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The COVID-19 outbreak has led to 80,409 diagnosed cases and 3,012 deaths in mainland China based on the data released on March 4, 2020. Approximately 3.2% of patients with COVID-19 required intubation and invasive ventilation at some point in the disease course. Providing best practices regarding intubation and ventilation for an overwhelming number of patients with COVID-19 amid an enhanced risk of cross-infection is a daunting undertaking. The authors presented the experience of caring for the critically ill patients with COVID-19 in Wuhan. It is extremely important to follow strict self-protection precautions. Timely, but not premature, intubation is crucial to counter a progressively enlarging oxygen debt despite high-flow oxygen therapy and bilevel positive airway pressure ventilation. Thorough preparation, satisfactory preoxygenation, modified rapid sequence induction, and rapid intubation using a video laryngoscope are widely used intubation strategies in Wuhan. Lung-protective ventilation, prone position ventilation, and adequate sedation and analgesia are essential components of ventilation management.

With the development of anesthesiology, patient safety has been remarkably improved, but the postoperative mortality rate at 30 days is still as high as 0.56%-4%, and the morbidity is even higher. Three years ago, the Chinese Society of Anesthesiology proposed that the direction of the anesthesiology development should be changed to perioperative medicine in China. Anesthesiologists should pay more attention to the long-term outcome. In this article, we introduced what we have done, what the challenges are, and what we should do in the future with regard to the practice of perioperative medicine in China.

Background Microglia can not only detrimentally augment secondary injury but also potentially promote recovery. However, the mechanism underlying the regulation of microglial phenotypes after stroke remains unclear. Methods Mice were subjected to middle cerebral artery occlusion for 60 min. At 3 days after reperfusion, the effects of activation and suppression of triggering receptor expressed on myeloid cells 2 on immunocyte phenotypes (n = 5), neurobehavioral scores (n = 7), infarct volumes (n = 8), and neuronal apoptosis (n = 7) were analyzed. In vitro, cultured microglia were exposed to oxygen–glucose deprivation for 4 h. Inflammatory cytokines, cellular viability (n = 8), neuronal apoptosis (n = 7), and triggering receptor expressed on myeloid cells 2 expression (n = 5) were evaluated in the presence or absence of triggering receptor expressed on myeloid cell-specific small interfering RNA or triggering receptor expressed on myeloid cells 2 overexpression lentivirus. Results Triggering receptor expressed on myeloid cells 2 expression in the ischemic penumbra peaked at 3 days after ischemia–reperfusion injury (4.4 ± 0.1-fold, P = 0.0004) and was enhanced in interleukin-4/interleukin-13–treated microglia in vitro (1.7 ± 0.2-fold, P = 0.0119). After oxygen–glucose deprivation, triggering receptor expressed on myeloid cells 2 conferred neuroprotection by regulating the phenotypic conversion of microglia and inflammatory cytokine release. Intraperitoneal administration of triggering receptor expressed on myeloid cells 2 agonist heat shock protein 60 or unilateral delivery of a recombinant triggering receptor expressed on myeloid cells 2 lentivirus into the cerebral ventricle induced a significant neuroprotective effect in mice (apoptotic neurons decreased to 31.3 ± 7.6%; infarct volume decreased to 44.9 ± 5.3%). All values are presented as the mean ± SD. Conclusions Activation or up-regulation of triggering receptor expressed on myeloid cells 2 promoted the phenotypic conversion of microglia and decreased the number of apoptotic neurons. Our study suggests that triggering receptor expressed on myeloid cells 2 is a novel regulator of microglial phenotypes and may be a potential therapeutic target for stroke.

The anesthetic propofol is thought to induce rapid hypnotic sedation by potentiating γ-aminobutyric acid receptor (GABAAR) activity. Little is known about the molecular mechanisms of propofol in modulating inhibitory synaptic transmission. We aimed to investigate the role of propofol in modulating surface expression of GABAARs.C57BL/6 mice received an intraperitoneal injection of propofol. Hippocampal pyramidal neurons were prepared from embryonic day-18 mice and were treated with propofol. Proteins on the plasma membrane were analyzed using cell surface biotinylation, immunoblotting and enzyme-linked immunosorbent assay. Electrophysiological activities were recorded from hippocampal cells in acute brain slices of mice. The interaction between GABAARs and clathrin adaptor protein 2 was assessed by immunoprecipitation. Phosphorylation of GABAARs was shown by in vitro kinase assay.Propofol facilitated membrane accumulation of GABAARβ3 subunits. Propofol mediated phosphorylation of GABAARβ3 by protein kinase Cε which blocked the interaction between GABAARβ3 and the β-adaptin subunit of adaptor protein 2, resulting in an inhibition of the receptor endocytosis in hippocampal pyramidal neurons. Coincident with increased GABAARs surface level, propofol enhanced evoked and miniature synaptic GABA receptor currents.This study offers new insight on the regulatory mechanism of propofol in inhibiting neuronal excitability.

