Effect of lumbar epidural blockade and propofol on mean arterial pressure, cardiac output and bispectral index: A randomised controlled and pharmacodynamic modelling study.

BACKGROUND: It is generally accepted that a neuraxial blockade strengthens the sedative effects of propofol. Deafferentation caused by neuraxial blockade is thought to play a key role. OBJECTIVES: The objective is to determine whether epidural blockade affects the bispectral index (BIS) of propofol and two other pharmacodynamic endpoints, mean arterial pressure (MAP) and cardiac output (CO). DESIGN: Randomised, placebo-controlled study. SETTING: University hospital. PATIENTS: Patients scheduled for surgery needing epidural analgesia. INTERVENTION: 28 ASA one or two patients received 0, 50, 100 or 150 mg of epidural ropivacaine. After stabilisation of the epidural blockade, propofol was given by target-controlled infusion. The propofol plasma target concentrations were increased at 6-min intervals from 0 to 1, 2.5, 4 and 6 µg ml-1. The study was performed before surgery. MAIN OUTCOME MEASURES: Three endpoints, BIS, mean arterial blood pressure and CO were measured from baseline (prior to the administration of epidural ropivacaine) until 2 h after the start of propofol infusion. The propofol concentration-effect data were analysed to determine the interaction between epidural blockade and propofol sedation. RESULTS: In the absence of propofol, the increase in number of epidural blocked segments from 0 to 15.5 (range 6 to 21) reduced the MAP by 30%, without affecting BIS or CO. In the absence of epidural blockade, the increase in propofol concentration to 6 µg ml-1 reduced BIS, MAP and CO. When combined, epidural anaesthesia and intravenous propofol exhibited no pharmacodynamic interaction on any of the three endpoints. In addition, epidural blockade did not affect the propofol effect-site equilibration half-life for its haemodynamic effects (11.5 ±â€Š0.5 min) or for its effects on the BIS (4.6 ±â€Š0.4 min). CONCLUSION: Epidural blockade reduces the propofol requirements for sedative end points. This is not the result of a pharmacodynamic interaction. TRIAL REGISTRATION: Dutch trial register CCMO, Central Committee on Research Involving Human Subjects, trial number NL 32295.058.10.

An Allometric Model of Remifentanil Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide range of age and weight. METHODS: Remifentanil pharmacokinetic data were obtained from three previously published studies of adults and children, one of which also contained pharmacodynamic data from adults. NONMEM was used to estimate allometrically scaled compartmental pharmacokinetic and pharmacodynamic models. Weight, age, height, sex, and body mass index were explored as covariates. Predictive performance was measured across young children, children, young adults, middle-aged, and elderly. RESULTS: Overall, 2,634 remifentanil arterial concentration and 3,989 spectral-edge frequency observations from 131 individuals (55 male, 76 female) were analyzed. Age range was 5 days to 85 yr, weight range was 2.5 to 106 kg, and height range was 49 to 193 cm. The final pharmacokinetic model uses age, weight, and sex as covariates. Parameter estimates for a 35-yr-old, 70-kg male (reference individual) are: V1, 5.81 l; V2, 8.82 l; V3, 5.03 l; CL, 2.58 l/min; Q2, 1.72 l/min; and Q3, 0.124 l/min. Parameters mostly increased with fat-free mass and decreased with age. The pharmacodynamic model effect compartment rate constant (ke0) was 1.09 per minute (reference individual), which decreased with age. CONCLUSIONS: We developed a pharmacokinetic-pharmacodynamic model to predict remifentanil concentration and effect for a wide range of patient ages and weights. Performance exceeded the Minto model over a wide age and weight range.

Disposition of Remifentanil in Obesity: A New Pharmacokinetic Model Incorporating the Influence of Body Mass.

