Kaija Peltola

Fibrinolysis, antithrombin III, and protein C in neonates during cardiac operations

Fibrinolysis and coagulation were studied in 10 neonates undergoing cardiac operations for congenital heart defects. Coagulation was activated during cardiopulmonary bypass as evidenced by highly increased prothrombin fragment 1 + 2 levels compared with preoperative values. Prothrombin fragment 1 + 2 levels remained elevated until postoperative day 3. Unlike coagulation, fibrinolysis was not activated during cardiopulmonary bypass but did show late activation on postoperative day 3, as evidenced by elevated levels of the fibrin degradation product D-dimer. Lack of fibrinolytic activation during bypass and its appearance on postoperative day 3 were partly explained by changes observed in tissue plasminogen activator and its inhibitor. During bypass, levels of tissue plasminogen activator and its inhibitor increased by 3.4-fold and 3.2-fold, respectively. In the postoperative period, levels of plasminogen activator inhibitor normalized rapidly whereas tissue plasminogen activator remained elevated, resulting in late fibrinolytic activation on postoperative day 3. In accordance with elevated prothrombin fragment 1 + 2, platelet count, antithrombin III, protein C, prothrombin, and factor VII were decreased on postoperative day 2, indicating ongoing consumptive coagulopathy. Nine patients had antithrombin III and six had protein C levels below age-specific normal ranges, consistent with an acquired deficiency state. Three had central venous thrombosis by postoperative day 4 or 5. In all three, thrombosis was preceded by antithrombin III deficiency, protein C deficiency, and highly elevated plasminogen activator inhibitor (3.7 to 37 times the mean of the other patients) on postoperative days 1 to 3. In conclusion, cardiopulmonary bypass in neonates caused rapid and profound alterations in the coagulation and fibrinolytic systems and initiated consumptive coagulopathy lasting until at least postoperative day 3. Thrombophilic abnormalities in antithrombin III, protein C, and fibrinolysis were frequently found and were associated with serious thrombotic complications.

Methylprednisolone in neonatal cardiac surgery: reduced inflammation without improved clinical outcome.

BACKGROUNDnCorticosteroids are widely used in pediatric open-heart surgery to reduce systemic inflammatory response and to mediate possible cardioprotective effects. However, the optimal dosing of corticosteroids is unknown and their administration varies considerably between different institutions.nnnMETHODSnForty neonates undergoing open-heart surgery were randomized in a double-blind fashion equally into 2 groups. After the induction of anesthesia, 1 group received 30 mg/kg intravenous methylprednisolone and the other a placebo. Concentrations in plasma of interleukin 6 (IL-6), IL-8, IL-10, free methylprednisolone and total methylprednisolone were obtained for the following: (1) at anesthesia induction before the study drug was administered; (2) 30 minutes on cardiopulmonary bypass; (3) 5 minutes after protamine administration; and (4) 6 hours after weaning from cardiopulmonary bypass. Troponin T was measured at time points T1, T3, T4, and also at 6:00 on the first postoperative morning. Physiological and clinical outcome parameters were also recorded.nnnRESULTSnIntravenous methylprednisolone resulted in high plasma drug concentrations that peaked at T2. Methylprednisolone significantly lowered concentrations of proinflammatory cytokines IL-6 and IL-8 and raised levels of anti-inflammatory IL-10. No significant differences in troponin T levels were detected. Blood glucose levels were significantly higher in the methylprednisolone group, and patients in this group received more often insulin therapy than controls. No significant differences were observed in other clinical or physiological outcome measurements.nnnCONCLUSIONSnIntravenous 30 mg/kg methylprednisolone administered before cardiopulmonary bypass resulted in high effective plasma drug concentrations and a decreased inflammatory response. However, no cardioprotective effect or better clinical outcome was noticed.

Regional generation of free oxygen radicals during cardiopulmonary bypass in children.

