Preoperative glucocorticoids decrease pulmonary hypertension in piglets after cardiopulmonary bypass and circulatory arrest.

Glucocorticoids during cardiopulmonary bypass benefit pediatric patients undergoing repair of congenital heart defects and are routine therapy, but underlying mechanisms have not been fully examined. The hypothesis was that glucocorticoids could improve cardiopulmonary recovery after cardiopulmonary bypass and deep hypothermic circulatory arrest. Crossbred piglets (5 to 7 kg) were cooled with cardiopulmonary bypass, followed by 120-min deep hypothermic circulatory arrest. Animals were then warmed to 38 degrees C, removed from bypass, and maintained for 120 min. Methylprednisolone (60 mg/kg) was administered in the cardiopulmonary bypass pump prime (intraoperative glucocorticoids) or 6 hours before bypass (30 mg/kg) in addition to the intraoperative dose (30 mg/kg; preoperative and intraoperative glucocorticoids). Controls (no glucocorticoids) received saline. Pulmonary vascular resistance in controls increased from a baseline of 152 +/- 40 to 364 +/- 29 dynes. s/cm(5) at 2 hours of recovery (p < 0.001). Intraoperative glucocorticoids did not alleviate the increase in pulmonary vascular resistance (301 +/- 55 dynes. s/cm(5) at 2 hours of recovery, p < 0.001). However, animals receiving pre and intraoperative glucocorticoids had no increase in pulmonary vascular resistance (155 +/- 54 dynes. s/cm(5)). Plasma endothelin-1 in controls increased from 1.3 +/- 0.2 at baseline to 9.9 +/- 2.0 pg/mL at 2 hours recovery (p < 0.01), whereas glucocorticoid-treated animals had lower endothelin-1 levels (4.5 +/- 2.1 pg/ml, preoperative and intraoperative glucocorticoids; 4.9 +/- 1.7 pg/mL, intraoperative glucocorticoids) at the end of recovery (p < 0.05). Intracellular adhesion molecule-1 in lung tissue was lower in animals receiving pre and intraoperative glucocorticoids (p < 0.05). Myeloperoxidase activity was elevated in control lungs at 2 hours of recovery compared with glucocorticoid-treated groups (p < 0.05). Inhibitor kappaBalpha, the inhibitor of nuclear factor-kappaB, was higher in lungs of animals receiving glucocorticoids compared with controls (p < 0.05). Glucocorticoids prevented pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest, which was associated with reduced plasma endothelin-1. Glucocorticoids also reduced pulmonary intercellular adhesion molecule-1 and myeloperoxidase activity. Inhibition of nuclear factor-kappaB, along with reduced neutrophil activation, contributed to glucocorticoid alleviation of pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest.

Pearl JM ，Schwartz SM ，Nelson DP ，Wagner CJ ，Lyons JM ，Bauer SM ，Duffy JY ... -  《ANNALS OF THORACIC SURGERY》

Deep hypothermic circulatory arrest and global reperfusion injury: avoidance by making a pump prime reperfusate--a new concept.

We sought to determine whether damage after deep hypothermic circulatory arrest can be diminished by changing pump prime components when reinstituting cardiopulmonary bypass. Fifteen piglets (2-3 months old) were cooled to 19 degrees C by using the alpha-stat pH strategy. Five were cooled and rewarmed without ischemia (control animals), and the other 10 piglets underwent 90 minutes of deep hypothermic circulatory arrest. Of these, 5 were rewarmed and reperfused without altering the cardiopulmonary bypass circuit blood prime. In the other 5 animals, the bypass blood prime was modified (leukocyte depleted, hypocalcemic, hypermagnesemic, pH-stat, normoxic, mannitol, and an Na(+)/H(+) exchange inhibitor) during circulatory arrest before starting warm reperfusion. Oxidant injury was assessed on the basis of conjugated dienes, vascular changes on the basis of endothelin levels, myocardial function on the basis of cardiac output and dopamine need, lung injury on the basis of pulmonary vascular resistance and oxygenation, and cellular damage on the basis of release of creatine kinase and aspartate aminotransferase. Neurologic assessment (score 0, normal; score 500, brain death) was done 6 hours after discontinuing cardiopulmonary bypass. Compared with animals undergoing cardiopulmonary bypass without ischemia (control animals), deep hypothermic circulatory arrest without modification of the reperfusate produced an oxidant injury (conjugated dienes increased 0.78 vs 1.71 absorbance (Abs) 240 nmol/L per 0.5 mL, P <.001 vs control animals), depressed cardiac output (6.0 vs 4.0 L/min, P <.05 vs control subjects), prolonged dopamine need (P <.001 vs control subjects), elevated pulmonary vascular resistance (74% vs 197%, P <.05 vs control subjects), reduced oxygenation (P <.01 vs control subjects), increased neurologic injury (56 vs 244, P <.001 vs control subjects), and increased release of creatine kinase (2695 vs 6974 U/L, P <.05 vs control subjects), aspartate aminotransferase (144 vs 229 U/L), and endothelin (1.02 vs 2.56 pg/mL, P <.001 vs control subjects). Conversely, the oxidant injury was markedly limited (conjugated dienes of 0.85 +/- 0.09 Abs 240 nmol/L per 0.5 mL, P <.001 vs unmodified pump prime) with modification of cardiopulmonary bypass prime, resulting in increased cardiac output (5.1 +/- 0.8 L/min), minimal dopamine need (P <.001 vs unmodified pump prime), no increase in pulmonary vascular resistance (44% +/- 31%, P <.01 vs unmodified pump prime) or endothelin levels (0.64 +/- 0.15 pg/mL, P <.001 vs unmodified pump prime), complete recovery of oxygenation (P <.01 vs unmodified pump prime), reduced neurologic damage (144 +/- 33, P <.05 vs unmodified pump prime), and lower release of aspartate aminotransferase (124 +/- 23 U/L, P <.05 vs unmodified pump prime) and creatine kinase (3366 +/- 918, P <.05 vs unmodified pump prime). A global reperfusion injury after deep hypothermic circulatory arrest was identified and changed. The injury is mediated by oxygen-derived free radicals, resulting in organ and endothelial dysfunction. Modification of global organ and endothelial damage is achieved by modifying the blood prime in the cardiopulmonary bypass circuit to deliver a controlled global reperfusate when reinstituting bypass.

