Hyperoxia but not high tidal volume contributes to ventilator-induced lung injury in healthy mice.

BACKGROUND: Mechanical ventilation is a supportive therapy used to maintain respiratory function in several clinical and surgical cases but is always accompanied by lung injury risk due to improper treatment. We investigated how tidal volume and oxygen delivery would contribute independently or synergistically to ventilator-induced lung injury (VILI). METHODS: Under general anesthesia and tracheal intubation, healthy female C57BL/6 N mice (9 weeks old) were randomly ventilated for 2 h by standard (7 ml/kg) or high (14 ml/kg) tidal volume at positive end-expiratory pressure (PEEP) of 2 cmH2O, with room air, 50% O2 (moderate hyperoxia), or 100% O2 (severe hyperoxia); respectively. Mice were sacrificed 4 h after mechanical ventilation, and lung tissues were collected for experimental assessments on lung injury. RESULTS: Compared with the healthy control, severe hyperoxia ventilation by either standard or high tidal volume resulted in significantly higher wet-to-dry lung weight ratio and higher levels of IL-1ß and 8-OHdG in the lungs. However, moderate hyperoxia ventilation, even by high tidal volume did not significantly increase the levels of IL-1ß and 8-OHdG in the lungs. Western blot analysis showed that the expression of RhoA, ROCK1, MLC2, and p-MLC2 was not significantly induced in the ventilated lungs, even by high tidal volume at 2 cmH2O PEEP. CONCLUSION: Severe hyperoxia ventilation causes inflammatory response and oxidative damage in mechanically ventilated lungs, while high tidal volume ventilation at a reasonable PEEP possibly does not cause VILI.

Prolonged oxygen exposure causes the mobilization and functional damage of stem or progenitor cells and exacerbates cardiac ischemia or reperfusion injury in healthy mice.

Oxygen is often administered to patients and occasionally to healthy individuals as well; however, the cellular toxicity of oxygen, especially following prolonged exposure, is widely known. To evaluate the potential effect of oxygen exposure on circulating stem/progenitor cells and cardiac ischemia/reperfusion (I/R) injury, we exposed healthy adult mice to 100% oxygen for 20 or 60 min. We then examined the c-kit-positive stem/progenitor cells and colony-forming cells and measured the cytokine/chemokine levels in peripheral blood. We also induced cardiac I/R injury in mice at 3 h after 60 min of oxygen exposure and examined the recruitment of inflammatory cells and the fibrotic area in the heart. The proportion of c-kit-positive stem/progenitor cells significantly increased in peripheral blood at 3 and 24 h after oxygen exposure for either 20 or 60 min (p < .01 vs. control). However, the abundance of colony-forming cells in peripheral blood conversely decreased at 3 and 24 h after oxygen exposure for only 60 min (p < .05 vs. control). Oxygen exposure for either 20 or 60 min resulted in significantly decreased plasma vascular endothelial growth factor levels at 3 h, whereas oxygen exposure for only 60 min reduced plasma insulin-like growth factor 1 levels at 24 h (p < .05 vs. control). Protein array indicated the increase in the levels of some cytokines/chemokines, such as CXCL6 (GCP-2) at 24 h after 60 min of oxygen exposure. Moreover, oxygen exposure for 60 min enhanced the recruitment of Ly6g- and CD11c-positive inflammatory cells at 3 days (p < .05 vs. control) and increased the fibrotic area at 14 days in the heart after I/R injury (p < .05 vs. control). Prolonged oxygen exposure induced the mobilization and functional impairment of stem/progenitor cells and likely enhanced inflammatory responses to exacerbate cardiac I/R injury in healthy mice.

The effect of transient oxygenation on stem cell mobilization and ischemia/reperfusion heart injury.

For general anesthesia, pre-oxygenation is routinely performed prior to intubation. It is well-known that ischemic/hypoxic preconditioning induces stem cell mobilization and protects against ischemia/reperfusion (I/R) injury. In this study, we investigated the effect of transient oxygenation on stem cell mobilization and I/R injury of the heart. Mice were exposed to 100% oxygen for 5 or 20 minutes. We evaluated the number of c-kit+ stem/progenitor cells and the levels of SDF-1α and VEGF in peripheral blood at 1, 3, 6, and 24 hours after oxygenation. We also induced I/R injury of the heart at 3 hours post-oxygenation for 5 minutes and then examined stem cell recruitment and fibrotic changes in the heart 3 or 14 days later. The number of c-kit+ cells in peripheral blood was significantly increased at 1 or 24 hours after oxygenation for either 5 or 20 minutes. Oxygenation for 5 or 20 minutes did not significantly change the SDF-1α level measured in plasma. However, the plasma VEGF level was decreased at 3 hours post-oxygenation for 20 minutes (p = 0.051). Oxygenation for 5 minutes did not significantly alter the fibrotic area or cell apoptosis. Although oxygenation for 5 minutes increased the number of c-kit+ cells in hearts damaged by I/R injury, this difference was not significant between groups due to large variation between individuals (p = 0.14). Although transient oxygenation induces stem cell mobilization, it does not appear to protect against I/R injury of the heart in mice.

