Nesiritide and Renal Function After the Total Artificial Heart

This is a randomized, double blinded placebo controlled study that will take place in the
Cardiac Surgery Intensive Care Unit, at Virginia Commonwealth University (VCU) Hospital
Center.

This study will enroll 20 adult patients who have undergone implantation of a circulatory
support device (10 TAH patients, 10 Left ventricular assist device (LVAD) patients).
Patients will receive standard postoperative care, including anticoagulation, continuous
hemodynamic monitoring with an arterial line and central venous line and hemodynamic support
as determine by the cardiac surgery clinical team. We will exclude patients who are
receiving renal replacement therapy at the time of device implantation or those that have
had previous solid organ transplantation in order to remove the confounding influence of
calcineurin inhibitor exposure on renal function. Patient unable to provide informed consent
will also be excluded.

Nesiritide Infusion

The patients will be randomized (stratified by device type) to either the study drug
(nesiritide at 0.005 mcg/kg/min without a bolus) or placebo. A fixed-dose infusion will be
initiated 6 hours after the patients having come off of cardiopulmonary bypass and continued
for 48 hours.

Laboratory Measurements

Acute and chronic effects of nesiritide on Glomerular Filtration Rate (GFR) and Renal Plasma
Flow (RPF) will be measured by continuous infusion of iothalamate (IOTH) and phenylalanine
hydroxylase (PAH), respectively. GFR and RPF will be measured at baseline (-3 to 0 hrs) and
at 3 intervals during drug/placebo administration as follows: 0 to 6, 6 to 16 and 16 to 40.
Intravenous catheters will be placed as needed for infusion of PAH and IOTH and for timed
blood collections.

Urine volume, creatinine, sodium excretion will also be measured. Neurohormones will be
measured at all time points 3-6. Plasma renin activity will be measured with an automated
chemiluminescent immunoassay (DiaSorin Liaison). Serum aldosterone concentration will be
determined by liquid chromatography-mass spectrometry (Agilent, AB Sciex API 5000). Serum
BNP concentration will be measured with a sandwich chemiluminescent immunoassay (Siemens
Healthcare Diagnostics, ADVIA Centaur BNP immunoassay).

Statistical Analysis Sample size was determined using urine output data from our preliminary
observations. Power calculations showed that a total of 10 patients in this two-treatment
parallel-design study to have 84 percent power to detect a change in urine output by 75
mL/hr at a two-sided 0.05 significance level (using standard deviation of 35 mL/hr for urine
output). Thus 10 patient were included in each device arm of the study.Chi-square analysis
was used to compare discrete variables.

A two tailed Student's t-test was used to compare continuous variables. A repeated measures
analysis of variance (ANOVA) was used to compare changes in clinical variables laboratory
measurements across time points. A P value < 0.05 was considered significant. For individual
comparisons post-hoc testing was performed with a paired t-test analysis with Bonferroni
correction for 2 comparisons and thus only a P value < 0.025 will considered significant for
the repeated measures analyses. A Student 2-tailed paired t test will be used to compare
placebo and active drug values for each individual time point.

Inclusion Criteria:

- Implanted with a total artificial heart (CardioWest) or Left ventricular assist
device (HeartMate II)

- Age > 18 years

Exclusion Criteria:

- Previous calcineurin inhibitor (CNI) exposure

- Hemodialysis prior to device implant