Consensus of the Brazilian association of hematology, hemotherapy and cellular therapy on patient blood management: Anemia tolerance mechanisms.

Understanding the physiological concepts of oxygen delivery is essential to discern the mechanisms that influence its increase, reduction or maintenance in the body. This text explores the different mechanisms that help maintain oxygen delivery even in the face of reduced hemoglobin levels. Adequate oxygen delivery ensures tissue and metabolic balance, which is crucial to avoid harmful consequences such as metabolic acidosis and cellular dysoxia. The complex interaction between variables such as cardiac output, hemoglobin and heart rate (HR) plays a fundamental role in maintaining oxygen delivery, allowing the body to temporarily adjust to situations of anemia or high metabolic demand. It is important to emphasize that blood transfusions should not be based on fixed values, but rather on individual metabolic needs. Strategies to reduce myocardial consumption and monitor macro and micro hemodynamics help in making rational decisions. Individualizing treatment and considering factors such as blood viscosity in relation to the benefits of transfusion are increasingly relevant to optimize therapy and minimize risks, especially in complex clinical scenarios, such as neurocritical patients and trauma victims.

Quantification and clinical validation of the selective MET kinase inhibitor DO-2 and its metabolites DO-5 and M3 in human plasma.

DO-2 is a highly selective MNNG HOS transforming (MET) inhibitor. This deuterated drug is thought to diminish the formation of the Aldehyde Oxidase 1 inactive metabolite M3. For various reasons, quantification of DO-2 and its metabolites M3 and DO-5 is highly relevant. In this study, we present an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to quantify DO-2, M3 and DO-5. Rolipram served as the internal standard. Aliquots of 25 µL were mixed with 100 µL internal standard consisting of 10 ng/mL rolipram in acetonitrile. Separation of the analytes was achieved on an Acquity UPLC ® HSS T3 column, utilizing gradient elution with water/formic acid and acetonitrile/formic acid at a flow-rate of 0.400 mL/min. Calibration curves were linear in the range of 1.00 - 1000 ng/mL for DO-2 and DO-5, and 2.00 - 2000 ng/mL for M3 in human plasma. The within-run and between-run precisions of DO-2, DO-5 and M3, also at the level of the LLQ, were within 12.1%, while the accuracy ranged from 89.5 to 108.7%. All values for accuracy, within-run and between-run precisions met the criteria set by the Food and Drug Administration. The method was effectively employed in the analysis of samples obtained from a clinical trial.

Consensus of the Brazilian association of hematology, hemotherapy and cellular therapy on patient blood management: Anemia tolerance mechanisms

Abstract Understanding the physiological concepts of oxygen delivery is essential to discern the mechanisms that influence its increase, reduction or maintenance in the body. This text explores the different mechanisms that help maintain oxygen delivery even in the face of reduced hemoglobin levels. Adequate oxygen delivery ensures tissue and metabolic balance, which is crucial to avoid harmful consequences such as metabolic acidosis and cellular dysoxia. The complex interaction between variables such as cardiac output, hemoglobin and heart rate (HR) plays a fundamental role in maintaining oxygen delivery, allowing the body to temporarily adjust to situations of anemia or high metabolic demand. It is important to emphasize that blood transfusions should not be based on fixed values, but rather on individual metabolic needs. Strategies to reduce myocardial consumption and monitor macro and micro hemodynamics help in making rational decisions. Individualizing treatment and considering factors such as blood viscosity in relation to the benefits of transfusion are increasingly relevant to optimize therapy and minimize risks, especially in complex clinical scenarios, such as neurocritical patients and trauma victims.

Nadir oxygen delivery during cardiopulmonary bypass in acute type A aortic dissection repair.

