Junzo Takeda

The Anti-Inflammatory and Proresolving Mediator Resolvin E1 Protects Mice from Bacterial Pneumonia and Acute Lung Injury

Whereas pneumonia is the most common cause of death and disability worldwide, most cases of pneumonia spontaneously resolve. Mechanisms that promote pneumonia resolution remain to be determined. Resolvin E1 (RvE1) is an endogenous mediator that displays proresolving actions in sterile inflammation. In this study, we developed a new model of aspiration pneumonia to evaluate the effect of RvE1 on acute lung injury caused by acid aspiration and subsequent bacterial challenge. Mice received hydrochloric acid into the left lung followed by the enteric pathogen Escherichia coli. I.v. administration of RvE1 (∼0.005 mg/kg) prior to acid injury selectively decreased lung neutrophil accumulation by 55% and enhanced clearance of E. coli. RvE1 significantly decreased lung tissue levels of several proinflammatory chemokines and cytokines, including IL-1β, IL-6, HMGB-1, MIP-1α, MIP-1β, keratinocyte-derived chemokine, and MCP-1, in a manner independent of the anti-inflammatory mediators IL-10 and lipoxin A4. In addition, animals treated with RvE1 had a marked improvement in survival. These findings in experimental aspiration pneumonia have uncovered protective roles for RvE1 in pathogen-mediated inflammation that are both anti-inflammatory for neutrophils and protective for host defense, suggesting that RvE1 represents the first candidate for a novel therapeutic strategy for acute lung injury and pneumonia that harnesses natural resolution mechanisms.

Infusion of the β-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats*

Objective:Since &bgr;-blocker therapy is known to be effective in patients with an injured heart, such as infarction, we designed the present study to examine the protective effects of infusion of the &bgr;1-selective blocker esmolol on myocardial function in peritonitis-induced septic rats using an isolated working heart preparation. Design:Randomized animal study. Setting:University research laboratory. Subjects:Thirty-one rats treated with cecal ligation and perforation to evoke peritonitis. Interventions:After cecal ligation and perforation, rats were randomly allocated to the control group (normal saline 2 mL/hr, n = 11), low-dose esmolol group (10 mg/kg/hr, n = 10), or high-dose esmolol group (20 mg/kg/hr, n = 10). After obtaining blood samples for measurement of arterial lactate and tumor necrosis factor-&agr; at 24 hrs, we assessed cardiac output, myocardial oxygen consumption, and cardiac efficiency (cardiac output × peak systolic pressure/myocardial oxygen consumption) at various preloads in an isolated perfused heart preparation. Measurements and Main Results:Esmolol infusion did not cause an elevation of arterial lactate levels but reduced tumor necrosis factor-&agr; concentrations vs. the control group (p < .05). Both cardiac output and cardiac efficiency in the esmolol-treated rats were significantly higher throughout the study periods vs. the control group (p < .05). Conclusions:Esmolol infusion in sepsis improved oxygen utilization of myocardium and preserved myocardial function.

New bronchoscopic microsample probe to measure the biochemical constituents in epithelial lining fluid of patients with acute respiratory distress syndrome

ObjectiveA noninvasive bronchoscopic microsampling (BMS) probe was developed to sample biochemical constituents of the epithelial lining fluid in small airways. DesignObservational, controlled study. SettingIntensive care unit of academic medical center. Patients and Procedure BMS was applied in a control group of seven patients who had hemoptysis or small solitary peripheral nodules but no hypoxemia or other signs of acute inflammation and in four patients with acute respiratory distress syndrome (ARDS), to test whether BMS can ascertain the presence of acute pulmonary inflammation without complications. Measurements and Results Complications, including a significant decrease in arterial oxygen saturation, were observed neither during nor after BMS. In the ARDS group, albumin, lactate dehydrogenase, interleukin-6, basic fibroblast growth factor, and neutrophil elastase concentrations in epithelial lining fluid were significantly higher (p < .0001, p = .012, p < .0001, p < .0001, and p < .0001, respectively) than in the control group. Serial BMS was safely performed in one patient with ARDS, allowing us to observe a correlation between changes in the concentration of inflammation-related biochemical markers and clinical course of the disease. ConclusionsThese results suggest that BMS is safe and useful to monitor pulmonary biochemical events in ARDS.

