Topical lyophilized thrombin application improves wound healing for posterior spinal surgery.

Background: The erector spinae plane block (ESPB) was proposed as a part of the postoperative multimodal analgesic regimen to improve pain management after posterior spinal surgery. However, ESPB might cause more surgical incisional wound exudate and poor wound healing, which might be improved after topical lyophilized thrombin application. Materials and methods: We performed a retrospective study on patients who received posterior spinal surgery between January 2018 and December 2021. These patients were assigned into three groups: group A (general anesthesia), group B (general anesthesia with ESPB), and group C (general anesthesia with ESPB and topical 1000-unit thrombin application). Postoperative outcomes, including times of dressing changes, duration of suture removal, and incisional wound healing, were compared among these groups. Results: Our study included 89 patients, with 48, 20, and 21 patients in groups A, B, and C, respectively. Baseline demographics, height, weight, comorbidities, and operation duration were comparable among the three groups. Group B required statistically significantly more dressing changes and had a prolonged duration of suture removal than group A (9.4 ± 4.7 versus 6.5 ± 2.0 times, 16.2 ± 3.7 versus 14.2 ± 1.4 days, respectively), which could be statistically significantly improved after the thrombin application in group C. Group B also had more frequent poor wound healing (25.0 %), which could also be improved after the thrombin application (0.0 %). Conclusions: ESPB could cause more dressing changes and poor surgical wound healing after posterior spinal surgery, which could be improved by topical lyophilized thrombin powder application.

Deferoxamine regulates neuroinflammation and iron homeostasis in a mouse model of postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially amongst elderly patients. Neuroinflammation and iron homeostasis are key hallmarks of several neurological disorders. In this study, we investigated the role of deferoxamine (DFO), a clinically used iron chelator, in a mouse model of surgery-induced cognitive dysfunction and assessed its neuroprotective effects on neuroinflammation, oxidative stress, and memory function. METHODS: A model of laparotomy under general anesthesia and analgesia was used to study POCD. Twelve to 14 months C57BL/6J male mice were treated with DFO, and changes in iron signaling, microglia activity, oxidative stress, inflammatory cytokines, and neurotrophic factors were assessed in the hippocampus on postoperative days 3, 7, and 14. Memory function was evaluated using fear conditioning and Morris water maze tests. BV2 microglia cells were used to test the anti-inflammatory and neuroprotective effects of DFO. RESULTS: Peripheral surgical trauma triggered changes in hippocampal iron homeostasis including ferric iron deposition, increase in hepcidin and divalent metal transporter-1, reduction in ferroportin and ferritin, and oxidative stress. Microglia activation, inflammatory cytokines, brain-derived neurotropic factor impairments, and cognitive dysfunction were found up to day 14 after surgery. Treatment with DFO significantly reduced neuroinflammation and improved cognitive decline by modulating p38 MAPK signaling, reactive oxygen species, and pro-inflammatory cytokines release. CONCLUSIONS: Iron imbalance represents a novel mechanism underlying surgery-induced neuroinflammation and cognitive decline. DFO treatment regulates neuroinflammation and microglia activity after surgery.

Deferoxamine pre-treatment protects against postoperative cognitive dysfunction of aged rats by depressing microglial activation via ameliorating iron accumulation in hippocampus.

Postoperative cognitive dysfunction (POCD) is a common complication of elderly patients after surgery. The mechanisms of POCD have not been clarified. Iron accumulation is a feature of neurodegeneration. Recent reports showed that iron content was increased with impaired cognition induced by surgery. We sought to investigate whether iron chelation would attenuate POCD. In this study, male aged (18 months) Sprague-Dawley rats received 100 mg/kg deferoxamine or saline solution (0.9%) for 6 days before exploratory laparotomy. Cognition was evaluated by Morris water maze before and after surgery. Additional rats received deferoxamine or saline were used to determine hippocampal iron content, iron transport-related proteins (transferrin receptor, divalent metal transporter 1, ferroportin 1 and hepcidin), oxidative stress, microglial activation and brain cell apoptosis. It was found that deferoxamine improved postoperative spatial memory in aged rats. Deferoxamine significantly reduced hippocampal iron concentration and ferritin. Surgery increased divalent metal transporter 1 and hepcidin, decreased transferrin receptor and ferroportin 1, and enhanced ferroportin 1 mRNA. However, deferoxamine reversed the changes of these proteins. Furthermore, deferoxamine sharply reduced the hippocampal reactive oxygen species, malondialdehyde concentration and OX-42 that is a marker of microglia, which might reduce postoperative brain cell apoptosis. This study showed that deferoxamine may improve postoperative cognition of aged rats by ameliorating oxidative stress induced by hippocampal iron accumulation, microglial activation and brain cell apoptosis. This study suggests a potential therapeutic method for reducing POCD.

