Comparison of cardiac output and blood volumes in intrathoracic compartments measured by ultrasound dilution and transpulmonary thermodilution methods

Purpose

To compare cardiac output (CO) and blood volumes measured by COstatus^® (Transonic Systems Inc., NY, USA) versus PiCCO (Philips IntelliVue MP40 with PiCCO-technology module M3012A#10, Netherlands) in adult ICU patients.

Methods

This was a prospective single-center study. Each of the 30 patients studied received a 5-Fr Pulsiocath femoral arterial and a standard central venous catheter. Twenty ml of iced 5% dextrose solution was injected for PiCCO measurements. For COstatus measurements, an extracorporeal arteriovenous loop, with two sensors placed on it, was connected between the Pulsiocath femoral arterial and central venous catheters. Blood was circulated through this loop at 12 ml/min for 5–8 min using a pump. Twenty ml of warm saline was injected into the venous side for measurements. For each method, three injections were averaged for comparison.

Results

A good agreement for measured CO (range 3.65–16.3 l/min) with a percentage error of 20% was observed, with r = 0.95, bias = ?0.037 l/min. PiCCO’s global end-diastolic volume (GEDV) was 2.5 times larger than the analogous COstatus’s total end-diastolic volume (TEDV) [TEDV = 0.28 × GEDV + 176 ml]. PiCCO’s intrathoracic blood volume (ITBV) was larger than the analogous COstatus’s central blood volume (CBV) [CBV = 0.73 × (ITBV) +78 ml].

Conclusions

CO measured by COstatus was found to be equivalent and hence interchangeable with PiCCO in this study population. COstatus blood volumes were found to be within the expected physiological range whilst PiCCO blood volumes were significantly higher, which was also observed in other studies. Future studies using 3D echo/MRI are required to validate these blood volumes.     

Improved outcome of percutaneous radiofrequency ablation in renal cell carcinoma: a retrospective study of intraoperative contrast-enhanced ultrasonography in 73 patients

Objectives

To evaluate the impact of contrast-enhanced ultrasonography (CEUS) during percutaneous radiofrequency ablation (PRFA) procedure in renal cell carcinoma (RCC).

Methods

From January 2008 to July 2010, 73 patients with sporadic unilateral RCC were enrolled to our study (57 men and 16 women, age range: 37–78 years, mean age 57.9 years). The diameter of the tumor was 1.7–5.8, 3.4 cm on average. The patients were divided into two groups depending on the intraoperative ultrasonography type: CEUS group and conventional ultrasound group. Patients in CEUS group received CEUS before insertion of the electrode, and the second CEUS was performed right after the initial ablation to dynamically evaluate the images. If there was highly suspicious residue, additional ablation and repeated CEUS were applied. Patients in the conventional ultrasound group received PRFA guided by gray-scale ultrasound. All of these patients received contrast-enhanced computed tomography (CT) examination 7 days after the procedure (patients in CEUS group received CEUS conducted with each CT scan), with subsequent CT and CEUS assessment at 3, 6, and every 6 months thereafter.

Results

The mean follow-up period was 22 months (range: 12–42 months). All tumors were biopsied before RFA. The local tumor control rate was 94.6% (35/37) in the CEUS group and 86.1% (31/36) in the conventional ultrasound group (P < 0.05); the cancer-specific survival rate and the overall survival rate were 100%. The post-RFA (12 months) mean GFR levels were 84.7 ± 27.5 mL/min/1.73 m² (P > 0.05, compared with pre-GFR: 86.4 ± 26.2 mL/min/1.73 m²) in the CEUS group and 81.9 ± 22.8 mL/min/1.73 m² (P > 0.05, compared with pre-GFR: 83.5 ± 23.7 mL/min/1.73 m²) in the conventional ultrasound group.

Conclusion

Intraoperative CEUS can “real-time” monitor the ablated area during PRFA procedure. This technique can help to achieve a higher success rate compared with conventional ultrasound. No impact of intraoperative CEUS has been found on GFR level.     

The impact of using estimated GFR versus creatinine clearance on the evaluation of recovery from acute kidney injury in the ICU

Purpose

To quantify the error in evaluating recovery from acute kidney injury (AKI) with estimated GFR (eGFR) in relation to ICU stay.

