THAM reduces CO2-associated increase in pulmonary vascular resistance - an experimental study in lung-injured piglets

Abstract

Introduction: Low tidal volume (VT) ventilation is recommended in patients with acute respiratory distress syndrome (ARDS). This may increase arterial carbon dioxide tension (PaCO2), decrease pH, and augment pulmonary vascular resistance (PVR). We hypothesized that Tris(hydroxymethyl)aminomethane (THAM), a pure proton acceptor, would dampen these effects, preventing the increase in PVR.

Methods: A one-hit injury ARDS model was established by repeated lung lavages in 18 piglets. After ventilation with VT of 6 ml/kg to maintain normocapnia, VT was reduced to 3 ml/kg to induce hypercapnia. Six animals received THAM for 1 h, six for 3 h, and six serving as controls received no THAM. In all, the experiment continued for 6 h. The THAM dosage was calculated to normalize pH and exhibit a lasting effect. Gas exchange, pulmonary, and systemic hemodynamics were tracked. Inflammatory markers were obtained at the end of the experiment.

Results: In the controls, the decrease in VT from 6 to 3 ml/kg increased PaCO2 from 6.0±0.5 to 13.8±1.5 kPa and lowered pH from 7.40±0.01 to 7.12±0.06, whereas base excess (BE) remained stable at 2.7±2.3 mEq/L to 3.4±3.2 mEq/L. In the THAM groups, PaCO2 decreased and pH increased above 7.4 during the infusions. After discontinuing the infusions, PaCO2 increased above the corresponding level of the controls (15.2±1.7 kPa and 22.6±3.3 kPa for 1-h and 3-h THAM infusions, respectively). Despite a marked increase in BE (13.8±3.5 and 31.2±2.2 for 1-h and 3-h THAM infusions, respectively), pH became similar to the corresponding levels of the controls. PVR was lower in the THAM groups (at 6 h, 329±77 dyn∙s/m(5) and 255±43 dyn∙s/m(5) in the 1-h and 3-h groups, respectively, compared with 450±141 dyn∙s/m(5) in the controls), as were pulmonary arterial pressures.

Conclusions: The pH in the THAM groups was similar to pH in the controls at 6 h, despite a marked increase in BE. This was due to an increase in PaCO2 after stopping the THAM infusion, possibly by intracellular release of CO2. Pulmonary arterial pressure and PVR were lower in the THAM-treated animals, indicating that THAM may be an option to reduce PVR in acute hypercapnia.

Fig. 1

Effects of Tris(hydroxymethyl)aminomethane on arterial pH, base excess, arterial carbon dioxide tension (PCO₂) and arteriovenous difference in PCO₂. The graph shows the progression over time, with the x-axes representing time points. Note the offset y-axes. The end of infusion for the 1-h and 3-h groups are marked with a darkened vertical bar. Values are means, and the error bars represent standard deviations

Fig. 2

Effects of Tris(hydroxymethyl)aminomethane on hemodynamics. The graph shows the progression over time, with the x-axes representing time points. Note the offset y-axes. The end of infusion for the 1-h and 3-h groups is marked with a darkened vertical bar. Values are means, and the represent standard deviations. SVR systemic vascular resistance

Fig. 3

Standard box-and-whisker plots of the cytokine levels stratified by amount of Tris(hydroxymethyl)aminomethane (THAM) given. Note that the two top panels depict tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid and interleukin (IL)-6 in plasma. CD dorsal, CM medial, CV ventral