Overexpression of glutaredoxin protects cardiomyocytes against nitric oxide-induced apoptosis with suppressing the S-nitrosylation of proteins and nuclear translocation of GAPDH.

There is increasing evidence demonstrating that glutaredoxin 1 (GRX1), a cytosolic enzyme responsible for the catalysis of protein deglutathionylation, plays distinct roles in inflammation and apoptosis by inducing changes in the cellular redox system. In this study, we investigated whether and how the overexpression of GRX1 protects cardiomyocytes against nitric oxide (NO)-induced apoptosis. Cardiomyocytes (H9c2 cells) were transfected with the expression vector for mouse GRX1 cDNA, and mock-transfected cells were used as a control. Compared with the mock-transfected cells, the GRX1-transfected cells were more resistant to NO-induced apoptosis. Stimulation with NO significantly increased the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a pro-apoptotic protein, in the mock-transfected cells, but did not change GAPDH localization in the GRX1-transfected cells. Furthermore, we found that NO stimulation clearly induced the oxidative modification of GAPDH in the mock-transfected cells, whereas less modification of GAPDH was observed in the GRX1-transfected cells. These data suggest that the overexpression of GRX1 could protect cardiomyocytes against NO-induced apoptosis, likely through the inhibition of the oxidative modification and the nuclear translocation of GAPDH.

Age-dependent relationship between bispectral index and sedation level.

STUDY OBJECTIVE: To determine the relationship between bispectral index (BIS) and sedation. DESIGN: Prospective, observational clinical study. SETTING: Intensive care unit of a public hospital in Japan. PATIENTS: 22 ASA physical status I, II, and III middle-aged (18-65 yrs) and elderly (>65 yrs) patients receiving postoperative sedation with midazolam. INTERVENTIONS: Patients were allocated to two groups: Group M was composed of middle-aged patients (<65 yrs) and Group H elderly patients (>65 yrs). Midazolam was administered at a bolus dose of 0.1 mg/kg, followed by a continuous dose of 0.04 mg/kg per hour, which was adjusted every two hours to achieve a target level of sedation at 3-6 on the Ramsay Sedation Scale (RSS); buprenorphine was administered at a constant rate (0.625 microg kg(-1) hr(-1)). MEASUREMENTS: BIS value, RSS, midazolam dose, body temperature (BT), heart rate, dopamine dose, and mean arterial pressure were recorded every two hours by an independent nurse. Data were analyzed using Spearman rank correlation and the Mann-Whitney U test. MAIN RESULTS: BIS values decreased depending on depth of sedation; a significant correlation was noted between groups in RSS and BIS. The BIS values at levels of RSS 5 and 6 were significantly lower in Group H than Group M. CONCLUSION: BIS correlated with sedation depth, with BIS scores in group H than group M at a deep sedation depth.

Comparison of oxygen consumption calculated by Fick's principle (using a central venous catheter) and measured by indirect calorimetry.

We investigated the clinical usefulness of the Fick method using central venous oxygen saturation ScvO2 and cardiac output (CO) measured by pulse dye densitometry (PDD) for monitoring oxygen consumption VO2. This prospective clinical study was performed in 28 mechanically ventilated postoperative patients after major abdominal surgery. VO2 was determined by two methods, i.e., the Fick method and indirect calorimetry. The Fick method was employed using CO measured by PDD and VO2 obtained from a central venous catheter (CVC). VO2 measured by indirect calorimetry was averaged for 15 min. Fifty-six sets of measurements were performed. VO2 values determined by the Fick method were significantly lower than those measured by indirect calorimetry (110 +/- 29 vs 148 +/- 28 ml x min(-1) x m(-2); P < 0.01). Bland and Altma analysis showed that the mean bias and precision were 33 ml x min(-1) x m(-2) and 32 ml x min(-1) x m(-2), respectively. The correlation between the two measurements of VO2 was weak (r (2) = 0.145; P = 0.0038), indicating that the Fick method using PDD and ScvO2 is not clinically acceptable for the monitoring of VO2.