Background: Acute type A aortic dissection (ATAAD) is associated with high mortality. Previous studies found that maintaining a high level of oxygen delivery (DO2) could decrease the postoperative mortality, but the minimum threshold of DO2 remained unclear. The present study aimed to investigate the relationship between maintaining intraoperative DO2 ≥280 mL/(min·m2) and the 90-day postoperative mortality of ATAAD patients. Methods: The clinical data of 178 ATAAD patients who underwent Sun's procedure in our center from January 2018 to July 2022 were retrospectively analyzed in the present cohort study. The included patients were divided into hypoxic group [DO2 <280 mL/(min·m2)] and normoxic group [DO2 ≥280 mL/(min·m2)]. The primary endpoint was the 90-day all-cause mortality, and the secondary endpoints were postoperative mechanical ventilation time, the application of continuous renal replacement therapy (CRRT), brain complications, and other postoperative complications. Results: Among all the patients, a total of 23 patients died 90 days postoperatively. Compared with the hypoxic group, blood flow, hematocrit (HCT), DO2, and DO2/VO2 ratio during cardiopulmonary bypass (CPB) were significantly higher, while the need for CRRT and the 90-day mortality were significantly lower in the normoxic group. The median follow-up time was 4 months. Kaplan-Meier curve indicated that the survival rate of ATAAD patients in the normoxic group was significantly higher. Univariate cox regression analysis demonstrated that 90-day mortality was reduced by 72.1% in the normoxic group. Conclusions: Maintaining DO2 ≥280 mL/(min·m2) during CPB by increasing CPB flow and HCT level is associated with decreased 90-day mortality of ATAAD patients.

Synthesis of a Bifunctional Cross-Bridged Chelating Agent, Peptide Conjugation, and Comparison of 68 Ga Labeling and Complex Stability Characteristics with Established Chelators.

[68 Ga]Ga3+ can be introduced into receptor-specific peptidic carriers via different chelators to obtain radiotracers for Positron Emission Tomography imaging and the chosen chelating agent considerably influences the in vivo pharmacokinetics of the corresponding radiopeptides. A chelator that should be a valuable alternative to established chelating agents for 68 Ga-radiolabeling of peptides would be a backbone-functionalized variant of the chelator CB-DO2A. Here, the bifunctional cross-bridged chelating agent CB-DO2A-GA was developed and compared to the established chelators DOTA, NODA-GA and DOTA-GA. For this purpose, CB-DO2A-GA(tBu)2 was introduced into the peptide Tyr3 -octreotate (TATE) and in direct comparison to the corresponding DOTA-, NODA-GA-, and DOTA-GA-modified TATE analogs, CB-DO2A-GA-TATE required harsher reaction conditions for 68 Ga-incorporation. Regarding the hydrophilicity profile of the resulting radiopeptides, a decrease in hydrophilicity from [68 Ga]Ga-DOTA-GA-TATE (logD(7.4) of -4.11±0.11) to [68 Ga]Ga-CB-DO2A-GA-TATE (-3.02±0.08) was observed. Assessing the stability against metabolic degradation and complex challenge, [68 Ga]Ga-CB-DO2A-GA demonstrated a very high kinetic inertness, exceeding that of [68 Ga]Ga-DOTA-GA. Therefore, CB-DO2A-GA is a valuable alternative to established chelating agents for 68 Ga-radiolabeling of peptides, especially when the formation of a very stable, positively charged 68 Ga-complex is pursued.

Chronic hypoxemia induces mitochondrial respiratory complex gene expression in the fetal sheep brain.

Objective: The molecular pathways underlying hypoxemia-induced alterations in neurodevelopment of infants with congenital heart disease have not been delineated. We used transcriptome analysis to investigate differential gene expression induced by hypoxemia in an ovine artificial-womb model. Methods: Mid-gestation fetal sheep (median [interquartile range] 109 [107-112] days' gestation) were cannulated via the umbilical vessels, attached to a pumpless, low-resistance oxygenator circuit, and incubated in a sterile, fluid environment for 22 [21-23] days. Fetuses were maintained with an oxygen delivery of 20-25 mL/kg/min (normoxemia, n = 3) or 14-16 mL/kg/min (hypoxemia, n = 4). Transcriptional profiling by RNA sequencing was carried out on left frontal brains and hypoxemia-regulated genes were identified by differential gene expression analysis. Results: A total of 228 genes whose expression was up or down regulated by ≥1.5-fold (false discovery rate ≤0.05) were identified. The majority of these genes were induced in hypoxemic animals compared to normoxemic controls, and functional enrichment analysis identified respiratory electron transport as a pathway strongly upregulated in the brain during chronic hypoxemia. Further examination of hypoxemia-induced genes showed robust induction of all 7 subunits of the mitochondrial NADH:ubiquinone oxidoreductase (complex I). Other hypoxemia-induced genes included cytochrome B, a component of complex III, and ATP6, ATP8, both of which are components of complex V. Conclusions: Chronic fetal hypoxemia leads to upregulation of multiple mitochondrial respiratory complex genes critical for energy production and reactive oxygen species generation, including complex I. These data provide valuable insight into potential pathways involved in chronic hypoxemia-induced neuropathology and offers potential therapeutic targets for fetal neuroprotection in fetuses with congenital heart defects.

