Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery

II. Background

1. Description of the Problem One of the effects of cardiac operations involving
cardiopulmonary bypass is reversible myocardial dysfunction lasting a number of days
postoperatively. Typically this period of myocardial dysfunction is treated with
vasoactive drugs aimed at improving contractility and reducing afterload. Problems
exist with the current vasodilator therapy, including: variable response, inadequate
response, complications of delivery mechanism with the potential for swings in blood
pressure and ongoing dose adjustments. These are necessary due to the patients'
autonomic nervous system reactivity changes during the post-cardiopulmonary bypass
period. Evidence to support therapies targeting control of systemic vascular resistance
include randomized controlled studies looking at the outcome of high risk neonates
undergoing open cardiac procedures with very high dose synthetic narcotic anesthesia.
This is known to reduce sympathetic nervous system activity. There exist numerous,
uncontrolled but widely accepted, studies documenting the adjunctive use of
vasodilators such as sodium nitroprusside, nitroglycerin and alpha-adrenergic blockers
including phenoxybenzamine in the perioperative period. The results of all of these
studies point towards a salutatory effect of measures to control vasoconstrictor
responses on blood flow to the organs at risk, primarily the organs in the splenic
circulation: the liver, kidneys, and intestines. Ischemia to these organs is
responsible for a significant amount of morbidity in the post-bypass period including
late onset sepsis and renal dysfunction. In addition, after myocardial injury the
natural vasoconstrictor responses that mammalian organisms have to falling cardiac
output are counterproductive and may initiate a cascade of responses, necessitating
medical interventions culminating in overt myocardial pump failure. This then can lead
to patient death or need for institution of extracorporeal circulatory support after
the initial cardiopulmonary bypass period.

2. Physiologic Role of Phenoxybenzamine Numerous reports have demonstrated that with
nearly complete blockage of alpha-adrenergic receptors (i.e. phenoxybenzamine) that
both infusions of exogenous catecholamines and the neural release of endogenous
catecholamines result not in vasoconstrictor responses but instead augmented myocardial
contractility without increases in afterload. While medical interventions to effect
circulatory responses are already in use commonly in the perioperative period,
including synthetic narcotic analgesia and the use of short-acting vasodilator agents,
these measures alone have not been universally effective in preventing the sort of
hemodynamic deterioration described above. Therefore, we propose to use
phenoxybenzamine, a drug which irreversibly binds to alpha-adrenergic receptors and
some dopamine receptors, as an adjunct to the management of the perioperative vascular
tone abnormalities in high risk infants and children undergoing cardiopulmonary bypass
for open heart procedures.

3. Existing pharmacologic and clinical data Phenoxybenzamine (Dibenzyline: Wellspring
Pharmaceutical Corporation, Bradenton, FL) is a haloalkylamine that irreversibly blocks
both α-1 and α-2 adrenergic receptors. The drug exhibits a slightly higher affinity for
the α-1 receptor. 12 There exists a body of literature concerning intravenous
administration of phenoxybenzamine in the setting of congenital heart disease surgery,
specifically in the Norwood repair for hypoplastic left heart syndrome. The use of
phenoxybenzamine during cardiac surgery has been demonstrated to facilitate higher pump
flow rates during cardiopulmonary bypass (CPB) and is associated with attenuation of
postoperative metabolic acidosis. 13 Specifically, phenoxybenzamine has been shown to
be more effective than sodium nitroprusside in improving tissue perfusion postbypass
(as demonstrated by a comparison of rewarming characteristics), with lower base
deficits in patients treated with phenoxybenzamine. 14 Indeed, to date there are many
congenital heart disease surgical centers in the United States who, prior to the
Norwood procedure, administer 0.25 mg/kg of phenoxybenzamine at the initiation of
cardiopulmonary bypass in an attempt to optimize systemic organ perfusion in the
perioperative period. Such a protocol, at this dose specifically, has been described to
improve systemic oxygen delivery in patients undergoing the Norwood procedure for
hypoplastic left heart syndrome, as well as an improvement in survival to future
surgical palliations. 10

III. Aims and Objectives

Our general hypothesis is that a blockade of vasoconstrictor responses in the period around
cardiopulmonary bypass will result in better organ preservation and improvement in cardiac
output postoperatively. More specifically, as serum lactate serves as a surrogate for
demonstrating the adequacy of end organ perfusion, we will utilize this continuous variable
as our primary endpoint for the purposes of this protocol. Our hypothesis is that the use of
phenoxybenzamine in this select population will reduce initial postoperative lactate levels
by a clinically-relevant level of 25%, relative to historical controls. Secondary endpoints
evaluated as well will include utilization of inotropic support, duration of
hospitalization, and time to resolution of postoperative lactic acidosis. Both physiologic
and outcome variables will be examined and compared to a matched cohort of patients drawn
from our recent experience without the use of phenoxybenzamine.

