Peri-operative oxygen consumption revisited: An observational study in elderly patients undergoing major abdominal surgery.

BACKGROUND: Monitoring oxygen consumption (VO2) is neither recommended nor included in peri-operative haemodynamic algorithms aiming at optimising oxygen delivery (DO2) in major abdominal surgery. Estimates of peri-operative VO2 changes are uncertain in earlier publications and have limited generalisability in the current high-risk surgical population. In a prospective non-interventional observational study in elderly patients undergoing major abdominal procedures, we investigated the change of VO2 after induction of anaesthesia and secondarily, the further changes during and after surgery in relation to DO2 and estimated oxygen extraction ratio (O2ER) by routine monitoring. METHODS: VO2 was determined by indirect calorimetry (QuarkRMR) in 20 patients more than 65 years (ASA II to IV), scheduled for elective open upper abdominal surgery with combined epidural and general anaesthesia. Data were collected during 20-minute periods pre-operatively and after anaesthesia induction, with subsequent measurements during surgery and postoperatively. Simultaneously, DO2 was monitored using LiDCOplus. The O2ER was estimated from arterial-central venous oxygen content calculation. Mixed models were used to analyse the peri-operative changes. RESULTS: VO2 decreased after induction of anaesthesia by a mean of 34% (95% CI, 28 to 39). After 2 h of surgery, VO2 was reduced by 24% (95% CI, 20 to 27) compared with the awake baseline measurements. Pre-operative mean DO2 was 440 (95% CI, 396 to 483) ml min m and decreased by a mean of 37% (95% CI, 30 to 43) during anaesthesia. The estimated O2ER did not change intra-operatively 0.24 (95% CI, 0.21 to 0.26) but increased postoperatively to 0.31 (95% CI, 0.27 to 0.36). The changes of VO2 were parallel with changes of DO2 and O2ER in the intra-operative period. CONCLUSION: General anaesthesia reduced VO2 by approximately a third in elderly patients undergoing major abdominal surgery. Parallel changes of intra-operative VO2 and delivery were demonstrated while oxygen extraction was low. The relevance of these changes needs further assessment in relation to outcomes and haemodynamic interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT03355118.

Perioperative estimations of oxygen consumption from LiDCO™plus-derived cardiac output and Ca-cvO2 difference: Relationship with measurements by indirect calorimetry in elderly patients undergoing major abdominal surgery.

BACKGROUND: Feasible estimations of perioperative changes in oxygen consumption (VO2) could enable larger studies of its role in postoperative outcomes. Current methods, either by reverse Fick calculations using pulmonary artery catheterisation or metabolic by breathing gas analysis, are often deemed too invasive or technically requiring. In addition, reverse Fick calculations report generally lower values of oxygen consumption. METHODS: We investigated the relationship between perioperative estimations of VO2 (EVO2), from LiDCO™plus-derived (LiDCO Ltd, Cambridge, UK) cardiac output and arterial-central venous oxygen content difference (Ca-cvO2), with indirect calorimetry (GVO2) by QuarkRMR (COSMED srl. Italy), using data collected 2017-2018 during a prospective observational study on perioperative oxygen transport in 20 patients >65 years during epidural and general anaesthesia for open pancreatic or liver resection surgery. Eighty-five simultaneous intra- and postoperative measurements at different perioperative stages were analysed for prediction, parallelity and by traditional agreement assessment. RESULTS: Unadjusted bias between GVO2 and EVO2 indexed for body surface area was 26 (95% CI 20 to 32) with limits of agreement (1.96SD) of -32 to 85 ml min-1m-2. Correlation adjusted for the bias was moderate, intraclass coefficient(A,1) 0.51(95% CI 0.34 to 0.65) [F (84,84) = 3.07, P<0.001]. There was an overall association between GVO2 and EVO2, in a random coefficient model [GVO2 = 73(95% CI 62 to 83) + 0.45(95% CI 0.29 to 0.61) EVO2 ml min-1m-2, P<0.0001]. GVO2 and EVO2 changed in parallel intra- and postoperatively when normalised to their respective overall means. CONCLUSION: Based on this data, estimations from LiDCO™plus-derived cardiac output and Ca-cvO2 are not reliable as a surrogate for perioperative VO2. Results were in line with previous studies comparing Fick-based and metabolic measurements but limited by variability of data and possible underpowering. The parallelity at different perioperative stages and the prediction model can provide useful guidance and methodological tools for future studies on similar methods in larger samples.

Bispecific antibody pretargeting PET (immunoPET) with an 124I-labeled hapten-peptide.

