Effects of intravenous diltiazem on a porcine model of endotoxin-induced pulmonary hypertension

Introduction

Pulmonary hypertension (PAH) is a life-threatening disease commonly seen in ICU septic patients. PAH is characterized by alterations in the pulmonary circulation leading to right ventricular failure and is associated with poor outcome in such patients. Various agents such as nitric oxide, prostaglandins and phosphodiesterase inhibitors have been used for its treatment. Drugs that induce pulmonary vasodilatation, increase contractility and maintain a stable haemodynamic profile seem an attractive treatment option in acute PAH patients. However, there is lack of evidence-based guidelines in the current medical literature. Although oral diltiazem has been shown to improve haemodynamics in chronic PAH patients, it has not been used for the treatment of acute PAH. The aim of the present study was to evaluate the effects of intravenous diltiazem on a porcine model of acute PAH during sepsis.

Methods

PAH was induced in 16 anaesthetized, mechanically ventilated pigs (25 kg) by intravenous infusion of 0.5 mg/kg LPS (Escherichia coli, 111: B4) in a period of 30 minutes. After LPS administration, animals were randomly divided into two groups. Group A received intravenous diltiazem 280 to 400 μg/kg, and Group B an equal dose of placebo (normal saline) and served as the control. Haemodynamic measurements, including parameters of systemic and pulmonary circulation, were performed before and after LPS administration and every 20 minutes for 2 hours.

Results

After LPS infusion, both systolic pulmonary pressure (PAPs) and diastolic pulmonary pressure (PAPd) exhibited a statistically significant increase (PAPs from 18 ± 1 to 48 ± 7 mmHg, P < 0.01 and PAPd, from 7.7 ± 0.7 to 27 ± 4 mmHg, P < 0.01) and remained elevated over time. Diltiazem administration reduced significantly both PAPs and PAPd in relation to placebo (P < 0.001), but not to baseline levels. The heart rate, cardiac output and systemic haemodynamics exhibited no difference between groups throughout the time period.

Conclusion

Intravenous diltiazem was associated with a reduction of pulmonary pressure without any systemic hypotension in a porcine model of endotoxin-induced acute PAH. This may represent a significant advance in the treatment of acute PAH. Potential clinical implications merit further study.