Pro-inflammatory S100 proteins are associated with glomerulonephritis and anti-dsDNA antibodies in systemic lupus erythematosus.

Objectives Systemic lupus erythematosus (SLE) is associated with elevated levels of S100A8/A9, pro-inflammatory proteins mainly secreted by activated polymorphonuclear neutrophils (PMNs). The underlying mechanisms for increased S100A8/A9 levels and their relation to the clinical phenotype have not been carefully investigated. We assessed S100A8/A9 and S100A12 levels in SLE patient sera in relation to disease activity, clinical phenotype, presence of anti-dsDNA antibodies and ability to promote phagocytosis of necrotic cells (NCs) by PMNs. Methods Serum levels of S100A8/A9 and S100A12 were measured by ELISA in paired samples of 100 SLE patients at time points of higher and lower disease activity. Serum-mediated phagocytosis of NCs by PMNs was analysed by flow cytometry. Clinical data were recorded at time points of blood sampling. Results Serum levels of S100A8/A9 and S100A12 were increased in SLE patients with high disease activity compared to paired samples at low disease activity ( p = 0.01 and p = 0.008, respectively). Elevated levels of S100A8/A9 were particularly seen in patients with anti-dsDNA antibodies ( p = 0.01) and glomerulonephritis before treatment ( p = 0.02). Immunosuppressive therapy was associated with a reduction of S100A8/A9 serum levels ( p = 0.002). The ability of serum to support phagocytosis of NCs by PMNs was related to increased S100A8/A9 levels ( p = 0.01). Conclusions Elevated serum levels of S100A8/A9 may be used to monitor disease activity and response to treatment in SLE patients, especially in patients with glomerulonephritis. S100A12 may be a marker of disease activity in SLE. Increased S100A8/A9 levels may reflect immune-pathological processes involving phagocytosis of immune complexes by PMNs.

Milrinone and levosimendan during porcine myocardial ischemia -- no effects on calcium overload and metabolism.

BACKGROUND: Although inotropic stimulation is considered harmful in the presence of myocardial ischaemia, both calcium sensitisers and phosphodiesterase inhibitors may offer cardioprotection. We hypothesise that these cardioprotective effects are related to an acute alteration of myocardial metabolism. We studied in vivo effects of milrinone and levosimendan on calcium overload and ischaemic markers using left ventricular microdialysis in pigs with acute myocardial ischaemia. METHODS: Anaesthetised juvenile pigs, average weight 36 kg, were randomised to one of three intravenous treatment groups: milrinone 50 µg/kg bolus plus infusion 0.5 µg/kg/min (n = 7), levosimendan 24 µg/kg plus infusion 0.2 µg/kg/min (n = 7), or placebo (n = 6) for 60 min prior to and during a 45 min acute regional coronary occlusion. Systemic and myocardial haemodynamics were assessed, and microdialysis was performed with catheters positioned in the left ventricular wall. (45) Ca(2+) was included in the microperfusate in order to assess local calcium uptake into myocardial cells. The microdialysate was analysed for glucose, lactate, pyruvate, glycerol, and for (45) Ca(2+) recovery. RESULTS: During ischaemia, there were no differences in microdialysate-measured parameters between control animals and milrinone- or levosimendan-treated groups. In the pre-ischaemic period, arterial blood pressure decreased in all groups while myocardial oxygen consumption remained stable. CONCLUSIONS: These findings reject the hypothesis of an immediate energy-conserving effect of milrinone and levosimendan during acute myocardial ischaemia. On the other hand, the data show that inotropic support with milrinone and levosimendan does not worsen the metabolic parameters that were measured in the ischaemic myocardium.

Transcranial Doppler-estimated versus thermodilution-estimated cerebral blood flow during cardiac operations. Influence of temperature and arterial carbon dioxide tension.