Allen BS ，Veluz JS ，Buckberg GD ，Aeberhard E ，Ignarro LJ ... -  《JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY》

Glucocorticoids reduce cardiac dysfunction after cardiopulmonary bypass and circulatory arrest in neonatal piglets.

The hypotheses were that glucocorticoid administration could improve ventricular recovery by reducing cardiopulmonary bypass (CPB)-induced inflammatory response and that presurgical administration might be more effective than intraoperative dosing. Animal case study. Crossbred piglets (5-7 kg). Piglets were cooled with CPB, followed by 120 mins of deep hypothermic circulatory arrest (DHCA). Animals were rewarmed to 38 degrees C, removed from CPB, and maintained for 120 mins. Methylprednisolone (60 mg/kg) was administered in the CPB pump prime (intraoperative glucocorticoid [intraop GC]) or 6 hrs before CPB (30 mg/kg) in addition to the intraoperative dose (30 mg/kg; pre- and intraop GC). Controls (no GC) received saline. In no GC, left ventricle (LV) positive change in pressure in time (+dP/dt) (mm Hg/sec) had a mean +/- SD of 1555 +/- 194 at baseline vs. 958 +/- 463 at 120 mins after CPB, p=.01). LV +dP/dt was maintained in glucocorticoid-treated animals (1262 +/- 229 at baseline vs. 1212 +/- 386 in intraop GC and 1471 +/- 118 vs. 1393 +/- 374 in pre-intraop GC). Glucocorticoids reduced myocardial interleukin-6 messenger RNA expression, measured by ribonuclease protection assay, at 120 mins after CPB compared with animals receiving saline (p<.05), although interleukin-6 plasma and LV protein concentrations were not affected. Interleukin-10 myocardial protein concentrations were elevated after CPB-DHCA with higher concentrations in glucocorticoid-treated animals (p<.05). Glucocorticoid treatment maintained myocardial concentrations of the inhibitor of nuclear factor-kappaB in the cytosol and decreased nuclear factor-kappaB concentrations detected in the nucleus in a DNA/protein interaction array. Glucocorticoids improved recovery of LV systolic function in neonatal animals undergoing CPB-DHCA. Animals receiving glucocorticoids before CPB had better postoperative oxygen delivery than those receiving only intraoperative treatment. Maintenance of cardiac function after glucocorticoids might be due, in part, to alterations in the balance of pro- and anti-inflammatory proteins, possibly through nuclear factor-kappaB-dependent pathways.

Duffy JY ，Nelson DP ，Schwartz SM ，Wagner CJ ，Bauer SM ，Lyons JM ，McNamara JL ，Pearl JM ... -  《Pediatric Critical Care Medicine》

Calpain inhibition decreases endothelin-1 levels and pulmonary hypertension after cardiopulmonary bypass with deep hypothermic circulatory arrest.

