Open-heart surgery increases cerebrospinal fluid levels of Alzheimer-associated amyloid ß.

BACKGROUND: Neurocognitive dysfunction occurs frequently after open-heart surgery. It has been suggested that cognitive decline after cardiac surgery with cardiopulmonary bypass (CPB) could be a functional consequence of Alzheimer's disease (AD)-like neuropathological changes. The aim of the present study was to evaluate the cerebrospinal fluid (CSF) levels of amyloid ß peptide (Aß(1-42) ) and soluble fragments of amyloid precursor protein (sAPP) as well as the cerebral inflammatory response to open-heart surgery. METHODS: Ten patients undergoing aortic valve replacement with CPB were included. CSF was obtained the day before and 24 h after surgery for assessment of CSF levels of Aß(1-42) α-cleaved sAPP and ß-cleaved sAPP (sAPP-ß). Furthermore, CSF and serum levels of the inflammatory cytokines: tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) were also assessed. RESULTS: Cardiac surgery with CPB increased CSF levels of Aß(1-42) from 447 ± 92 to 641 ± 83 ng/l (P = 0.011), while CSF levels of sAPP-ß decreased from 276 ± 35 to 192 ± 21 ng/ml (P = 0.031). CSF levels of TNF-α increased from ≤ 0.60 to 0.79 ± 0.26 ng/l (P = 0.043), IL-6 from 1.89 ± 0.53 to 22.8 ± 6.9 ng/l (P = 0.003) and IL-8 from 39.8 ± 7.8 to 139 ± 18.3 ng/l (P < 0.001). CONCLUSIONS: Cardiac surgery with CPB causes a profound cerebral inflammatory response, which was accompanied by increased post-operative CSF levels of the AD biomarker Aß(1-42) . We hypothesize that these changes may be relevant to Alzheimer-associated amyloid build-up in the brain and cognitive dysfunction after cardiac surgery with CPB.

Transcranial Doppler microembolic signals and serum marker evidence of brain injury during transcatheter aortic valve implantation.

BACKGROUND: Recent studies have shown that transcatheter aortic valve implantation (TAVI) is associated with new foci of restricted diffusion on cerebral magnetic resonance imaging suggestive of cerebral microembolism. The aim of the present investigation was to quantify the cerebral embolic load and to evaluate during which phase of the TAVI procedure microembolism occurs. We also evaluated the association between the cerebral embolic load and post-procedural release of S100B, a serological marker of cerebral injury. METHODS: In 21 patients, we described the extent and intra-procedural distribution of microemboli during the TAVI procedure using the transcranial Doppler technique. S100B, a marker of astroglial injury, was measured for 24 h after the procedure, and the area under the curve (AUC(24h) ) relating S100B to time was calculated. RESULTS: During the TAVI procedure, a mean of 282 ± 169 emboli was detected, 37% occurred during manipulation of the aortic arch/root/valve by guide wires and catheters, 22% occurred immediately after balloon dilatation of the native valve and 41% occurred during frame expansion of the valve prosthesis. S100B increased in all patients with a peak at 1 h after the procedure and returned to baseline after 4 h. There was a positive correlation between the total amount of cerebral microemboli and the AUC(24h) for S100B (r = 0.68, P < 0.001). None of the patients developed neurological impairment. CONCLUSION: TAVI is associated with a substantial amount of cerebral microemboli. The microembolic load correlates to the degree of post-procedural release of a marker of cerebral injury.

The effects of sevoflurane on cerebral blood flow autoregulation and flow-metabolism coupling during cardiopulmonary bypass.