Evaluation of pathogen detection from clinical samples by real-time polymerase chain reaction using a sepsis pathogen DNA detection kit

IntroductionSepsis is a serious medical condition that requires rapidly administered, appropriate antibiotic treatment. Conventional methods take three or more days for final pathogen identification and antimicrobial susceptibility testing. We organized a prospective observational multicenter study in three study sites to evaluate the diagnostic accuracy and potential clinical utility of the SeptiFast system, a multiplex pathogen detection system used in the clinical setting to support early diagnosis of bloodstream infections.MethodsA total of 212 patients, suspected of having systemic inflammatory response syndrome (SIRS) caused by bacterial or fungal infection, were enrolled in the study. From these patients, 407 blood samples were taken and blood culture analysis was performed to identify pathogens. Whole blood was also collected for DNA Detection Kit analysis immediately after its collection for blood culture. The results of the DNA Detection Kit, blood culture and other culture tests were compared. The chosen antimicrobial treatment in patients whose samples tested positive in the DNA Detection Kit and/or blood culture analysis was examined to evaluate the effect of concomitant antibiotic exposure on the results of these analyses.ResultsSeptiFast analysis gave a positive result for 55 samples, while 43 samples were positive in blood culture analysis. The DNA Detection Kit identified a pathogen in 11.3% (45/400) of the samples, compared to 8.0% (32/400) by blood culture analysis. Twenty-three pathogens were detected by SeptiFast only; conversely, this system missed five episodes of clinically significant bacteremia (Methicillin-resistant Staphylococcus aureus (MRSA), 2; Pseudomonas aeruginosa, 1; Klebsiella spp, 1; Enterococcus faecium, 1). The number of samples that tested positive was significantly increased by combining the result of the blood culture analysis with those of the DNA Detection Kit analysis (P = 0.01). Among antibiotic pre-treated patients (prevalence, 72%), SeptiFast analysis detected more bacteria/fungi, and was less influenced by antibiotic exposure, compared with blood culture analysis (P = 0.02).ConclusionsThis rapid multiplex pathogen detection system complemented traditional culture-based methods and offered some added diagnostic value for the timely detection of causative pathogens, particularly in antibiotic pre-treated patients. Adequately designed intervention studies are needed to prove its clinical effectiveness in improving appropriate antibiotic selection and patient outcomes.

Serum and urinary inorganic fluoride concentrations after prolonged inhalation of sevoflurane in humans.

Serum and urinary concentrations of inorganic fluoride were measured before and after sevoflurane anesthesia in 10 patients without renal disease, who were scheduled for surgery lasting 13.4 ± 0.9 h (mean ± se). The mean concentration of serum inorganic fluoride reached a maximal value of 42.5 ± 4.5 μmol/L at the end of anesthesia. However, 5 of 10 patients had serum inorganic fluoride concentrations that exceeded 50 μmol/L (i.e., the nephrotoxic dose). A positive correlation was found between serum inorganic fluoride concentration and anesthetic dose. The largest urinary excretion of inorganic fluoride was 1804 ± 378 μmol/day in the first postoperative day and rapidly decreased thereafter. We concluded that lengthy sevoflurane anesthesia created serum inorganic fluoride concentrations that could influence renal function, although nephrotoxicity was not demonstrated in our biochemical study.

Reversal with sugammadex in the absence of monitoring did not preclude residual neuromuscular block.