Regional tissue oxygenation and conventional indicators of red blood cell transfusion in anaemic preterm infants.

Background: It is unresolved whether low haemoglobin (Hb) and symptoms of anaemia reflect oxygen delivery-consumption imbalances (fractional tissue oxygen extraction [FTOE]). Here, we test whether pre-transfusion Hb and symptoms of anaemia correlate with pre-transfusion cerebral and splanchnic FTOE. Methods: This prospective cohort study was carried out between Sept 1, 2014 and Nov 30, 2016 at Nepean Hospital, Sydney, Australia. The study enroled haemodynamically stable preterm infants: gestation <32 weeks; birth weight <1500 gs; postmenstrual age <37weeks, who received 15 mL/kg packed red blood cell transfusion (PRBCT) based on low Hb and symptoms of anaemia. FTOE was determined using simultaneous monitoring of near-infrared spectroscopy and pulse oximetry for 4 h before PRBCT. Findings: The study enroled 29 infants born with a median gestation of 26.4 weeks (IQR 25.4-28.1), birth weight 922 g (655-1064), at postmenstrual age 33.6 weeks (31.7-34.9), and weight 1487 g (1110-1785). There was no significant correlation between Hb (median 97 g/L, IQR 87-100) and cerebral FTOE (r=-0.12, 95% CI -0.47 to 0.27; p = 0.54, n = 29) as well as splanchnic FTOE (r=-0.09, 95% CI -0.45 to 0.29; p = 0.64, n = 29). Median cerebral FTOE (p = 0.67) and splanchnic FTOE (p = 0.53) did not differ between symptomatic and asymptomatic groups. Interpretation: Our preliminary findings suggest that pre-transfusion Hb and symptoms of anaemia might not accurately reflect oxygen delivery-consumption imbalances in both the brain and the gut. A lack of correlation with cerebral FTOE might be presumed to be due to the brain-sparing effect. However, the lack of correlation with splanchnic FTOE is more concerning. Hence, these results warrant larger studies incorporating FTOE along with the conventional criteria in the transfusion algorithm. Funding: The study was funded (for the purchase of NIRS sensors) by the Australian Women and Children's Research Foundation.

To RAP or Not to RAP: A Retrospective Comparison of the Effects of Retrograde Autologous Priming.

Retrograde autologous priming (RAP) is a process used to reduce hemodilution associated with the initiation of cardiopulmonary bypass (CPB). Previous studies have reported potential benefits to RAP; however, many of these studies do not evaluate the benefits of RAP with limited preoperative fluid administration combined with a condensed CPB circuit. We examined clinical metrics of patients who underwent RAP versus those who did not undergo RAP prior to the initiation of CPB. This was a retrospective data review of 1,303 patients who underwent CPB in the setting of open-heart surgery for a 2-year period. RAP was used on all patients between June 1, 2017 and June 30, 2018 (n = 519) and not used on patients between July 1, 2018 and June 30, 2019 (n = 784). Both groups were subjected to a low-prime CPB circuit volume of 800-900 mL. We compared the clinical metrics for packed red blood cell (PRBC) transfusion, oxygen delivery, postoperative acute kidney injury (AKI), Albumin utilization, ventilator time, Intensive Care Unit length of stay (ICU LOS), and 30-day mortality between the two groups. Our data analysis showed there were no statistically significantly differences between the two groups on the incidence of postoperative AKI, PRBC administration, ventilator time, ICU LOS or 30-day mortality. In the RAP group, there was a statistically significant lower oxygen delivery and a statistically significant increased volume of Albumin administered postoperatively, although those differences were so small, they were potentially not clinically significant. Our analysis revealed no significant benefit to performing RAP with limited preoperative fluid administration and minimized CPB circuit prime volume. We formalized a process that included limiting preoperative fluid administration and minimizing the CPB circuit volume so that we were not required to RAP and did not simultaneously sacrifice patient outcomes in other areas.