BACKGROUND: The influence of obesity on the pharmacokinetic (PK) behavior of remifentanil is incompletely understood. The aim of the current investigation was to develop a new population PK model for remifentanil that would adequately characterize the influence of body weight (among other covariates, e.g., age) on the disposition of remifentanil in the general adult population. We hypothesized that age and various indices of body mass would be important covariates in the new model. METHODS: Nine previously published data sets containing 4,455 blood concentration measurements from 229 subjects were merged. A new PK model was built using nonlinear mixed-effects modeling. Satisfactory model performance was assessed graphically and numerically; an internal, boot-strapping validation procedure was performed to determine the CIs of the model. RESULTS: Body weight, fat-free body mass, and age (but not body mass index) exhibited significant covariate effects on certain three-compartment model parameters. Visual and numerical assessments of model performance were satisfactory. The bootstrap procedure showed satisfactory CIs on all of the model parameters. CONCLUSIONS: A new model estimated from a large, diverse data set provides the PK foundation for remifentanil dosing calculations in adult obese and elderly patients. It is suitable for use in target-controlled infusion systems and pharmacologic simulation.

Epidural Blockade Affects the Pharmacokinetics of Propofol in Surgical Patients.

BACKGROUND: Neuraxial blockade reduces the dose requirements of sedative agents. It is unclear whether neuraxial blockade affects the pharmacokinetics and/or the pharmacodynamics of IV hypnotics. We therefore studied the influence of epidural blockade on the pharmacokinetics of propofol in patients scheduled for general surgery. METHODS: Twenty-eight patients were randomly divided into 4 groups, in a double-blind manner, to receive 0, 50, 100, or 150 mg epidural ropivacaine. When the epidural blockade had stabilized, a target-controlled infusion of propofol was started at a target concentration of 1, 2.5, 4, and 6 µg/mL at 0, 6, 12, and 18 minutes, respectively. The infusion was terminated at 24 minutes. Arterial blood samples for blood propofol concentration determination were taken during and up to 150-minute postinfusion. The influence of epidural blockade on propofol pharmacokinetics was determined by mixed-effects modeling. RESULTS: With a ropivacaine dose increasing from 0 to 150 mg, the number of blocked segments (median [range]) increased from 0 (0-3) to 16 (6-21). With increasing epidural dose, blood propofol concentration increasingly exceeded target concentration. An epidural blockade of 20 segments reduced propofol's elimination clearance from 2.64 ± 0.12 to 1.87 ± 0.08 L/min. Adjusting for weight and sex further improved the propofol pharmacokinetic model. CONCLUSIONS: Epidural blockade affects the pharmacokinetics of propofol and the performance of a target-controlled infusion of propofol. At an epidural ropivacaine dose that blocks 20 segments, the propofol dosage or target concentration may be reduced by 30% compared with when no epidural blockade is present. An epidural-induced reduction in hepatic and/or renal blood flow may explain this pharmacokinetic interaction.

Circulatory model of vascular and interstitial distribution kinetics of rocuronium: a population analysis in patients.

The time-course of the neuromuscular blocking effect of rocuronium depends on circulatory mixing and the rate of distribution into the interstitial space. In order to quantitatively evaluate these processes, a physiologically meaningful model of distribution kinetics based on circulatory transport and interstitial diffusion, was fitted to rocuronium disposition data in 10 patients using a population approach. Information on cardiac output and circulatory mixing was obtained from the kinetics of indocyanine green (ICG), which was injected simultaneously with rocuronium. As a compromise between physiological reality and parameter identifiability, the organs of the systemic circulation were lumped into a heterogeneous subsystem, described by an axially distributed model of extravascular diffusion. Diffusion into the interstitial space determines the rate of rocuronium distribution in the body (diffusional time constant 89 min). The resulting whole body distribution kinetics depends both on cardiac output and on the apparent permeability surface area product (0.16 l/min). The analysis of the ICG data revealed that heterogeneity of blood transit time through the systemic circulation decreased and that cardiopulmonary volume increased, respectively, with cardiac output. The approach should be useful for studying the effect of disease states on distribution kinetics of drugs.

Propofol reduces the distribution and clearance of midazolam.

