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The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin. Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated. A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (Bmax). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8 mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16 mg/L was proposed. PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.

To investigate the effects of alveolar recruitment maneuver (ARM) during one-lung ventilation (OLV) on end-expiratory lung volume (EELV) of the dependent lung. Patients who were planned to undergo lung resection surgery for lung tumors and needed OLV for at least 1 h were included in the study. After turning the patients into the lateral position under total intravenous anesthesia, OLV was commenced using a double-lumen endobronchial tube. EELV was measured using the nitrogen washout technique at 20 min after OLV started (baseline) and 15, 30, 45, 60 min after ARM was performed on the dependent lung. Among 42 patients who completed the study, EELV increased at 15 min after ARM by 20% or greater compared with baseline in 21 patients (responders). Responders were significantly shorter in height (158 vs. 165 cm, p = 0.01) and had smaller preoperative functional residual capacity (2.99L vs. 3.65L, p = 0.02) than non-responders. Before ARM, responders had significantly higher driving pressure (14.2 vs. 12.4 cmH2O, p = 0.01) and lower respiratory system compliance (23.6 vs. 31.4 ml/cmH2O, p = 0.0002) than non-responders. Driving pressure temporarily dropped after ARM in responders, while no significant change was observed in non-responders. Fourteen out of 21 responders kept EELV 20% or more increased EELV than baseline at 60 min after ARM. EELV of the dependent lung was increased by 20% or greater in half of the patients responding to ARM. The increased volume of the dependent lung caused by ARM was maintained for 60 min in two-thirds of the responders.

This study aimed to identify the incidence and risk factors for acute kidney injury (AKI) after liver resection surgery and to clarify the relationship between postoperative AKI and outcome. We conducted a historical cohort study of patients who underwent liver resection surgery with sevoflurane anesthesia from January 2004 to October 2011. Acute kidney injury was diagnosed based on the Acute Kidney Injury Network classification within 72 hr after the surgery. Patient data, surgical and anesthetic data, and laboratory data were extracted manually from the patients’ electronic charts. Multivariable logistic regression analysis was used to identify perioperative risk factors for postoperative AKI. Acute kidney injury was diagnosed in 78 of 642 patients (12.1%; 95% confidence interval [CI]: 9.7 to 14.9). Multivariable analysis showed an independent association between postoperative AKI and preoperative estimated glomerular filtration rate (adjusted odds ratio [aOR] 0.74; 95% CI: 0.64 to 0.85), preoperative hypertension (aOR 2.10; 95% CI: 1.11 to 3.97), and intraoperative red blood cell transfusion (aOR 1.04; 95% CI: 1.01 to 1.07). Development of AKI within 72 hr after liver resection surgery was associated with increased hospital mortality, prolonged length of stay, and increased rates of mechanical ventilation, reintubation, and renal replacement therapy. Perioperative risk factors for AKI after liver resection surgery are similar to those established for other surgical procedures. Further studies are needed to establish causality and to determine whether interventions on modifiable risk factors can reduce the incidence of postoperative AKI and improve patient outcome. This study was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN 000008089).

Background Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal cardiovascular disease if left untreated. In patients with IPAH with psychiatric illness or other complications, careful attention is required when administering medical therapies that may affect their hemodynamics. Patients suffering from IPAH who undergo anesthesia and surgery have a high mortality and morbidity rate. We describe the treatment of intractable psychiatric symptoms with electroconvulsive therapy (ECT) in a patient with IPAH. Case presentation A 23-year-old woman with IPAH and type I diabetes mellitus (DM) presented with malignant catatonia. Her heart function was classified as New York Heart Association (NYHA) class III. She required a rapid cure and ECT due to various psychiatric symptoms resistant to conventional medications. Pulmonary hypertensive (PH) crisis is the most concerning complication that can be induced by the sympathetic stimulation of ECT. To avoid PH crisis, we administered oxygen using a laryngeal mask and administered remifentanil for anesthesia. We also prepared standby nitric oxide for possible PH crisis, although it was ultimately not needed. With 14 ECT sessions, her malignant catatonia was ameliorated without physical complications. Conclusion ECT is an acceptable option for the treatment of medication-refractory psychiatric disturbances in patients with IPAH, provided careful management is assured to prevent or address complications.

