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Inhaled and intravenous application of a stimulator of the soluble guanylate cyclase (BAY 41-8543) reduces pulmonary vascular resistance in a model of septic shock

Background

Cardiac failure in septic shock usually originates from hypovolaemia, impaired global contractility or right ventricular failure (RVF). Acute RVF due to endotoxin-mediated pulmonary hypertension results in global hypoperfusion. However, the treatment of pulmonary vascular resistance (PVR) in septic patients remains a black box.

Methods

After ethical approval, septic shock was induced in 32 pigs ( 25 ± 3 kg) by continuous infusion of endotoxin (Escherichia coli serotype 0111:B4). The animals received a protocol-based treatment with fluids and vasopressors according to the surviving sepsis campaign guidelines. Then, they were randomized to either inhaled (i.h.) (240μg kg-1) or intravenous (i.v.) (24μg kg-1) treatment with BAY 41-8543 or controls. Heart rate (HR (bpm)), mean arterial pressure (MAP (mmHg)), mean pulmonary artery pressure (MPAP (mmHg)), cardiac output (CO (l min-1)) and PVR (dyn sec cm-5) were assessed every 15 minutes for 1 h after starting the treatment. Following a wash out period of 1 h, the animals were once more randomized to double dose (D2) i.h. or i.v. respectively or to simultaneous administration of Bay 41-8543 at a single dose together with NO (i.h.) at 20 ppm. Hemodynamic measurements were taken for another hour. Data are expressed as mean ± SD at shock and 30 minutes after treatment. Differences between groups were analyzed using a linear mixed-effects model.

Results

Both during i.h. and i.v. application of BAY 41-8543, a significant decrease in PVR and an increase in CO was observed. Additive inhaled NO decreased PVR more than doubling the dose of BAY 41-8543 (Table 1).

Table 1 Table 1

Conclusion

The stimulator of the soluble guanylate cyclase BAY 41-8543 offers a treatment option for pulmonary hypertension in septic shock. Both inhalative and intravenous administration of BAY 41-8543 reduces PVR and increase CO. Further, there seems to be an additive effect of inhaled NO.

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Correspondence to Jens C Kubitz.

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Kronas, N., Peters, B., Goetz, A.E. et al. Inhaled and intravenous application of a stimulator of the soluble guanylate cyclase (BAY 41-8543) reduces pulmonary vascular resistance in a model of septic shock. BMC Pharmacol 11, P41 (2011). https://doi.org/10.1186/1471-2210-11-S1-P41

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Keywords

  • Septic Shock
  • Pulmonary Hypertension
  • Septic Patient
  • Pulmonary Artery Pressure
  • Pulmonary Vascular Resistance