Methods

Secondary analysis performed on the database of the EPaNIC trial. In a cohort of patients who developed AKI during ICU stay we compared eGFR with measured creatinine clearance (Clcr) at ICU discharge. Recovery of kidney function was assessed by comparison with baseline eGFR and the accuracy of eGFR to detect “potential CKD status” defined by Clcr was quantified. The same analysis was performed in subgroups with different ICU stay. Multivariate regression was performed to determine independent predictors of the eGFR–Clcr difference.

Results

A total of 757 patients were included. The bias (limits of agreement (LOA)) between eGFR and Clcr at ICU discharge related to ICU stay, increasing from +1.3 (?37.4/+40) ml/min/1.73 m² in patients with short stay to +34.7 (?54.4/+123.8) ml/min/1.73 m² in patients with ICU stay of more than 14 days. This resulted in a significantly different incidence of complete recovery with the two evaluation methods and reduced sensitivity to detect “potential CKD status” with eGFR in patients with prolonged ICU stay. Independent predictors of the bias included creatinine excretion on the last day in ICU, baseline eGFR, ICU stay, gender, and age.

Conclusion

Compared to Clcr, discharge eGFR results in overestimation of renal recovery in patients with prolonged ICU stay and in reduced accuracy of “CKD staging”. Since age, gender and race do not change during ICU stay the same conclusion can be drawn with regard to plasma creatinine.     

Analysis of the accuracy of continuous thermodilution cardiac output measurement

Objective

To evaluate the accuracy of cardiac output measurement obtained by a new continuous thermodilution cardiac output (CCO) pulmonary artery catheter compared to intermittent thermodilution (TCO) and the direct Fick method.

Design

Prospective open trial.

Setting

University hospital, intensive care unit.

Patients

23 patients (15 surgical, 8 non-surgical) were monitored with the Intellicath pulmonary catheter. Cardiac output was evaluated by the three methods every 4 to 6 h as long as the pulmonary artery catheter was necessary (8–96h).

Results

The correlation coefficient between CCO and TCO was 0.92, no systematic bias was observed, and the relative error increased from 13.9% for a cardiac output of 1 l/min to 23.7% for an output of 10 l/min. When comparing CCO and Fick, the correlation coefficient was 0.89, no bias was detected, and the relative error increased from 20.4% for outputs of 2 l/min to 27.2% for outputs of 10 l/min.

Conclusions

CCO provides clinically acceptable measurements. At high cardiac outputs, the difference with other methods increases and the results must be cautiously interpreted.     

Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility

Objective

Prostacyclins have been suggested to exert positive inotropic effects which would render them particularly suitable for the treatment of right ventricular (RV) dysfunction due to acute pulmonary hypertension (PHT). Data on this subject are controversial, however, and vary with the experimental conditions. We studied the inotropic effects of epoprostenol at clinically recommended doses in an experimental model of acute PHT.

Design and setting

Prospective laboratory investigation in a university hospital laboratory.

Subjects

Six pigs (36?±?7?kg).

Interventions

Pigs were instrumented with biventricular conductance catheters, a pulmonary artery (PA) flow probe, and a high-fidelity pulmonary pressure catheter. Incremental doses of epoprostenol (10, 15, 20, 30, 40?ng?kg^–1?min^–1) were administered in undiseased animals and after induction of acute hypoxia-induced PHT.

Measurements and results

In acute PHT epoprostenol markedly reduced RV afterload (slopes of pressure-flow relationship in the PA from 7.0?±?0.6 to 4.2?±?0.7?mmHg?min?l^–1). This was associated with a paradoxical and dose-dependent decrease in RV contractility (slope of preload-recruitable stroke-work relationship from 3.0?±?0.4 to 1.6?±?0.2?mW?s?ml^–1; slope of endsystolic pressure-volume relationship from 1.5?±?0.3 to 0.7?±?0.3?mmHg?ml^–1). Left ventricular contractility was reduced only at the highest dose. In undiseased animals epoprostenol did not affect vascular tone and produced a mild biventricular decrease in contractility.

Conclusions

Epoprostenol has no positive inotropic effects in vivo. In contrast, epoprostenol-induced pulmonary vasodilation in animals with acute PHT was associated with a paradoxical decrease in RV contractility. This effect is probably caused indirectly by the close coupling of RV contractility to RV afterload. However, data from normal animals suggest that mechanisms unrelated to vasodilation are also involved in the observed negative inotropic response to epoprostenol.     