BACKGROUND: previous studies on non-cardiac surgical patients have shown that cerebral pressure-flow autoregulation and cerebral flow-metabolism coupling are maintained with sevoflurane. The effects of sevoflurane on cerebral blood flow (CBF) autoregulation and flow-metabolism coupling during cardiopulmonary bypass (CPB) have not been studied previously. METHODS: the effects of sevoflurane-induced burst suppression, monitored with electroencephalography (EEG), on cerebral blood flow velocity (CBFV), cerebral oxygen extraction (COE) and flow autoregulation, were studied in 16 patients undergoing cardiac surgery. The experimental procedure was performed during non-pulsatile CPB with mild hypothermia (34 degreesC) in fentanyl/droperidol-anesthetized patients. Middle cerebral artery transcranial Doppler flow velocity, right jugular vein bulb oxygen saturation and jugular venous pressure were measured continuously. Autoregulation was tested during changes in the mean arterial pressure (40-90 mmHg), induced by sodium nitroprusside and norepinephrine before (control), and during additional sevoflurane administration, in a dose that resulted in an EEG burst-suppression level of 4-6/min. RESULTS: sevoflurane, at an inspired concentration of 3.36 ± 0.03%, induced a 17% decrease in CBFV (P<0.05) and a 22% decrease in COE (P<0.05) compared with the control. The slope of the positive relationship between CBFV and cerebral perfusion pressure was steeper with sevoflurane (p<0.01) compared with control measurements, as was the slope of the negative relationship between cpp and coe (p<0.01). CONCLUSION: burst-suppression doses of sevoflurane exert an intrinsic cerebral vasodilatory effect, which impairs CBF autoregulation during mildly hypothermic CPB. Furthermore, during sevoflurane administration, CBF is in excess relative to oxygen demand, indicating a partial loss of the cerebral flow-metabolism coupling.

Long-term outcome in heart failure patients evaluated for heart transplantation but considered too well.

Patients referred for heart transplantation evaluation may be accepted for transplantation, or denied due to existing contraindications or judged to be too well. There is little knowledge about long-term outcome in patients considered too well for transplantation. Ninety-five patients (mean age 47 +/- 12 years, 73% men) judged "too well" at evaluation were included in this study. Acceptance for transplantation followed international guidelines. The follow-up (mean 4.5 years) was complete. Twenty of the 95 patients (21%) were eventually accepted for transplantation during the follow-up period. Twenty-one patients (22%) died, 13 without preceding acceptance for transplantation, 4 on the waiting list for transplantation, and 4 after transplantation. Cumulative and transplant-free survival at 1, 5, and 10 years were 91%, 82%, and 65%, and 90%, 70%, and 50%, respectively. In conclusion, long-term survival in patients considered too well for transplantation is better than in most contemporary series of heart transplant recipients, which suggests that the guidelines for acceptance are appropriate. However, almost one fifth of the patients die without preceding acceptance for transplantation or while on the waiting list, which illustrates the need for frequent reevaluation and tools to identify heart failure patients with an increased risk for sudden death.

Clinical signs of heart failure are associated with increased levels of natriuretic peptide types B and A in children with congenital heart defects or cardiomyopathy.

AIM: To study whether natriuretic peptide types B (BNP) and A (ANP) reflect clinical signs of heart failure (CSHF) in children with congenital heart defects or cardiomyopathy resulting in different types of haemodynamic situations, such as pressure overload in coarctation of the aorta (CoA), volume overload in ventricular septal defect (VSD) or systolic dysfunction in dilated cardiomyopathy (DCM). METHODS: Blood samples for plasma P-BNP and P-ANP were taken before procedures during regular investigation from 26 children (9 CoA, 11 VSD and 6 DCM). The ordinary paediatric cardiologist performed the cardiac evaluation and the data were retrieved from medical charts. CSHF was considered positive if two of the following criteria were fulfilled: reduced physical capacity, feeding disorders, dyspnoea, tachypnoea, hepatomegaly and oedema. The statistical methods were non-parametric. RESULTS: 0/9 children with CoA, 5/11 with VSD and 6/6 with DCM had CSHF. In children with CSHF, P-BNP and P-ANP were higher, 263 ng l(-1) (range 47.5-1300) and 303 ng l(-1) (range 168-466), than in those without CSHF, 12.3 ng l(-1) (range 4.8-30.8) and 42.9 ng l(-1) (range 13.7-189), respectively (p < 0.001, Mann-Whitney U-test), irrespective of the diagnosis. The same relationship was also found in the group of children with VSD. CONCLUSION: Plasma levels of ANP and BNP increase in children with CSHF. This increase is seen irrespective of whether it is due to systolic dysfunction, as in children with DCM, or to a volume overload with a normal systolic function, as in children with VSD.

Insulin (GIK) improves central mixed and hepatic venous oxygenation in clinical cardiac surgery.