The ability of the noninvasive continuous transcranial Doppler technique to reflect changes in cerebral blood flow during cardiac operations was evaluated in seven adults. Middle cerebral artery blood flow velocity changes were compared with simultaneous thermodilution measurements of venous blood flow in the ipsilateral internal jugular vein during 11 preset stages of the procedure. Cerebral blood flow was varied by changes in arterial carbon dioxide tension and temperature. High-dose fentanyl-droperidol anesthesia and alpha-stat pH management were employed. To facilitate comparisons between the two methods, the individual awake values of middle cerebral artery flow velocity (45.1 +/- 3.3 cm/sec, mean +/- standard error of the mean) and jugular venous blood flow (382 +/- 37 ml/min) were normalized (100%). Cerebral metabolic rate for oxygen was calculated as the product of jugular arteriovenous oxygen content difference and middle cerebral artery flow velocity or jugular venous blood flow, respectively. The individual correlations between the two flow estimates varied between 0.76 and 0.87 (median 0.83), and the correlation of the combined data from all seven patients was 0.77 (p less than 0.0001). Variations in arterial carbon dioxide tension induced significant changes in the two flow estimates both during normothermia before cardiopulmonary bypass and at deep hypothermia (20 degrees C) during cardiopulmonary bypass. The significant arterial carbon dioxide tension changes had no significant effects either on Doppler- or thermodilution-estimated cerebral metabolic rate for oxygen. Deep hypothermia (20 degrees C) reduced Doppler- and thermodilution-estimated cerebral metabolic rate for oxygen to 22.0% +/- 3.9% and 20.6% +/- 6.9% of the awake levels, respectively. The study supports the validity of using middle cerebral arterial flow velocity changes as an estimate of changes in volume flow through the brain during cardiac operations.

Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations.

Myocardial metabolism seems to be markedly abnormal during the first hours of reperfusion after aortic crossclamping. Thus we previously demonstrated no uptake of carbohydrate or lipid substrates 1 hour after coronary operations. Amino acids were the only exogenous substrates taken up by the heart. The aim of the present study was to examine if this metabolic abnormality persisted a few hours later. This was done by measuring coronary sinus blood flow and arterial-coronary sinus differences of oxygen, glucose, free fatty acids, glycerol, lactate, beta-OH-butyrate, and amino acids in a similar group of 19 patients 4 to 5 hours after coronary operations. The results demonstrate a change toward normalization of myocardial free fatty acid use, although the threshold for free fatty acid uptake seemed elevated in comparison with that in the normal postabsorptive state. No correlation was found between free fatty acid uptake and myocardial oxygen consumption. Despite elevated arterial levels of glucose, lactate, pyruvate, and beta-OH-butyrate, no uptake was observed. Myocardial amino acid exchange demonstrated a pattern suggestive of postischemic metabolic adaptation. Several amino acids were extracted, glutamate and branched chain amino acids being the quantitatively most important. The uptake of glutamate and branched chain amino acids correlated with myocardial oxygen consumption, which suggests a direct link to myocardial energy metabolism. Myocardial glutamate uptake seemed to be limited by substrate availability.

Cerebral perfusion and metabolism during profound hypothermia in children. A study of middle cerebral artery ultrasonic variables and cerebral extraction of oxygen.

Flow velocity of the right middle cerebral artery was studied in eight children during cardiac operations performed with profound hypothermia. Cerebral oxygen consumption was estimated by relating the difference in oxygen content between arterial and venous blood (jugular bulb) to flow velocity. In another six children, also during profound hypothermic procedures, the diameter of the middle cerebral artery was studied with an electronic echo-tracking instrument connected to a real-time ultrasound scanner. Flow velocity and estimated oxygen consumption decreased during cooling in proportion to the temperature decrease (r = 0.67, p less than 0.001, and r = 0.86, p less than 0.001, respectively), whereas the diameter was unaffected by temperature. At a nasopharyngeal temperature of 16.9 degrees +/- 1.9 degrees C flow velocity was reduced to 33.1% +/- 7.0% of the value obtained at 35 degrees C after induction of anesthesia. Correspondingly, the oxygen consumption decreased to 20.1% +/- 6.4%. The increase in oxygen consumption per 10 degrees C change in temperature was 3.6 (2.0 to 3.9) during surface cooling, 2.6 (1.9 to 2.7) during cardiopulmonary bypass cooling, and 2.7 (1.5 to 4.6) during rewarming. Flow velocity was not influenced by perfusion pressure during profound hypothermia within the range of 20 to 42 mm Hg (r = 0.14, p = 0.52) but was related to pump flow (r = 0.73, p less than 0.001). A pump flow down to 0.5 L/min/m2 was found to be adequate during stable profound hypothermia, as judged from the maintained high jugular bulb venous oxygen saturation (70% to 80%). It is concluded that flow velocity is reduced at hypothermia in proportion to the reduced metabolic rate, although modified by other factors that influence cerebral blood flow.

Adverse effects on the brain in cardiac operations as assessed by biochemical, psychometric, and radiologic methods.