[Change of sedation depth, oxygen consumption index and hemodynamics after withdrawal of midazolam sedation].

BACKGROUND: The change of oxygen consumption after withdrawal of sedation is controversial. We evaluated the changes of sedation depth, oxygen consumption and hemodynamics after withdrawal of midazolam sedation in the patients undergoing major abdominal surgery. METHODS: We evaluated 18 patients after major abdominal surgery. Midazolam was used for intravenous sedation after admission to the ICU. Midazolam was administered at a bolus dose of 0.1 mg kg(-1), followed by continuous infusion at 0.04 mg kg(-1) hr(-1), which was adjusted every 2 hrs to achieve a desired level of sedation of 4 on Ramsay sedation scale (RSS). After about 14 hours of sedation, we stopped the infusion of midazolam. From that time, we measured systolic and mean arterial pressure, heart rate, minute volume and oxygen consumption, and evaluated RSS every 5 minutes for 1 hour. We evaluated RSS as sedation depth, oxygen consumption index (V(O2)I) and rate pressure product (RPP=systolic arterial pressure x heart rate) as hemodynamic parameters. RESULTS: RSS significantly decreased gradually, but the other parameters including V(O2)I and RPP were unchanged. CONCLUSIONS: After withdrawal of midazolam sedation in the patients undergoing major abdominal surgery, the sedation depth became lighter, but V(O2)I and RPP were unchanged.

Preadministration of flurbiprofen suppresses prostaglandin production and postoperative pain in orthopedic patients undergoing tourniquet inflation.

STUDY OBJECTIVES: To evaluate the effect of preadministration of flurbiprofen on the plasma concentrations of prostaglandin E2 (PGE2) and postoperative pain. DESIGN: Prospective, randomized, controlled and double-blind study. SETTING: Inpatient surgery at Nagasaki Rosai Hospital. PATIENTS: 32 ASA physical status I to II patients scheduled for total knee arthroplasty or open anterior cruciate ligament reconstruction. INTERVENTIONS: Patients were randomly assigned to two groups. Five minutes before tourniquet inflation (350 mmHg), group A (n = 16) received placebo (intralipid, one mL . kg(-1)), and group B (n = 16) received flurbiprofen one mg . kg(-1) IV. Catheters were placed in the ipsilateral femoral vein for collection of local blood and in a cubital vein for sampling of systemic blood. MEASUREMENTS: Prostaglandin E2 (femoral vein and cubital vein) was measured before tourniquet inflation (T1), before tourniquet deflation (T2), and immediately after tourniquet deflation (T3). Postoperative analgesia was provided with intravenous buprenorphine, 0.1 mg, on patient demand. Pain (Visual Analog Scale) was assessed at 0.5, one, two, 4, 6, 12 and 24 hours after surgery. MAIN RESULTS: Visual Analog Scale and buprenorphine consumptions in group B were significantly lower than those in group A during the first 4 postoperative hours. In group A, PGE2 in femoral vein increased significantly at T2 (359 +/- 105 pg mL(-1), P < 0.0001), compared with T1 (211 +/- 61 pg mL(-1)) and returned to control values at T3 (252 +/- 77 pg mL(-1)), whereas PGE2 in the cubital vein showed no change. In group B, PGE2 in either the femoral vein or cubital vein showed no change throughout the time course. CONCLUSIONS: Preadministration of flurbiprofen suppresses the local production of PGE2 during tourniquet ischemia, resulting in reduced early postoperative pain in patients undergoing knee surgery.

Human middle cerebral artery flow velocity during controlled hypotension combined with hemodilution-transcranial Doppler study.