OBJECTIVE: Insulin is a vasodilating agent and it was hypothesized that insulin (GIK) could improve systemic and regional oxygenation in cardiac surgery with cardiopulmonary bypass (CPB). Two questions were addressed: 1) Does insulin improve central mixed and hepatic venous oxygenation during CPB? and 2) Does this treatment reduce systemic levels of the proinflammatory mediators C3a and IL-6? DESIGN: Prospective, randomized, controlled study at a university hospital. Thirty patients were included and 16 of these received an infusion of insulin, glucose and potassium (GIK) using an euglycemic clamp technique. The insulin infusion was started during hypothermia, 15 min before rewarming. Blood gases and hemodynamic parameters were measured during hypothermia (before the insulin infusion was started), during rewarming at 35 degrees C, and 30 min after CPB was discontinued. Inflammatory markers were measured: preoperatively, during hypothermia and 2 h after CPB. RESULTS: GIK was associated with reduced systemic vascular resistance (p = 0.02 vs the control group), higher bypass pump flow (p = 0.001). higher central mixed oxygen saturation (p = 0.036) and oxygen tension (p = 0.001) and higher hepatic venous oxygen saturation (p = 0.04) and oxygen tension (p = 0.006). C3a and IL-6 increased during surgery in both groups but there were no differences between the groups. CONCLUSION: 1) GIK infusion improved central mixed and hepatic venous oxygenation in patients undergoing heart surgery. 2) During the conditions of this study, this had no effect on the proinflammatory mediators C3a and IL-6.

The use of continuous positive airway pressure by face mask and thoracic epidural analgesia after lung transplantation. Gothenburg Lung Transplant Group.

OBJECTIVE: To evaluate the clinical use of continuous positive airway pressure (CPAP) and thoracic epidural analgesia (TEA) after lung transplantation (LTx). DESIGN: Retrospective case series. SETTING: Cardiothoracic intensive care unit (ICU) at a university hospital. PARTICIPANTS: All heart-lung, bilateral, and single-lung transplant recipients between 1990 and 1996 at this institution (n = 102). INTERVENTIONS: Postoperative pain was controlled by a thoracic epidural infusion of bupivacaine, 1 mg/mL, and sufentanil, 1 microg/mL. After extubation, CPAP, 5 to 10 cm H2O by face mask, was used to prevent reperfusion edema. MEASUREMENTS AND MAIN RESULTS: In 99 patients, the length of ventilation (LOV) was a median of 4.3 hours (range, 1.0 to 312.0 hours). The median LOV was 8.0 hours (range, 1.5 to 41.0 hours) in the heart-lung recipients, 4.5 hours (range, 2.0 to 47.0 hours) in the bilateral-lung recipients, and 3.5 hours (range, 1.0 to 312.0 hours) in the single-lung recipients. Three transplant recipients, all with primary pulmonary hypertension, were prematurely extubated and reintubated because of pulmonary edema. Twelve hours after extubation, the median oxygenation index (PaO2/F(I)O2, PaO2 in kilopascal units) was greater than 35. The median ICU length of stay for all transplant recipients was 4 days (range, 2 to 270 days). CONCLUSION: The postoperative use of CPAP and TEA is associated with early and safe tracheal extubation after LTx and may shorten ICU stay.

The effects of propofol on cerebral blood flow velocity and cerebral oxygen extraction during cardiopulmonary bypass.