Nitrogen washout/washin, helium dilution and computed tomography in the assessment of end expiratory lung volume

Introduction

End expiratory lung volume (EELV) measurement in the clinical setting is routinely performed using the helium dilution technique. A ventilator that implements a simplified version of the nitrogen washout/washin technique is now available. We compared the EELV measured by spiral computed tomography (CT) taken as gold standard with the lung volume measured with the modified nitrogen washout/washin and with the helium dilution technique.

Methods

Patients admitted to the general intensive care unit of Ospedale Maggiore Policlinico Mangiagalli Regina Elena requiring ventilatory support and, for clinical reasons, thoracic CT scanning were enrolled in this study. We performed two EELV measurements with the modified nitrogen washout/washin technique (increasing and decreasing inspired oxygen fraction (FiO₂) by 10%), one EELV measurement with the helium dilution technique and a CT scan. All measurements were taken at 5 cmH₂O airway pressure. Each CT scan slice was manually delineated and gas volume was computed with custom-made software.

Results

Thirty patients were enrolled (age = 66 +/- 10 years, body mass index = 26 +/- 18 Kg/m², male/female ratio = 21/9, partial arterial pressure of carbon dioxide (PaO₂)/FiO₂ = 190 +/- 71). The EELV measured with the modified nitrogen washout/washin technique showed a very good correlation (r² = 0.89) with the data computed from the CT with a bias of 94 +/- 143 ml (15 +/- 18%, p = 0.001), within the limits of accuracy declared by the manufacturer (20%). The bias was shown to be highly reproducible, either decreasing or increasing the FiO₂ being 117+/-170 and 70+/-160 ml (p = 0.27), respectively. The EELV measured with the helium dilution method showed a good correlation with the CT scan data (r² = 0.91) with a negative bias of 136 +/- 133 ml, and appeared to be more correct at low lung volumes.

Conclusions

The EELV measurement with the helium dilution technique (at low volumes) and modified nitrogen washout/washin technique (at all lung volumes) correlates well with CT scanning and may be easily used in clinical practice.

Trial Registration

Current Controlled Trials NCT00405002.     

Basal renal function reserve and mean kidney dose predict future radiation-induced kidney injury in stomach cancer patients

Background

Adjuvant chemoradiotherapy (CRT) improves the survival in patients with locally advanced stomach cancer. The kidneys are the major dose-limiting organs for radiotherapy (RT) in upper abdominal cancers. We aimed to evaluate the impact of adjuvant CRT on renal function of patients with stomach cancer.

Material and methods

Fifty-nine stomach cancer patients who underwent postoperative CRT were included. Demographic parameters (age, gender), and basal and 12th-month biochemical parameters were recorded. Mean kidney dose (MKD) administered was determined. Estimated glomerular filtration rate (eGFR) was calculated by modification of diet in renal disease formula.

Results

Fifty-nine patients were recruited (age 60.8?±?11.9 years; female/male 25/34; follow-up duration 15.6?±?9.8 months). Twenty-one patients (35.6 %) had basal eGFR <90 ml/min/1.73 m². When the basal and 12th-month eGFR was compared, eGFR decreased in 27 patients (45.8 %), whereas eGFR remained stable in 32 (54.2 %) patients. Cox regression analyses revealed that a MKD ≥1,500 cGy and basal eGFR <90 ml/min/1.73 m² significantly increased the risk of a decreased eGFR at 12th month (HR?=?2.288, 95 % CI 1.009–5.188, p?=?0.048 and HR?=?2.854, 95 % CI 1.121–7.262, p?=?0.028, respectively).

Conclusion

MKD ≥1,500 cGy and a basal eGFR <90 ml/min/1.73 m² significantly increased the risk of a decreased eGFR at 12th month. We suggest that patients with stomach cancer be evaluated for their basal renal reserve prior to RT, and it may be more convenient to further minimize the dose to the kidneys with more sophisticated RT techniques in patients with stomach cancer, more specifically in patients with decreased renal reserve.     

Ultrasound image-guided therapy enhances antitumor effect of cisplatin

Purpose

The aim of this study was to clarify whether ultrasound image-guided cisplatin delivery with an intratumor microbubble injection enhances the antitumor effect in a xenograft mouse model.

