Dynamic Cerebral Autoregulation after Cardiopulmonary Bypass.

Background Cerebral hemodynamic disturbances in the peri- or postoperative period may contribute to postoperative cognitive dysfunction (POCD) in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). We therefore examined dynamic cerebral autoregulation (dCA) post-CPB and changes in neurocognitive function in patients that had undergone CABG. Materials and Methods We assessed dCA by transfer function analysis of spontaneous oscillations between arterial blood pressure and middle cerebral artery blood flow velocity measured by transcranial Doppler ultrasound in eight patients 6 hours after the cessation of CPB; 10 healthy volunteers served as controls. Neurocognitive function was assessed by four specific tests 1 day prior to and 3 days after CPB. Results Even though patients exhibited systemic inflammation and anemic hypoxemia, dCA was similar to healthy volunteers (gain: 1.24 [0.94-1.49] vs. 1.22 [1.06-1.34] cm mm Hg-1 s-1, p = 0.97; phase: 0.33 [0.15-0.56] vs. 0.69 [0.50-0.77] rad, p = 0.09). Neurocognitive testing showed a perioperative decline in the Letter Digit Coding Score (p = 0.04), while weaker dCA was associated with a lower Stroop Color Word Test (rho = - 0.90; p = 0.01). Discussion and Conclusion We found no changes in dCA 6 hours after CPB. However, based on the data at hand, it cannot be ruled out that changes in dCA predispose to POCD, which calls for larger studies that assess the potential impact of dCA in the early postoperative period on POCD.

No change in [¹¹C]CUMI-101 binding to 5-HT(1A) receptors after intravenous citalopram in human.

The main objective of this study was to determine the sensitivity of [¹¹C]CUMI-101 to citalopram challenge aiming at increasing extracellular 5-HT. CUMI-101 has agonistic properties in human embryonic kidney 293 cells transfected with human recombinant 5-HT(1A) receptors (Hendry et al. [2011] Nucl Med Biol 38:273-277; Kumar et al. [2006] J Med Chem 49:125-134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243-249). We studied six healthy individuals. Two PET-scans were performed on the same day in each individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference in regional distribution volume or non-displaceable binding potential values before and after citalopram infusion. The mean receptor occupancy was 0.03 (range -0.14 to 0.17). Our data imply that [¹¹C]CUMI-101 binding is not sensitive to citalopram infusion in humans.

Design of Infusion Schemes for Neuroreceptor Imaging: Application to [(11)C]Flumazenil-PET Steady-State Study.

This study aims at developing a simulation system that predicts the optimal study design for attaining tracer steady-state conditions in brain and blood rapidly. Tracer kinetics was determined from bolus studies and used to construct the system. Subsequently, the system was used to design inputs for bolus infusion (BI) or programmed infusion (PI) experiments. Steady-state quantitative measurements can be made with one short scan and venous blood samples. The GABAA receptor ligand [(11)C]Flumazenil (FMZ) was chosen for this purpose, as it lacks a suitable reference region. Methods. Five bolus [(11)C]FMZ-PET scans were conducted, based on which population-based PI and BI schemes were designed and tested in five additional healthy subjects. The design of a PI was assisted by an offline feedback controller. Results. The system could reproduce the measurements in blood and brain. With PI, [(11)C]FMZ steady state was attained within 40 min, which was 8 min earlier than the optimal BI (B/I ratio = 55 min). Conclusions. The system can design both BI and PI schemes to attain steady state rapidly. For example, subjects can be [(11)C]FMZ-PET scanned after 40 min of tracer infusion for 40 min with venous sampling and a straight-forward quantification. This simulation toolbox is available for other PET-tracers.

Quantification of 123I-PE2I binding to dopamine transporter with SPECT after bolus and bolus/infusion.