Propofol postsynaptically suppresses stellate neuron excitability in the entorhinal cortex by influencing the HCN and TREK-2 channels.

The entorhinal cortex (EC) provides a majority of the excitatory inputs to the hippocampus and is part of the neural circuitry that is involved in memory formation. Although many studies have investigated the effects of propofol in the hippocampus, the function of propofol in the EC remains unclear. Here, using whole-cell patch clamp recordings, we found that propofol induced a postsynaptic outward current and dramatically suppressed the firing rates in the entorhinal stellate neurons, the axons of which form the perforant pathway and relay the main inputs to hippocampus. Propofol-induced inhibition in the EC was mediated by a dual ionic mechanism, including both HCN channel inhibition and TREK-2 channel activation, which form a subtype of two-pore-domain K(+) channels. The inhibitory action of propofol observed in the EC might provide a mechanism for the anesthetic effect of propofol. Considering the crucial role of the EC in learning and memory, our findings may provide insight into the acute amnesic effect induced by propofol.

microRNA-23b regulates the expression of inflammatory factors in vascular endothelial cells during sepsis.

miR-23b is a multifunctional microRNA that contributes to the regulation of multiple signaling pathways. It has been reported that miR-23b prevents multiple autoimmune diseases through the regulation of inflammatory cytokine pathways. In addition, the function and underlying mechanisms of miR-23b on sepsis are currently being investigated. In the present study, miR-23b inhibitor and mimics sequences were transfected into human vascular endothelial cells to inhibit and upregulate the expression of miR-23b, respectively. In addition, respective negative control (NC) sequences were transfected. The expression of miR-23b was found to be downregulated in the cells transfected with the mimics NC or inhibitor NC sequences following stimulation with lipopolysaccharide (LPS; P<0.01); however, higher expression levels were maintained in the cells transfected with the mimics sequence and very low levels were observed in the cells transfected with the inhibitor sequence. In addition, the expression levels of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-6, intercellular adhesion molecule (ICAM)-1, E-selectin and vascular cell adhesion molecule (VCAM)-1 were shown to increase following induction by LPS in the cells transfected with inhibitor/mimics NC sequences (P<0.05). However, the expression levels of these inflammatory factors decreased in the cells transfected with the mimics sequence, and increased to a greater degree in the cells transfected with the inhibitor sequence, as compared with the inhibitor NC sequences (P<0.05). Therefore, miR-23b may play a significant role in the pathogenesis and progression of sepsis by inhibiting the expression of inflammatory factors, including NF-κB, TNF-α, IL-6, ICAM-1, E-selectin and VCAM-1.

Landiolol in the treatment of the intraoperative supraventricular tachycardia: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Supraventricular tachycardia during the induction of anesthesia may carry a higher risk. STUDY OBJECTIVE: The aim of this study was to evaluate efficacy and safety of intravenous landiolol in Chinese patients with intraoperative supraventricular tachycardia during anesthesia. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 2 study. SETTING: Eight sites of Chinese hospitals. PATIENTS: Men and women aged 18 to 70 years with the intraoperative supraventricular tachycardia (heart rate [HR], ≥100 beats/min) or the supraventricular tachycardia outside of the sinus tachycardia lasting more than 1 minute. INTERVENTIONS: Patients received landiolol or placebo-0.125 mg kg(-1) min(-1) (1 minute) loading→0.04 mg kg(-1) min(-1) (10 minutes) continuous. MEASUREMENTS: The proportion of patients receiving rescue medication (esmolol) when the reduction of HR did not exceed 10% after intravenous landiolol for 5 minutes. Other secondary efficacy end points include HR, blood pressure, rate pressure product, and electrocardiogram; the improvement of supraventricular tachycardia; the time it takes for the decrease of the HR to reach more than 10%; and the time it takes for the HR to reach <100 beats/min. MAIN RESULTS: Efficacy and safety were evaluated for 240 patients who received study drug. Lower proportions of patients received rescue medication in the landiolol group (7.63%) compared with that in the placebo group (80.33%) (P < .0001). Suppression of HR and rate pressure product was generally more potent(P < .0001), and higher proportions of patients improved supraventricular tachycardia (P < .0001) in the landiolol group. The most frequent adverse event was hypotension. CONCLUSION: Intravenous landiolol (loading dose of 0.125 mg/kg) may effectively control intraoperative supraventricular tachycardia during anesthesia. It inhibited the increases in HR during the induction of anesthesia. The effect of landiolol on blood pressure was minimal without decreasing diastolic blood pressure and with the minor reduction of systolic blood pressure (ClinicalTrials.gov number, ChiCTR-TRC-12003021).

