Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass in adult patients undergoing cardiac surgery.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.

Presence of aberrant adrenocorticotropic hormone precursors in two cases of McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a rare disorder. MAS is classically defined by the occurrence of fibrous dysplasia, café-au-lait skin macules, and precocious puberty. In addition to precocious puberty, other hyperfunctioning endocrinopathies may occur. We evaluated hypothalamic-pituitary-adrenal function in two cases of typical MAS associated with fibrous dysplasia and growth hormone excess. Pituitary adenoma or hyperplasia was not detected by magnetic resonance imaging. Hormonal data showed normal or low cortisol levels, despite high ACTH levels in the blood. A high ratio of circulating ACTH to cortisol was found in the two cases. Insulin tolerance and CRH tests showed hyper-responses of ACTH and an insufficient increase in cortisol levels. No involvement of 11ß-HSD1 by GH excess was suggested because basal levels of ACTH and cortisol showed no changes, even after therapy for acromegaly by somatostatin analogues. Patients with Cushing's disease cases of pituitary macroadenoma can have high circulating ACTH precursor levels, and elevated ACTH precursors have been observed in ectopic ACTH syndrome. Autonomous cortisol excess was excluded by the level of midnight cortisol and the level of cortisol after a low-dose dexamethasone suppression test in the two cases. Finally, the gel filtration profiles of immunoreactive ACTH contents showed the presence of aberrant ACTH precursors. To the best of our knowledge, there have been no reports of MAS associated with aberrant ACTH precursors. Our findings in these cases emphasize that attention should be to secretion of inactive ACTH precursors in MAS.

Effects of alveolar recruitment maneuver on end-expiratory lung volume during one-lung ventilation.

PURPOSE: To investigate the effects of alveolar recruitment maneuver (ARM) during one-lung ventilation (OLV) on end-expiratory lung volume (EELV) of the dependent lung. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes.

PURPOSE: Propofol infusion syndrome (PRIS) is a lethal condition caused by propofol overdose. Previous studies suggest that pathophysiological mechanisms underlying PRIS involve mitochondrial dysfunction; however, these mechanisms have not been fully elucidated. This study aimed to establish an experimental model of propofol-induced cytotoxicity using cultured human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to determine the mechanisms behind propofol-induced mitochondrial dysfunction, and to evaluate the protective effects of coenzyme Q10 (CoQ10). METHODS: Human iPSC-derived cardiomyocytes were exposed to propofol (0, 2, 10, or 50 µg/ml) with or without 5 µM CoQ10. Mitochondrial function was assessed by measuring intracellular ATP, lactate concentrations in culture media, NAD+/NADH ratio, and the mitochondrial membrane potential. Propofol-induced cytotoxicity was evaluated by analysis of cell viability. Expression levels of genes associated with mitochondrial energy metabolism were determined by PCR. Intracellular morphological changes were analyzed by confocal microscopy. RESULTS: Treatment with 50 µg/ml propofol for 48 h reduced cell viability. High concentrations of propofol (≥ 10 µg/ml) induced mitochondrial dysfunction accompanied by downregulation of gene expression of PGC-1alpha and its downstream targets (NDUFS8 and SDHB, which are involved in the respiratory chain reaction; and CPT1B, which regulates beta-oxidation). Cardiomyocytes co-treated with 5 µM CoQ10 exhibited resistance to propofol-induced toxicity through recovery of gene expression. CONCLUSIONS: Propofol-induced cytotoxicity in human iPSC-derived cardiomyocytes may be associated with mitochondrial dysfunction via downregulation of PGC-1alpha-regulated genes associated with mitochondrial energy metabolism. Co-treatment with CoQ10 protected cardiomyocytes from propofol-induced cytotoxicity.

Efficacy of Supraglottic Airway for Preventing Lung Injury Associated with Coughing at Extubation after Pulmonary Lobectomy.

