Clinical variables and pro-inflammatory activation in paediatric heart surgery.

OBJECTIVES: The first aim was to analyse the role of preoperative characteristics and perioperative variables in predicting the inflammatory response during and early after operations for congenital heart malformations of moderate to severe complexity. The second aim was to correlate complement and cytokine activation during the same period with clinical variables reflecting the postoperative course. METHODS: Prospective descriptive clinical study that involved 22 consecutive children (1-28 months). Five children had Down's syndrome. Concentrations of C3a, C5b-9 and IL-6 were measured. RESULTS: C3a, C5b-9 and IL-6 increased significantly during the study period (ANOVA: C3a, p = 0.001; C5b-9, p = 0; IL-6, p = 0). C3a correlated with preoperative haemoglobin (r = 0.71, p = 0.0002) and CPB time (r = 0.72, p=0.0005). C5b-9 correlated with CPB time (r= 0.58, p=0.004). IL-6 related to presence of Down's syndrome (p=0.0001) and correlated with preoperative haemoglobin (r=0.55, p=0.02), preoperative weight deviation (r = -0.52, p = 0.03) and time in the ventilator (r = 0.68, p = 0.002). CONCLUSIONS: Preoperative and perioperative characteristics predict the inflammatory response during open heart surgery in infants and small children. IL-6 response is related to the postoperative course.

Insulin(GIK) improves myocardial metabolism in patients during blood cardioplegia.

The aim of this study was to test the hypothesis that abnormalities of myocardial substrate metabolism during blood cardioplegic aortic cross-clamping and early reperfusion are attenuated further by insulin(GIK) than by alpha-ketoglutarate enrichment of blood cardioplegia alone. Twenty-eight males (47 to 78 years) undergoing coronary artery bypass grafting (CABG) participated in a prospective, controlled, randomized study. All patients had alpha-ketoglutarate-enriched blood cardioplegia. Insulin(GIK) was infused in 13 patients during aortic cross-clamping. Insulin(GIK) prevented lactate release during cardioplegia (1.5+/-15 vs -44+/-14 micromol/min, p = 0.04), and a significant extraction of lactate was induced shortly after declamping the aorta (15+/-3 vs 2+/-1%, p = 0.001). Free fatty acid uptake was reduced after cardioplegic cross-clamping (5.7+/-1.6 vs 16.0+/-3.8 micromol/min, p = 0.02). More positive/less negative levels of alanine, aspartate, glutamine, glycine, ornithine, taurine and tyrosine were found in all the insulin-treated patients. We conclude that insulin(GIK) attenuates abnormalities of myocardial substrate metabolism during blood cardioplegic aortic cross-clamping and early reperfusion further than is obtained with alpha-ketoglutarate enrichment of blood cardioplegia alone.

Renal effects of amino acid infusion in cardiac surgery.

OBJECTIVE: To evaluate effects of amino acids on renal function and oxygen consumption and the role of individual amino acids on renal blood flow (RBF) changes. DESIGN: Prospective, randomized, controlled study. SETTING: Operating room in cardiothoracic surgery department, university hospital. PARTICIPANTS: Twenty-two male patients submitted to elective first-time coronary artery bypass surgery. INTERVENTIONS: A catheter was placed in the left renal vein for thermodilution RBF measurements and blood sampling. In 11 patients, a balanced mixed amino acid infusion was infused (200 mL/hr) for 30 minutes immediately after the operation. MEASUREMENTS AND MAIN RESULTS: RBF and glomerular filtration rate increased during amino acid infusion compared with the control group. Renal oxygen consumption increased in the amino acid group and correlated with the increase in RBF (r = 0.70, p<0.001). Amino acid infusion induced two- to fourfold increases in plasma concentrations of individual amino acid concentrations and promoted renal extraction of aspartate, glutamate, glycine, and histidine. No correlation was observed between arterial concentration or uptake of individual amino acids and RBF. CONCLUSIONS: The increase in RBF from a mixed amino acid infusion was associated with increased glomerular filtration rate and renal consumption of oxygen. Changes in RBF of a mixed amino acid infusion could not be linked to plasma level or renal uptake of any individual amino acids.