Continuous and noninvasive measurement of systolic and diastolic blood pressure by one mathematical model with the same model parameters and two separate pulse wave velocities.

There is keen interest in continuous and noninvasive blood pressure (BP) measurement. However, many technologies have a shortcoming of complex mechanical structure. In our study, two arterial pulses are acquired by photoplethysmography (PPG) at ear and toe in order to explore a new method of measuring BP by pulse wave velocity (PWV). We previously validated and reported a BP-PWV mathematical model with measurements from humans with no evidence of cardiovascular disease, but were only able to determine PWV related to diastolic blood pressure (DBP). In this paper, we propose methods of identifying pulse transmit time (PTT) in low, normal and high systolic blood pressure (SBP) conditions. By averaging the PTT's of incident wave and reflected wave for non-systematic error reduction, we obtain a PWV that is suitable for estimating SBP. SBP and DBP are estimated by two separate PWV's based on the previously calibrated models. Experimental measurements are conducted on 26 subjects (age 19 ± 1 and 60 ± 1) with no evidence of cardiovascular disease. The measurement errors (Mean Deviation = 2.16 mmHg (SBP) and 1.49 mmHg (DBP); Standard Deviation = 6.23 mmHg (SBP) and 6.51 mmHg (DBP)) satisfy the accuracy criteria of Association for the Advancement of Medical Instrumentation. The results verify that SBP and DBP can be estimated by one mathematical model with the same model parameters and two separate PWV's.

Statistical analysis of blood pressure measurement errors by oscillometry during surgical operations.

OBJECTIVES: Although a validated oscillometry sphygmomanometer satisfies the accuracy criteria of Advancement of Medical Instrumentation (AAMI), its long-term blood pressure (BP) measurement error during operations remains to be determined. We aim to (a) compare the error range throughout surgical operations with the accuracy criteria of AAMI, and (b) investigate the probabilities of occurrence of abnormal, large errors and clinically meaningful errors. METHODS: BP level were measured from 270 participants using oscillometry and arterial cannulation (invasive method) in the same BP monitor throughout surgeries. Mean deviation and SD (oscillometry vs. invasive method) were calculated from 6640 sets of data and presented in the Bland-Altman Plots. Also, the average, the largest, and the smallest measurement errors (errormean, errormax, and errormin) per patient were obtained. The probability distributions of the three types of errors were shown using histograms (percentage vs. SD). In addition, the clinically meaningful large errors (≥ 10 mmHg) of the adult patients when their systolic blood pressure (SBP) values were around 90 mmHg were investigated. RESULTS: The mean deviation (1.98 mmHg for SBP and 4.31 mmHg for diastolic blood pressure (DBP) satisfies the AAMI criterion (≤ 5 mmHg), but the SD (14.87 mmHg for SBP and 11.21 mmHg for DBP) exceeds the AAMI criterion (≤ 8 mmHg). The probability of errormax more than 40 mmHg is 14% for SBP and 6% for DBP. The probability of errormean more than 24 mmHg (4.07% for SBP and 1.48% for DBP), and that of errormin more than 24 mmHg (0.37% for SBP and 0.37% for DBP) are all greater than the criterion of 0.26%. The clinically meaningful errors are found in 28.78% of the adult patients. CONCLUSION: The SD of long-term BP measurement by our oscillometric method during operations exceeds AAMI accuracy criteria. And it is important to be aware of the abnormal large errors and clinically meaningful errors as their probabilities are rather significant. We analyze the possible cause of the major errors and deduce that similar errors may also happen with other oscillometric devices.

Adenosine A3 receptor agonist reduces early brain injury in subarachnoid haemorrhage.

Inflammation plays an important role in the pathogenesis of early brain injury after subarachnoid haemorrhage. Adenosine A3 receptor (A3R) activation produces anti-inflammatory effects. In this study, the effects of a selective A3R agonist, 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (CL-IB-MECA), on early brain injury and inflammatory response after subarachnoid haemorrhage were studied. Our results showed that mortality, neurological impairment and brain oedema were significantly attenuated after the administration of CL-IB-MECA. Moreover, treatment with CL-IB-MECA inhibited microglial activation and reduced the expression of proinflammatory cytokines including tumour necrosis factor-α and interleukin-1ß. These data suggest that activation of A3R provides a neuroprotective effect against brain injury after subarachnoid haemorrhage, and that these effects may be associated with the anti-inflammatory properties of A3R.