BACKGROUND: The use of double-lumen endobronchial tubes (DLTs) is necessary for differential lung ventilation during pulmonary lobectomy. However, when used with conventional extubation procedures, coughing is more likely and is associated with an increased risk for parenchymal air leak along the staple line and possible subsequent lung injury. We examined the prevalence of coughing-associated air leaks at extubation and the efficacy of using supraglottic airways (SGAs) to prevent air leaks with post-lobectomy extubation. METHODS: This study included 150 patients with pulmonary emphysema diagnosed using preoperative computed tomography, who underwent pulmonary lobectomy between April 2010 and March 2015. The patients were chronologically enrolled in two groups: the DLT group (60 patients) from April 2010 to August 2012, and the SGA group (90 patients) from September 2012 to March 2015. (Note: the DLT group only included cases without air leak present just prior to extubation). Data were collected on specific patient characteristics and operative and postoperative factors. RESULTS: Coughing at extubation occurred in 15 (25.0 %) of 60 DLT patients, and parenchymal air leaks developed in 10 (66.7 %) of these 15. Comparison of groups revealed the SGA group was significantly lower for the following: patients with coughing at extubation (P < 0.001), coughing-associated air leaks at extubation (P < 0.001), air leaks >7 days (P = 0.006), reoperation due to air leaks (P = 0.013), and duration of chest tube drainage (P < 0.001). CONCLUSIONS: The SGA is effective for preventing air leaks associated with coughing during conventional DLT extubation in post-lobectomy patients.

A case of malignant catatonia with idiopathic pulmonary arterial hypertension treated by electroconvulsive therapy.

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.

Perioperative risk factors for acute kidney injury after liver resection surgery: an historical cohort study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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).

Effects of xenon irradiation of the stellate ganglion region on fibromyalgia.

[Purpose] The aim of the study was to determine the effect of xenon irradiation of the stellate ganglion region on fibromyalgia. [Subjects] The study included 5 men and 22 women (age, 56.4 ± 16.3 years [range, 25-84 years]) who were diagnosed with fibromyalgia according to the modified 2010 criteria of the American College of Rheumatology between July and August 2013. [Methods] Bilateral xenon light irradiation (0.38-1.1 µm) around the stellate ganglion was performed in the supine position by physical therapists using a xenon phototherapy device. We evaluated pain before and after irradiation using the visual analogue scale. [Results] We did not observe a relationship between the change in the visual analogue scale score and duration of fibromyalgia. However, we observed a relationship between the change in the visual analogue scale score and the score for the Japanese version of the Fibromyalgia Impact Questionnaire using the Cochran-Armitage test for trend. [Conclusion] Xenon light irradiation of the stellate ganglion significantly decreased the visual analogue scale score in patients with fibromyalgia having a higher score in the Fibromyalgia Impact Questionnaire, suggesting that a stronger effect could be obtained in patients with more severe fibromyalgia.

Elevated levels of angiopoietin-2 as a biomarker for respiratory failure after cardiac surgery.

OBJECTIVES: Angiopoietin-1 and angiopoietin-2 are important factors in regulating endothelial vascular permeability. This study evaluated perioperative changes in serum levels of angiopoietin-1 and -2 in patients undergoing cardiac surgery. DESIGN: Measurement of serum levels of angiopoietin-1 and angiopoietin-2 in samples collected during a previously conducted prospective, multicenter, observational study. SETTING: Three university hospitals. PARTICIPANTS: Eighty-four adult patients undergoing cardiac surgery. INTERVENTION: Serum levels of angiopoietins were measured at baseline, immediately after surgery, and the day after surgery (POD-1). MEASUREMENTS AND MAIN RESULTS: Serum levels of angiopoietin-2 were elevated by POD-1 (median 3.3 ng/mL, interquartile range [IQR] 2.5-4.6 ng/mL) compared with baseline (median 1.6 ng/mL, IQR 1.3-2.1 ng/mL, p < 0.0001), and angiopoietin-1 levels were decreased immediately after surgery (baseline median 23.2 ng/mL, IQR 10.2-32.8 ng/mL; postoperative median 8.0 ng/mL, IQR 1.5-13.2 ng/mL, p<0.0001). Angiopoietin-2 levels on POD-1 in patients undergoing off-pump coronary artery bypass grafting were significantly lower than those in patients undergoing aortic surgery (p = 0.0009) and valve surgery (p = 0.008). Angiopoietin-2 levels on POD-1 had a predictive performance of the area under the curve (AUC) of the receiver operating characteristic curve 0.74 for mechanical ventilation>3 days. Angiopoietin-1 levels and the angiopoietin-2/angiopoietin-1 ratio showed lower predictive performance (AUC values 0.58 and 0.68, respectively). CONCLUSIONS: Angiopoietin-2 serum levels were elevated after cardiac surgery. Elevated angiopoietin-2 had a good predictive performance for respiratory failure after cardiac surgery, perhaps reflecting the severity of lung dysfunction related to postoperative increases in vascular permeability.