Cardiopulmonary Bypass Mean Global Oxygen Delivery May Be Associated with Neurocognitive Preservation during Hypothermic Aortic Surgery.

The purpose of this retrospective research was to investigate the relationship between mean global oxygen delivery (DO2) and neurocognitive function in adult patients who presented for aortic surgery with deep hypothermic circulatory arrest using cardiopulmonary bypass (CPB). From a pool of 132 patients, data from 100 CPB patients from 2012 to 2014 aged 50 years or older were randomly selected and analyzed, and global DO2 on CPB was used to categorize patients into those for whom the mean indexed cerebral oxygen delivery (DO2i) was either ≥272 mL O2/min/m2 (critical DO2 [DO2crit]) or less than DO2crit. Ten patients experienced either stroke or expired in the perioperative course. The proportion of patients with evidence of neurocognitive preservation was 98.3% in the group in which the DO2crit was met, compared with 80.6% in the group where DO2crit was not met (X 2 [1, 100] = 3.27, p = .07). Potentially, because of causes other than DO2, the subset of patients with stroke and/or death were removed, and data from 90 cases were analyzed, and a global mean DO2i value of 239.9 mL O2/min/m2 was identified. A larger sample size with controls may yield deeper insights into the hypothesis that a mean global CPB DO2i of 239.9 mL O2/min/m2 may play a role in predicting neurocognitive preservation in this patient population.

Physiological and microvascular responses to hemoglobin concentration-targeted hemolytic anemia in rats.

Hemolytic anemia (HA) is reduced blood oxygen-carrying capacity resulting from the depletion of red blood cells. Treatment for severe cases involves transfusion to improve oxygen delivery (Do2), which carries risk. In humans, a total hemoglobin (tHb) concentration of 8 g/dL is severe, and <7 g/dL indicates transfusion. Some evidence suggests that compensatory mechanisms maintaining Do2 are not compromised until <5 g/dL rendering transfusion at 7 g/dL premature. A Sprague-Dawley rat model of phenylhydrazine-induced HA was assessed over decreasing tHb for a Do2 decompensation point. Three groups (100, 50, or 25% tHb, equating to 16.4, 7.4, or 3.2 g/dL) were generated. Cardiopulmonary, blood chemistry, and oxygenation parameters were measured under anesthesia. Vasoconstrictive responsiveness to phenylephrine was assessed in the exteriorized spinotrapezius. For 50% tHb, cardiopulmonary parameters, Do2, and lactate levels were similar to those for 100% tHb. Enhanced vasoconstriction occurred with 50% tHb (P < 0.0001), not 25% tHb. The 25% group showed decreases in cardiopulmonary parameters, Do2, and lactate levels compared with the 100% and 50% groups (P < 0.05). Do2 showed a positive correlation with lactate levels at 25% tHb, but decompensation, defined by peripheral hypoxia, was not reached. This is the first study relating Do2 to tHb in rats. A 50% reduction in tHb was supported by vascular compensation, whereas 25% tHb levied the cardiopulmonary system. A decompensation point was not identified. A rising need for treatment as tHb levels decline below 8 g/dL is evident, but, as compensatory mechanisms remain intact as tHb approaches 3.2 g/dL in rats, a transfusion limit of 5 g/dL in healthy patients is supported.NEW & NOTEWORTHY Early, chronic compensation to severe hemolytic anemia is vascular, switching to cardiopulmonary support as hemoglobin levels decline. Oxygen delivery does not correlate with serum lactate level until total hemoglobin is reduced by 75%.

Associations between oxygen delivery and cardiac index with hyperlactatemia during cardiopulmonary bypass.