Pharmacokinetics of propofol and extrahepatic UGT1A6 gene expression in anhepatic rats.

OBJECTIVE: The metabolic enzyme of UDP-glucuronosyltransferase 1A6 (UGT1A6) has been considered to metabolize propofol intra- or extrahepatically. The aim of the present study was to investigate the pharmacokinetics of propofol and UGT1A6 mRNA expression in extrahepatic organs before and during the anhepatic status in rats. METHODS: Male Sprague-Dawley rats were injected with propofol (10 mg/kg) intravenously and a blood sample was taken at 2-60 min after injection. The hepatic hilum was occluded under laparotomy and then the propofol injection and blood sampling were repeated as above 24 h later. The plasma concentrations of propofol were analyzed and UGT1A6 mRNA expression in the kidney, small intestine, lung and brain from other cohort rats at 30 and 60 min of anhepatic status were semiqualified by RT-PCR. RESULTS: T(1/2)(alpha), T(1/2)(beta) and V(d) of propofol were not changed significantly before and during the anhepatic status. The area under curve, derived from a time-dependent concentration response curve, was significantly increased whereas plasma clearance rate was decreased significantly in the anhepatic period when compared to that in the control period, respectively. UGT1A6 mRNA expression in extrahepatic organs was significantly increased at 30 or 60 min of the anhepatic status when compared to those in the control status. CONCLUSION: The pharmacokinetics of propofol during the prehepatic and anhepatic status are largely similar, which is associated with the upregulation of extrahepatic UGT1A6 gene. The marginal accumulation of propofol during anhepatic period is likely to be due to both the limited function of this metabolic pathway and physiological disturbance induced by hepatic hilum occlusion.

Continuous and noninvasive blood pressure measurement: a novel modeling methodology of the relationship between blood pressure and pulse wave velocity.

In this paper, we aim to establish a new mathematical model that relates pulse wave velocity (PWV) to blood pressure (BP) for continuous and noninvasive BP measurement. For the first time, we derive an ordinary differential equation (ODE) expressing the fundamental relation between BP, elastic modulus G and PWV. The general solution of this ODE is the mathematical BP-PWV model. In our model, the elastic modulus G is included in model parameters, unlike the existing theoretical models. This enables us to express the BP-PWV relationship for subjects of different ages and genders. A family of BP-PWV functions for specific age and gender groups can be obtained using statistical methods based on clinical trial data, which serve as the calibrated benchmark models for continuous and noninvasive BP measurement. To illustrate the modeling methodology, we construct benchmark models for people aged 19 and 60 and apply them to continuous diastolic blood pressure (DBP) measurement without individual calibration. The results of clinical tests meet the test standard in ANSI/AAMI SP10, which attests the feasibility of the modeling methodology.

Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury.

Xenon-induced neuroprotection has been well studied both in vivo and in vitro. In this study, the neuroprotective properties of the other noble gases, namely, krypton, argon, neon and helium, were explored in an in vitro model of neuronal injury. Pure neuronal cultures, derived from foetal BALB/c mice cortices, were provoked into injury by oxygen and glucose deprivation (OGD). Cultures were exposed to either nitrogen hypoxia or noble gas hypoxia in balanced salt solution devoid of glucose for 90min. The cultures were allowed to recover in normal culture medium for a further 24h in nitrogen or noble gas. The effect of noble gases on cell reducing ability in the absence of OGD was also investigated. Cell reducing ability was quantified via an MTT assay and expressed as a ratio of the control. The OGD caused a reduction in cell reducing ability to 0.56+/-0.04 of the control in the absence of noble gas (p<0.001). Like xenon (0.92+/-0.10; p<0.001), neuroprotection was afforded by argon (0.71+/-0.05; p<0.01). Neon and krypton did not have a protective effect under our experimental conditions. Helium had a detrimental effect on the cells. In the absence of OGD, krypton reduced the reducing ability of uninjured cells to 0.84+/-0.09 (p<0.01), but argon showed an improvement in reducing ability to 1.15+/-0.11 (p<0.05). Our data suggest that the cheap and widely available noble gas argon may have potential as a neuroprotectant for the future.

Vasoplegic syndrome during liver transplantation.