[Potential influence of pre and intraoperative factors on postoperative recurrence and survival in patients undergoing radical resection of esophageal cancer].

BACKGROUND: Several papers report that preoperative and intraoperative factors influence postoperative recurrence of malignancy. The purpose of this study is to define which factors affect the recurrence and survival of patients after the surgical resection of the esophageal cancer. METHODS: Ninety five patients underwent complete elective resection of the esophageal cancer. All patients were without preoperative chemotherapy and radiotherapy. We extracted 12 parameters, and cox regression analyses were used to assess the relation of 12 factors and the outcomes of patients. The 12 factors included preoperative factors (age, sex, weight stage of cancer, ASA PS, serum creatinine and total bilirubin), intraoperative variables (duration of anesthesia, blood transfusion, fluid balance, hypotensive episodes) and surgical Apgar score. Hypotensive episodes were defined as the systolic pressure lower than 70 mmHg occurring from the introduction of anesthesia to the end of anesthesia. RESULTS: Hypotensive episodes and blood transfusion significantly affected 1 year cancer specific survival. Stage of cancer and blood transfusion affected 5 year cancer specific survival. CONCLUSIONS: We found that intraoperative hypotension affected 1-year cancer specific survival; however, the stage of cancer affected long-term survival instead of intraoperative factors. A low 5-year survival rate in esophageal cancer may have affected this result.

[Anesthetic management of a pregnant woman with brain tumor].

A 35-year-old parturient, 35 weeks pregnant, pre- sented with intracranial tumor with increased intracra- nial pressure. She underwent emergency cesarean section under general anesthesia, followed by craniotomy. The intraoperative and postoperative courses were uneventful. The occurrence of brain tumors during pregnancy is very rare; meanwhile pregnancy may aggravate the natural history of an intracranial tumor, and may even unmask previously unknown diagnosis. The decision to proceed with cesarean section and neurosurgery depends on the site, size, type of tumor, neurological signs and symptoms, age of the fetus, and the patient's wishes. Therefore, close communication between the neurologist, neurosurgeon, anesthesiologist, obstetrician and the patient is very important.

Inhaled aerosolized insulin ameliorates hyperglycemia-induced inflammatory responses in the lungs in an experimental model of acute lung injury.

INTRODUCTION: Previous studies have shown that patients with diabetes mellitus appear to have a lower prevalence of acute lung injury. We assumed that insulin prescribed to patients with diabetes has an anti-inflammatory property and pulmonary administration of insulin might exert beneficial effects much more than intravenous administration. METHODS: Twenty-eight mechanically ventilated rabbits underwent lung injury by saline lavage, and then the animals were allocated into a normoglycemia group (NG), a hyperglycemia group (HG), an HG treated with intravenous insulin (HG-VI) group or an HG treated with aerosolized insulin (HG-AI) group with continuous infusion of different fluid solutions and treatments: normal saline, 50% glucose, 50% glucose with intravenous insulin, or 50% glucose with inhaled aerosolized insulin, respectively. After four hours of treatment, the lungs and heart were excised en bloc, and then high-mobility group B1 concentration in bronchoalveolar lavage fluid, interleukin-8 and toll-like receptor 4 mRNA expression in bronchoalveolar lavage fluid cells, and lung myeloperoxidase activity were measured. RESULTS: Treatment with both aerosolized insulin and intravenous insulin attenuated toll-like receptor 4 mRNA expressions in the bronchoalveolar lavage fluid cells. Interleukin-8 and toll-like receptor 4 mRNA expression was significantly lower in the HG-AI group than in the HG-IV group. The lung myeloperoxidase activity in the normal healthy group showed significantly lower levels compared to the NG group but not different compared to those of the HG, HG-VI and HG-AI groups. CONCLUSIONS: The results suggest that insulin attenuates inflammatory responses in the lungs augmented by hyperglycemia in acute lung injury and the insulin's efficacy may be better when administered by aerosol.