OBJECTIVE: Metabolism management plays an essential role during cardiopulmonary bypass (CPB). There are different metabolic management devices integrated to heart-lung machines; the most commonly used and accepted metabolic target is indexed oxygen delivery (DO2i) (280 mL/min/m2) and cardiac index (CI) (2.4 L/min/m2), which can be managed independently or according to other metabolic parameters. Our objective was to compare lactate production during CPB procedures using different metabolic management: DO2i in relation to indexed oxygen extraction ratio (O2ERi) and CI in relation to mixed venous oxygen saturation (SvO2). METHODS: Data on 500 CPB procedures were retrospectively collected in a specialized regional tertiary cardiac surgery center in Italy between September and 2012 and November 2019. In group A, the DO2i with 280 mL/min/m2 target in relation to O2ERi 25% was used; in group B, CI with 2.4 L/min/m2 target in relation to SvO2 75% was used. During CPB, serial arterial blood gas analyses with blood lactate and glucose determinations were obtained. Hyperlactatemia (HL) was defined as a peak arterial blood lactate concentration >3 mmol/L. The postoperative outcome of patients with or without HL was compared. RESULTS: Eight pre- and intraoperative factors were found to be significantly associated with peak blood lactate level during CPB at univariate analysis. HL (>3 mmol/L) was detected in 15 (6%) patients of group A and in 42 (16.8%) patients of group B (P = .022); hyperglycemia (>160 mg/dL) was found in 23 (9.2%) patients of group A and in 53 (21.2%) patients of group B (P = .038). Patients with HL during CPB had a significant increase in serum creatinine value, higher rate of prolonged mechanical ventilation time and intensive care unit stay. A cutoff of DO2i <270 mL/min/m2 in relation to O2ERi >35% in group A and a cutoff of CI <2.4 L/min/m2 in relation to SvO2 <65% in group B were found to have a positive predictive value of 80% and 75% for HL, respectively. A cutoff of DO2i >290 mL/min/m2 in relation to O2ERi 24% in group A and a cutoff of CI >2.4 L/min/m2 in relation to SvO2 >75% in group B were found to have a negative predictive value of 78% and 62% for HL, respectively. CONCLUSIONS: This retrospective observational analysis showed that management of DO2i in relation to O2ERi was 16% more specific in terms of negative predictive value for HL during CPB compared with the use of CI in relation to SvO2. Group A reported a significant reduction in the incidence of intraoperative lactate peak, correlated with postoperative reduction of serum creatinine value, mechanical ventilation time, and intensive care unit stay, compared with group B.

Usefulness of venous-to-arterial partial pressure of CO2 difference to assess oxygen supply to demand adequacy: effects of dobutamine.

The central venous O2 saturation value and lactic acid levels are part of the diagnostic and therapeutic work up of patients in shock. These usual indicators of tissue hypoxia don't fully describe the adequacy of tissue perfusion. There is ample evidence that supplementing this data with the venous-to-arterial partial pressure of CO2 (PCO2) difference (ΔPCO2) complements the clinician's tools when treating patients with shock. Based on a modified Fick equation as it applies to CO2, in patients in a steady state, the ΔPCO2 reflects the cardiac output (CO). This observation has been shown to be of clinical value in resuscitating patients in shock. Moreover, the ΔPCO2 can be used to titrate inotropes, and differentiate the hemodynamic from the metabolic effect of dobutamine.

Accounting for the role of hematocrit in between-subject variations of MRI-derived baseline cerebral hemodynamic parameters and functional BOLD responses.