BACKGROUND: Midazolam, at sedative levels, increases blood propofol concentrations by 25%. We evaluated the reverse interaction and determined the influence of propofol on the pharmacokinetics of midazolam. METHODS: Eight healthy male volunteers were studied on 2 occasions in a random crossover manner. During session A, volunteers received midazolam 0.035 to 0.05 mg x kg(-1) IV for 1 minute followed by an infusion of 0.035 to 0.05 mg x kg(-1) x h(-1) for 59 minutes. During session B, in addition to this midazolam infusion scheme, a target-controlled infusion of propofol (constant C(T): 0.6 or 1.0 microg x mL(-1)) was given from 15 minutes before the start until 6 hours after termination of the midazolam infusion. Arterial blood samples for propofol and midazolam concentration analysis were taken until 6 hours after termination of the midazolam infusion. Nonlinear mixed-effect models examining the influence of propofol and hemodynamic variables on midazolam pharmacokinetics were constructed using Akaike's information-theoretic criterion for model selection. RESULTS: In the presence of a mean blood propofol concentration of 1.2 microg x mL(-1), the plasma midazolam concentration was increased by 26.9% + or - 9.4% compared with midazolam given as a single drug. Propofol (C(blood): 1.2 microg x mL(-1)) reduced midazolam central volume of distribution from 5.37 to 2.98 L, elimination clearance from 0.39 to 0.31 L x min(-1), and rapid distribution clearance from 2.77 to 2.11 L x min(-1). Inclusion of heart rate further improved the pharmacokinetic model of midazolam. CONCLUSIONS: Propofol reduces the distribution and clearance of midazolam in a concentration-dependent manner. In addition, inclusion of heart rate as a covariate improved the pharmacokinetic model of midazolam predominantly through a reduction in the intraindividual variability.

Pulse dye densitometry and indocyanine green plasma disappearance in ASA physical status I-II patients.

BACKGROUND: Indocyanine green plasma disappearance rate (ICG-PDR) is used to evaluate hepatic function. Although hepatic failure is generally said to occur with an ICG-PDR <18%/min, ICG disappearance rate is poorly defined in the healthy population, and a clear cutoff value of ICG-PDR that discriminates between normal hepatic function and hepatic failure has not yet been described. We therefore defined the ICG disappearance rate in an otherwise healthy patient population. In addition, we evaluated the noninvasive measurement of ICG-PDR (transcutaneously by pulse dye densitometry [PDD] at the finger and the nose) and compared these with the simultaneously performed invasive measurements of ICG-PDR (in arterial blood). METHODS: In patients without signs of liver disease, scheduled for elective nonhepatic surgery, 10 mg ICG was administered IV and ICG-PDR measured by PDD (DDG-2001, Nihon Kohden, Tokyo, Japan). In a subset of patients, arterial blood samples were gathered to compare PDD with invasive ICG measurements. Methods were compared using Bland-Altman analysis. The results of our study and reported studies on discriminative use of ICG-PDR in assessing liver failure were used to construct receiver operating characteristic curves. RESULTS: Forty-one patients were studied: 33 using the finger probe and 8 using the nose probe. The mean +/- SD noninvasive ICG-PDR in this patient population is 23.1% +/- 7.9%/min (n = 41) with a range of 9.7% to 43.2%/min. Bias (+/-2 sd, limits of agreement) for ICG-PDR measured by PDD compared with those measured in arterial blood were 1.6%/min (-5.2% to 8.3%/min) for the finger probe and -6.0%/min (-15.5% to 3.4%/min) for the nose probe. CONCLUSION: ICG-PDR values in a population without liver failure ranged well below 18%/min, cited as the cutoff value for hepatic failure. This cutoff value needs reconsideration. In addition, we conclude that the ICG concentration is adequately determined noninvasively by PDD.

Mixed-effects modeling of the influence of midazolam on propofol pharmacokinetics.

BACKGROUND: The combined administration of anesthetics has been associated with pharmacokinetic interactions that induce concentration changes of up to 30%. Midazolam is often used as a preoperative sedative in advance of a propofol-based anesthetic. In this study, we identified the influence of midazolam on the pharmacokinetics of propofol. METHODS: Eight healthy male volunteers were studied on two occasions in a random crossover manner. During Session A, volunteers received propofol 1 mg/kg in 1 min followed by an infusion of 2.5 mg x kg(-1) x h(-1) for 59 min. During Session B, in addition to this propofol infusion scheme, a target-controlled infusion of midazolam (constant C(t): 125 ng/mL) was given from 15 min before the start until 6 h after termination of the propofol infusion. Arterial blood samples for blood propofol and plasma midazolam concentration analysis were taken until 6 h after termination of the propofol infusion. Nonlinear mixed-effects models examining the influence of midazolam and hemodynamic variables on propofol pharmacokinetics were constructed using Akaike criterion for model selection. RESULTS: In the presence of midazolam (C(blood): 224.8 +/- 41.6 ng/mL), the blood propofol concentration increased by 25.1% +/- 13.3% compared with when propofol was given as single drug. Midazolam (C(blood): 225 ng/mL) reduced propofol Cl(1) from 1.94 to 1.61 L/min, Cl(2) from 2.86 to 1.52 L/min, and Cl(3) from 0.95 to 0.73 L/min. Inclusion of mean arterial blood pressure further improved the propofol pharmacokinetic model. CONCLUSIONS: Midazolam reduces the metabolic and rapid and slow distribution clearances of propofol. In addition, a reduction in mean arterial blood pressure is associated with propofol pharmacokinetic alterations that increase the blood propofol concentration.