UNLABELLED: We previously described a highly flexible bispecific antibody (bs-mAb) pretargeting procedure using a multivalent, recombinant anti-CEA (carcinoembryonic antigen) x anti-HSG (histamine-succinyl-glycine) fusion protein with peptides radiolabeled with 111In, 90Y, 177Lu, and 99mTc. The objective of this study was to develop a radioiodination procedure primarily to assess PET imaging with 124I. METHODS: A new peptide, DOTA-D-Tyr-D-Lys(HSG)-D-Glu-D-Lys(HSG)-NH2 (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), was synthesized and conditions were established for radioiodination with yields of approximately 70% for 131I and 60% for 124I. Pretargeting with the 131I- and 124I-labeled peptide was tested in nude mice bearing LS174T human colonic tumors that were first given the anti-CEA x anti-HSG bs-mAb. Imaging (including small-animal PET) and necropsy data were collected at several intervals over 24 h. Comparisons were made between animals given 124I-anti-CEA Fab', 18F-FDG, the same peptide radiolabeled with 111In and pretargeted with the bs-mAb, and the radioiodinated peptide alone. RESULTS: The radioiodinated peptide alone cleared quickly from the blood with no evidence of tumor targeting, but when pretargeted with the bs-mAb, tumor uptake increased 70-fold, with efficient and rapid clearance from normal tissues, allowing clear visualization of tumor within 1-2 h. Tumor uptake measured at necropsy was 3- to 15-fold higher and tumor-to-blood ratios were 10- to 20-fold higher than those for 124I-Fab' at 1 and 24 h, respectively. Thyroid and stomach uptake was observed with the radioiodinated peptide several hours after injection (animals were not premedicated to reduce uptake in these tissues), but gastric uptake was much more pronounced with 124I-Fab'. Tumor visualization with 18F-FDG at approximately 1.5 h was also good but showed substantially more uptake in several normal tissues, making image interpretation in the pretargeted animals less ambiguous than with 18F-FDG. CONCLUSION: Bispecific antibody pretargeting has a significant advantage for tumor imaging over directly radiolabeled antibodies and could provide additional enhancements for oncologic imaging, particularly for improving targeting specificity as compared with 18F-FDG.

Lack of pharmacokinetic drug interaction between oral posaconazole and caspofungin or micafungin.

The objective of this phase 1, open-label, parallel, randomized study was to determine the effect of posaconazole on the pharmacokinetics of caspofungin and micafungin in 67 healthy subjects. Caspofungin (70 mg on day 1, 50 mg on days 2-14 once daily; 1-hour intravenous infusion) (cohort 1) or micafungin (150 mg once daily days 1-7; 1-hour IV infusion) (cohort 2) was administered alone or with posaconazole oral suspension 400 mg twice daily, on days 1 to 14 (cohort 1) or days 1 to 7 (cohort 2). Pharmacokinetic parameters, maximum plasma concentration (C(max)), steady-state area under the plasma concentration-time curve over the dosing interval (AUC[τ]), and time to C(max) (T(max)) were assessed. Safety assessments included adverse events, clinical laboratory tests, vital signs, and electrocardiograms. Repeated posaconazole dosing did not affect caspofungin or micafungin pharmacokinetics. Log-transformed ratio estimates of caspofungin with posaconazole C(max) and AUC(τ) were 90% and 98%, respectively, of those with caspofungin alone at day 14; ratio estimates of micafungin with posaconazole C(max) and AUC(τ) were 104% and 109%, respectively, of those with micafungin alone at day 7. Median T(max) (1 hour) did not change. Coadministration of posaconazole with caspofungin or micafungin was generally well tolerated and did not affect the pharmacokinetics of either echinocandin.

A high-throughput LC-MS/MS method for the quantitation of posaconazole in human plasma: Implementing fused core silica liquid chromatography.

A rapid and robust liquid chromatographic tandem mass spectrometric (LC-MS/MS) method for the determination of posaconazole concentrations in human plasma was validated. Posaconazole was extracted from human plasma using mixed-mode cation exchange solid phase extraction in a 96-well plate format followed by gradient separation on a fused-core Halo C18 column. The analyte and its corresponding internal standard were detected using a Sciex API 4000 triple quadrupole LC-MS/MS system equipped with a TurboIonSpray ionization source operated in the positive ion mode. The calibration range of the method was 5.00-5000ng/mL using a 50microL aliquot of plasma. The assay inter-run accuracy and precision were-4.6-2.8% and 2.3-8.7%, respectively (n=18). The results from method validation indicate the method to be sensitive, selective, accurate, and reproducible. The method was successfully applied to the routine analysis of clinical samples with the fused-core silica columns providing excellent reproducibility for greater than 1000 injections per column.