BACKGROUND: In Japan, routine clinical care does not normally involve the use of a monitoring device to guide the administration of neuromuscular blocking drugs or their antagonists. Although most previous reports demonstrate that sugammadex offers more rapid and reliable antagonism from rocuronium-induced neuromuscular blockade, this advantage has not been confirmed in clinical settings when no neuromuscular monitoring is used. In this multicenter observational study, we sought to determine whether sugammadex reduces the incidence of postoperative residual weakness compared with neostigmine when the administration of rocuronium and its antagonists is not guided by neuromuscular monitoring. METHODS: This study was conducted in two 5-month periods that preceded and followed the introduction of sugammadex into clinical practice in Japan. Five university-affiliated teaching hospitals participated in this study. Neostigmine was used to antagonize rocuronium-induced neuromuscular blockade in the first phase, and sugammadex was used in the second phase. The timing and doses of rocuronium, neostigmine, and sugammadex were determined by the attending anesthesiologists without the use of neuromuscular function monitoring devices. To ascertain the incidence of postoperative residual neuromuscular weakness, the train-of-four ratio (TOFR) was determined acceleromyographically after tracheal extubation. Since our practice also does not usually involve calibration and normalization of accelerographic responses, both TOFR <0.9 and TOFR <1.0 were used as the criteria for defining postoperative residual weakness. RESULTS: In the first phase, 109 patients received neostigmine (average dose 33 µg/kg) and 23 patients were considered (by clinical criteria) to have adequate recovery and did not receive neostigmine (spontaneous recovery group). In the second phase, 117 patients received sugammadex (average dose 2.7 mg/kg) for antagonism of rocuronium-induced blockade. The incidence (95% confidence interval) of TOFR <0.9 under spontaneous recovery, after neostigmine, and after sugammadex, was 13.0% (2.8%–33.6%), 23.9% (16.2%–33.0%), and 4.3% (1.7%–9.4%), respectively. The incidence (95% confidence interval) of TOFR <1.0 in these groups was 69.6% (47.1%–86.6%), 67.0% (57.3%–75.7%), and 46.2% (36.9%–55.6%), respectively. The use of sevoflurane in the neostigmine group and the short interval between the administration of the last doses of rocuronium and sugammadex were associated with a higher incidence of postoperative residual weakness. CONCLUSIONS: This study demonstrated that the risk of TOFR <0.9 after tracheal extubation after sugammadex remains as high as 9.4% in a clinical setting in which neuromuscular monitoring (objective or subjective) was not used. Our finding underscores the importance of neuromuscular monitoring even when sugammadex is used for antagonism of rocuronium-induced neuromuscular block.

Performance of noninvasive partial CO2 rebreathing cardiac output and continuous thermodilution cardiac output in patients undergoing aortic reconstruction surgery

Background In the partial CO2 rebreathing method, monitored changes in CO2 elimination and end-tidal CO2 in response to a brief rebreathing period are used to estimate cardiac output. However, dynamic changes in CO2 production during ischemia and reperfusion may affect the accuracy of these estimates. This study was designed to compare measurements of cardiac output as produced by the partial CO2 rebreathing (NICO), bolus (BCO), and continuous thermodilution (CCO) methods of monitoring cardiac output. Methods Cardiac output was continuously monitored using both NICO and CCO in 28 patients undergoing aortic reconstruction. BCO measurements were taken at the following intervals when hemodynamic stability was achieved: (1) after anesthetic induction; (2) during aortic cross-clamp; (3) at reperfusion of the iliac artery; and, (4) during peritoneal closure. Results The bias and precision (1 SD) derived from all the measurements between NICO and BCO was −0.58 ± 0.9 l/min, whereas for CCO and BCO it was 0.38 ± 1.17 l/min. The bias between NICO and BCO was small after anesthetic induction and during cross-clamp, but increased following reperfusion. The bias between CCO and BCO was relatively small until reperfusion but increased significantly at peritoneal closure. Conclusions Results indicate that in aortic reconstruction surgery the performance of NICO monitoring is comparable with that of CCO; however, the direction of bias in these continuous measurement devices is the opposite.

Comparison of early postoperative quality of life in minimally invasive versus conventional valve surgery