Cardiovascular monitoring by pulse dye densitometry or arterial indocyanine green dilution.

BACKGROUND: Noninvasive cardiac output (CO) monitoring is possible by indocyanine green (ICG) dilution measured by pulse dye densitometry (PDD). To validate the precision of this method, we compared hemodynamic variables derived from PDD (DDG-2001, Nihon Kohden, Japan) with those derived from simultaneously taken arterial blood ICG concentrations. METHODS: In 20 patients (6 M/14 F), ASA I or II, 36 sessions were performed (n = 24 with the PDD-finger probe, n = 10 with the PDD-nose probe). After IV administration of 10 mg ICG, 34 arterial blood samples were taken during each session, with 20 samples taken during the first 2 min. CO, central blood volume (CBV), and total blood volume (TBV) were calculated independently from ICG and PDD and the results compared between methods using Bland-Altman analysis. The results are reported as mean difference (bias) and limits of agreement (LOA = +/- 2 sd). RESULTS: PDD using the finger probe underestimated CO (LOA) by 5% (-56% and 47%); overestimated CBV by 21% (-54% and 96%) and underestimated TBV by -15% (-38% and 8%). PDD using the nose probe overestimated CO (LOA) by 30% (-67% and 127%); CBV by 48% (-98% and 193%) and underestimated TBV by -10% (-47% and 27%). CONCLUSION: Despite the permissible bias, the wide LOA of the PDD-derived hemodynamic variables CO and CBV, compared with those simultaneously obtained by invasive arterial ICG measurements, suggest that PDD is unsuitable for evaluation of cardiovascular variables in the individual patient. Hence, the reliability and clinical use of this method seem limited.

Cardiovascular parameters and liver blood flow after infusion of a colloid solution and epidural administration of ropivacaine 0.75%: the influence of age and level of analgesia.

BACKGROUND AND OBJECTIVE: Lumbar epidural anaesthesia induces cardiovascular changes and decreases liver blood flow (Qh). We studied the effects of age on haemodynamics, blood volumes and Qh before and after epidural anaesthesia. METHODS: Thirty-six patients were enrolled as follows: group 1, 20-44 years; group 2, 45-70 years; group 3, >70 years. Using pulse dye densitometry, in addition to heart rate and arterial blood pressure (arterial BP), cardiac output, total blood volume, central blood volume and Qh were measured, before and after colloid infusion (500 ml hydroxyethyl starch, 6%) and after epidural administration of 15 ml of 0.75% ropivacaine. RESULTS: With age the level of analgesia [median (range)] increased from T7 (L2-T4) in group 1 to T4 (T10-C7) in group 3 (P = 0.04). After colloid infusion, heart rate (mean difference +/- SE; 2.1 +/- 0.7 beats min(-1)), systolic BP (4.1 +/- 2.2 mmHg) and Qh 162 ml min(-1) (ratio 0.90, 95% confidence interval 0.81-0.99) increased slightly but significantly, and were unaffected by age. Epidural anaesthesia induced a significant decrease in Qh (265 ml min(-1); ratio 1.20, 95% confidence interval 1.07-1.35) and arterial pressure (for systolic BP: P = 1 x 10(-7)). A significantly larger decrease in systolic BP occurred in the older, compared with the middle, age group (P = 0.04). Age did not affect epidural-induced changes in cardiac output, total and central blood volumes, and Qh. CONCLUSION: Age increases the level of analgesia after epidural ropivacaine and is associated with a more pronounced decrease in arterial pressure. A colloid preload mildly increases haemodynamics, but this insufficiently prevents younger and elderly patients from a decrease in Qh after lumbar epidural anaesthesia.