Renal hypoxanthine balance in cardiac surgery: effects of felodipine.

OBJECTIVE: To test the hypothesis that felodipine, a renal vasodilator, can prevent a release of hypoxanthine during rewarming after moderate hypothermic cardiopulmonary bypass and that this is related to improved renal oxygen supply. DESIGN: A prospective, randomized, and controlled study. SETTING: Operating room in the cardiothoracic surgery department of a university hospital. PARTICIPANTS: Twenty-two patients submitted to elective first-time coronary bypass surgery. INTERVENTIONS: A catheter was placed in the left renal vein for thermodilution renal blood flow (RBF) measurement and blood sampling. In 11 patients, felodipine was infused during the hypothermic period of cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Renal uptake (renal arteriovenous concentration difference x RBF) of hypoxanthine was maintained during rewarming in felodipine-treated patients but not in control patients (55+/-28 v. -39+/-1 nmol/min, p<0.05). Oxygen consumption was higher after felodipine infusion despite unchanged total RBF. A positive correlation between renal oxygen consumption and hypoxanthine uptake and release (r = 0.74, p<0.01) was observed. CONCLUSIONS: Felodipine maintained renal uptake of hypoxanthine during rewarming after hypothermic cardiopulmonary bypass. This maintenance is the effect of improved renal oxygen supply secondary to improved nutritive blood flow at the expense of nonnutritive renal blood flow.

Renal effects of alpha-ketoglutarate early after coronary operations.

BACKGROUND: Alpha-ketoglutarate (alpha-KG) is a Krebs cycle intermediate and the carbon skeleton of glutamate. Alpha-ketoglutarate has provoked interest in heart surgery because of its proposed critical role in myocardial metabolism. This study investigates the role of alpha-KG in renal function after cardiac surgical procedures. METHODS: Twenty-two patients with normal preoperative renal function were included in a prospective, randomized, and controlled study. Eleven patients received intravenous infusion of 30 g alpha-KG/hour after the operation. Measurements were performed before operation, immediately after operation, and after 30 minutes of alpha-KG infusion. RESULTS: Renal blood flow was higher during alpha-KG infusion, 297% +/- 97% (of preoperative value), than in controls, 125% +/- 20% (p < 0.05). Filtration fraction was lower (12.3% +/- 0.05% versus 17.2% +/- 1.1%, p < 0.01), which prevented a significant difference in glomerular filtration rate. The renal arteriovenous differences of lactate, glutamate, glutamine, and glycine changed toward a net release during alpha-KG infusion. CONCLUSIONS: Infusion of alpha-KG enhances renal blood flow early after coronary surgical procedures in patients with normal renal function. The mechanism is unclear, but could be associated with primarily metabolic effects, and may potentially convey a beneficial effect for renal function.

Addition of alpha-ketoglutarate to blood cardioplegia improves cardioprotection.

BACKGROUND: We hypothesized that myocardial content of alpha-ketoglutarate (alpha-KG), an intermediate of the Krebs cycle, can be critically low during heart operations, and that provision of alpha-KG could reduce metabolic abnormalities and lead to improved myocardial protection. METHODS: Twenty-four men aged 46 to 78 years who were undergoing heart operations participated in a prospective, controlled, randomized study. In 13 patients, an average of 28 g of alpha-KG was added to blood cardioplegia. Plasma creatine kinase isoenzyme MB and troponin T, and myocardial extraction of oxygen, substrates, and amino acids were measured. RESULTS: alpha-Ketoglutarate treatment was associated with lower creatine kinase isoenzyme MB (F = 39.6, df = 1.172, p < 0.001) and lower troponin (F = 12.9, df = 1.172, p < 0.001). The values at 4 hours were 31 +/- 2.4 microg/L versus 49 +/- 4.9 microg/L (creatine kinase isoenzyme MB) and 1.1 +/- 0.05 microg/L versus 2.0 +/- 0.34 microg/L (troponin T). Myocardial oxygen extraction was higher during alpha-KG cardioplegia (p < 0.01), but there were no significant differences in myocardial uptake or release of substrates or amino acids. Lactate release was observed in both groups during cardioplegia. Myocardial lactate release had ceased after 30 minutes of reperfusion in nearly half the alpha-KG-treated patients (6 of 13) but remained in all the control patients (11 of 11, p = 0.016). There were no other differences after 30 minutes of reperfusion. CONCLUSION: Provision of alpha-KG during blood cardioplegia improves myocardial protection in patients undergoing coronary operations. This may be linked to enhanced oxidation.