Methods

Canine thyroid adenocarcinoma cells were used for all experiments. Before in vivo experiments, the cisplatin and microbubble concentration and ultrasound exposure time were optimized in vitro. For in vivo experiments, cells were implanted into the back of nude mice. Observed by a diagnostic ultrasound machine, a mixture of cisplatin and ultrasound contrast agent, Sonazoid, microbubbles was injected directly into tumors. The amount of injected cisplatin and microbubbles was 1 μg/tumor and 1.2 × 10⁷ microbubbles/tumor, respectively, with a total injected volume of 20 μl. Using the same diagnostic machine, tumors were exposed to ultrasound for 15 s. The treatment was repeated four times.

Results

The combination of cisplatin, microbubbles, and ultrasound significantly delayed tumor growth as compared with no treatment (after 18 days, 157 ± 55 vs. 398 ± 49 mm³, P = 0.049). Neither cisplatin alone nor the combination of cisplatin and ultrasound delayed tumor growth. The treatment did not decrease the body weight of mice.

Conclusion

Ultrasound image-guided anticancer drug delivery may enhance the antitumor effects of drugs without obvious side effects.     

Evolution of haemodynamics and outcome of fluid-refractory septic shock in children

Background

Maintaining threshold values of cardiac output (CO) and systemic vascular resistance (SVR) when used as part of the American College of Critical Care Medicine (ACCM) haemodynamic protocol improves the outcomes in paediatric septic shock.

Objective

We observed the evolution of CO and SVR during the intensive care admission of children with fluid-refractory septic shock and report this together with the eventual outcomes.

Design

Prospective observational study.

Setting

Tertiary care Paediatric Intensive Care Unit (PICU) in London.

Methods

Children admitted in fluid refractory septic shock to the Intensive Care Unit over a period of 36 months were studied. Post liver re-transplant children and delayed septic shock admissions were excluded. A non-invasive ultrasound cardiac output monitor device (USCOM) was used to measure serial haemodynamics. Children were allocated at presentation into one of two categories: (1) hospital-acquired infection and (2) community-acquired infection. Vasopressor, inotrope or inodilator therapies were titrated to maintain threshold cardiovascular parameters as per the ACCM guidelines.

Results

Thirty-six children [19 male, mean age (SD) 6.78 (5.86) years] were admitted with fluid-refractory septic shock and studied. At presentation, all 18 children with hospital-acquired (HA) sepsis and 3 from among the community-acquired (CA) sepsis group were in ‘warm shock’ (SVRI < 800 dyne s/cm⁵/m²) whereas 15 of the 18 children with community-acquired sepsis and none in the hospital-acquired group were in ‘cold shock’ [cardiac index (CI) < 3.3 l/min/m²]. All 21 children in ‘warm shock’ were initially commenced on a vasopressor (noradrenaline). Despite an initial good response, four patients developed low CI and needed adrenaline. Similarly, all 15 children in cold shock were initially commenced on adrenaline. However, two of them subsequently required noradrenaline. Five others needed milrinone as an inodilator. In general, both groups of children had normalised SVRI and CI within 42 h of therapy but required variable doses of vasopressors, inotropes or inodilators in a heterogeneous manner. The overall 28-day survival rate was 88.9 % in both groups. Central venous oxygen saturation (ScvO2) was significantly (p = 0.003) lower in the community-acquired group (mean 51.72 % ± 4.26) when compared to the hospital-acquired group (mean 58.72 % ± 1.36) at presentation but showed steady improvement during therapy. Gram-positive organisms were predominant in blood cultures, 61 % in HA and 56 % in CA groups.

Conclusions

In general, we found children with community-acquired septic shock presented in cold shock whereas hospital-acquired septic shock children manifested warm shock. Both types evolved in a heterogeneous manner needing frequent revision of cardiovascular support therapy. However the 28-day survival in both groups was the same at 89 %. Frequent measurements of haemodynamics using non-invasive ultrasound helped in fine tuning cardiovascular therapies.     

Fully Automated Radiosynthesis of 2-[18F]Fludarabine for PET Imaging of Low-Grade Lymphoma

Purpose

An efficient and fully automated radiosynthesis of 2-[¹⁸F]fluoro-9-β-d-arabinofuranosyl-adenine (2-[¹⁸F]fludarabine, [¹⁸F]-5) based on a GE TRACERlab? FX-FN module has been developed.