In order to describe subclinical brain injury in conjunction with cardiac operations 94 patients were prospectively studied with three brain injury assessment methods: CSF analyses 24 hours after bypass, psychometry, and computed tomography of the brain. Adenylate kinase (AK), a marker of ischemic brain cell injury, was measured in cerebrospinal fluid (CSF) and in serum. In 13% of the patients, a considerable increase in CSF-AK was seen, in 46% there was a moderate increase, and in 41% no or trivial increase. Psychometry measured as change between preoperative scores in a test battery (SS3) revealed a moderate decrease in intellectual function after operation. There was a significant inverse correlation between CSF-AK and SS3 (r = -0.46, p less than 0.001, r2 = 0.21, n = 71). Computed tomography (CT) of the brain was performed preoperatively and postoperatively in 54 patients. Two of these had cerebral infarctions visible on the CT, despite an essentially normal postoperative state. There was no correlation between indices of brain injury and patient diagnosis and length of perfusion. It is concluded that subclinical brain injury is often seen after cardiac operations. Most often the injury appears trivial and/or reversible, but in a minority of cases there is evidence that the brain injury is irreversible. Factor analysis favors the view that the microembolism theory might no longer be a valid concept in modern cardiopulmonary bypass (CPB). Instead, circumstances in the operative field seem more likely to be important causative factors. This interpretation calls for new principles in the search for an improved cerebral protection during cardiac operations.

High-dose intravenous beta 1-blockade in patients early after cardiac operations. Negative inotropism versus myocardial oxygen economy.

A high adrenergic strain during reperfusion after ischemia impedes functional recovery. Conversely, adrenergic blockade may be beneficial during reperfusion. Negative inotropic effects may outweigh the expected benefit, however. Against this background hemodynamic and metabolic effects of early postoperative infusion with the beta 1-selective agent metoprolol were studied in 22 patients after coronary operations. During basal postoperative conditions, intravenous metoprolol reduced cardiac index and stroke volume index compared with control patients, while other variables were unaffected. During the higher adrenergic level of a dopamine infusion (7 micrograms/kg per minute), the heart rate, rate pressure product, and myocardial oxygen uptake were attenuated in proportion to the plasma level of metoprolol. Intravenous beta 1-blockade did not affect the cardiac output or stroke volume responses to dopamine (the cardiac output was still, however, 19% lower than in control patients). A release of myocardial creatinine kinase isoenzyme myocardial band was observed during dopamine infusion, suggesting that myocardial ischemia was induced. The release was not influenced by metoprolol, but it correlated with heart rate (r = 0.60; p < 0.01). It is concluded that infusion of metoprolol early after coronary operations depresses myocardial contractility with some 19%, which was without clinical significance in straightforward patients; the increased myocardial metabolic demand during a period of increased adrenergic stress was attenuated by metoprolol. This may be of importance for myocardial recovery.

Influence of beta 1-blockade on myocardial substrates early after a coronary operation.

A high adrenergic strain during reperfusion after ischemia impedes functional recovery. Conversely, adrenergic blockade may be beneficial during reperfusion. This study was undertaken to find out if early postoperative high-dose infusion of the selective beta 1-blocking agent metoprolol tartrate has additional effects on metabolic variables related to myocardial energy supply/demand balance compared with those obtained with a late preoperative oral dose. The study included 21 male patients undergoing coronary bypass grafting. All patients received an oral dose of metoprolol before the operation. After the operation, patients were randomized to a control group or a group receiving intravenous infusion of metoprolol. Myocardial uptake of oxygen and substrates was determined before and during atrial pacing. Metoprolol reduced arterial concentrations of free fatty acids, reduced myocardial uptake of free fatty acids, and enhanced myocardial uptake of lactate. During paced tachycardia, the metoprolol concentration correlated negatively with myocardial uptake of free fatty acids (r = -0.80; p < 0.001) and positively with myocardial uptake of lactate (r = 0.53; p < 0.05). It is concluded that postoperative infusion of metoprolol induces myocardial metabolic changes compatible with an improved energy supply/demand balance.

Thoracic epidural anesthesia does not influence the occurrence of postoperative sustained atrial fibrillation.

BACKGROUND: To evaluate whether thoracic epidural anesthesia (TEA) can reduce the incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG). METHODS: Forty-one patients undergoing CABG were treated with TEA intraoperatively and postoperatively. Another 80 patients served as the control group. The sympathetic and parasympathetic activities were evaluated by analysis of neuropeptides, catecholamines and heart rate variability (HRV), preoperatively and postoperatively. RESULTS: Postoperative AF occurred in 31.7% of the TEA-treated patients and in 36.3% of the untreated patients (p = 0.77). TEA significantly suppressed sympathetic activity, as indicated by a less pronounced increase of norepinephrine and epinephrine (p = 0.03, p = 0.02) and a significant decrease of neuropeptide Y (p = 0.01) postoperatively in TEA-treated patients compared to untreated patients. The HRV variable expressing sympathetic activity was significantly lower and the postoperative increase in heart rate was significantly less in the TEA group than in the control group after surgery (p = 0.01, p < 0.001). Among patients developing AF, the maximal number of supraventricular premature beats per minute increased significantly in untreated patients postoperatively but remained unchanged in TEA-treated patients (p = 0.004 versus p = 0.86). CONCLUSIONS: TEA has no effect on the incidence of postoperative sustained AF, despite a significant reduction in sympathetic activity.