Baseline hematocrit fraction (Hct) is a determinant for baseline cerebral blood flow (CBF) and between-subject variation of Hct thus causes variation in task-based BOLD fMRI signal changes. We first verified in healthy volunteers (n = 12) that Hct values can be derived reliably from venous blood T1 values by comparison with the conventional lab test. Together with CBF measured using phase-contrast MRI, this noninvasive estimation of Hct, instead of using a population-averaged Hct value, enabled more individual determination of oxygen delivery (DO2 ), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ). The inverse correlation of CBF and Hct explained about 80% of between-subject variation of CBF in this relatively uniform cohort of subjects, as expected based on the regulation of DO2 to maintain constant CMRO2 . Furthermore, we compared the relationships of visual task-evoked BOLD response with Hct and CBF. We showed that Hct and CBF contributed 22%-33% of variance in BOLD signal and removing the positive correlation with Hct and negative correlation with CBF allowed normalization of BOLD signal with 16%-22% lower variability. The results of this study suggest that adjustment for Hct effects is useful for studies of MRI perfusion and BOLD fMRI. Hum Brain Mapp 39:344-353, 2018. © 2017 Wiley Periodicals, Inc.

(177)Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment.

BACKGROUND: Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [(89)Sr]SrCl2 and [(153)Sm]Sm-EDTMP. No-carrier-added (n.c.a.) (177)Lu is remarkably suitable for an application in this scope. METHODS: Five 1,4,7,10-tetraazacyclododecane N,N',N'',N''-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. (177)Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [(177)Lu]citrate. RESULTS: Radiolabelling yields for [(177)Lu]Lu-DOTA and [(177)Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All (177)Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. (177)Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [(177)Lu]Lu-DO2A(P(BP))2; SUVfemur = 5.41 ± 0.46 for [(177)Lu]Lu-DOTA(M(BP))2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [(177)Lu]Lu-DO2A(P(BP))2; SUVblood = 1.43 ± 0.32 for [(177)Lu]Lu-DOTA(M(BP))2). CONCLUSIONS: Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.

MEMRI and tumors: a method for the evaluation of the contribution of Mn(II) ions in the extracellular compartment.

The purpose of the work was to set-up a simple method to evaluate the contribution of Mn(2+) ions in the intra- and extracellular tumor compartments in a MEMRI experiment. This task has been tackled by "silencing" the relaxation enhancement arising from Mn(2+) ions in the extracellular space. In vitro relaxometric measurements allowed assessment of the sequestering activity of DO2A (1,4,7,10-tetraazacyclododecane-1,7-diacetic acid) towards Mn(2+) ions, as the addition of Ca-DO2A to a solution of MnCl2 causes a drop of relaxivity upon the formation of the highly stable and low-relaxivity Mn-DO2A. It has been proved that the sequestering ability of DO2A towards Mn(2+) ions is also fully effective in the presence of serum albumin. Moreover, it has been shown that Mn-DO2A does not enter cell membranes, nor does the presence of Ca-DO2A in the extracellular space prompt migration of Mn ions from the intracellular compartment. On this basis the in vivo, instantaneous, drop in SE% (percent signal enhancement) in T1 -weighted images is taken as evidence of the sequestration of extracellular Mn(2+) ions upon addition of Ca-DO2A. By applying the method to B16F10 tumor bearing mice, T1 decrease is readily detected in the tumor region, whereas a negligible change in SE% is observed in kidneys, liver and muscle. The relaxometric MRI results have been validated by ICP-MS measurements.

Rapid synthesis of 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester).

A three-step route was used to synthesize 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester) from 1,4,7,10-tetraazacyclododecane (cyclen). The overall time of reaction was reduced from a combined ~56 h to 2.3 h with an overall yield comparable to previously reported methods.

The incidence and significance of bacteremia in out of hospital cardiac arrest.

BACKGROUND: The most common etiology of cardiac arrest is presumed of myocardial origin. Recent retrospective studies indicate that preexisting pneumonia, a form of sepsis, is frequent in patients who decompensate with abrupt cardiac arrest without preceding signs of septic shock, respiratory failure or severe metabolic disorders shortly after hospitalization. The contribution of pre-existing infection on pre and post cardiac arrest events remains unknown and has not been studied in a prospective fashion. We sought to examine the incidence of pre-existing infection in out-of hospital cardiac arrest (OHCA) and assess characteristics associated with bacteremia, the goal standard for presence of infection. METHODS AND RESULTS: We prospectively observed 250 OHCA adult patients who presented to the Emergency Department (ED) between 2007 and 2009 to an urban academic teaching institution. Bacteremia was defined as one positive blood culture with non-skin flora bacteria or two positive blood cultures with skin flora bacteria. 77 met pre-defined exclusion criteria. Of the 173 OHCA adults, 65 (38%) were found to be bacteremic with asystole and PEA as the most common presenting rhythms. Mortality in the ED was significantly higher in bacteremic OHCA (75.4%) compared to non-bacteremic OHCA (60.2%, p<0.05). After adjustment for potential confounders, predictive factors associated with bacteremic OHCA were lower initial arterial pH, higher lactate, WBC, BUN and creatinine. CONCLUSIONS: Over one-third of OHCA adults were bacteremic upon presentation. These patients have greater hemodynamic instability and significantly increased short-term mortality. Further studies are warranted to address the epidemiology of infection as possible cause of cardiac arrest.