[A case of prolonged neuromuscular blockade possibly related to a high anti-acetylcholine receptor antibody level].

Prolonged neuromuscular blockade is a relatively common complication of general anesthesia. Some previous reports have shown that positive serum anti-acetylcholine receptor antibody (AChR Ab) might contribute to this complication. We experienced a case of a 69-year-old woman with prolonged neuromuscular blockade after laparoscopic sigmoid colectomy under general anesthesia using rocuronium. A high level of anti-AChR Ab (45 nmol x l-1) was found in postoperative examination and the patient had progressive muscle weakness for six months after the operation. Although this patient had mediastinal tumor diagnosed as thymic carcinoma two years before the operation, preoperative clinical evaluation was negative for myasthenia gravis (MG) and the tumor was in remission at the operation. These observations suggest that preoperative measurement of anti-AChR Ab level might be recommended for patients with mediastinal tumor regardless of symptoms of MG and that neuromuscular blocking agents should be administrated carefully in anti-AChR Ab positive patients under monitoring of the neuromuscular blockade.

[Resveratrol did not prevent sevoflurane-induced neuroapoptosis in the neonatal mice brain].

BACKGROUND: In an animal model, neonatal exposure to sevoflurane induces neuroapoptosis, leading to memory deficits in adulthood. A recent study showed that resveratrol (20 mg x kg(-1)) prevent alcohol-induced cognitive deficits and neural apotosis in rat pups postnatally exposed to ethanol. We investigated if resveratorol prevent sevoflurane induced neuroapotosis. METHODS: Six-day-old mice were divided into two groups: resveratorol and control groups. Pups were given resveratrol orally 24h and 1h before sevoflurane anesthesia. Anesthesia was maintained for 6h. After anesthesia, apotosis was evaluated by immunohistochemical staining for activated caspase-3. Western blot analysis for cleaved poly-(adenosine diphosphate-ribose) polymerase was performed to examine apotosis. RESULTS: Neonatal exposure to sevoflurane induced severe neuroapotosis. There were no differences between control groups and resveratrol groups with regards to immunohistochemical staining and western blot analysis. CONCLUSIONS: Resveratrol did not prevent sevoflurane-induced neuroapoptosis in the neonatal mice brain.

[Ultrasound-guided peripheral nerve block for high-risk patients with arteriosclerosis obliterans in lower limb surgery--a report of nine cases].

Most patients with arteriosclerosis obliterans (ASO) have severe complications such as coronary artery disease, congestive heart failure and chronic kidney disease. They receive long-term antithrombotic therapy which is a contraindication to neuraxial anesthesia. In this retrospective study, we reviewed nine high-risk patients with ASO (revised cardiac risk index more than three) who underwent an urgent lower limb surgery under ultrasound-guided peripheral nerve block (PNB). In all cases, intraoperative hemodynamic changes remained minimized. In eight of the nine cases, analgesics are not required until 10 hours after the operation. No complication related to PNB occurred. Ultrasoundguided PNB for patients with ASO undergoing lower limb surgery can be a useful anesthetic technique, providing cardiovascular stability and good postoperative analgesia.

[Two cases showing the absence of motor evoked potentials without developing postoperative paraplegia following thoracoabdominal aortic repair--role of epidural cooling, spinal drainage and aorto-iliac side-arm conduit distal perfusion].

We describe two cases which developed loss of motor evoked potentials from bilateral lower limbs following thoracoabdominal aortic repair. Paraplegia was suspected in both cases; however, one case of Crawford type 2 aneurysm showed transient left leg monoplegia with a sensory deficit and the other case of aortic pseudoaneurysm showed no neurologic dysfunction postoperatively. We employed epidural cooling and spinal drainage for spinal protection and distal perfusion was provided through aorto-iliac side-arm conduit. Despite the prolonged spinal ischemia during thoracoabdominal aortic repair, spinal drainage and epidural cooling were very helpful for protecting the spinal cord from ischemia. The interpretation of MEPs seems very difficult especially when the potentials remain absent even after reconstruction or reperfusion of segmental arteries, because variety of intraoperative factors may affect them.

Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells.

Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 µg/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces.

Reversible cerebral vasoconstriction syndrome with limb myoclonus following intravenous administration of methylergometrine.

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.