AbstractPurpose. Minimally invasive cardiac surgery (MICS), an approach in which full sternotomy is avoided and the surgical incision is minimal, has been shown to produce less postoperative discomfort and to enable earlier mobilization and discharge than conventional cardiac surgery (CCS). This study was performed to retrospectively evaluate quality of life following MICS in comparison with CCS valve surgery. Methods. Sixty-six patients scheduled for MICS and 50 patients scheduled for CCS for isolated aortic or mitral valve surgery from January 1999 to June 2001 were enrolled in the study. The clinical records for the two groups were compared across intraoperative parameters and those associated with postoperative quality of life. Results. The aortic clamp and cardiopulmonary bypass times in the MICS group were longer than those in the CCS group (144 ± 42 and 224 ± 58 min vs 112 ± 21 and 179 ± 27 min, P ≪ 0.001). Postoperative pain medication (rectal buprenorphine and intramuscular pethidine) was administered to 18 of the 66 MICS patients (27%), as compared with 26 of the 50 CCS patients (52%, P = 0.007). Postoperative delirium was less frequent in the MICS group than the CCS group (26% vs 44%, P = 0.039). Initial postoperative food intake and urine catheter removal were possible earlier in the MICS than in the CCS group. MICS patients had shorter stays in the intensive care unit than CCS patients (37.4 ± 7.3 vs 45.9 ± 8.7 h, P ≪ 0.001). Conclusion. Although longer aortic clamp and cardiopulmonary bypass times remain a problem in MICS procedures, our results suggest that MICS, as compared with CCS, facilitates earlier recovery of daily activities and provides improved quality of life in the early postoperative period.

The relationship between modified pulse wave transit time and cardiovascular changes in isoflurane anesthetized dogs.

Objective.To clarify the relationship between blood pressure andpulse wave transit time at the peripheral artery from the R wave of theelectrocardiogram (m-PWTT), the effects of cardiovascular interventions onthis relationship was evaluated. Methods.Ten mongrel dogs wereanesthetized by isoflurane inhalation, and catheter tip pressure transducerswere inserted into the ascending aorta and at the bifurcation of abdominalaorta to measure central and peripheral pulse wave arrival. Pulse wave arrivalat the ascending aorta from the R wave represents pre-ejection period (PEP)and pulse wave arrival between the ascending aorta and bifurcation of aortarepresents pulse wave transit time (PWTT), thus m-PWTT = PEP + PWTT.Hypertension was induced by the continuous infusion of dobutamine andphenylephrine, and hypotension was induced by deepening isoflurane anesthesia,acute blood loss and nitroglycerine infusion. The relationship between timingcomponents (PWTT, PEP, and m-PWTT) and blood pressure was recorded andanalyzed by using the least squares method. Results.The relationshipbetween timing components (PWTT, PEP and, m-PWTT) and blood pressure wassignificant and highly correlated. When the change in blood pressure was dueto the myocardial contractility, such as after dobutamine infusion, therelationship between all timing components and blood pressure was consistentand negative. However, when the change in blood pressure was due to thevasoactive agents, such as phenylephrine, the relationship between timingcomponents and blood pressure was dependent on the reflex change in PEP.Conclusions.Change in m-PWTT is a good parameter to predict bloodpressure changes, although the absolute blood pressure value cannot beobtained.

Epidural anesthesia retards intestinal acidosis and reduces portal vein endotoxin concentrations during progressive hypoxia in rabbits

BackgroundBecause it is postulated that gut is important via bacterial translocation in the development of the systemic inflammatory response and multiple organ dysfunction, the preservation of gut integrity is a therapeutic goal for physicians who care for critically ill patients. The aim of the current study was to evaluate whether epidural anesthesia prevented gut injury and subsequent translocation of endotoxin during acute progressive hypoxia in rabbits. MethodsAfter the placement of an epidural catheter, 18 male rabbits, anesthetized with buprenorphine–midazolam, were allocated randomly to two groups: 0.5% lidocaine (group E) and saline (group C) groups. The solutions (0.4 ml/kg) were injected epidurally, followed by continuous infusion (0.1 ml·kg-1·h-1) during the study period. Portal blood flow, portal endotoxin concentrations, and intramucosal pH (pHi) of the ileum were measured at baseline and during two stages of progressive hypoxia (fraction of inspired oxygen [Fio2] = 0.15 and 0.10). ResultsIn both study groups, the portal blood flow was preserved to a similar extent during acute hypoxia. However, pHi was reduced to a lesser extent in group E (7.33 ± 0.12 versus 7.22 ± 0.12 at an Fio2 of 0.15 and 7.13 ± 0.15 versus 7.03 ± 0.12 at an Fio2 of 0.10; mean ± SD, P < 0.01), concurrently with lower portal endotoxin concentrations (P < 0.05) compared with group C. ConclusionsThe current study showed that epidural anesthesia slowed the progression of intestinal ischemia during acute hypoxia, subsequently preventing translocation of endotoxin through the gut mucosa.