Cavoaortic shunt improves hemodynamics with preserved oxygen delivery in experimental right ventricular failure during left ventricular assist device therapy.

OBJECTIVE: Right heart failure is a major cause of morbidity and mortality after left ventricular assist device (LVAD) implantation. This study evaluated the approach of a cavoaortic shunt included in the LVAD circuit, which would aim to relieve venous congestion and improve hemodynamics with preserved oxygen delivery during induced right ventricular failure. METHODS: Right ventricular failure was induced by coronary ligation in 10 pigs. An LVAD was implanted and a cavoaortic shunt was created from the right atrium and included in the assist circuit. Hemodynamic measures and blood gas analyses were analyzed. Oxygen delivery and oxygen consumption were estimated. RESULTS: Right atrial pressure decreased from more than 20 mm Hg to 17.2 mm Hg (14.8-18.4) with the LVAD and to 14.1 mm Hg (11.2-15.5) (P < .01) with the LVAD and cavoaortic shunt. Mean arterial pressure increased from 70.9 mm Hg (67.6-79.8) to 81.5 mm Hg (70.8-92.6) (P = .02) with addition of the shunt into the assist circuit. Cardiac output increased from 3.5 L/min (2.6-4.2) to 4.9 L/min (3.5-5.6) (P < .01) with cavoaortic shunting. Oxygen delivery with the cavoaortic shunt was 337 mL/min (± 70) as compared with left ventricular assist alone at 258 mL/min (± 52) (P < .01). Oxygen consumption was restored during use of the cavoaortic shunt. CONCLUSIONS: A cavoaortic shunt combined with an LVAD during right ventricular failure reduces central venous pressures, increases systemic arterial pressure, and enables increased cardiac output compared with device therapy alone. This was feasible with preserved oxygen delivery.

Sivelestat attenuates lung injury in surgery for congenital heart disease with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension associated with congenital heart disease increases the risk of surgery using cardiopulmonary bypass. Sivelestat is a neutrophil elastase inhibitor thought to have a prophylactic effect against lung injury after surgery using bypass. We elucidated that Sivelestat had the protective effect on lung in patients with congenital heart disease and pulmonary hypertension who underwent surgery using bypass. METHODS: This study was a controlled prospective randomized trial and enrolled 13 neonates or infants with ventricular septal defect and pulmonary hypertension. The patients were assigned to either sivelestat with the dose of 0.2 mg/kg per hour (sivelestat group, n = 7) or saline (placebo group, n = 6) from the start of bypass until 6 hours after bypass. Proinflammatory cytokines and adhesion molecules on leukocytes were measured at 10 time points during the above period. Pulmonary function was assessed perioperatively. RESULTS: Compared with the placebo group, the sivelestat group had significantly lower values of alveolar-arterial oxygen tension gradient at 24 hours (p = 0.038) and at 48 hours (p = 0.028) after bypass, and significantly better balance of hydration at 48 hours after bypass (p = 0.012). The sivelestat group also showed significantly lower plasma levels of interleukin-8 immediately after bypass (p = 0.041) and interleukin-10 at 15 minutes after removal of the aortic cross-clamp (p = 0.048), and immediately after bypass (p = 0.037). CONCLUSIONS: Administration of sivelestat during bypass prevented pulmonary damage and activities of proinflammatory cytokines at the cardiac operation in neonates or infants. Our results show that sivelestat may be considered to protect pulmonary function against the injury by bypass.