Procedures

A 2-nitro purine derivative 3 was developed as precursor for labeling with fluorine-18. The radiosynthesis of [¹⁸F]-5 was performed in two steps in a single reactor with an intermediary purification on Sep-Pak® silica which involved the addition of a three-way valve on the original module. After hydrolysis, [¹⁸F]-5 was purified by semi-preparative high-pressure liquid chromatography (HPLC) and a quality control was established.

Results

The labeling precursor 3 was obtained in 45 % overall yield. Nucleophilic substitution with K¹⁸F/K_2.2.2 afforded protected 2-[¹⁸F]fludarabine ([¹⁸F]-4) in 73?±?4 % , radiochemical yield (decay corrected to the end of bombardment (EOB)) and based on the initial [¹⁸F]F^? activity. An aqueous ammonia/methanol solution was used for the deprotection reaction and gave the desired [¹⁸F]-5 in 67?±?3 % yield after 20 min at 70 °C based on HPLC profile.

Conclusions

The process afforded pure 2-[¹⁸F]fludarabine in 48?±?3 % yield (decay corrected to the EOB) in 85 min, with a specific activity of 310?±?72 GBq/μmol at the end of synthesis (EOS) and a radiochemical purity up to 99 %.     

Daptomycin use in neutropenic patients with documented gram-positive infections

Purpose

The goal of this study was to describe the outcomes associated with daptomycin treatment of documented gram-positive infections in patients with neutropenia.

Methods

All patients with neutropenia (≤500 cells/m³) and at least one documented gram-positive culture from 2006–2009 were identified from a retrospective, multicenter, and observational registry (Cubicin® Outcome Registry and Experience (CORE®)). Investigators assessed patient outcome (cured, improved, failed, nonevaluable) at the end of daptomycin therapy. All patients were included in the safety analysis.

Results

The efficacy population had 186 patients; 159 (85 %) patients had either cure (n?=?108, 58 %) or improved (n?=?51, 27 %) as an outcome. Success rates (cure plus improved) by the lowest WBC during daptomycin were 98/116 (84 %) for ≤100 cells/m³ and 61/70 (87 %) for 101–499 cells/m³, P?=?0.6. Most patients had cancer; 135/186 (73 %) had hematological malignancy; 26/186 (14 %) had solid tumors, and 9 (5 %) had both. One hundred fifty-six (84 %) patients received other antibiotics before daptomycin treatment; 82 % vancomycin, of which 31 % failed vancomycin. The most common infections were bacteremia (78 %), skin and skin structure infections (8 %), and urinary tract infections/pyelonephritis (6 %). The most common pathogens were vancomycin-resistant Enterococcus faecium (47 %), methicillin-resistant Staphylococcus aureus (20 %), and coagulase-negative staphylococci (19 %). The median (min, max) initial daptomycin dose was 6 mg/kg (3.6, 8.3). The median (min, max) daptomycin duration of therapy was 14 days (1, 86). Possibly related adverse events occurred in 12/209 patients (6 %), and 13 patients (6 %) discontinued daptomycin due to adverse event.

Conclusions

The results suggest that daptomycin appeared useful and well tolerated in neutropenic patients, and the degree of neutropenia did not affect daptomycin success rates. Comparative clinical trials are needed to confirm these findings.     

Non-invasive cardiac output and oxygen delivery measurement in an infant with critical anemia

Objective

To assess the combination of a non-invasive blood oxygen content (CaO₂) monitor and a non-invasive cardiac output (CO) monitor to continuously measure oxygen delivery (DO₂; DO₂ = CaO₂ × CO).

Methods

DO₂ was assessed during blood transfusions in an infant with acute hemolytic anemia following admission (~48 h). CaO₂ was measured by Pulse Co-Oximetry, which also provides estimates of hemoglobin (Hgb) concentration and percent oxygen saturation. CO was measured by Electrical Velocimetry, which also provides an estimate of stroke volume (SV). Lactate levels, an indirect measure of adequate DO₂, were assessed during the initial 8 h following admission.

Results

Incremental blood transfusions during the first 36 h increased Hgb from 2.7 to 9.5 g/dL during which time heart rate (HR) normalized from 156 to 115 beats/min. Lactate levels decreased from 20 to 0.8 mmol/L in the first 7 h. Non-invasive Hgb and CaO₂ measurements were well correlated with invasive Hgb and CaO₂ measures (r ² = 0.88; P = 0.019; r ² = 0.86; P = 0.0074, respectively). CO decreased from 2.47 ± 0.06 to 1.28 ± 0.02 L/min and SV decreased from 15.9 ± 0.4 to 11.1 ± 0.2 mL/beat. Mean arterial blood pressure was stable throughout the admission with systemic vascular resistance increasing from 407.6 ± 15.2 to 887.7 ± 30.1 dynes-s/cm⁵. DO₂ was estimated to increase from 120.2 ± 18.9 to 182.4 ± 5.6 mL O₂/min.