Epidural and Non-epidural Analgesia in Patients Undergoing Open Pancreatectomy: a Retrospective Cohort Study.

BACKGROUND: The use of epidural analgesia (EA) in pancreatic surgery remains under debate. This study compares patients treated with EA versus non-EA after open pancreatectomy in a tertiary referral center. METHODS: All patients undergoing open pancreatectomy from 2013 to 2017 were retrospectively reviewed. (Non-)EA was terminated on postoperative day (POD) 3 or earlier if required. RESULTS: In total, 190 (72.5%) patients received EA and 72 (27.5%) patients received non-EA (mostly intravenous morphine). EA was terminated prematurely in 32.6% of patients and non-EA in 10.5% of patients. Compared with non-EA patients, EA patients had significantly lower pain scores on POD 0 (1.10 (0-3.00) versus 3.00 (1.67-5.00), P < 0.001) and POD 1 (2.00 (0.50-3.41) versus 3.00 (2.00-3.80), P = 0.001), though significantly higher pain scores on POD 3 (3.00 (2.00-4.00) versus 2.33 (1.50-4.00), P < 0.001) and POD 4 (2.50 (1.50-3.67) versus 2.00 (0.50-3.00), P = 0.007). EA patients required more vasoactive medication perioperatively and had higher cumulative fluid balances on POD 1-3. Postoperative complications were similar between groups. CONCLUSIONS: In our cohort, patients with EA experienced significantly lower pain scores in the first PODs compared with non-EA, yet higher pain scores after EA had been terminated. Although EA patients required more vasoactive medication and fluid therapy, the complication rate was similar.

Folate receptor-α targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study.

OBJECTIVE: Detection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor-α (FRα) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRα and assess feasibility of intraoperative EC detection using OTL-38. RESULTS: FRα expression on TMA was significantly correlated with tumor type (p < 0.01). Eighty-two percent of serous and clear cell carcinomas showed FRα expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental (n = 3) and lymph node (LN) metastases (n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false-positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL-38 targeting of FRß, expressed by tumor-associated activated macrophages. CONCLUSIONS: This study describes high FRα expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRα-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated. METHODS: Immunohistochemical (IHC) staining of FRα expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRα and tumor status.

A decrease in blood pressure is associated with unfavorable outcome in patients undergoing thrombectomy under general anesthesia.

BACKGROUND: Up to two-thirds of patients are either dependent or dead 3 months after thrombectomy for acute ischemic stroke (AIS). Loss of cerebral autoregulation may render patients with AIS vulnerable to decreases in mean arterial pressure (MAP). OBJECTIVE: To determine whether a fall in MAP during intervention under general anesthesia (GA) affects functional outcome. METHODS: This subgroup analysis included patients from the MR CLEAN trial treated with thrombectomy under GA. The investigated variables were the difference between MAP at baseline and average MAP during GA (ΔMAP) as well as the difference between baseline MAP and the lowest MAP during GA (ΔLMAP). Their association with a shift towards better outcome on the modified Rankin Scale (mRS) after 90 days was determined using ordinal logistic regression with adjustment for prognostic baseline variables. RESULTS: Sixty of the 85 patients treated under GA in MR CLEAN had sufficient anesthetic information available for the analysis. A greater ΔMAP was associated with worse outcome (adjusted common OR (acOR) 0.95 per point mm Hg, 95% CI 0.92 to 0.99). An average MAP during GA 10 mm Hg lower than baseline MAP constituted a 1.67 times lower odds of a shift towards good outcome on the mRS. For ΔLMAP this association was not significant (acOR 0.97 per mm Hg, 95% CI 0.94 to 1.00, p=0.09). CONCLUSIONS: A decrease in MAP during intervention under GA compared with baseline is associated with worse outcome. TRIAL REGISTRATION NUMBER: NTR1804; ISRCTN10888758; post-results.

Prospective Clinical and Pharmacological Evaluation of the Delcath System's Second-Generation (GEN2) Hemofiltration System in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan.