UNLABELLED: We investigated the effects of burst-suppression doses of propofol on cerebral blood flow velocity (CBFV), cerebral oxygen extraction (COE), and dynamic autoregulation in 20 patients undergoing cardiac surgery. The experimental procedure was performed during nonpulsatile cardiopulmonary bypass (CPB) with stable hypothermia (32 degrees C) in fentanyl-anesthetized patients. Middle cerebral artery transcranial Doppler flow velocity, right jugular bulb oxygen saturation, and jugular venous pressure (JVP) were continuously measured. Dynamic autoregulation was tested by stepwise changes in mean arterial pressure (MAP) within a range of 40-80 mm Hg by sodium nitroprusside and phenylephrine before (control) and during propofol infusion, with a stable plasma concentration (approximately 9 microg/mL). Propofol induced a 35% decrease in CBFV (P < 0.0001) and a 10% decrease in COE (P < 0.05) compared with control. The slopes of the curves relating CBFV and COE to cerebral perfusion pressure (CPP = MAP - JVP) were less pronounced with propofol (P < 0.01 and P < 0.05, respectively). We conclude that propofol decreases CBFV and improves dynamic autoregulation during moderate hypothermic CPB. Furthermore, during propofol infusion, cerebral blood flow was in excess relative to oxygen demand, as indicated by the decrease in COE. IMPLICATIONS: In this study, we evaluated the effects of propofol on continuously measured cerebral blood flow velocity (CBFV) and cerebral oxygen extraction as a function of perfusion pressure. Propofol induced 35% and 10% decreases in CBFV and cerebral oxygen extraction, respectively. The slope of the curve relating cerebral perfusion pressure to CBFV decreased with propofol.

Effects of propranolol pretreatment on cerebral blood flow, oxygen uptake and catecholamines during metabolic acidosis following E. coli endotoxin in dogs.

After an intravenous injection of E. coli endotoxin in dogs a decrease in cerebral blood flow (CBF) and an increase in cerebral metabolic rate of oxygen (CMRo2) have been shown to occur. In metabolic acidosis following endotoxin CMRo2 increased with decreasing pH. A possible explanation for the increased CMRo2 after endotoxin and metabolic acidosis seems to be a damage of the blood-brain barrier (BBB) by endotoxin. This gives possibilities for a leakage of hydrogen ions and circulating monoamines from the blood to the brain, thus affecting the cerebral blood flow and metabolism. The effects of an E. coli endotoxin injection on CBF and CMRo2 during metabolic acidosis and beta-adrenoceptor blockade were studied in eight anaesthetized dogs. All the dogs were pretreated with propranolol (PPL), per os 12.5 mg.kg-1 twice a day for one week. Metabolic acidosis (pH 7.01-7.30) was achieved by an intravenous infusion of hydrochloric acid. Endotoxin E. coli lipopolysaccharide O 111:B 4 was given as an intravenous injection of 1 mg.kg-1 bodyweight over a 5 min period. Another five animals, published earlier, with the same experimental protocol but without PPL, constituted a control group. After endotoxin no increase in CMRo2 or CBF was observed with increasing acidosis in the PPL-group. In the control group, after endotoxin, both CBF and CMRo2 increased with decreasing pH. This resulted in a significant difference in both CBF and CMRo2 between the groups in the pH range 7.01-7.15. The present results indicate that the increase in CMRo2 and CBF with metabolic acidodis in endotoxinaemia is mediated via beta-adrenoceptors.

Effects of arterial hypoxia and beta-adrenoceptor blockade on cerebral blood flow and oxygen uptake following E. coli endotoxin in dogs.

Earlier studies in normoxia have shown that an endotoxin injection in dogs leads to an increase in cerebral metabolic rate of oxygen (CMRo2), a decrease in cerebral blood flow (CBF) and increased concentrations of monoamines in blood and cerebrospinal fluid (CSF). In animals pretreated with propranolol (PPL) the CMRo2 increase was abolished and thus beta-adrenoceptor mediated. Arterial hypoxia normally increases CBF without any influence on CMRo2. The aim of this study was to investigate the effects of moderate arterial hypoxia on CBF, CMRo2 and catecholamine concentrations in blood and CSF after endotoxin with and without pretreatment with PPL. Three groups of dogs were studied. Group 1: Six animals were subjected to arterial hypoxia without any other intervention. Group 2: Six animals were given an endotoxin injection (E. coli lipopolysaccharide O 111: B 4), before the induction of hypoxia. Group 3: Eight animals were pretreated with PPL per os, 12.5 mg.kg-1 twice a day for one week before the experiments, and the effects of arterial hypoxia were studied both before and after an intravenous injection of endotoxin. Two levels of hypoxia were studied; oxygen saturation in arterial blood aiming at 75 and 50%. Endotoxin was given intravenously in a dose of 1 mg.kg-1 bodyweight over a 5 minute period. After an endotoxin injection, the response to arterial hypoxia was an increase in CMRo2, in contrast to the unchanged CMRo2 without endotoxin. After pretreatment with PPL the increase in CMRo2 after endotoxin was prevented. The CBF reaction to hypoxia was uniformly an increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of metabolic pH-alterations on cerebral blood flow and oxygen uptake following E. coli endotoxin in dogs.