Neurological deficits associated with methylergometrine have been reported primarily as a result of reversible cerebral vasoconstriction syndromes (RCVS). RCVS are characterized by reversible multifocal vasoconstrictions of the cerebral arteries heralded by acute severe headache with or without neurological deficits. Here, we present the first case of suspected RCVS with transient limb myoclonus following the intravenous administration of methylergometrine during cesarean section. A 31-year-old woman who received slowly infused intravenous methylergometrine during a cesarean section suddenly reported severe occipital headache after 40 min, followed by apnea and unconsciousness for 8 min. A second administration of methylergometrine to treat the weakness of her uterine contractions resulted in a repeated loss of consciousness within minutes and the development of limb myoclonus. No abnormalities were detected by brain computerized tomography, magnetic resonance imaging, and electroencephalogram. She fully recovered spontaneously within 12 h. We consider that the transient limb myoclonus in our patient appeared as a result of RCVS caused by the intravenous administration of methylergometrine.

We previously showed that compression of the nondependent lung during one-lung ventilation (OLV) in patients undergoing esophagectomy improves arterial oxygenation but impairs cardiac output (CO) and systemic oxygen delivery (DO(2)). The objective of this study was to test the hypothesis that the combination of nondependent lung compression and ephedrine improves arterial oxygenation without compromising DO(2).Twenty patients undergoing esophagectomy through a right thoracotomy were studied. Under general anesthesia, a left-sided double-lumen tube was placed, and the dependent lung was mechanically ventilated with a tidal volume of 8 ml/kg and a fraction of inspiratory oxygen of 0.8 during OLV. When nondependent lung was compressed by surgeons to improve surgical exposure, a randomly determined intravenous bolus of either ephedrine 4 mg (group E) or an identical volume of saline (group S) was administered. Arterial blood was sampled during two-lung ventilation (TLV), at 10 min of OLV (OLV1), and 5 min after nondependent lung compression (OLV2).The initiation of OLV resulted in a significant drop in PaO(2) at OLV1 (group E, 136 ± 69 mmHg; group S, 138 ± 83 mmHg; P 0.01) compared with TLV (group E, 404 ± 44 mmHg; group S; 367 ± 51 mmHg) and tended to improve at OLV2 (group E, 170 ± 63 mmHg; group S; 196 ± 121 mmHg). However, although CO and DO(2) significantly decreased in group S at OLV2 (4.0 ± 0.8 l/min, 621 ± 116 ml/min; P 0.01) compared with OLV1 (5.1 ± 0.7 l/min, 811 ± 140 ml/min), there was no significant difference in these parameters in group E for the two time points.Although arterial oxygenation was not significantly improved by the nondependent lung compression, the addition of intravenous ephedrine to nondependent lung compression prevented the decrease in systemic oxygen delivery without deterioration of arterial oxygenation during OLV in patients undergoing esophagectomy.

We have previously found that compression of the non-dependent lung improves arterial oxygenation during one-lung ventilation (OLV) in patients undergoing esophagectomy. The purpose of this study was to investigate the effects of compression of the non-dependent lung on hemodynamic indices and oxygen delivery using a minimally invasive cardiac output (CO) monitor.Sixteen consecutive patients undergoing esophagectomy through a right thoracotomy were studied. Under general anesthesia, a left-sided double-lumen tube was placed for OLV, and the dependent lung was mechanically ventilated with a tidal volume of 8 ml kg(-1) body weight and a fraction of inspiratory oxygen of 0.8 during OLV. CO was monitored continuously using a FloTrac/Vigileo (Edwards Lifesciences) system. Surgeons compressed the non-dependent lung several times during surgery using a lung retractor to improve exposure of the surgical field. The oxygen delivery index was roughly estimated as the product of the cardiac index (CI) and arterial oxygen saturation as monitored by pulse oximetry (Spo2).Just before non-dependent lung compression, mean (+/- SD) CI and Spo2 were 2.6 +/- 0.6 L min(-1) m(-2) and 95.0 +/- 3.9%, respectively. At 1 min after non-dependent lung compression, Spo2 increased significantly to 97.8 +/- 2.2% (P0.05), but CI decreased significantly to 2.0 +/- 0.4 L min(-1) m(-2) (P0.05). The product of CI and Spo2 at 1 min was significantly lower (192.7 +/- 37.3) than baseline levels (250.5 +/- 66.3, P0.05).Although non-dependent lung compression may be a potentially effective measure to treat hypoxemia during OLV, it should be noted that CO and systemic oxygen delivery may be decreased by this maneuver.