Clinical buffering of metabolic acidosis: problems and a solution.

Traditionally sodium bicarbonate has been the buffer of first choice in the treatment of metabolic acidosis. This treatment, however, involves risks of developing a hyperosmolar state, a high sodium concentration in the blood, increased arterial carbon dioxide tension and, as a result of the latter, intracellular and intracerebral acidosis and also cerebral oedema. The buffering effect occurs slowly and as a consequence of this, and of the titration curve of sodium bicarbonate, overcorrection of metabolic acidosis is often seen. Tris buffer was introduced as an alternative and has been claimed to solve most of these problems, but on the other hand it entails a very high risk of peripheral venous thrombosis and thrombophlebitic lesions owing to its local irritative effect. In order to overcome these disadvantages a new mixture of Tris, acetate, bicarbonate and phosphate has been designed. In the studies described it was shown to have an adequate buffering effect and to provide a solution to most of the problems connected with buffering of metabolic acidosis. The new Tris buffer mixture has a buffering effect in blood equivalent to 0.5 mol/l sodium bicarbonate, although its sodium content has been decreased to one-third of pure sodium bicarbonate. Its administration also results in predictable buffering in cerebrospinal fluid and skeletal muscle. In a clinical study it was demonstrated that the new Tris buffer mixture results in sufficient and adequate buffering without significant side-effects.

Fragmin (LMWH) vs heparin for anticoagulation during in vitro recycling of human blood in cardiopulmonary bypass circuits: dose-dependence and mechanisms of clotting.

Low-molecular-weight heparin (LMWH) (Fragmin) vs heparin was studied in vitro in order to investigate its antithrombotic efficacy in the isolated thrombogenic link of cardiopulmonary bypass (CPB). Fresh human blood (400 ml) with various dosages of the anticoagulant was recycled in a CPB circuit for 120 min. The standard dosage of heparin (1,500 IU, n = 6) was compared with a lower dosage (1,000 IU, n = 3) and several dosages of Fragmin (IU anti-FXa): 750 (n = 1), 1,500 (n = 3), 2,100 (n = 4) and 2,500 (n = 3). Clotting occurred in three Fragmin experiments at dosages of 750, 1,500 and 2,100 IU. This was associated with short activated clotting time (ACT) and activated partial thromboplastin time (aPTT) but was independent of the levels of anti-FXa, FVIII, von Willebrand factor and prothrombin complex. It was concluded that at least twice the dose of Fragmin (anti-FXa), compared with heparin, was required, suggesting that thrombin inhibition is crucial for the antithrombotic efficacy of heparin in CPB circuits. Absence of fibrinolytic markers suggests that the well known enhancement of fibrinolysis often seen during CPB, is not due to heparin interaction with normally circulating blood components, but rather to interaction with the vessel walls or to the surgical trauma itself.

Low-molecular-weight heparin (Fragmin) versus heparin for anticoagulation during cardiopulmonary bypass in open heart surgery, using a pig model.

Fragmin and heparin were studied in pigs during 120 min of cardiopulmonary bypass (CPB) and up to 240 min postoperatively, with respect to clotting, bleeding and the effects of protamine. Thirty-three pigs received bolus injections of 300 IU/kg with or without additional dosage during CPB and with or without subsequent protamine sulphate. Doses of Fragmin 60% higher were necessary to prevent clotting. These had 100% higher anti-FXa levels but about 50% shorter activated coagulation time (ACT) compared with heparin. Anti-FXa increased with cumulative doses of heparin and Fragmin but ACT and activated partial thromboplastin time (aPTT) did not, indicating a larger loss of thrombin inhibition compared with anti-FXa in both drugs during CPB. Thrombin inhibition was crucial for prevention of clotting. Protamine efficiently normalized ACT in the Fragmin group but left a residual 20% anti-FXa, which did not increase the bleeding tendency. Fragmin could adequately be monitored with ACT and would be a safe alternative to heparin in CPB.

Is cerebral blood flow/metabolic mismatch during rewarming a risk factor after profound hypothermic procedures in small children?