Cardiopulmonary bypass in infants and children can result in cardiopulmonary dysfunction through ischemia and reperfusion injury. Pulmonary hypertension and injury are particularly common and morbid complications of neonatal cardiac surgery. Inhibition of calpain, a cysteine protease, has been shown to inhibit reperfusion injury in adult organ systems. The hypothesis is that calpain inhibition can alleviate the cardiopulmonary dysfunction seen in immature animals following ischemia and reperfusion with cardiopulmonary bypass. Animal case study. Medical laboratory. Crossbred piglets (5-7 kg). Piglets were cooled with cardiopulmonary bypass to 18 degrees C followed by deep hypothermic circulatory arrest for 120 mins. Animals were rewarmed to 38 degrees C on cardiopulmonary bypass and maintained for 120 mins. Six animals were administered calpain inhibitor (Z-Leu-Leu-Tyr-fluoromethyl ketone; 1 mg/kg, intravenously) 60 mins before cardiopulmonary bypass. Nine animals were administered saline as a control. Plasma endothelin-1, pulmonary and hemodynamic function, and markers of leukocyte activity and injury were measured. Calpain inhibition prevented the increased pulmonary vascular resistance seen in control animals (95.7 +/- 39.4 vs. 325.3 +/- 83.6 dyne.sec/cm, respectively, 120 mins after cardiopulmonary bypass and deep hypothermic circulatory arrest, p = .05). The attenuation in pulmonary vascular resistance was associated with a blunted plasma endothelin-1 response (4.91 +/- 1.72 pg/mL with calpain inhibition vs. 10.66 +/- 6.21 pg/mL in controls, p < .05). Pulmonary function after cardiopulmonary bypass was better maintained after calpain inhibition compared with controls: Po2/Fio2 ratio (507.2 +/- 46.5 vs. 344.7 +/- 140.5, respectively, p < .05) and alveolar-arterial gradient (40.0 +/- 17.2 vs. 128.1 +/- 85.2 mm Hg, respectively, p < .05). Systemic oxygen delivery was higher after calpain inhibition compared with controls (759 +/- 171 vs. 277 +/- 46 mL/min, respectively, p < .001). In addition, endothelial nitric oxide synthase activity in lung tissue was maintained with calpain inhibition. The reduction in plasma endothelin-1 and maintenance of lung endothelial nitric oxide levels after cardiopulmonary bypass and deep hypothermic circulatory arrest with calpain inhibition were associated with reduced pulmonary vascular resistance. Improved gas exchange and higher systemic oxygen delivery suggest that calpain inhibition may be advantageous for reducing postoperative cardiopulmonary dysfunction commonly associated with pediatric heart surgery and cardiopulmonary bypass.

Duffy JY ，Schwartz SM ，Lyons JM ，Bell JH ，Wagner CJ ，Zingarelli B ，Pearl JM ... -  《CRITICAL CARE MEDICINE》

Effects of moderate versus deep hypothermic circulatory arrest and selective cerebral perfusion on cerebrospinal fluid proteomic profiles in a piglet model of cardiopulmonary bypass.

Our objective was to compare protein profiles of cerebrospinal fluid between control animals and those subjected to cardiopulmonary bypass after moderate versus deep hypothermic circulatory arrest with selective cerebral perfusion. Immature Yorkshire piglets were assigned to one of four study groups: (1) deep hypothermic circulatory arrest at 18 degrees C, (2) deep hypothermic circulatory arrest at 18 degrees C with selective cerebral perfusion, (3) moderate hypothermic circulatory arrest at 25 degrees C with selective cerebral perfusion, or (4) age-matched control animals without surgery. Animals undergoing cardiopulmonary bypass were cooled to their assigned group temperature and exposed to 1 hour of hypothermic circulatory arrest. After arrest, animals were rewarmed, weaned off bypass, and allowed to recover for 4 hours. Cerebrospinal fluid collected from surgical animals after the recovery period was compared with cerebrospinal fluid from controls by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Protein spectra were analyzed for differences between groups by Mann-Whitney U test and false discovery rate analysis. Baseline and postbypass physiologic parameters were similar in all surgical groups. A total of 194 protein peaks were detected. Compared with controls, groups 1, 2, and 3 had 64, 100, and 13 peaks that were significantly different, respectively (P < .05). Three of these peaks were present in all three groups. Cerebrospinal fluid protein profiles in animals undergoing cardiopulmonary bypass with moderate hypothermic circulatory arrest (group 3) were more similar to controls than either of the groups subjected to deep hypothermia. The mass spectra of cerebrospinal fluid proteins are altered in piglets exposed to cardiopulmonary bypass and hypothermic circulatory arrest. Moderate hypothermic circulatory arrest (25 degrees C) with selective cerebral perfusion compared with deep hypothermic circulatory arrest (18 degrees C) is associated with fewer changes in cerebrospinal fluid proteins, when compared with nonbypass controls.

Allibhai T ，DiGeronimo R ，Whitin J ，Salazar J ，Yu TT ，Ling XB ，Cohen H ，Dixon P ，Madan A ... -  《-》