Effects of inhaled nitric oxide on inflammation and apoptosis after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB), a procedure often used during cardiac surgery, is associated with an inflammatory process that leads to lung injury. We hypothesized that inhaled nitric oxide (INO), which has anti-inflammatory properties, possesses the ability to modulate lung cell apoptosis and prevent CPB-induced inflammation. METHODS: Twenty male pigs were randomly classified into four groups: sham, sham plus INO, CPB, and CPB plus INO. INO (20 ppm) was administered for 24 h after anesthesia. CPB was performed 90 min into INO treatment. BAL fluid and blood were collected at time 0 (before CPB), at 4 h after beginning CPB, and 24 h after beginning CPB (T24). RESULTS: At T(24), BAL interleukin (IL)-8 levels and neutrophil percentages were elevated significantly in the CPB group. At T(24), INO reduced IL-8 concentrations and attenuated the increase of neutrophil percentage in the CPB-plus-INO group. Nitrite-plus-nitrate (NOx) concentrations were decreased significantly in groups without INO. Moreover, animals treated with INO showed higher rates of pulmonary apoptosis compared to their respective control groups except for the sham-plus-INO group, in which they were diminished. CONCLUSION: These results demonstrate that NOx production is reduced after CPB, and that INO acts as an anti-inflammatory agent by decreasing neutrophil numbers and their major chemoattractant, IL-8. INO also increases cell apoptosis in the lungs during inflammatory conditions, which may explain, in part, how it resolves pulmonary inflammation.

Impact of 6 % hydroxyethyl starch (HES) 130/0.4 on the correlation between standard laboratory tests and thromboelastography (TEG®) after cardiopulmonary bypass.

BACKGROUND: Hydroxyethyl starches (HES) affect the results of thromboelastography (TEG®). We sought to determine whether using HES rather than crystalloids for cardiopulmonary bypass (CPB) prime and intraoperative fluid therapy changes the TEG cutoff values best identifying patients with a low platelet count or a low fibrinogen level after CPB. METHODS: Data from 96 patients who had on-pump cardiac surgery, a TEG® (kaolin-heparinase) and standard investigations of blood clotting performed after separation from CPB and protamine administration were retrospectively reviewed. Patients were assigned to the HES or crystalloid group according to whether balanced 6% HES 130/0.4 or balanced crystalloids were used for intraoperative fluid therapy and pump prime. Mutlivariable linear regression models with computation of the standardized regression coefficients were used to identify independent associations between the four main TEG parameters (R time, alpha angle, K time and MA) and the type of fluid used, the INR, the aPTT, the fibrinogen level and the platelet count. Receiver-operating-characteristic curves were used to assess the effect of HES on the ability of TEG parameters to identify patients with a platelet count<80.000µl(-1) or a fibrinogen level<1.5 gr l(-1) and on the cutoff values best identifying these patients. RESULTS: The type of fluid used significantly affected the MA (P<0.001), the K time (P<0.001) and the alpha angle (P<0.001) regardless of the results of the standard clotting tests. According to standardized ß regression coefficients the platelet count and the type of fluid used were stronger predictors of the MA, the alpha angle and the K time than the fibrinogen level. MA better predicted platelets<80.000µl(-1) than K time and alpha angle (P=0.023). The best cutoff value of MA identifying patients with platelets<80.000µl(-1) was 62mm in the crystalloid group and 53mm in the HES group. MA, K time and alpha angle were poor predictors of the postoperative fibrinogen level. CONCLUSION: HES significantly changes the cutoff value of TEG® MA best identifying patients<80.000µl(-1) after on-pump cardiac surgery.

Pre-emptive and continuous inhaled NO counteracts the cardiopulmonary consequences of extracorporeal circulation in a pig model.

Cardiopulmonary bypass (CPB) activates a systemic inflammatory response characterized clinically by alterations in cardiovascular and pulmonary function. The aim of this study was to measure the cardiopulmonary consequences in sham-operated pigs, and in animals subjected to CPB in the presence or absence of lipopolysaccharide (LPS). We also investigated, if the perioperative administration of inhaled NO exerts significant cardiopulmonary effects in an anaesthetized and mechanically ventilated pig model of extracorporeal circulation. Thirty pigs were randomized into six equal groups (sham; sham+INO; CPB; CPB+INO; CPB+LPS; CPB+LPS+INO) and subjected to anaesthesia with mechanical ventilation for up to 24h. We found that CPB+LPS group has the highest degree of lung injury. We also demonstrated that there was a significant difference on the cardiovascular parameters (heart rate, central venous pressure, stroke volume index, and mean systemic arterial blood pressure) between the CPB groups and the sham groups. The deteriorated lung mechanics was associated with a decrease in active subfraction of surfactant (LA) with time during the procedure (P=0.0003), on which inhaled NO had only an initial beneficial effect. In our model, inhaled NO had no long-term beneficial effect on lung mechanics and surfactant homeostasis despite improving lung haemodynamics, inflammation, and oxygenation. We conclude from this study that the use of pre-emptive and continuous inhaled NO therapy has protective and safe effects against lung ischemia/reperfusion associated with CPB.

Increased alveolar and plasma gelatinases activity during postpump syndrome: Inhibition by inhaled nitric oxide.

Postpump syndrome is associated with systemic inflammation. Matrix metalloproteinases (MMP)-2 and -9 contribute to proinflammatory and platelet-activator reactions. Nitric oxide (NO) is involved in the regulation of MMPs. The objectives of our study were to investigate the intensity of inflammation induced by 3 different surgical procedures, the effects of inflammation on the activity of MMPs, and the regulation of inflammation by inhaled NO (20 ppm). Inhaled NO was initiated immediately after tracheal intubation and maintained for the total duration of the experiments. Thirty pigs were equally randomized into 6 groups [sham; sham + NO; cardiopulmonary bypass; bypass + NO; bypass + lipopolysaccharide (1 microg/kg for 50 min); bypass + lipopolysaccharide + NO] and animals were subjected to anesthesia and mechanical ventilation up to 24 h. The levels of MMP-2 and MMP-9 in plasma and bronchoalveolar lavage were measured using zymography. Bypass resulted in a time-dependent rise in MMP activity, an effect potentiated by lipopolysaccharide. Inhaled NO attenuated the effects of bypass + lipopolysaccharide. These results confirm that MMP-2 and MMP-9 are associated with the inflammatory process causing the postpump syndrome. Preemptive and continuous administration of inhaled NO helps to prevent increased MMP-2 and MMP-9 activity.