IV. Patient Selection and Clinical Management

Patient selection will be determined by an assessment of the risk of systemic ventricular
dysfunction following open cardiac repair in a population of infants undergoing stage I
palliation (Norwood procedure) for the diagnosis of either hypoplastic left heart syndrome
or similar left-sided obstructive lesions in the setting of single-ventricle physiology.
Eligible neonates and infants include those aged 0 days to 6 months. These patients will be
evaluated on an individual basis and the decision to give phenoxybenzamine would be
determined by the attending surgeon, anesthesiologist, and cardiologist. No other change in
the patients' perioperative management will occur. Efficacy will be assessed by evaluating
the need for vasodilators and inotropic agents, as well as by evaluating the effects of
alpha-blockade on the clinical course and hemodynamics of the patient. Comparison to a
matched historical cohort of patients not receiving the drug will be performed. Likewise,
the historical cohort population to be included in this population include all infants who
have undergone the Norwood procedure for either hypoplastic left heart syndrome or those
with a similar univentricular lesion requiring aortic arch reconstruction. Aside from the
importance of meeting protocol inclusion criteria, there are no specific criteria to exclude
subjects

V. Drug Administration and Safety Monitoring

Parenteral phenoxybenzamine requires an IND for human administration, which has been
submitted to the FDA and is pending (see attached). The only significant risk of parenteral
phenoxybenzamine has been excessive alpha-adrenergic blockade resulting in diastolic
hypotension. This problem has been treated with intravenous adrenergic support in the form
of norepinephrine or vasopressin. Precautions in place during the use of phenoxybenzamine
will include physician presence during administration, invasive arterial blood pressure
monitoring, and inotropic agents available for immediate use. This drug will be obtained
from WellSpring Pharmaceuticals and stored in the Investigational Drug Pharmacy.

The drug will be administered in the operating room. After induction of anesthesia and the
pIacement of appropriate cardiovascular monitoring lines, an initial loading dose of 0.25
mg/kg will be administered intravenously immediately prior to cardiopulmonary bypass.For up
to 72 hours postoperatively, 0.25 mg/kg/day will be administered Based on published
pharmacokinetic data these doses should block 90 -95% of alpha-peripheral receptors with a
half life of 24 - 36 hours for regeneration. This period of time corresponds nicely with the
period of highest hemodynamic vulnerability of this patient population. No alteration in
usual perioperative monitoring will occur solely to allow drug administration. Monitoring of
anesthesia, preload, afterload, contractility, and cardiac output will be maintained
throughout the period of administration and recovery in ways which are at present, performed
in this patient population: invasive transthoracic cardiac lines, echocardiography, venous
and systemic oximetry, and analysis of acid/base abnormalities. Secondary end-organ function
will be monitored including kidneys (urine output, creatinine,) and brain (cerebral
oximetry).

Potential toxicity of the drug is related to the effects of excessive vasodilatation.
Subjects will be monitored for toxicity through both frequent physical examination as well
as continuous blood pressure monitoring in the immediate postoperative period. The ultimate
rescue therapy for excessive vasodilation and hypotension would be the institution of high
flow extracorporeal circulation, which we would be in a position to provide in a most timely
fashion in both the operating room and intensive care unit. Pharmacologic management to
counteract adverse effects of alpha-adrenergic blockade would be norepinephrine,
administered in the dose 0.01-0.05 mcglkglmin. Epinephrine may be relatively contraindicated
in this setting because beta-adrenergic receptors are left unopposed. Therefore, drugs that
stimulate both types of receptors (e.g., epinephrine) may produce an exaggerated hypotensive
response and tachycardia. Those subjects experiencing hypotension refractory to conventional
postoperative management, who are experiencing end-organ dysfunction related to hypotension,
or who require norepinephrine reversal of the previous dose of phenoxybenzamine would be
strongly considered for withdrawal from the study.

Adverse reactions reported in oral administration include nasal congestion, mycosis,
tachycardia, drowsiness and fatigue. This drug has been FDA approved for oral administration
in treatment of pheochromocytoma to control episodes of hypertension and sweating. It has
also shown efficacy in micturition disorders resulting from neurogenic bladder, functional
outlet obstruction and partial prosthetic obstruction.