Insulin and amino acid infusion after cardiac operations: effects on systemic and renal perfusion.

OBJECTIVE: The purpose of this study was to answer two questions: (1) Does a mixed amino acid infusion enhance systemic and renal perfusion in the early postoperative period after heart operations? (2) Does the addition of insulin (glucose-insulin-potassium solution) provide additional effects to those of an amino acid infusion? METHODS: Thirty-three male patients undergoing coronary artery bypass grafting (mean age 65.9 +/- 1.2 years) were included in a prospective, controlled, randomized study. Eleven patients (AA group) received infusion of mixed amino acids (11.4 gm), 11 patients (AA + GIK group) received infusion of mixed amino acids (11.4 gm) and insulin solution (225 IU insulin, glucose with glucose clamp technique, and potassium), and 11 patients served as control subjects. RESULTS: Amino acid infusion alone had no effect on systemic vascular resistance or cardiac index but increased renal blood flow 51% +/- 11% (from 114 +/- 13 to 172 +/- 24 ml.min-1.m-2 in one kidney, p < 0.05 vs the control group). Insulin solution in addition to amino acid infusion reduced systemic vascular resistance 24% +/- 3% (from 1280 +/- 85 to 960 +/- 57 dyn.sec.cm-5, p < 0.05 vs the control and AA groups) and increased cardiac index 13% +/- 3% (from 2.3 +/- 0.2 to 2.6 +/- 0.2 L.min-1.m-2, p < 0.05 vs the control and AA groups). Insulin had no significant additive effect on renal blood flow. CONCLUSIONS: Our data imply that (1) infusion of mixed amino acids enhances renal blood flow after cardiac operations but has no effect on systemic perfusion and (2) the addition of insulin solution improves systemic perfusion. The combined treatment may potentially reduce the risk of renal hypoperfusion injury in the postoperative period after coronary artery bypass grafting.

Renal function during cardiopulmonary bypass: influence of the calcium entry blocker felodipine.

Glomerular filtration and tubular activity are decreased during hypothermic cardiopulmonary bypass (CPB). The role of vasoconstriction to explain these changes is not known. The calcium entry blocking drug felodipine dilates constricted arterioles and reduces renal vascular resistance during noncardiac surgery. The present study was initiated to evaluate the effects of felodipine on renal perfusion and function during hypothermic, low pressure CPB. Twenty-two male patients (aged 61.7 +/- 2.3 y) were included in a prospective, randomized, controlled study. Renal blood flow was measured with thermodilution technique; renal extraction of 51Cr-EDTA and p-aminohippurate (PAH) were used to evaluate glomerular and tubular function. Systemic blood flow during hypothermic CPB was varied experimentally between 1.45 and 2.2 L.min-1.m-2. Felodipine reduced systemic vascular resistance but did not reduce the total renal vascular resistance during CPB. On the contrary, renal vascular resistance was increased at low CPB flow rates. The extraction of PAH (signifying tubular activity) was higher during felodipine infusion (0.74 +/- 0.04 vs 0.64 +/- 0.03 during low CPB flow, and 0.64 +/- 0.03 vs 0.57 +/- 0.05 during high CPB flow), whereas 51Cr-EDTA extraction was not influenced. The mechanism of enhanced PAH extraction may involve reduced regional vasoconstriction in PAH-extracting areas.

Impaired endothelium-mediated vasodilatation in the peripheral vasculature of patients with acute pulmonary allograft rejection.