Background Bone marrow-derived mesenchymal stem cells (BMSCs) reduced the severity of acute lung injury after transplantation in multiple experimental studies, and several paracrine soluble factors secreted by the cells likely contribute to their therapeutic effect. The direct interactions between BMSCs and alveolar epithelial cells (AECs) may be an important part of their beneficial effects. Therefore, we assessed the interactions between BMSCs and AECs using a co-culture model of these two cell types from rats. Methods BMSCs and AECs were co-cultured using a Transwell system under the following conditions: (1) separated co-culture—AECs seeded on the insert and BMSCs in the base of the well; and (2) mixed co-culture—AECs on top of the monolayer of BMSCs on the culture insert and no cells in the base of the well. After 21 days of culture, the cells on the membrane of the culture insert were fixed and stained with antibodies against the receptor for advanced glycation end-products (RAGE), surfactant protein D (SP-D), and zona occludens protein-1, and then analyzed by confocal microscopy. Results In the separated co-culture condition, the phenotype of the AECs was maintained for 21 days, and cluster formation of SP-D-positive cells was induced in the AEC monolayer. We also found cluster formations of phospholipid-positive cells covered with RAGE-positive epithelial cells. In the mixed co-culture condition, the BMSCs induced alveolar-like structures covered with an epithelial cell layer. To determine the effect of keratinocyte growth factor (KGF) on this three-dimensional structure formation, we treated the mixed co-cultures with siRNA for KGF. While KGF siRNA treatment induced a significant reduction in surfactant protein transcript expression, formation of the alveolar-like structure was unaffected. We also assessed whether Gap26, a functional inhibitor of connexin-43, could mitigate the effect of the BMSCs on the AECs. However, even at 300 μM, Gap26 did not inhibit formation of the alveolar-like structure. Conclusions BMSCs release soluble factors that help maintain and sustain the AEC phenotype for 21 days, and direct interaction between these two cell types can induce a cyst-like, three-dimensional structure covered with AECs.

To investigate whether pyrrolidinone derivative (N2733), an inhibitor of nuclear factor (NF)-kappaB activation, improves altered metabolic and hemodynamic changes and organ dysfunctions caused by endotoxic shock.Prospective, randomized, animal study in a laboratory at a university hospital.Twenty-three anesthetized male beagle dogs (10-14 kg).Dogs were mechanically ventilated and monitored with a pulmonary arterial catheter and a gastric tonometer. A central venous catheter was inserted into the femoral vein, and lactated Ringer's solution (10 ml/kg per hour) was administered throughout the study period. Three groups of animals were studied: (a) the lipopolysaccharide (LPS) group (n=8), which received LPS (250 ng/kg per minute for 2 h); (b) the LPS plus N2733 group (n=8), which received N2733 (30 mg/kg intravenously and 10 mg/kg hour for 6 h) after the start of LPS; and (c) the N2733 group (n=7), which received N2733 (30 mg/kg intravenously and 10 mg/kg per hour for 6 h).Changes in hemodynamics, blood gas, gastric intramural pH, and renal and hepatic function were measured for 6 h. Coadministration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension, metabolic acidosis, and gastric mucosal acidosis but did not affect renal or hepatic function.Administration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension and metabolic and gastric mucosal acidosis in an anesthetized canine endotoxic shock model, suggesting its beneficial effect on local blood flow against tissue hypoxia. These findings suggest that blockade of NF-kappaB activation prevents hypodynamic shock and gastric hypoperfusin in endotoxic shock.

We have previously shown that hyperglycemia enhances inflammatory responses and that aerosolized insulin ameliorates inflammatory responses compared to identical doses of intravenous insulin in an experimental model of acute lung injury [1].

Objective: The purpose of this study was to investigate the effects of aerosolized prostacyclin (A-PGI2) and intratracheally instilled prostacyclin (I-PGI2) during partial liquid ventilation (PLV) on gas exchange and pulmonary circulation in rabbits with acute respiratory distress. Design: Prospective control study. Setting: A research laboratory at a university medical centre. Subjects: Sixty-nine Japanese white rabbits. Intervention: Lung injury was induced by oleic acid and the animals were divided into five groups of ten each: a mechanical gas ventilation (GV) group, an A-PGI2 group, a PLV group, an A-PGI2+PLV group and an I-PGI2+PLV group. PLV, A-PGI2+PLV and I-PGI2+PLV groups received 15 ml/kg perflubron intratracheally while receiving mechanical GV. A-PGI2 and A-PGI2+PLV groups received aerosolized PGI2 (50 ng/kg/min) in combination with GV or PLV, respectively. The I-PGI2+PLV group was instilled 50 ng/kg/min PGI2 intratracheally in combination with PLV. Result: After lung injury, all animals developed hypoxia, hypercarbia and pulmonary hypertension. The improvement of partial pressure of arterial oxygen (PaO2) in the A-PGI2 and PLV groups was transient, whereas the A-PGI2+PLV and I-PGI2+PLV groups showed consistent improvement throughout the experiment. The PaO2 values of the I-PGI2+PLV group were significantly higher than those of the other groups 120 min after treatment. The mean pulmonary artery pressure (PAP) significantly decreased after treatment in the A-PGI2, A-PGI2+PLV and I-PGI2+PLV groups. Conclusions: The results suggest that both aerosolized and intratracheally instilled PGI2 improve oxygenation and reduce PAP during PLV in oleic acid lung injury.