Studies on free radical generation during cardiopulmonary bypass have focused mainly on the heart and the lungs. However, low pumping pressure, nonpulsatile perfusion, and hypothermia affect the entire circulation, resulting in decreased splanchnic blood flow, increased intestinal permeability, and endotoxemia. To evaluate regional phenomena, we studied 16 children undergoing cardiopulmonary bypass. Free radical production, granulocyte activation, and hypoxanthine metabolism were assessed separately in the circulations drained by the inferior and superior venae cavae, as well as in the oxygenator. Three minutes after the onset of cardiopulmonary bypass, significant gradients between the inferior vena cava and the arterial line of the oxygenator existed in malondialdehyde (+0.60 +/- 0.12 mumol/L, lactoferrin (+18.21 +/- 7.65 micrograms/L), myeloperoxidase (+53.75 +/- 16.50 micrograms/L), hypoxanthine (-0.62 +/- 0.15 mumol/L), and urate (+8.87 +/- 4.03 mumol/L). These gradients decreased in parallel with decreasing body temperature. Except for a transient gradient in malondialdehyde at 3 minutes after the onset of cardiopulmonary bypass (+0.23 +/- 0.08 mumol/L), no changes were detected between the superior vena cava and the arterial line. In the oxygenator, granulocyte activation was observed only after aortic declamping. We conclude that during cardiopulmonary bypass, significant free radical generation, granulocyte activation, hypoxanthine elimination, and urate production take place in the region drained by the inferior vena cava. In the oxygenator, granulocyte activation occurs only after aortic declamping.

Correlation of Hypotensive Effect of Plasma Protein Fraction with Prekallikrein Activator Activity: A Clinical Study in Patients Having Open-Heart Surgery

We studied the hemodynamic responses to the administration of 20 ml of three protein solutions having different prekallikrein activator (PKA) activities in patients undergoing cardiac operation. PKA levels of the two plasma protein fraction (PPF) solutions studied were 193% and 60%, respectively, while that of the albumin solution was less than or equal to 3%. A significant correlation was found between the PKA activity of the test solutions and the decrease in systemic vascular resistance produced by the solutions during cardiopulmonary bypass and in the postoperative period. Vasodilatation was considerably more marked in the postoperative phase than during cardiopulmonary bypass. Since cardiac output increased simultaneously with the decrease in vascular resistance in the postoperative period, the hypotension observed did not fully reflect the degree of vasodilatation. In some patients, substantial vasodilatation was observed also after the administration of albumin solution with low PKA level. We conclude that although the PPF-induced vasodilatation correlates with the PKA activity of the solution, occasional hypotensive reactions are probably due to mechanisms other than those linked with increased PKA level.

Effect of Timing and Route of Methylprednisolone Administration During Pediatric Cardiac Surgical Procedures

BACKGROUNDnWe compared the antiinflammatory and cardioprotective effects of the two most common regimens of corticosteroid administration in pediatric cardiac surgical procedures: a single dose delivered either at anesthesia induction or by cardiopulmonary bypass (CPB) prime.nnnMETHODSnForty-five children, aged between 1 and 18 months and undergoing ventricular septal or atrioventricular septal defect correction, were randomized in double-blind fashion into three groups. The anesthesia induction group received 30 mg/kg methylprednisolone intravenously after anesthesia induction, and the CPB-prime group received 30 mg/kg methylprednisolone by CPB circuit. The placebo group received saline solution. Plasma concentrations of methylprednisolone, interleukin (IL)-6, IL-8 and IL-10, and troponin were measured at anesthesia induction before the study drug, 30 minutes on CPB, after patients were weaned from CPB, and 6 hours after cessation of CPB.nnnRESULTSnEqually high methylprednisolone concentrations were detected in both methylprednisolone groups, but the measured peak concentration occurred earlier in the induction group. Significantly lower IL-8 concentrations were observed just after patients were weaned from and 6 hours after CPB in the anesthesia induction group compared with the placebo (p = 0.002, p = 0.001) and prime groups (p = 0.003, p = 0.006). Significant reductions of troponin were detected in both methylprednisolone groups compared with placebo (induction, p = 0.001; prime, p = 0.002) 6 hours after patients were weaned from CPB.nnnCONCLUSIONSnMethylprednisolone administration at anesthesia induction was superior in terms of antiinflammatory action. Methylprednisolone administration in CPB-prime only a few minutes before aortic cross-clamping and cardioplegia resulted in mean troponin reductions similar to those of administration at anesthesia induction. Corticosteroids may have direct cardioprotective properties, as reported in experimental studies.