UNLABELLED: The aim of the present study was to describe a method combining easy implementation in a clinical setting with accuracy and precision in quantification of 123I-labeled N-(3-iodoprop-(2E)-enyl)-2beta-carboxymethoxy-3beta-(4'-methylphenyl)nortropane (PE2I) binding to brain dopamine transporter. METHODS: Five healthy subjects (mean age, 50 y; range, 40-68 y) were studied twice. In the first experiment, dynamic SPECT data and arterial plasma input curves obtained after 123I-PE2I bolus injection were assessed using Logan, kinetic, transient equilibrium, and peak equilibrium analyses. Accurate and precise determination of BP1 (binding potential times the free fraction in the metabolite-corrected plasma compartment) and BP2 (binding potential times the free fraction in the intracerebral nonspecifically bound compartment) was achieved using Logan analysis and kinetic analysis, with a total study time of 90 min. In the second experiment, (123)I-PE2I was administrated as a combined bolus and constant infusion. The bolus was equivalent to 2.7 h of constant infusion. RESULTS: The bolus-to-infusion ratio of 2.7 h was based on the average terminal clearance rate from plasma in the bolus experiments. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 2 h. Even when an average bolus-to-infusion ratio was used, the striatal BP1 and BP2 values calculated with kinetic analysis (BP1 = 21.1 +/- 1.1; BP2 = 4.1 +/- 0.4) did not significantly differ from those calculated with bolus/infusion analysis (BP1 = 21.0 +/- 1.2; BP2 = 4.3 +/- 0.3). Computer simulations confirmed that a 2-fold difference in terminal clearance rate from plasma translates into only a 10% difference in BP1 and BP2 calculated from 120 to 180 min after tracer administration. CONCLUSION: The bolus/infusion approach allows accurate and precise quantification of 123I-PE2I binding to dopamine transporter and is easily implemented in a clinical setting.

[18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge.

The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]altanserin. [18F]altanserin studies were conducted in seven subjects using the bolus/infusion approach designed for attaining steady state in blood and brain 2 hours after the initial [18F]altanserin administration. Three hours after commencement of radiotracer administration, 0.25 mg/kg of the selective serotonin reuptake inhibitor, citalopram (Lundbeck, Valby, Denmark), was administered to all subjects as a constant infusion for 20 minutes. To reduce 5-HT1A-mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT-induced adverse effect, cortical [18F]altanserin binding was insensitive to the citalopram challenge, even after pindolol pretreatment. The biochemical and cellular events possibly affecting the unsuccessful translation of the citalopram/pindolol challenge into a change in 5-HT2A receptor binding of [18F]altanserin are discussed.

Cerebral blood flow and cognitive dysfunction after coronary surgery.

BACKGROUND: Postoperative cognitive dysfunction after cardiac surgery has been attributed both to embolic events and periods with reduced cerebral perfusion. We investigated whether cognitive dysfunction after coronary surgery is associated with changes in regional cerebral blood flow (CBF) using single photon emission computed tomography. METHODS: Before surgery and at discharge, 15 coronary surgery patients were studied. Global and regional CBF were measured using a brain-dedicated single photon emission computed tomography scanner, and neuropsychological testing with seven subtests was performed. Postoperative cognitive dysfunction was defined as a Z score above 2. Normative single photon emission computed tomography data were available from 26 healthy age-matched controls. RESULTS: Preoperative global CBF was significantly lower in patients compared with controls (53.7 versus 46.1 mL/100 g/min, p = 0.006). After surgery, global CBF significantly decreased in the patient group (46.1 versus 38.6 mL/100 g/min, p = 0.0001). No significant differences were detected in regional CBF. Cognitive dysfunction was identified in 4 of the 15 patients (26.7%, 95% CI 7.8% to 55.1%). No correlation was found between the neuropsychological Z score and global or regional CBF. CONCLUSIONS: The significant decrease in CBF after coronary surgery was uniformly distributed and was not correlated to postoperative cognitive dysfunction.

Outcome of accidental hypothermia with or without circulatory arrest: experience from the Danish Præstø Fjord boating accident.

BACKGROUND: Resuscitation guidelines for the treatment of accidental hypothermia are based primarily on isolated cases. Mortality rates are high despite aggressive treatment aimed at restoring spontaneous circulation and normothermia. METHODS: The present report is based on a boating accident where 15 healthy subjects (median age 16 (range 15-45) years) were immersed in 2 °C salt water. Seven victims were recovered in circulatory arrest with a median temperature of 18.4 °C (range 15.5-20.2 °C). They were all rewarmed with extracorporeal membrane oxygenation (ECMO) and were subsequently evaluated with advanced neuroradiological and functional testing. The remaining 7 had established spontaneous circulation without the use of ECMO. One victim drowned in the accident. RESULTS: The victims that survived the accident without circulatory arrest were predominantly females with a higher body mass index. Victims with circulatory arrest pH on arrival was a median of 6.61 (range 6.43-6.94), with ECMO being established a median of 226 (178-241)min after the accident. Magnetic resonance spectroscopy showed neuronal dysfunction in five. In five victims initial normal white matter spectra progressed to show evidence of abnormal axonal membranes. Based on the seven-level Functional Independence Measure test functional outcome was good in six circulatory arrest victims and in all without circulatory arrest. Mild to moderate cognitive dysfunction was seen in six and severe dysfunction in one circulatory arrest victim. CONCLUSION: Seven patients with profound accidental hypothermic circulatory arrest were successfully resuscitated using a management approach that included extracorporeal rewarming, followed by successive periods of therapeutic hypothermia and sedated normothermia and intensive neurorehabilitation. Seven other hypothermic victims (core temperature as low as 23 °C) that did not suffer circulatory arrest also survived the accident.

Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial.

OBJECTIVES: To evaluate the long term effects of perioperative beta blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery. DESIGN: Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat. SETTING: University anaesthesia and surgical centres and one coordinating centre. PARTICIPANTS: 921 patients aged > 39 scheduled for major non-cardiac surgery. INTERVENTIONS: 100 mg metoprolol controlled and extended release or placebo administered from the day before surgery to a maximum of eight perioperative days. MAIN OUTCOME MEASURES: The composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity. RESULTS: Mean duration of intervention was 4.6 days in the metoprolol group and 4.9 days in the placebo group. Metoprolol significantly reduced the mean heart rate by 11% (95% confidence interval 9% to 13%) and mean blood pressure by 3% (1% to 5%). The primary outcome occurred in 99 of 462 patients in the metoprolol group (21%) and 93 of 459 patients in the placebo group (20%) (hazard ratio 1.06, 0.80 to 1.41) during a median follow-up of 18 months (range 6-30). All cause mortality was 16% (74/462) in the metoprolol group and 16% (72/459) in the placebo group (1.03, 0.74 to 1.42). The difference in risk for the proportion of patients with serious adverse events was 2.4% (- 0.8% to 5.6%). CONCLUSIONS: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. Confidence intervals, however, were wide, and the issue needs reassessment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58485613.

Early extubation after single-lung transplantation: analysis of the first 106 cases.

OBJECTIVE: To determine if a modern anesthetic approach permits extubation immediately after surgery for single-lung transplantation. DESIGN: A retrospective study of all patients undergoing single-lung transplantation from June 1993 to December 1999 in Denmark. SETTING: Rigshospitalet, Copenhagen University hospital. PARTICIPANTS: One hundred six consecutive patients scheduled for single-lung transplantation. INTERVENTIONS: From July 1997, the anesthetic approach was changed to facilitate early extubation. The changes included epidural analgesia and short-acting anesthetic drugs. MEASUREMENTS AND MAIN RESULTS: One hundred six patients were anesthetized for single-lung transplantation. The first 33 patients were moved to the intensive care unit for postoperative mechanical ventilation. After the change of anesthesia technique, 53 of 73 patients were extubated in the operating room. Eleven patients needed reintubation within the first 24 hours because of respiratory insufficiency, pulmonary edema, hemorrhage, or pneumothorax. The need for reintubation increased the length of stay in the intensive care unit by 1 day from 2 to 3 days (NS). The possibility of early extubation or the need for reintubation was not related to age, weight, sex, preoperative condition, mode of transport of the graft, duration of graft ischemia, or side of transplantation. CONCLUSION: This study has shown that it is possible to extubate patients in the operating room immediately after single-lung transplantation in the majority of cases.

Quantification of [(123)I]PE2I binding to dopamine transporters with SPET.

The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with single-photon emission tomography (SPET). The aim of the present study was to describe a method for accurate quantification of binding data following a bolus injection of [(123)I]PE2I. Six healthy subjects (age 51+/-24 years) underwent xenon-133 SPET for quantification of regional CBF and [(123)I]PE2I SPET for quantification of DAT binding. rCBFs were within normal limits in all subjects. Fitting data to a two-tissue compartment model resulted in striatal K(1) values of 0.39+/-0.08 ml ml(-1) min(-1), equal to a first-pass extraction fraction of 0.72+/-0.13. Distribution volumes (DVs) were calculated using compartment analysis, area under the curve analysis and Logan analysis. Logan analysis is preferred since stable DV values were already obtained 120 min after [(123)I]PE2I injection. Mean striatal DV was 37.9+/-9.6 ml ml(-1) and mean occipital cortex DV was 5.5+/-0.7 ml ml(-1). In the absence of local pathology in a reference tissue, Logan analysis without blood sampling is an attractive method for accurate quantification of striatal [(123)I]PE2I binding. The distribution volume ratio (DVR) (6.6+/-1.4) was in good agreement with the DVR calculated with blood (6.7+/-1.4).