Objective: To investigate the regional partial pressure of oxygen (PO2) and partial pressure of carbon dioxide (PCO2) of the perfluorocarbon liquid (PpfcO2, PpfcCO2) during partial liquid ventilation (PLV). Design: Prospective, controlled study. Setting: A research laboratory at a university medical center. Subjects: Thirteen Japanese white rabbits. Interventions: After the tracheostomy, PLV was started with perflubron (15 ml/kg) following saline lung lavage. Fractional inspired oxygen (FIO2) was 1.0, respiratory rate was 30 bpm and tidal volume (VT) was 30 ml. Two epidural catheters (18 gauge) were inserted from the rubber diaphragm interposed in the respiratory circuit to sample perflubron. One catheter was inserted into the left lower lobe bronchus and placed at 5–6 cm distal from the carina (DISTAL). The other one was inserted at the tip of the endotracheal tube (PROXIMAL). Then the effect of the larger VT (50 ml) or positive end-expiratory pressure (PEEP; 10 cmH2O) to the gas tension in perflubron was examined. Measurements and main results: (1) In the lower VT (30 ml) with 0 cmH2O PEEP, DISTAL PpfcO2 was significantly lower than PROXIMAL PpfcO2 (265±72 vs 386±47 mmHg, p

Objective: To elucidate the change in pulmonary blood flow brought about by nitric oxide (NO) inhalation during partial liquid ventilation (PLV).¶Design: Prospective, controlled study.¶Setting: A research laboratory at a university medical center.¶Subjects: Fourteen Japanese white rabbits (3.2 ± 0.05 kg body weight).¶Interventions: Animals were mechanically ventilated in the right decubitus position. Following saline lung lavage, PLV was started with perflubron (15 ml/kg). In the NO group (n = 7), PLV was supplemented by a 30-min challenge of NO inhalation (10 ppm) from 30 min after the initiation of PLV. In the control group (n = 7), PLV was continued for 60 min.¶Measurements and main results: For the pulmonary blood flow analysis, colored microspheres were administered from the right atrium at 30 min (TPLV1) and 60 min (TPLV2) after the initiation of PLV. The percentage of the left lung blood flow in the total pulmonary blood flow (%QL/QT) was significantly increased by NO inhalation in the NO group (p = 0.0164), while that in the control group was significantly decreased during the same period (p = 0.0107). PaO2 in the NO group was significantly increased by NO inhalation (p = 0.0153), but not in the control group (p = 0.7911).¶Conclusion: Inhaled NO during PLV shifted the pulmonary blood flow to the non-dependent region and improved pulmonary gas exchange. This result suggested that inhaled NO took effect predominantly in the non-dependent region during PLV.

Purpose: Previous pharmacokinetic studies of fluorinated anesthetics using19F-magnetic resonance spectroscopy (19F-MRS) have focused on the brain. Investigation of other tissues would give more precise information about the pharmacokinetics of inhalational anesthetics. In this study we investigated the pharmacokinetics of uptake and elimination of sevoflurane in brain, liver, musde, venous blood and arterial blood of rabbits. Methods: Twenty rabbits were examined by19F-MRS conducted at 4.7 Tesla using a 1-cm-diameter surface coil for brain (n=4), liver (n=5) and muscle (n=5), and a 1.3-cm-diameter surface coil for arterial (n=3) and venous (n=3) blood. Sevoflurane, 4% in oxygen, was administered for 120 min, followed by 120 min elimination. Results: Both the uptake and elimination kinetics were best fitted by a biexponential curve which was divided into fast and slow components. During the uptake experiment the time required to reach half of the maximum spectroscopic intensity in each tissue was 1.6 min in arterial blood, 4.7 min in liver, 12.2 min in venous blood, 14.4 min in brain and 20.9 min in muscle. During the elimination experiment the time required to reach half maximum intensity was 2.4 min in arterial blood, 6.3 min in liver, 13.4 min in venous blood, 19.6 min in brain and 28.7 min in muscle. Conclusions: Sevoflurane uptake or elimination in the tissues examined followed biexponential kinetics. In this rabbit model, sevoflurane uptake and elimination were fastest in arterial blood, followed, in order, by liver, venous blood, brain and muscle.

To investigate the ventilatory effect of laparoscopic cholecystectomy in patients under general anesthesia with epidural block.We measured arterial blood gas, pulmonary carbon dioxide elimination (0000126;After starting peritoneal insufflation the PaCOThese results suggest that (1) transperitoneal absorption of CO