oxygen
consumption, ventricular tachyarrhythmias, and myocardial dysfunction during the period
after resuscitation. The current International Guidelines on Emergency Cardiac Care cite
both epinephrine and vasopressin as acceptable vasopressor drugs for treatment of refractory
VF but neither drug is acknowledged to be of proven benefit.

Beta blockers might improve patient outcomes by blunting the adverse affects of a
hyperadrenergic state that occurs during a cardiac arrest and by improving the balance
between myocardial oxygen supply and demand. Ditchey et al showed in an animal model that
pretreatment with a beta blocker prior to cardiac arrest followed by standard epinephrine
therapy results in reduced myocardial injury during CPR without compromising successful
defibrillation or post resuscitation left ventricular function.

The current research protocol was formulated in an attempt to develop new treatment options
for patients who develop an in-hospital VF or pVT arrest refractory to electrical
defibrillation with the specific goal of improving patient outcomes. The trial will utilize
pre-filled, blinded syringes of Metoprolol in patients who develop an in-hospital cardiac
arrest due to ventricular fibrillation or pulseless ventricular tachycardia (see study
protocol).

Sudden cardiac death (SCD) claims approximately 250,000 persons annually in the United
States. Ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) appear to
be responsible for 25-35% of all out of hospital episodes of sudden cardiac death. The
reported average survival to hospital discharge following in-hospital arrest is just as poor
at approximately 14-17% despite the development of widespread implementation of basic and
advanced cardiac life support. Current American Heart Association (AHA) guidelines
recommend prompt electrical defibrillation to reestablish organized electrical activity.
Increasing duration of VF (i.e. "shock resistant VF") can result in two major adverse
effects. First, an increased duration can reduce the ability to terminate the arrhythmia8.
Second, if VF continues for more than four minutes, there is irreversible damage to the
central nervous system and other organs. Despite aggressive efforts, successful
resuscitation from out-of-hospital cardiac arrest occurs in only one third of patients and
only about 10% of all patients are ultimately discharged from the hospital, many of whom are
neurologically impaired. Also, the outcome of patients who suffer an in-hospital cardiac
arrest is poor with reported survival to hospital discharge rates of 10-15%. Thus, despite
improvements and advances in the treatment of heart disease, the outcome of patients
experiencing SCD remains poor.

Prompt and early defibrillation of VF or pVT has become the standard of care. Drug therapy
for shock resistant VF or pVT has been relegated to a secondary role since there is little
evidence that these agents are of benefit. As a result, their use is considered
indeterminate or class IIB. In addition, cardiac arrest and cardiopulmonary resuscitation
are extreme forms of stress that lead to the highest catecholamine levels ever recorded in
both human or experimental animal models. Endogenous catecholamine concentrations are high
during ventricular fibrillation even in the absence of epinephrine administration.
Currently, epinephrine is the vasopressor of choice for the treatment of cardiac arrest
although vasopressin has been used as an alternative. Of note, vasopressin has been shown
to be superior to epinephrine in patients with asystole however, its effects were similar to
those of epinephrine in the management of VF or pulseless electrical activity. Furthermore,
previous studies have raised concern that epinephrine's beta adrenergic effect may increase
the myocardial oxygen consumption of the fibrillating heart and predispose to
post-defibrillation dysfunction and cardiac arrhythmias.

Numerous animal studies have shown that beta adrenergic blockade reduces myocardial injury
and improves survival. Kudenchuk, et al undertook a study in patients with out of hospital
cardiac arrest due to ventricular fibrillation. Patients were randomized to receive either
amiodarone or placebo after three consecutive defibrillations and one dose of epinephrine.
The authors concluded that patients who received amiodarone had a higher rate of survival to
hospital admission. It is felt that the beneficial effects are related to the initial class
II or beta blocking properties of amiodarone. Furthermore, Dorian, et al reported a higher
rate of survival to hospital admission in patients who received amiodarone as compared to
lidocaine for shock resistant out-of-hospital ventricular fibrillation. Analysis from the
European Myocardial Infarct Amiodarone Trial and the Canadian Amiodarone Myocardial
Infarction Trial revealed an interaction between beta-blockers and amiodarone, specifically,
the combination group had a better survival and the interaction was statistically
significant for arrhythmic death or resuscitated arrest.