A 56-yr-old woman with chronic hepatitis B and decompensated hepatic cirrhosis was treated with liver transplantation. At the beginning of the neohepatic phase, her arterial blood pressure remained at 60/40 mm Hg for approximately 40 min and did not respond to vasoconstrictive drugs. Her other clinical and laboratory values remained normal, apart from a high cardiac output and low systemic vascular resistance. This patient was diagnosed with vasoplegic syndrome and was treated with i.v. infusion of methylene blue (0.5 mg/kg) and norepinephrine. This report has potential significance to treatment in patients who undergo orthotopic liver transplantation.

Thirty-five percent oxygen pre-conditioning protects PC12 cells against death induced by hypoxia.

The present study is designed to investigate the effect of pre-conditioning with 35% O2 on PC12 cell death induced by hypoxia. This study investigated whether 35% O2 pre-conditioning for 3 h, followed by 12 h recovery, can protect PC12 cells against death induced by subsequent exposure to hypoxia for 72 h. The result showed that pre-conditioning with 35% O2 partly blocked the decrease in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction induced by hypoxia in PC12 cells. PC12 cells pre-conditioned with 35% O2 could generate a small quantity of reactive oxygen species (ROS), which activated the extracellular signal-regulated kinase (ERK) signalling pathway, then the over-expression of the B-cell lymphoma/leukaemia-2 (Bcl-2) was induced, which subsequently protected PC12 cell against death resulting from hypoxia exposure. In conclusion, 35% O2 pre-conditioning could protect PC12 cells against hypoxic insult.

[Propofol ameliorates rat liver ischemia-reperfusion injury possibly by inhibiting nuclear factor-kappaB expression].

OBJECTIVE: To explore the role of nuclear factor-kappaB (NF-kappaB) in the protective effects of propofol against liver ischemia-reperfusion (IR) injury. METHODS: Forty male rats were randomized into 4 equal groups, namely the sham operation (N) group, IR group with hepatic IR injury (induced by ischemia of the left, right and median hepatic lobes for 1 h followed by reperfusion for 2 h), propofol (P) group with sham operation and propofol perfusion at 10 mg kg(-1) h(-1), and propofol treatment (PIR) group with IR injury and propofol perfusion. RT-PCR was used to detect the transcription level of NF-kappaB, and Western blotting was used for assaying NF-kappaB protein expression in the liver. RESULTS: Compared with either the N or the P group, the IR group showed obvious swelling, fatty degeneration and scatter focal necrosis of the hepatocytes as well as mild congestion in the hepatic sinusoid, with significantly increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and NF-kappaB expressions at both mRNA and protein levels (P<0.05). In the PIR group, the histopathological changes of the liver was lessened as compared with the IR group, and ALT and AST elevation was significantly inhibited (P<0.05) as was the protein expression of NF-kappaB (P<0.05), but NF-kappaB transcription level was further enhanced (P<0.05). CONCLUSION: Propofol can protect the liver from IR injury possibly by inhibiting NF-kappaB expression.

[Role of Janus kinase/signal transducer and activator of transcription pathway in mediating mRNA expression of high mobility group box1 protein in the liver in septic rats].

OBJECTIVE: To investigate the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in mediating mRNA expression of high mobility group box 1 protein (HMGB1) in the liver in septic rats. METHODS: Using a sepsis model of cecal ligation and puncture (CLP), 98 male Wistar rats were randomly divided into normal control group (n=10), CLP group (n=40), AG490 treatment group (n=24), and Rapamycin (RPM) treatment group (n=24). At serial time points animals in each group were sacrificed, and blood as well as hepatic tissue samples were harvested to determine HMGB1 mRNA expression and serum aspartate aminotransferase (AST) as well as alanine aminotransferase (ALT) contents. RESULTS: Compared with normal controls, HMGB1 mRNA levels were significantly increased in the liver during 6-48 hours after CLP (P<0.01), and serum AST and ALT contents were significantly elevated at different time points respectively (P<0.05 or P<0.01). Treatment with AG490 and RPM could markedly inhibit HMGB1 mRNA expression in the liver at 24 hours, 48 hours, 6 hours and 24 hours after CLP, respectively. In addition, compared to CLP group, serum AST and ALT contents in both treatment groups could be markedly reduced at various intervals after CLP (P<0.05 or P<0.01). CONCLUSION: These data suggest that the activation of JAK/STAT pathway might be involved in mediating up-regulation of HMGB1 mRNA expression in the liver in CLP-induced sepsis. Treatment with inhibitors of JAK/STAT pathway could markedly down-regulate HMGB1 mRNA expression and attenuate acute liver injury associated with sepsis.