The relation between cerebral blood flow and oxygen consumption was studied in six children during cardiac operations with profound hypothermia. A combination of topical cooling and core cooling was used to reduce the nasopharyngeal temperature to 15 degrees C. The alpha-stat principle for pH management was used. Blood flow and oxygen consumption decreased significantly with temperature. At a nasopharyngeal temperature of 15 degrees C, blood flow was reduced to 25% of the awake level, corresponding to 34% of the asleep value obtained 15-30 min after intubation. Oxygen consumption decreased to 25% of the asleep value. During stable profound hypothermia, venous saturation in the jugular bulb was at the same level as 15 min after intubation (70%). Markedly lower values were observed during topical cooling, and particularly during rewarming (down to 21%), indicating a mismatch between cerebral blood flow and oxygen consumption. The speed of rewarming correlated with the fall in venous oxygen saturation (rs = 0.82, P less than 0.05). It is suggested that periods of cerebral blood flow/metabolic mismatch during topical cooling and rewarming may explain postoperative cerebral dysfunction after deep hypothermic procedures. A moderate speed of rewarming is advocated.

Myocardial uptake and release of lactate after high dose neurolept endotracheal intubation in coronary surgery.

To evaluate the relationship between the hemodynamic and ECG variables used in routine surveillance of coronary surgery and myocardial lactate metabolism, 23 middle-aged, male, beta 1-blocked patients about to undergo coronary surgery were monitored before and after endotracheal intubation with high dose (30 micrograms/kg) fentanyl-midazolam anesthesia. The induction of anesthesia was followed by a mean arterial pressure decrease (from 98 +/- 4 to 76 +/- 3 mm Hg) and heart rate increase (from 53 +/- 3 to 66 +/- 2 beats/min). After intubation the hemodynamic variables were stable except for a further, transient increase in heart rate (to 69 +/- 2 beats/min). The myocardial uptake of lactate decreased after intubation, from 48 +/- 5 mumol/min to a lowest level of 24 +/- 3 mumol/min. A lactate release was exhibited in 7/23 patients (30%). No ST-segment changes were observed. The correlation between the myocardial lactate uptake/release and hemodynamic or ECG variables was unimpressive or non-existent (r < or = 0.20). Thus, a reduced uptake and even a release of lactate occurred irrespective of the ST-segment, heart rate, or systemic or pulmonary artery pressures. In conclusion, endotracheal intubation in patients with coronary disease was consistently (17/23 patients) followed by a reduced myocardial uptake of lactate, in spite of high dose neurolept anesthesia and beta 1-blockade. This metabolic event was not consistently related to hemodynamic changes.

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.

Surgery of extracranial carotid artery aneurysm using cardiopulmonary bypass, hypothermia and circulatory arrest.

A patient with a large, rapidly expanding extracranial carotid artery aneurysm was successfully operated upon during intentional arrest of the circulation. This was accomplished with cardiopulmonary bypass and hypothermia. The advantages and disadvantages of this technique are discussed.

Middle cerebral artery flow velocity during coronary surgery; influence of clinical variables.

The flow velocity in the middle cerebral artery was measured continuously with a noninvasive transcranial Doppler in 18 patients during coronary artery surgery. Neurolept anesthesia and alpha-static acid-base management were employed. The flow velocity data were expressed as a percent of the awake level. During intubation, there was a transient flow velocity increase, which was related to a concomitant increase in mean arterial pressure (r = 0.67, p less than 0.01). Prior to cardiopulmonary bypass, flow velocity had decreased to 52.4% +/- 3.0% (mean +/- SEM). At the onset of cardiopulmonary bypass, flow velocity values were transiently doubled. Flow velocity then reached a stable level of 63% to 65% during hypothermia (25 degrees C to 30 degrees C). The increase from 52.4% to 63% to 65% was related to the reduction in hematocrit (r = -0.62, p less than 0.02). With rewarming, flow velocity increased to 101% +/- 5.2%. Flow velocity was found to correlate with temperature during cardiopulmonary bypass (median rs = 0.84, range 0.61 to 0.99, p less than 0.0001). No positive correlation was found between mean arterial pressure (MAP) and flow velocity during cardiopulmonary bypass. Although no direct metabolic measurements were performed, it is concluded that these findings are compatible with a maintained cerebral blood flow/metabolic coupling during cardiopulmonary bypass.

Cannulation of the internal jugular vein - 500 cases.

Five hundred consecutive cases of internal jugular vein catheterization are presented. The success rate varied from 88% to infants under 1 year of age to 99% in adults. There were 16 arterial punctures (3.2%). In one patient surgical removal of a haematoma was necessary. No pneumothorax occurred. Compared to other techniques for central venous catheterization, the internal jugular vein approach gives a high incidence of correct catheter positions and few complications, and is thus recommended.