The aim of the present study was to investigate if metabolic pH-alterations have an influence on cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) after an injection of E. coli endotoxin. Following endotoxin in dogs with normal pH a decreased CBF and an increased CMRO2 have earlier been found. Thirteen anaesthetized dogs were subjected to metabolic pH-variations in blood by infusion of hydrochloric acid or sodium bicarbonate. Ten dogs received E. coli endotoxin in a dose of 1 mg.kg-1 bodyweight. CBF, CMRO2 and noradrenaline and adrenaline concentrations in blood and cerebrospinal fluid were measured repeatedly during normoxia and normocarbia. Measurements before endotoxin served as controls, together with three additional animals, where endotoxin was never given. In control measurements pH showed no influence on the variables studied. After endotoxin CBF, CMRO2 and noradrenaline in cerebrospinal fluid increased with decreasing arterial blood pH. The influence exerted by metabolic pH alterations in blood after endotoxin may be explained by hydrogen ions and monoamines passing over a blood-brain barrier (BBB), damaged by endotoxin, into the brain tissue causing vasodilation and neuronal activation.

Distribution of radioactive microspheres injected into the vertebral artery of the dog.

The aim of the present study was to evaluate the use of the vertebral artery for cerebral blood flow studies. In eight dogs a small catheter was introduced into an unligated a. vertebralis sin. Radioactive microspheres (141Cerium) were injected and detected with a gamma camera. The microspheres were distributed to all parts of the brain. The concentrations were highest in the cerebellum, pons and medulla oblongata, while the total activity was greatest in the cerebrum because of its higher weight. The activity in the extracerebral tissues in the head was found to be less than 5% of the brain activity.

Prevention of endotoxin-induced increase of cerebral oxygen consumption in dogs by propranolol pretreatment.

Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were studied in experimental endotoxic shock in dogs. Eight animals were pretreated with a beta-adrenoceptor blocking agent, propranolol (PPL), per os 12 mg/kg once a day for 7 days. Ten animals served as controls. After an intravenous injection of endotoxin, 1 mg/kg, CBF decreased in both groups, with no significant differences between the groups. CMRO2 increased in the control animals by about 18% from the baseline value both 1 and 2 h after the injection of endotoxin. CMRO2 in the PPL-pretreated animals was unchanged after endotoxin. The CMRO2-reactions to endotoxin in control and PPL animals were significantly different after both 1 and 2 h (P less than 0.05). The present results indicate that the increase in CMRO2 following intravenous endotoxin is mediated via beta-adrenoceptors.

Cerebral hemodynamics, oxygen uptake and cerebral arteriovenous differences of catecholamines following E. coli endotoxin in dogs.

In experimental endotoxic shock in dogs, a decrease in cerebral blood flow and an increase in cerebral metabolic rate of oxygen (CMRO2) have been shown to occur. In this situation the blood levels of adrenaline and noradrenaline are markedly elevated. The aim of the present study was to investigate whether a cerebral uptake of circulating catecholamines with a possible influence on CMRO2 takes place in the brain. In eight anaesthetized dogs, arterial blood, superior sagittal sinus blood and cerebrospinal fluid were analyzed for the concentrations of adrenaline, noradrenaline and dopamine before and up to 4 h after an injection of E. coli endotoxin 1.0-1.5 mg . kg-1. The blood levels of adrenaline and noradrenaline, but not dopamine, increased in response to the endotoxin. From about 30 min after the endotoxin injection, arteriovenous adrenaline and noradrenaline differences indicating a cerebral uptake were most often seen. Increased concentrations of noradrenaline, adrenaline and dopamine in cerebrospinal fluid were observed. Noradrenaline gave the highest concentrations and these were correlated to the CMRO2. In some animals the blood and cerebrospinal fluid concentrations of adrenaline seemed to be related. These results indicate that catecholamines might be of importance for the development of an increased CMRO2 in endotoxic shock.