BACKGROUND: Experimental studies have provided evidence that, during acute pulmonary allograft rejection, endothelial dysfunction occurs not only in the transplanted lung but also in arteries of organs native to the transplant recipient. We therefore tested the hypothesis that allograft rejection leads to the release of factors into the circulation that could affect the endothelial function in lung transplant recipients. METHODS: Acetylcholine (10, 30, and 60 micrograms/min) and sodium nitroprusside (1, 3, and 6 micrograms/min) were infused into the brachial artery in nine transplant recipients (five single lung, one double lung, three heart-lung) 2 to 37 weeks after transplantation, during both acute rejection and rejection-free episodes. Changes in forearm blood flow were assessed with venous occlusion plethysmography. Plasma levels of interleukin-2, -6, and -8, endothelin-1, L-arginine, and asymmetric dimethylarginine were measured and correlated to rejection episodes. RESULTS: The vasodilatory response to acetylcholine was significantly reduced during acute rejection compared with rejection-free episodes (percentage increase from basal flow: 156% +/- 21%, 395% +/- 65%, and 585% +/- 87% during rejection versus 272% +/- 75%, 633% +/- 113%, and 933% +/- 158% during absence of rejection, p < 0.05). No statistically significant difference was found between vasodilatory responses to nitroprusside during acute rejection and rejection-free episodes. Plasma levels of L-arginine, asymmetric dimethylarginine, interleukin-6, and endothelin-1 were not significantly altered during lung rejection. CONCLUSIONS: These data indicate that a reversible peripheral decrease in endothelium-dependent vasodilatation occurs during acute rejection in lung transplant recipients. This result may be due to interactions among circulating cytokines and leukocytes activated by the rejection process and the endothelium.

Thoracolumbar epidural blockade as adjunct to high dose fentanyl/midazolam anesthesia in coronary surgery: effects of sternotomy.

The present study tests the hypothesis that the changes in myocardial lactate metabolism in the early period of coronary surgery are caused by raised adrenergic activity, and that these are preventable by the addition of thoracolumbar epidural blockade to high dose fentanyl/midazolam anesthesia. Twenty-seven male beta 1-blocked patients undergoing coronary surgery were included in a prospective, controlled, randomized study. High dose fentanyl/midazolam anesthesia alone (control) or supplemented with thoracolumbar epidural blockade (treatment) was used. Measurements were performed before the induction of anesthesia and after sternotomy. After sternotomy adrenaline (A) and noradrenaline (NA) had decreased and were both in the low range, especially in the epidural group (P < 0.01). Arterial pressures decreased in both groups, especially in the epidural group, where coronary perfusion pressure (CPP) decreased from 61 (42-88) to 48 (33-64) mm Hg; Systemic vascular resistance (SVR) decreased with 30% in the epidural group (P < 0.01), but not significantly in the control group. The myocardial fractional extraction of lactate decreased in both groups, from 33 (10-45) to 13 (0-42)% in the control group (P < 0.01), and from 36 (19-43) to 10 (2-20)% in the epidural group. It is concluded that high dose fentanyl/midazolam anesthesia prevents hyperadrenergic activity in the early phase of coronary surgery, but cannot eliminate changes in myocardial lactate metabolism. The addition of the thoracolumbar epidural blockade to high dose fentanyl/midazolam anesthesia offers no obvious benefits in the early phase of coronary surgery.

Alpha-ketoglutarate for myocardial protection in heart surgery.

A low myocardial content of alpha-ketoglutarate during heart surgery might aggravate ischaemic injury. 24 men undergoing coronary surgery participated in a randomised controlled study. 28 g alpha-ketoglutarate was added to blood cardioplegia for intermittent antegrade intracoronary perfusion in 13 cases. alpha-ketoglutarate reduced the appearance in blood of the ischaemic markers creatine kinase MB and troponin T (at 4 h after release of aortic cross-clamp; median [95% CI] 49 [37-60] micrograms/L in controls vs 32 [27-37] micrograms/L for creatine kinase MB, 2.0 [1.2-2.8] vs 1.1 [0.8-1.4] micrograms/L for troponin T). These findings signify attenuated ischaemic injury, possibly secondary to enhanced myocardial oxidative capacity.

Glucose-insulin-potassium (GIK) prevents derangement of myocardial metabolism in brain-dead pigs.

