Effects of Beta-Blocker Therapy and Phosphodiesterase Inhibition on Cardiac Neurohormonal Activation

Previous clinical investigations have demonstrated the utility of β-adrenergic blockade in reducing perioperative ischaemic events, ultimately translating into a decrease in cardiac morbidity and mortality. However, β-blocker therapy remains underutilized in clinical practice because of concerns of potential adverse effects such as a reduced inotropic state, which might result in acute congestive heart failure or hypotension. Therefore, additional treatment with a positive inotropic agent might be needed. Phosphodiesterase inhibitors (PDEIs) offer a favourable pharmacological profile in this setting and stimulate cardiac function in the absence of the β-adrenergic receptor.

We hypothesize that the combination of PDEI and β-blocker therapy would decrease perioperative plasma concentrations of brain natriuretic peptide (BNP) in patients requiring major vascular surgery. BNP is chosen as our primary outcome variable because of its importance as a sensitive correlate of myocardial dysfunction and its prognostic value for predicting the risk of cardiac death across the entire spectrum of acute coronary syndromes.

Cardiac complications, such as, myocardial infarction, heart failure, and life-threatening dysrhythmias, are the leading cause of perioperative death among patients undergoing major vascular surgery.

The pathogenesis of perioperative ischaemic events is most certainly multifactorial and includes persistent activation of several neurohormonal pathways, such as the natriuretic peptide system.

Previous clinical investigations have demonstrated the utility of β-adrenergic blockade in reducing perioperative ischaemic events, ultimately translating into a decrease in cardiac morbidity and mortality especially in patients who had or were at high risk for coronary artery disease. Therefore, the administration of β-blockers to all patients at high risk for coronary events who are scheduled to undergo major noncardiac surgery is strongly supported by consensus recommendations and clinical guidelines. Despite the evidence of benefit, β-blockers remain underutilized in clinical practice because of concerns of potential adverse effects such as a reduced inotropic state, which might result in myocardial depression, acute congestive heart failure, and hypotension \[13\]. Therefore, additional treatment with a positive inotropic agent might be needed.

Phosphodiesterase inhibitors (PDEIs) offer a favourable pharmacological profile in this setting and retain their haemodynamic effects in the face of full β-blockade. Preliminary data suggest that the combination of PDEI and β-blocker therapy may be better tolerated and allows for expression of the known effects of β-blocker therapy and improved myocardial functioning without the adverse effects of either therapy alone.

We therefore hypothesize that the combination of PDEI and β-blocker therapy would decrease perioperative plasma concentrations of brain natriuretic peptide (BNP) in patients requiring major vascular surgery documented to have a high prevalence of coronary artery disease and limited coronary reserve. BNP is chosen because of its pivotal role as a sensitive correlate of myocardial dysfunction and its prognostic value for predicting the short- and long-term risk of cardiac death across the entire spectrum of acute coronary syndromes.

Eligibility Criteria:
Inclusion Criteria:

* scheduled for major vascular surgery
* can sign informed consent before surgery
* documented CAD or risk factors for CAD

Exclusion Criteria:

* Preoperative treatment with beta-adrenergic agonists or glucocorticoids,
* electrocardiographic (ECG) abnormalities like nonsinus rhythm, second- or third degree heart block, or left bundle branch block,
* cardiac pacemaker dependency,
* symptomatic mitral or aortic valvular disease,
* a history of asthma, bronchospasm, or severe chronic obstructive pulmonary disease necessitating bronchodilator therapy,
* severe liver dysfunction
* known allergies against the study drugs