IntroductionHypercapnic acidosis (HCA) that accompanies lung-protective ventilation may be considered permissive (a tolerable side effect), or it may be therapeutic by itself. Cardiovascular effects may contribute to, or limit, the potential therapeutic impact of HCA; therefore, a complex physiological study was performed in healthy pigs to evaluate the systemic and organ-specific circulatory effects of HCA, and to compare them with those of metabolic (eucapnic) acidosis (MAC).MethodsIn anesthetized, mechanically ventilated and instrumented pigs, HCA was induced by increasing the inspired fraction of CO2 (n = 8) and MAC (n = 8) by the infusion of HCl, to reach an arterial plasma pH of 7.1. In the control group (n = 8), the normal plasma pH was maintained throughout the experiment. Hemodynamic parameters, including regional organ hemodynamics, blood gases, and electrocardiograms, were measured in vivo. Subsequently, isometric contractions and membrane potentials were recorded in vitro in the right ventricular trabeculae.ResultsHCA affected both the pulmonary (increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR)) and systemic (increase in mean arterial pressure (MAP), decrease in systemic vascular resistance (SVR)) circulations. Although the renal perfusion remained unaffected by any type of acidosis, HCA increased carotid, portal, and, hence, total liver blood flow. MAC influenced the pulmonary circulation only (increase in MPAP and PVR). Both MAC and HCA reduced the stroke volume, which was compensated for by an increase in heart rate to maintain (MAC), or even increase (HCA), the cardiac output. The right ventricular stroke work per minute was increased by both MAC and HCA; however, the left ventricular stroke work was increased by HCA only. In vitro, the trabeculae from the control pigs and pigs with acidosis showed similar contraction force and action-potential duration (APD). Perfusion with an acidic solution decreased the contraction force, whereas APD was not influenced.ConclusionsMAC preferentially affects the pulmonary circulation, whereas HCA affects the pulmonary, systemic, and regional circulations. The cardiac contractile function was reduced, but the cardiac output was maintained (MAC), or even increased (HCA). The increased ventricular stroke work per minute revealed an increased work demand placed by acidosis on the heart.
In a clinically relevant porcine model, hyperdynamic septic shock induced shortening of ventricular repolarization and reduction of L-type calcium current. The contribution of L-type calcium current to the action potential in septic ventricular myocytes was significantly diminished. Tumor necrosis factor-alpha probably did not contribute to this effect.
Accumulating evidence suggests that heart rate variability (HRV) alterations could serve as an indicator of sepsis progression and outcome, however, the relationships of HRV and major pathophysiological processes of sepsis remain unclear. Therefore, in this experimental study HRV was investigated in a clinically relevant long-term porcine model of severe sepsis/septic shock. HRV was analyzed by several methods and the parameters were correlated with pathophysiological processes of sepsis. In 16 anesthetized, mechanically ventilated, and instrumented domestic pigs of either gender, sepsis was induced by fecal peritonitis. Experimental subjects were screened up to the refractory shock development or death. ECG was continuously recorded throughout the experiment, afterwards RR intervals were detected and HRV parameters computed automatically using custom made measurement and analysis MATLAB routines. In all septic animals, progressive hyperdynamic septic shock developed. The statistical measures of HRV, geometrical measures of HRV and Poincaré plot analysis revealed a pronounced reduction of HRV that developed quickly upon the onset of sepsis and was maintained throughout the experiment. The frequency domain analysis demonstrated a decrease in the high frequency component and increase in the low frequency component together with an increase of the low/high frequency component ratio. The reduction of HRV parameters preceded sepsis-associated hemodynamic changes including heart rate increase or shock progression. In a clinically relevant porcine model of peritonitis-induced progressive septic shock, reduction of HRV parameters heralded sepsis development. HRV reduction was associated with a pronounced parasympathetic inhibition and a shift of sympathovagal balance. Early reduction of HRV may serve as a non-invasive and sensitive marker of systemic inflammatory syndrome, thereby widening the therapeutic window for early interventions.
The main components responsible for the mechanical behavior of the arterial wall are collagen, elastin, and smooth muscle cells (SMCs) in the medial layer. We determined the structural and mechanical changes in porcine carotid arteries after administration of Triton® X-100, elastase, and collagenase using the inflation-deflation test. The arteries were intraluminarly pressurized from 0 to 200 mmHg, and the outer diameter of the artery was measured. The pressure-strain elastic modulus was determined based on the pressure/diameter ratio. The intima-media thickness, wall thickness, thickness of the tunica adventitia layer, and the area fractions of SMCs, elastin, and collagen within the arterial wall (A(A)(SMC/elastin/collagen, wall)) were measured using stereological methods. The relative changes in the relevant components of the treated samples were as follows: the decrease in A(A)(SMC, wall) after administration of Triton® X-100 was 11% ± 7%, the decrease in A(A)(elastin, wall) after administration of elastase was 40% ± 22%, and the decrease in A(A)(collagen, wall) after the application of collagenase was 51% ± 22%. The Triton® X-100 treatment led to a decrease in the SMC content that was associated with enlargement of the arterial wall (outer diameter) for pressures up to 120 mmHg, and with mechanical stiffening of the arterial wall at higher pressures. Elastase led to a decrease in the elastin content that was associated with enlargement of the arterial wall, but not with stiffening or softening. Collagenase led to a decrease in collagen content that was associated with a change in the stiffness of the arterial wall, although the exact contribution of mechanical loading and the duration of treatment (enlargement) could not be quantified.
Objectives: To investigate the potential benefits of vagus nerve stimulation in a clinically-relevant large animal model of progressive sepsis. Design: Prospective, controlled, randomized trial. Setting: University animal research laboratory. Subjects: Twenty-five domestic pigs were divided into three groups: 1) sepsis group (eight pigs), 2) sepsis + vagus nerve stimulation group (nine pigs), and 3) control sham group (eight pigs). Interventions: Sepsis was induced by cultivated autologous feces inoculation in anesthetized, mechanically ventilated, and surgically instrumented pigs and followed for 24 hours. Electrical stimulation of the cervical vagus nerve was initiated 6 hours after the induction of peritonitis and maintained throughout the experiment. Measurements and Main Results: Measurements of hemodynamics, electrocardiography, biochemistry, blood gases, cytokines, and blood cells were collected at baseline (just before peritonitis induction) and at the end of the in vivo experiment (24 hr after peritonitis induction). Subsequent in vitro analyses addressed cardiac contractility and calcium handling in isolated tissues and myocytes and analyzed mitochondrial function by ultrasensitive oxygraphy. Vagus nerve stimulation partially or completely prevented the development of hyperlactatemia, hyperdynamic circulation, cellular myocardial depression, shift in sympathovagal balance toward sympathetic dominance, and cardiac mitochondrial dysfunction, and reduced the number of activated monocytes. Sequential Organ Failure Assessment scores and vasopressor requirements significantly decreased after vagus nerve stimulation. Conclusions: In a clinically-relevant large animal model of progressive sepsis, vagus nerve stimulation was associated with a number of beneficial effects that resulted in significantly attenuated multiple organ dysfunction and reduced vasopressor and fluid resuscitation requirements. This suggests that vagus nerve stimulation might provide a significant therapeutic potential that warrants further thorough investigation.
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