Conclusions

Non-invasive contin- uous CO and CaO₂ monitors are shown in this single case to provide continuous DO₂ measurement. The ability to assess DO₂ may improve hemodynamic monitoring during goal directed therapies.     

Effects of Tirofiban Maintenance Duration on Myocardial Perfusion Defect Severity in Anterior Myocardial Infarction

Introduction

Percutaneous coronary intervention (PCI) does not often produce optimal results, despite restoration of coronary blood flow at myocardial recovery, because of impaired microvascular perfusion. This study aimed to investigate and evaluate with ^99mTc-sestamibi scan whether the results of PCI can be changed by maintenance infusion of tirofiban for 24 or 48 h in patients presenting with anterior ST-elevation myocardial infarction (STEMI).

Methods

The study included 84 patients with anterior STEMI who were candidates for primary PCI and whose occlusion was in the proximal or mid-left anterior descending artery. Patients were given 25 μg/kg/3 min tirofiban and randomized to receive maintenance infusion at 0.15 μg/kg/min for 24 or 48 h. A resting ^99mTc sestamibi scan was performed on the 5th day post-procedure before discharge. The primary efficacy endpoint was a patient’s score on a 5-point scoring system for perfusion defect severity. Major adverse cardiac events (MACE) were defined as death from any cause, re-infarction, and clinically driven target-vessel revascularization within the first 6 months.

Results

Baseline characteristics of the patients were similar in the two infusion groups (n = 42 per group). There was no significant difference in the symptom onset-to-presentation time or door-to-balloon time between the two groups. With the exception of basal anteroseptal and basal anterior segments, significant reductions were obtained on the 5-point scoring system for perfusion defect severity in segments and in the summed rest scores. No significant differences were observed between the two groups in the incidence of MACE at 6 months. The safety profile did not differ between 24 and 48 h infusions of tirofiban.

Conclusion

The use of tirofiban, when administered at a high bolus dose and maintained for 48 h, was safe and significantly reduced perfusion defect severity in patients with anterior STEMI presenting early after symptom onset and undergoing primary PCI.     

Comparison of modification of diet in renal disease and chronic kidney disease epidemiology collaboration formulas in predicting long-term outcomes in patients undergoing stent implantation due to stable coronary artery disease

Introduction

The aim was to assess the predictive value of estimated glomerular filtration rate (eGFR) using two formulas: modification of diet in renal disease (MDRD) and chronic kidney disease epidemiology collaboration (CKD-EPI), in a population with stable coronary artery disease (SCAD) undergoing percutaneous coronary revascularization (PCI).

Methods

The analyzed cohort included 3,141 consecutive patients with SCAD who underwent PCI, between January 2006 and December 2011. Follow-up data were available for 3,123 (99.4 %) patients.

Results

The median follow-up was 1,127 days (interquartile range 566–1,634 days). During the observation period, 330 deaths were reported. In patients with serum creatinine (S-Cr) within normal range, eGFR by CKD-EPI equation predicted long-term outcome more accurately, than eGFR by MDRD formula—continuous Net Reclassification Improvement: 0.296 (95 % CI, 0.08–0.5 p = 0.03). In patients with elevated S-CR, eGFR calculated by both formulae had similar efficacy in assessing death risk. After adjustment for differences in clinical characteristics, both formulae were associated with mortality, but only in patients with elevated S-Cr: eGFR by MDRD (per 10 ml/min/1.73 m²) HR: 0.74 [95 % CI, 0.61–0.89, p = 0.002], eGFR by CKD-EPI (per 10 ml/min/1.73 m²) HR: 0.75 (95 % CI, 0.63–0.89, p = 0.001). After adjustment for covariates, eGFR by CKD-EPI equation did not offer more appropriate categorization of individuals with respect to long-term mortality.

Conclusion

Our results indicate that in multivariable analysis eGFR calculated by MDRD and CKD-EPI equations has similar predictive value. In a population of patients with SCAD and S-Cr within normal range, eGFR calculated by CKD-EPI equation outperforms eGFR calculated by MDRD equation in assessing death risk.     