INTRODUCTION: Percutaneous hepatic perfusion (PHP) with melphalan is an effective treatment for patients with hepatic metastases, but associated with high rates of bone marrow depression. To reduce systemic toxicity, improvements have been made to the filtration system. In pre-clinical studies, the Delcath System's GEN2 filter was superior to the first-generation filters. In this clinical study, we analysed the pharmacokinetics and toxicity of PHP using the new GEN2 filter. METHODS AND MATERIALS: Starting February 2014, two prospective phase II studies were initiated in patients with hepatic metastases from ocular melanoma or colorectal cancer. In 10 PHP procedures performed in the first 7 enrolled patients, blood samples were obtained to determine filter efficiency and systemic drug exposure. PHP was performed with melphalan 3 mg/kg with a maximum of 220 mg. Complications were assessed according to CTCAE v4.03. Response was assessed according to RECIST 1.1. RESULTS: Pharmacokinetic analysis of blood samples showed an overall filter efficiency of 86% (range 71.1-95.5%). The mean filter efficiency decreased from 95.4% 10 min after the start of melphalan infusion to 77.5% at the end of the procedure (p = 0.051). Bone marrow depression was seen after up to 80.0% of 10 procedures, but was self-limiting and mostly asymptomatic. No hypotension-related complications or procedure-related mortality occurred. CONCLUSION: The GEN2 filter has a higher melphalan filter efficiency compared to the first-generation filters and a more consistent performance. PHP with the GEN2 filter appears to have an acceptable safety profile, but this needs further validation in larger studies.

Acetazolamide improves cerebral oxygenation during exercise at high altitude.

Vuyk, Jaap, Jan Van Den Bos, Kees Terhell, Rene De Bos, Ad Vletter, Pierre Valk, Martie Van Beuzekom, Jack Van Kleef, and Albert Dahan. Acetazolamide improves cerebral oxygenation during exercise at high altitude. High Alt. Med. Biol. 7:290-301, 2006.--Acute mountain sickness is thought to be triggered by cerebral hypoxemia and be prevented by acetazolamide (Actz). The effect of Actz on cerebral oxygenation at altitude remains unknown. In 16 members of the 2005 Dutch Cho Oyu (8201 m, Tibet) expedition, the influence of Actz and exercise (750 mg PO daily) on heart rate, peripheral and regional cerebral oxygen saturation (Sa(O(2) ) and rS(O(2) )), the Lake Louise score (LLS), and psychomotor function were studied at 0 m 14 days prior to the expedition, after arrival at 3700 m on day 3, after arrival at 5700 m on day 29, and again at 5700 m before the end of the expedition on day 51. After arrival at 3700 m, the LLS of the climbers taking Actz (n = 8) was significantly lower compared to those who did not take Actz (n = 8): 0.75 +/- 1.0 versus 2.9 +/- 2.0, p < 0.05 (ANOVA). High LLSs were associated with low rS(O(2) ) values in rest and exercise (p < 0.01 and p < 0.001). With altitude, resting Sa(O(2) ) and resting rS(O(2) ) decreased significantly (p < 0.001), irrespective of Actz use. Exercise at 3700 m and 5700 m reduced Sa(O(2) ) and rS(O(2) ) even further compared to rest (p < 0.001), although at 3700 m the rS(O(2) ) was preserved better in those who took Actz (55.3 +/- 4.3% versus 47.9 +/- 5.7%, p < 0.05). Irrespective of Actz use, with altitude, the percentage of omissions in the vigilance and tracking test increased while the climbers' scores on vigor decreased (p < 0.05). In conclusion, at altitude, exercise-induced reduction in cerebral oxygenation is less in climbers on Actz compared to climbers not taking Actz. This effect is nullified after several weeks at altitude due to acclimatization in climbers not taking Actz.

Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver.

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure.

Intraoperative imaging of folate receptor alpha positive ovarian and breast cancer using the tumor specific agent EC17.