Subjects will be followed throughout their hospital course until the time of discharge home.
There will be no further follow up asked of subjects related to this study. Historical
cohort analysis will include analysis of clinically-relevant endpoints as noted below, as
well as laboratory values and vital signs during the perioperative period and until time of
discharge home.

A three-physician panel, comprised of those involved in operative and postoperative care of
this particular patient population (but not an investigator in this study) will be appointed
to review subject cases. The panel will meet at 5-subject intervals to review the data and
safety profile from each case.

VI. Data Storage, Acquisition, and Analysis An electronic database, which is
password-protected and available only to the PI and co-investigators will be utilized for
the purposes of data analysis. A copy of the data acquisition form accompanies this
application. The data will be destroyed 5 years following completion of the study and
analysis of the resulting data. Data acquired for the study will be stored in a
password-protected database. Only the PI and the co-investigators will have access to this
password and the database. Upon identification of eligible historical cohorts, their charts
will be reviewed with pertinent data entered in the above-described database. The data of
historical cohorts will be de-identified as an attempt to maintain confidentiality. Subject
ID numbers in the historical cohort group will be assigned only to differentiate between
subjects for the purpose of data analysis, and will not specifically identify subjects.

Data analysis will include several clinically-relevant endpoints, including overall surgical
mortality (survival to discharge), time to initial extubation and cessation of mechanical
ventilation, and length of hospital stay. End-organ function status post cardiopulmonary
bypass will be assessed by evaluating lab values currently studied, including serum lactate.
Monitoring of hemodynamic values including blood pressure and left atrial pressure will be
utilized to indirectly assess cardiac output. Other end organs evaluated will include kidney
(urine output and other tests of renal function such as creatinine) and brain (clinical
evaluation and tests ordered as indicated, as well as cerebral oximetry). We will also
evaluate the need for inotropic and/or vasodilator support (both dose and duration). The
study will not require additional lab or radiology testing based on patient inclusion. Data
reviewed from historical cohorts include those as specified in the data collection sheet,
namely the above-described clinically-relevant endpoints, as well as laboratory values
(serum lactate, serum creatinine), vital signs (blood pressure, cerebral oximetry, and left
atrial pressure), evidence of end organ perfusion (urine output), and postoperative inotrope
requirements.

As serum lactate serves as a surrogate for demonstrating the adequacy of end organ
perfusion, we will utilize this continuous variable as our primary endpoint for the purposes
of this protocol. Our hypothesis is that the use of phenoxybenzamine in this select
population will reduce initial postoperative lactate levels by a clinically-relevant level
of 25%, relative to historical controls. Secondary endpoints evaluated as well will include
utilization of inotropic support, duration of mechanical ventilation and overall
hospitalization, and time to resolution of postoperative lactic acidosis.

Recent experience with the Norwood procedure, the conventional palliative surgical therapy
for hypoplastic left heart syndrome, demonstrated a mean initial serum lactate of 7.3 ± 3.3
mmol/L in 21 neonates. 15 Assuming a clinically significant reduction by 25% to 5.5 mmol/L
(at 80% power and an assumed p ≤ 0.05 demonstrating statistical significance), one would
require a total of 54 study subjects. Given an anticipated surgical volume of approximately
20 Norwood procedures annually, along with a 15% dropout or refusal rate, we would expect to
accrue a total required volume of 62 subjects in approximately 3 years. We will also compare
data with data that already exists within our cardiac registry for further evaluation.

VII. Consent and Peer Judgement

The drug will not be administered without the knowledge of attending surgeon and
anesthesiologist and after discussion with the perfusionists in order to ensure safety and
advisability. In the postoperative period the drug will not be administered without
discussion with all relevant participants in the patient's postoperative care. Informed
consent will be obtained from the patients family and documented in the chart prior to
administration of the drug. Because this drug is not yet FDA approved in the United States,
specific consent is necessary. An investigational new drug application has been filed and
permission from the FDA is pending. Significant adverse effects will be reported to the Food
and Drug Administration and to the Vanderbilt University Institutional Review Board Health
Sciences Committee within 24 hours, and annual status reports will be filed with Food and
Drug Administration according to their policies.

Patient selection will be determined by an assessment of the risk of systemic ventricular
dysfunction following open cardiac repair in a population of infants undergoing stage I
palliation (Norwood procedure) for the diagnosis of either hypoplastic left heart syndrome
or similar left-sided obstructive lesions in the setting of single-ventricle physiology.
Eligible neonates and infants include those aged 0 days to 6 months. These patients will
be evaluated on an individual basis and the decision to give phenoxybenzamine would be
determined by the attending surgeon, anesthesiologist, and cardiologist.