Brain death is associated with neuroendocrine changes resulting in reduced myocardial glycogen content. The purpose of this study was to investigate the effects of glucose-insulin-potassium (GIK), on myocardial metabolism in brain-dead pigs. Sixteen brain-dead pigs were given GIK infusion (n = 8), or Ringer solution (n = 8). At end-point (7 h post brain death) arterial concentrations and myocardial arteriovenous (a-v) concentration differences of glucose, lactate and free fatty acids (FFA) were assessed, and myocardial biopsy specimens were taken from the right atrium and left ventricle. Biopsies were also taken from five normal pigs. Myocardial glycogen content in the GIK group was significantly higher compared to the control group, but comparable to the non-brain-dead animals. There was a higher and significant myocardial uptake of glucose and lactate in the GIK group compared to the controls. Plasma levels of FFA were significantly lower in the GIK group, and the myocardial uptake of FFA was 5 times higher in the control group compared to the GIK group. There were no significant differences in hemodynamic variables among the groups. In conclusion, intravenous supply of GIK to brain-dead pigs results in increased myocardial glycogen content and seems to prevent abnormal myocardial metabolism, which may have clinical implications for the myocardial protection of donor hearts.

Renal function during cardiopulmonary bypass: influence of pump flow and systemic blood pressure.

The influence of systemic blood flow (pump flow) and arterial blood pressure on renal function was studied during hypothermic cardiopulmonary bypass (CPB) in 14 male patients where the pump flow rate was varied between 1.45 and 2.20 l.min-1 m-2. Renal blood flow (RBF) was measured in the left renal vein with retrograde thermodilution technique and urinary flow and circulatory variables were measured with an on-line computer set-up. During CPB the RBF comprised 12-13% of the systemic blood flow and was positively related to systemic blood pressure (r = 0.71; P < 0.001) and pump flow rate (r = 0.69; P < 0.001). These findings indicate that the renal autoregulation was not operative during the hypothermic CPB period. According to multiple regression analysis, RBF was primarily determined by the pump flow rate and systemic blood pressure was of secondary importance. Urinary flow increased during hypothermic CPB and became closely related to blood pressure and pump flow. According to multiple regression analysis, urinary flow was primarily determined by systemic blood pressure.

Myocardial metabolism 8 hours after coronary surgery: effects of dopamine.

Myocardial substrate metabolism is abnormal in the early period after cardiac surgery. Myocardial uptake of substrates remains restricted 6 hours postoperatively and cannot match the demand during periods of increased energy requirements. We investigated the relationship between myocardial oxidative rate and substrate uptake in 22 men c. 8 hours after coronary surgery. Myocardial energy demand was raised experimentally by infusing dopamine. The influence of selective beta 1-blockade was analyzed. The uptake of free fatty acids dominated (34.74 +/- 8.83 mmol/min*10(-3) and sufficed to explain the oxygen consumption in basal postoperative conditions (0.468 +/- 0.051 mumol/min) and during amplified energy requirements (0.881 +/- 0.117, r = 0.71). Although the capacity to adjust substrate uptake to energy requirements thus was regained, the uptake of glucose and of lactate (6.14 +/- 13.13 and 2.29 +/- 20.31 mmol/min*10(3) respectively) was marginal, which may be important for ischaemic tolerance. Metoprolol influenced oxygen consumption during amplified adrenergic activity, but did not markedly affect substrates.

Calculation of renal extraction during high diuresis and low renal plasma flow conditions.

The renal fractional extraction (Ex) is a parameter describing the ability of the kidneys to remove a substance x from the circulating plasma. Ex is calculated often as the ratio between the arteriovenous concentration difference and the arterial concentration. This method simplifies the calculations but it is associated with an underestimation of Ex. In the study described here, a theoretical analysis of the error is made, with a graphical presentation of its magnitude in different diuresis/renal plasma flow (RPF) ratios and at different levels of Ex. The error was analysed also in a clinical situation where the renal extraction of PAH (EPAH) and EDTA (EEDTA) were determined in six patients during different stages of cardiac surgery. The underestimation of EPAH was seldom more than 4%, while EEDTA was underestimated often with more than 20%. It is concluded that the simplified formula is accurate when calculating the renal extraction for substances like PAH, with a normally high extraction, even if the diuresis/RPF ratio is high. For substances with low extractions, e.g. filtration markers, in some clinical and experimental situations it is necessary to take the renal plasma flows into consideration or to arrange for low urine production to avoid significant errors.