Immediate Hemodynamic Effects of Pericardial Closure After Open-Heart Surgery

Acute hemodynamic effects of a routine pericardial closure after cardiopulmonary bypass was studied in 29 patients undergoing cardiac surgery. Clinically, the pericardial closure was well tolerated. Pericardial closure resulted in an 8% decrease of cardiac output (p less than 0.01) while cardiac index remained normal (2.9 l/min/m2 +/- 0.6 SD). The effect of the pericardium on pulmonary arterial and wedge pressures, and on systemic arterial pressure was not significant. Central venous pressure increased from 8 +/- 2 mmHg to 9 +/- 3 mmHg (p less than 0.05) after pericardial closure and decreased to 7 +/- 3 mmHg (p less than 0.05) when the pericardium was reopened. Left ventricular end-diastolic cavity diameter by echocardiography decreased in 19 of the patients studied from 46 +/- 6 mm to 41 +/- 5 mm (p less than 0.01) when the pericardium was closed, and increased to 45 +/- 6 mm (p less than 0.01) after re-opening of the pericardiotomy incision. The hemodynamic effects of pericardial closure seem to result from limited ventricular filling.

Thrombin regulation in neonates undergoing cardiopulmonary bypass

Satu Långström1, Paula Rautiainen2, Leena Mildh2, Kaija Peltola2, Ulla Wartiovaara-Kautto3, Markku Heikinheimo1,4, Jari Petäjä1,5 1Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; 2Department of Anesthesia and Intensive Care, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; 3Helsinki University Central Hospital Laboratory Services (HUSLAB), Department of Clinical Chemistry, Laboratory of Hematology, University of Helsinki, Finland; 4Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA; 5Department of Pediatrics, Jorvi Hospital, University of Helsinki, Espoo, Finland

Fresh frozen plasma does not reduce in vivo thrombin formation after neonatal cardiopulmonary bypass surgery.

Fresh frozen plasma does not reduce in vivo thrombin formation after neonatal cardiopulmonary bypass surgery -

CEREBRAL ENERGY METABOLISM AFTER TOTAL CIRCULATORY ARREST (TCA) IN OPEN HEART SURGERY IN INFANTS † 300

Total circulatory arrest (TCA) with hypothermia in open heart surgery is associated with a risk for brain ischemia. We studied cerebral energy metabolism in 8 patients (0.02-1.17 yr) undergoing TCA (7-56 min) by measuring degradation products of ATP, ie. hypoxanthine (HX) and xanthine (X), in simultaneously collected v. jugularis bulb and arterial samples. Before TCA the gradient of HX across the cerebral circulation (v. jugularis bulb - artery) was 0.32 ± 0.53 and that of X was 0.28 ± 0.40 μmol/l. After reconstitution of cerebral circulation (=reperfusion) the gradient remained unchanged at 2, 7 and 15 min, whereas significant (p<0.05) increases were found at 30 min (HX: 2.67 ± 1.27 μmol/l), 60 min (HX: 3.44 ± 1.08, X:1.76 ± 0.39), and 120 min (HX: 1.83 ± 1.21, X: 0.95 ± 0.50). At 6 and 10 h after reperfusion the gradients had disappeared. During rewarming (≅30 min after reperfusion) correlations existed between nasopharyngeal temperature and gradients of HX(R=0.50, p=0.006) and X (R=0.43, p=0.018). During 2 h after reperfusion an inverse correlation was found between HX gradient and hemoglobin oxygen saturation in jugular bulb (R=0.36, p=0.029). TCA causes a cerebral energy debt that increases in parallel with rise in body temperature and culminates at the end of the rewarming period. The magnitude of the energy debt may be indicative of cerebral ischemia and damage.

Prenatal muscle relaxation in congenital diaphragmatic hernia

An infant with congenital diaphragmatic hernia was given 2 mg vecuronium bromide intramuscularly in utero 40 min before vaginal delivery at 40 weeks gestation. At birth the infant had complete muscle relaxation, which facilitated decompression of the bowel and surgical correction. Prenatal muscle relaxation may improve the care of infants with congenital diaphragmatic hernia