Development of Antibody-Carrying Microbubbles Based on Clinically Available Ultrasound Contrast Agent for Targeted Molecular Imaging: A Preliminary Chemical Study

Purpose

The purpose of the study was to examine the feasibility of an antibody-carrying targeted-bubble preparation using clinically available phosphatidylserine (PS)-containing perfluorobutane-filled microbubbles for molecular ultrasound imaging.

Procedures

Firstly, we examined whether PS on the surface of perfluorobutane-filled microbubbles could be detected by means of flow cytometry (fluorescence activated cell sorting (FACS)) using annexin V. After conjugation with fluorescein isothiocyanate (FITC)-labeled annexin V (up to 50 ??L) for 15 min on ice, microbubbles were assessed using a FACSCalibur. Secondly, we examined whether phycoerythrin (PE)-labeled streptavidin could be attached onto PS-containing perfluorobutane-filled microbubbles through the intermediacy of biotinylated annexin V. Microbubbles conjugated with biotinylated annexin V were incubated with PE?Cstreptavidin for 30 min on ice, then FACS analysis was performed. Finally, we examined whether attachment of biotinylated IgG onto PS-containing perfluorobutane-filled microbubbles could be accomplished using biotinylated annexin V and avidin?Cbiotin binding. Microbubbles with avidin?Cbiotin complexes were incubated with Alexa488-labeled biotinylated IgG for 30 min on ice.

Results

FITC-positive microbubbles could be detected after conjugation with FITC?Cannexin V. Additionally, the mean fluorescence intensity of Sonazoid bubbles increased in a dose-dependent manner (0 ??L, 3.3 vs. 50 ??L, 617.1). The PE signal of microbubbles in the presence of biotinylated annexin V was higher than that in the absence of biotinylated annexin V (mean fluorescence intensity, 327.1 vs. 14.8). Significant amplification of the Alexa488-signal was accomplished through the intermediation of biotinylated annexin V and streptavidin.

Conclusions

Our results support the feasibility of an antibody-carrying targeted-bubble preparation based on clinically available PS-containing perfluorobutane-filled microbubbles. Although further study is needed, this technique could be applicable for in vivo molecular ultrasound imaging.     

Direct, Quantitative, and Noninvasive Imaging of the Transport of Active Agents Through Intact Brain with Positron Emission Tomography

Purpose

Our goal was to use positron emission tomography (PET) to analyze the movement of radiolabeled agents in tissue to enable direct measurement of drug delivery to the brain.

Procedures

Various ¹¹C- and ¹⁸?F-labeled compounds were delivered directly to an agarose phantom or rat striatum. Concentration profiles were extracted for analysis and fitted to diffusion models.

Results

Diffusion coefficients ranged from 0.075?±?0.0026 mm²/min ([¹⁸?F]fluoride ion, 18 Da) to 0.0016?±?0.0018 mm²/min ([¹⁸?F]NPB4-avidin, 68 kDa) and matched well with predictions based on molecular weight (R ²?=?0.965). The tortuosity of the brain extracellular space was estimated to be 1.56, with the tissue clearance halftime of each tracer in the brain varying from 19 to 41 min.

Conclusions

PET is an effective modality to directly quantify the movement of locally delivered drugs or drug carriers. This continuous, noninvasive assessment of delivery will aid the design of better drug delivery methods.     

Syntheses and Radiosyntheses of Two Carbon-11 Labeled Potent and Selective Radioligands for Imaging Vesicular Acetylcholine Transporter

Purpose

The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. The syntheses and C-11 labeling of two potent enantiopure VAChT inhibitors are reported here.

Procedures

Two VAChT inhibitors, (±)-2 and (±)-6, were successfully synthesized. A chiral HPLC column was used to resolve the enantiomers from each corresponding racemic mixture for in vitro characterization. The radiosyntheses of (?)-[¹¹C]2 and (?)-[¹¹C]6 from the corresponding desmethyl phenol precursor was accomplished using [¹¹C]methyl iodide or [¹¹C]methyl triflate, respectively.

Results

The synthesis of (?)-[¹¹C]2 was accomplished with 40–50 % radiochemical yield (decay-corrected), SA?>?480 GBq/μmol (EOB), and radiochemical purity >99 %. Synthesis of (?)-[¹¹C]6 was accomplished with 5–10 % yield, SA?>?140 GBq/μmol (EOB), and radiochemical purity >97 %. The radiosynthesis and dose formulation of each tracer was completed in 55–60 min.