Cerebral lactate release after circulatory arrest but not after low flow in pediatric heart operations.

Arteriovenous (jugular bulb) differences in blood lactate were followed throughout the procedure and until 18 hours postoperatively in 17 children undergoing congenital heart operations during profound hypothermia. Transcranial Doppler sonography was used to monitor changes in blood flow velocity in the middle cerebral artery. Ten children had a period of total circulatory arrest (39 +/- 6 minutes) during profound hypothermia (arrest group). Another 7 children had continuous but reduced pump flow (0.6 to 1.2 L/m2) throughout hypothermic cardiopulmonary bypass (low-flow group). The mean age was 7.3 +/- 1.3 months in the arrest group and 7.9 +/- 2.2 months in the low-flow group. The mean time on bypass was 90 +/- 10 minutes in the arrest group and 75 +/- 9 minutes in the low-flow group. The velocity of blood flow in the middle cerebral artery decreased significantly (p < 0.05) in both groups to less than 50% of the preoperative level during hypothermia and increased during and after rewarming. Differences in blood lactate level were significantly less than zero (p < 0.05) from the start of rewarming until 3 hours after the end of cardiopulmonary bypass in the arrest group, whereas differences in blood lactate level remained close to zero in the low-flow group. We conclude that circulatory arrest during profound hypothermia is followed by a period with release of lactate from the brain, indicating anaerobic cerebral metabolism and possibly disturbed cerebral aerobic metabolism. This study argues for the avoidance of circulatory arrest whenever possible.

Cytokine production and hemofiltration in children undergoing cardiopulmonary bypass.

Multiorgan dysfunction still occurs after cardiopulmonary bypass and remains a major cause of morbidity and mortality, especially in the pediatric age group. This is consequent upon the so-called systemic inflammatory response to bypass with an increase in inflammatory mediators. Hemofiltration may be able to attenuate the effects of this response by elimination of some or all of these mediators. We undertook a prospective, randomized study to investigate the effect of hemofiltration on plasma levels of the cytokines tumor necrosis factor alpha, interleukin-8, and interleukin 6 in 18 infants and children undergoing deep hypothermic bypass. Serial plasma samples were taken before, during, and after bypass. Assay of the plasma samples revealed presence of the cytokines in a number of subjects in both groups, in some cases before operation. There were significant reductions in levels of tumor necrosis factor after hemofiltration, with no reduction noted in the group not undergoing hemofiltration. A similar difference (p < 0.05) was detected in the levels of interleukin-6 between the two groups after bypass, although this was largely due to changes in 2 subjects. Interleukin-8 was detected in a small number of subjects insufficient for statistical analysis, but with higher values in the group undergoing hemofiltration. We conclude that hemofiltration has the potential to remove cytokines from the circulation, with consequent beneficial effects.

Absent diastolic cerebral blood flow velocity after circulatory arrest but not after low flow in infants.

It is controversial whether profound hypothermia (15 degrees C) provides adequate cerebral protection during a limited period of total circulatory arrest during pediatric cardiac surgery. In the present study, transcranial Doppler echography was used to monitor the blood flow velocity (BFV) pattern in the middle cerebral artery (MCA). The purpose of the study was to investigate the influence of a period of circulatory arrest on MCA BFV, as judged from the reperfusion flow velocity pattern. The MCA BFV was studied in 22 small children undergoing profound hypothermic cardiac operations after induction of anesthesia. Twelve of the children had a period of profound hypothermic circulatory arrest (15 to 74 minutes; arrest group). Circulation was maintained in the remaining 10 children (nonarrest group). Time-averaged MCA BFV was decreased and diastolic BFV was absent immediately after cardiopulmonary bypass in 10 of 12 children in the arrest group. In contrast, only 1 of 10 patients in the nonarrest group (p < 0.05) showed this pattern. Diastolic BFV normalized 54 to 328 minutes after the arrest in the arrest group. Circulatory arrest during profound hypothermia is followed by a period of low cerebral perfusion, whereby time-averaged MCA BFV is decreased and MCA BFV is absent during diastole. We speculate that this can be explained by an increase in intracranial pressure after brain edema.