STUDY OBJECTIVE: To evaluate the effects of controlled hypotension combined with hemodilution on human middle cerebral artery flow velocity (Vmca) by transcranial Doppler ultrasonography. DESIGN: Randomized prospective study. SETTING: Inpatient surgery at Nagasaki Rosai Hospital. PATIENTS: Thirty American Society of Anesthesiologists physical status I and II patients scheduled for total hip arthroplasty. INTERVENTIONS: Anesthesia was maintained with nitrous oxide-oxygen (N(2)O-O(2)) and sevoflurane during normocapnia. Hemodilution was carried out after induction of anesthesia, in which blood was withdrawn then replaced with the same amount of hydroxyethyl starch to achieve a final hematocrit level of 32% (group A = mild hemodilution group, N = 15) or 24% (group B = moderate hemodilution group, N = 15). In both groups, controlled hypotension was induced with prostaglandin E(1) to maintain mean arterial pressure at approximately 55 mm Hg for 80 minutes. MEASUREMENTS AND MAIN RESULTS: Vmca and blood gas were measured before hemodilution, after hemodilution, 80 minutes after starting hypotension, and 60 minutes after recovery from hypotension. Vmca significantly increased in group A (+122%) and group B (+156%) after each hemodilution. In group B, Vmca was significantly greater than baseline values at 80 minutes after starting hypotension (+135%) and 60 minutes after recovery from hypotension (+140%). CONCLUSION: The combination of moderate hemodilution, such as hematocrit value of 24%, and prostaglandin E(1)-induced hypotension would not impair middle cerebral artery flow during sevoflurane-N(2)O-O(2) anesthesia during normocapnia.

[Management of postoperative pharyngeal swelling after anterio-posterior cervical fusion under pharyngoscopy].

A 47-year-old man with traumatic cervical spinal cord injury underwent anterio-posterior cervical fusion, which accompanied high-risk of upper airway obstruction by postoperative reactive pharyngeal swelling. After the operation, we ascertained that he had no paralysis of his extremities, and sedation and mechanical ventilation were started at ICU. We evaluated the degree of edema in the hypopharyngeal and supraglottic regions with pharyngoscopy. On postoperative day 3, the direct fiberoptic evaluation showed postoperative swelling of the upper airway. On postoperative day 8, extubation was performed after confirming the healing pharyngeal edema by fibroptic evaluation. To achieve successful extubation, fibroptic pharyngoscopy should show that the pharynx around the endotracheal tube wide enough to see the larynx including epiglottis. Pharyngoscopy is a useful method to evaluate the upper airway.

Increased incidence of emergency airway management after combined anterior-posterior cervical spine surgery.

Among some kinds of cervical spine surgeries, combined anterior-posterior cervical spine surgery (CAP-CS surgery) requires prolonged operative time and highly invasive procedure. This study was performed to determine whether CAP-CS surgery was associated with increased risk of emergency airway management compared with other cervical spine surgeries (O-CS surgeries). The records of the patients who underwent cervical spine surgery between July 2001 and March 2003 at our institution were reviewed retrospectively, and we determined whether the CAP-CS surgery was associated with an increased risk of emergency airway management in comparison with O-CS surgeries, using the logistic regression analysis. A total of 165 were eligible for inclusion in the study. A total of 127, 20, 11, 5, and 2 patients suffered from cervical myelopathy, traumatic cervical spinal cord injury, atlantoaxial dislocation, cervical spinal tumors, and cervical pyogenic spondylitis, respectively. The operative approaches were CAP-CS surgery, anterior surgery, posterior surgery, and atlantoaxial surgery in 10, 56, 88, and 11 patients, respectively. Thus, the operative approaches were CAP-CS surgery in 10 patients and O-CS surgeries in 155 patients. Postoperative emergency airway management was required in 7 of the 10 patients (70%) who underwent CAP-CS surgery, and 2 of the 155 patients (1%) who underwent O-CS surgeries. The increased risk of postoperative emergency airway management imposed by CAP-CS surgery was 178.5 by an odds ratio, with a 95% confidence interval of 25.6 to 1246. The results show that CAP-CS surgery provides a major risk factor for postoperative emergency airway management.

[A case of acute respiratory distress syndrome (ARDS) caused by splenic infarction].

Acute respiratory distress syndrome (ARDS) is the most severe lung injury caused by many pathologic states. We treated a patient who suffered from ARDS caused by splenic infarction. A 75-year-old patient had a gastric cancer with multiple lung and liver metastasis. During anti-cancer therapy, she developed a high fever (above 39 degrees C) and a chest and an abdominal CT scan revealed splenic infarction. Hypoxia progressed gradually and she was transferred to ICU with tracheal intubation. Mechanical ventilation was performed according to open lung strategy, but she did not recover. On ICU day 3, the bilateral infiltration shadow on her chest X-ray was pointed out, and she had a low central venous pressure. We diagnosed her ARDS. The administration of methylprednisolone was started according to Meduri's report. Hypoxia was improved gradually and on ICU day 7, she was weaned from mechanical ventilation, and extubated. On ICU day 8, she was returned to her ward without ventilatory support.