Conclusions

Two potent enantiopure VAChT ligands were synthesized and ¹¹C-labeled with good radiochemical yield and specific activity.     

In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter

Purpose

The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective ¹¹C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.

Procedures

For both (?)-[¹¹C]2 and (?)-[¹¹C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (?)-[¹¹C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.

Results

The resolved enantiomers (?)-2 and (?)-6 were very potent and selective for VAChT in vitro (K _i ?35-fold selectivity for VAChT vs. σ receptors); both radioligands, (?)-[¹¹C]2 and (?)-[¹¹C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (?)-[¹¹C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550?±?0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (?)-[¹¹C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (?)-[¹¹C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (?)-[¹¹C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.

Conclusions

The radioligand (?)-[¹¹C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.     

Reduction of health risk factors through an adapted physical activity program in patients with breast cancer

Purpose

After a breast cancer diagnosis, patients are at high risk of reducing their physical activity and gaining weight. Lack of physical activity and weight gain are known negative but modifiable prognostic factors. An observational study of a 3-month adapted physical activity (APA) program was performed to assess its effectiveness in improving physical activity level and reducing risk factors related to health during or after breast cancer treatments.

Method

Height, weight, and waist circumference (WC) were measured at the beginning and end of the 26-session program. Body mass index (BMI) and WC to height ratio (WHtR) were calculated. Physical activity profile, aerobic capacity, and usual average daily energy expenditure were estimated. Median values were compared using nonparametric tests.

Results

Sixty-one (61) voluntary breast cancer patients attended 80 % of the sessions. At baseline, median (minimum–maximum) BMI was 23.3 (16.1–36.8)?kg.m^?2 and WC and WHtR showed metabolic risks. After 3 months, anthropometric data remained stable. Moderate physical activity significantly improved (+13 min/day) and sedentary tended to decrease (?18 min/day).

Conclusion

A 3-month APA program allows patients to limit risk factors related to health such as physical inactivity and metabolic risks. This study reinforces the need to promote physical activity as early as possible in cancer patients' care.     

Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults

Purpose

This study was designed to optimize the latest generation venovenous (vv)-extracorporeal membrane oxygenation (ECMO)-circuit configuration and settings based on the evaluation of blood oxygenation and CO₂ removal determinants in patients with severe acute respiratory distress syndrome (ARDS) on ultraprotective mechanical ventilation.

Methods

Blood gases and hemodynamic parameters were evaluated after changing one of three ECMO settings, namely, circuit blood flow, FiO_2ECMO (fraction of inspired oxygen in circuit), or sweep gas flow ventilating the membrane, while leaving the other two parameters at their maximum setting.

Results

Ten mechanically ventilated ARDS patients (mean age 44 ± 16 years; 6 males; mean hemoglobin 8.0 ± 1.8 g/dL) on ECMO for a mean of 9.0 ± 3.8 days) receiving femoro–jugular vv-ECMO were evaluated. vv-ECMO blood flow and FiO_2ECMO determined arterial oxygenation. Decreasing the ECMO flow from its baseline maximum value (5.8 ± 0.8 L/min) to 40 % less (2.4 ± 0.3 L/min) significantly decreased mean PaO₂ (arterial oxygen tension; 88 ± 24 to 45 ± 9 mm Hg; p < 0.001) and SaO₂ (oxygen saturation; 97 ± 2 to 82 ± 10 %; p < 0.001). When the ECMO flow/cardiac output was >60 %, SaO₂ was always >90 %. Alternatively, the rate of sweep gas flow through the membrane lung determined blood decarboxylation, while PaCO₂ (arterial carbon dioxide tension) was unaffected when the ECMO blood flow and FiO_2ECMO were reduced to <2.5 L/min and 40 %, respectively. In three additional patients evaluated before and after red blood cell transfusion, O₂ delivery increased after transfusion, allowing lower ECMO flows to reach adequate SaO₂.

Conclusions

For severe ARDS patients receiving femoro–jugular vv-ECMO, blood flow was the main determinant of arterial oxygenation, while CO₂ elimination depended on sweep gas flow through the oxygenator. An ECMO flow/cardiac output >60 % was constantly associated with adequate blood oxygenation and oxygen transport and delivery.