Ethanol-induced acute pulmonary hypertension and right ventricular dysfunction in pigs
Gainesville, FL, USA
* E-mail: asidi{at}anest.ufl.edu
Editor—Absolute ethyl alcohol (ETOH) is used with increased frequency in the treatment of conditions such as percutaneous ablation of unresectable hepatic tumours, sclerotherapy of oesophageal varices, ventricular septal ablation, and i.v. embolization of arteriovenous malformations.1–3 Although the incidence of complications with the use of ETOH is relatively low, episodes of cardiopulmonary collapse have been described.4 The postulated mechanism is severe pulmonary vasoconstriction from the sudden passage of ETOH into the pulmonary circulation,5 causing pulmonary hypertension (PHTN) and right ventricular (RV) strain.6 However, there is limited information on the effects of i.v. ETOH on heart function, pulmonary and systemic haemodynamics,7 and in clinical conditions similar to those encountered during therapeutic procedures.
We have studied the causal relationship between the i.v. administration of ETOH and alterations in systemic and pulmonary haemodynamics, and examined the duration of such changes in an intact porcine model. An additional purpose was to create a basis for investigating possible treatment in such catastrophes.
After approval by the University of Florida Institutional Animal Care and Use Committee, eight domestic pigs (45–50 kg) were studied and handled according to NIH guidelines. The animals were anaesthetized with isoflurane in O2 50%. Animals were mechanically ventilated to maintain normocarbia. A 7-French (Fr), pressure-tipped, flotation pulmonary artery catheter (Millar Instruments Inc., Houston, TX, USA) was inserted via the right internal jugular vein into the main pulmonary artery. A 7-Fr, triple lumen, central venous catheter was placed through the left internal jugular vein. The left carotid artery was exposed, and a 5-Fr pressure-tipped catheter (Millar Instruments Inc.) was placed and advanced into the ascending aorta for continuous arterial pressure monitoring. A median sternotomy was then performed and the heart placed in a pericardial cradle. A 5-Fr pressure-tipped catheter was inserted via a small stab wound into the RV cavity for measurement of RV pressure (RVP) and RV dP/dT. Cardiac output (CO) was measured with a 10 mm perivascular ultrasound probe placed in the main pulmonary artery. All animals were allowed to stabilize (arterial pressure, temperature) for 60 min after the surgical preparation before data collection. Haemodynamic measurements included systemic mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), RVP, central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP), and CO. Pulmonary and systemic haemodynamics and RV dP/dT, as an index of contractility, were measured. PVR and systemic vascular resistance (SVR) were calculated using standard formulas.
Undiluted ETOH was infused via a central venous catheter at a rate of 2 ml min–1 (approximately 50 mg kg–1 min–1) until a two-fold increase in MPAP was reached or a maximum of 20 ml were infused. Two previous animals (not included in this study) suffered from acute cor pulmonale when a dose of 5 ml of ETOH was administered as a rapid i.v. bolus (as is frequently administered for ablation procedures) and could not be resuscitated. Therefore, we decided to proceed with the slower infusion of ETOH. When the target MPAP was reached, the infusion was discontinued and the animals observed until haemodynamics returned to within 10% of baseline.
Data were collected at baseline, when the target MPAP was achieved, and after discontinuation of the infusion until haemodynamics returned to within 10% of baseline. After discontinuation of ETOH, the animals received only an infusion of 2 ml kg–1 of normal saline (NS). At the end of the experiment, the animals were euthanized. Data were expressed as mean (SD). A two-way analysis of variance was used, followed by Student–Newman–Keuls test for multiple comparisons. A P-value of <0.05 was considered significant.
A rate of 50 mg kg–1 (approximately 2.5 ml of ETOH per min) was sufficient to induce significant PHTN within 3 min. The infusion of ETOH achieved a two-fold elevation in MPAP at a mean dose of 188 (22) mg kg–1. During the ETOH infusion, CO was maintained (Table 1), heart rate (HR) increased, and stroke volume remained stable. After ETOH infusion, CVP and MPAP increased significantly (Table 1), resulting in significantly increased PVR [from 289 (94) to 564 (118) dyn s cm–5; P<0.05], although MAP and PAOP (Table 1) and SVR remained relatively unchanged. The SVR/PVR ratio decreased by 49%, after ETOH infusion (P<0.05; Table 1). RV dP/dT decreased by approximately 41% during ETOH infusion, with recovery noted 10 min after the infusion was stopped. The effects of ETOH were relatively short-lived because baseline haemodynamic values (MPAP, HR, PVR, SVR/PVR ratio, but not CVP) (Table 1) returned to baseline approximately 10 min after the drug was stopped.
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P<0.05 compared with ETOH effect. Values represent mean (SD). ETOH, absolute ethanol; NS, normal saline; CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure; MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; CO, cardiac output; HR, heart rate; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; PHTN, pulmonary hypertension (when target MPAP was achieved)The results of this study demonstrate that the intravascular infusion of a small dose of ETOH can trigger severe pulmonary vasoconstriction, leading to RV dysfunction. Ethanol has been shown to cause pulmonary vasoconstriction in several species. Several investigators documented variable increases in PAP and PVR with i.v. infusions of ETOH,6 8 the magnitude of which are dose- and concentration-dependent. The mechanisms for ETOH-induced pulmonary vasoconstriction are believed to involve the release of secondary mediators such as catecholamines or histamines,7 or arachidonic acid metabolites.9 The effects of ETOH in the vasculature are complex and involve both vasoconstriction and vasodilatation.10 It was demonstrated that intracellular Ca2+ in a vascular smooth muscle cell preparation increased with ETOH, even in the presence of Ca2+ channel blockade.11
The effects of ETOH on pulmonary and systemic haemodynamics in our study were short-lived and vascular resistances returned to baseline values approximately 10 min after the discontinuation of ETOH, whereas depression of RV contractility persisted. The absence of hypotension and preservation of CO during the phase of marked PHTN and RV dysfunction can be explained by the increased sympathetic outflow, as evidenced by a 40% increase in HR, with the calculated stroke volume essentially unchanged.
Our study differs from previous investigations in that the concentration of ETOH used is that commonly used in ablation procedures.1–3 We established that 50 mg kg–1 given at approximately 2.5 ml min–1 was sufficient to induce significant PHTN within 3 min. This result, extrapolated to clinical use, suggests that a slow rate of ETOH infusion should be considered, in conjunction with careful monitoring of the patient's haemodynamic status, in conditions where the risk of intravascular absorption is high.
In our study, systemic haemodynamics were relatively preserved probably because of an otherwise intact cardiovascular system in our experimental animals. We postulate that in otherwise healthy patients, small amounts of ETOH may not have a measurable clinical effect, as brief, moderate increases in PVR may be tolerated without haemodynamic compromise. In contrast, patients with pre-existing PHTN or myocardial disease will be more susceptible to haemodynamic instability.
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