INTRODUCTION: Intraoperative fluorescence imaging of the folate-receptor alpha (FRα) could support completeness of resection in cancer surgery. Feasibility of EC17, a FRα-targeting agent that fluoresces at 500nm, was demonstrated in a limited series of ovarian cancer patients. Our objective was to evaluate EC17 in a larger group of ovarian cancer patients. In addition, we assessed the feasibility of EC17 in patients with breast cancer. METHODS: Two-to-three hours before surgery 0.1mg/kg EC17 was intravenously administered to 12 patients undergoing surgery for ovarian cancer and to 3 patients undergoing surgery for biopsy-proven FRα-positive breast cancer. The number of lesions/positive margins detected with fluorescence and concordance between fluorescence and tumor- and FRα-status was assessed in addition to safety and pharmacokinetics. RESULTS: Fluorescence imaging in ovarian cancer patients allowed detection of 57 lesions of which 44 (77%) appeared malignant on histopathology. Seven out of these 44 (16%) were not detected with inspection/palpation. Histopathology demonstrated concordance between fluorescence and FRα- and tumor status. Fluorescence imaging in breast cancer patients, allowed detection of tumor-specific fluorescence signal. At the 500nm wavelength, autofluorescence of normal breast tissue was present to such extent that it interfered with tumor identification. CONCLUSIONS: FRα is a favorable target for fluorescence-guided surgery as EC17 produced a clear fluorescent signal in ovarian and breast cancer tissue. This resulted in resection of ovarian cancer lesions that were otherwise not detected. Notwithstanding, autofluorescence caused false-positive lesions in ovarian cancer and difficulty in discriminating breast cancer-specific fluorescence from background signal. Optimization of the 500nm fluorophore, will minimize autofluorescence and further improve intraoperative tumor detection.

A Novel Tumor-Specific Agent for Intraoperative Near-Infrared Fluorescence Imaging: A Translational Study in Healthy Volunteers and Patients with Ovarian Cancer.

PURPOSE: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers. EXPERIMENTAL DESIGN: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging. RESULTS: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha-positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation. CONCLUSIONS: This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929-38. ©2016 AACR.

Strategies to optimise propofol-opioid anaesthesia.

Propofol-opioid combinations are widely used in today's anaesthetic practice. Over the past 20-30 years the pharmacology of these agents has been described in increasingly greater detail. Together with novel intravenous administration devices and improved anaesthetic depth monitoring, this has created a basis for the optimisation of the administration of propofol-opioid anaesthesia. This article describes the current strategies regarding the application of this type of anaesthesia, focusing on three strategic tools: (i) application of pharmacokinetic-pharmacodynamic knowledge of propofol and the opioids, with particular attention to pharmacodynamic interactions between them; (ii) the use of state-of-the-art administration techniques; and (iii) the application of bispectral index monitoring. Together, these techniques have improved the level of control, the flexibility and the safety of anaesthetic practice.

Effect of deafferentation from spinal anesthesia on pain sensitivity and resting-state functional brain connectivity in healthy male volunteers.

Patients may perceive paradoxical heat sensation during spinal anesthesia. This could be due to deafferentation-related functional changes at cortical, subcortical, or spinal levels. In the current study, the effect of spinal deafferentation on sensory (pain) sensitivity was studied and linked to whole-brain functional connectivity as assessed by resting-state functional magnetic resonance imaging (RS-fMRI) imaging. Deafferentation was induced by sham or spinal anesthesia (15 mg bupivacaine injected at L3-4) in 12 male volunteers. RS-fMRI brain connectivity was determined in relation to eight predefined and seven thalamic resting-state networks (RSNs) and measured before, and 1 and 2 h after spinal/sham injection. To measure the effect of deafferentation on pain sensitivity, responses to heat pain were measured at 15-min intervals on nondeafferented skin and correlated to RS-fMRI connectivity data. Spinal anesthesia altered functional brain connectivity within brain regions involved in the sensory discriminative (i.e., pain intensity related) and affective dimensions of pain perception in relation to somatosensory and thalamic RSNs. A significant enhancement of pain sensitivity on nondeafferented skin was observed after spinal anesthesia compared to sham (area-under-the-curve [mean (SEM)]: 190.4 [33.8] versus 13.7 [7.2]; p<0.001), which significantly correlated to functional connectivity changes observed within the thalamus in relation to the thalamo-prefrontal network, and in the anterior cingulate cortex and insula in relation to the thalamo-parietal network. Enhanced pain sensitivity from spinal deafferentation correlated with functional connectivity changes within brain regions involved in affective and sensory pain processing and areas involved in descending control of pain.