Sudden cardiac arrest is a leading cause of death worldwide. Three-fourths of cardiac arrest patients die before hospital discharge or experience significant neurological damage. Hydrogen-rich saline, a portable, easily administered, and safe means of delivering hydrogen gas, can exert organ-protective effects through regulating oxidative stress, inflammation, and apoptosis. We designed this study to investigate whether hydrogen-rich saline treatment could improve survival and neurological outcome after cardiac arrest and cardiopulmonary resuscitation, and the mechanism responsible for this effect.Sprague-Dawley rats were subjected to 8 minutes of cardiac arrest by asphyxia. Different doses of hydrogen-rich saline or normal saline were administered IV at 1 minute before cardiopulmonary resuscitation, followed by injections at 6 and 12 hours after restoration of spontaneous circulation, respectively. We assessed survival, neurological outcome, oxidative stress, inflammation biomarkers, and apoptosis.Hydrogen-rich saline treatment dose dependently improved survival and neurological function after cardiac arrest/resuscitation. Moreover, hydrogen-rich saline treatment dose dependently ameliorated brain injury after cardiac arrest/resuscitation, which was characterized by the increase of survival neurons in hippocampus CA1, reduction of brain edema in cortex and hippocampus, preservation of blood-brain barrier integrity, as well as the decrease of serum S100β and neuron-specific enolase. Furthermore, we found that the beneficial effects of hydrogen-rich saline treatment were associated with decreased levels of oxidative products (8-iso-prostaglandin F2α and malondialdehyde) and inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and high-mobility group box protein 1), as well as the increased activity of antioxidant enzymes (superoxide dismutase and catalase) in serum and brain tissues. In addition, hydrogen-rich saline treatment reduced caspase-3 activity in cortex and hippocampus after cardiac arrest/resuscitation.Hydrogen-rich saline treatment improved survival and neurological outcome after cardiac arrest/resuscitation in rats, which was partially mediated by reducing oxidative stress, inflammation, and apoptosis.

Objective: Hyperglycemia often occurs in severe burns; however, the underlying mechanisms and importance of managing postburn hyperglycemia are not well recognized. This study was designed to investigate the dynamic changes of postburn hyperglycemia and the underlying mechanisms and to evaluate whether early glycemic control is beneficial in severe burns. Design: Prospective, randomized experimental study. Setting: Animal research laboratory. Subjects: Sprague-Dawley rats. Interventions: Anesthetized rats were subjected to a full-thickness burn injury comprising 40% of the total body surface area and were randomized to receive vehicle, insulin, and a soluble form of receptor for advanced glycation endproducts treatments. An in vitro study was performed on cultured H9C2 cells subjected to vehicle or carboxymethyllysine treatment. Measurements and Main Results: We found that blood glucose change presented a distinct pattern with two occurrences of hyperglycemia at 0.5- and 3-hour postburn, respectively. Acute insulin resistance evidenced by impaired insulin signaling and glucose uptake occurred at 3-hour postburn, which was associated with the second hyperglycemia and positively correlated with mortality. Mechanistically, we found that serum carboxymethyllysine, a dominant species of advanced glycation endproducts, increased within 1-hour postburn, preceding the occurrence of insulin resistance. More importantly, treatment of animals with soluble form of receptor for advanced glycation endproducts, blockade of advanced glycation endproducts signaling, alleviated severe burn–induced insulin resistance. In addition, early hyperglycemic control with insulin not only reduced serum carboxymethyllysine but also blunted postburn insulin resistance and reduced mortality. Conclusions: These findings suggest that severe burn–induced insulin resistance is partly at least mediated by serum advanced glycation endproducts and positively correlated with mortality. Early glycemic control with insulin or inhibition of advanced glycation endproducts with soluble form of receptor for advanced glycation endproducts ameliorates postburn insulin resistance.

Notch signaling, a critical pathway in cell fate determination, is well known to be involved in immune and inflammatory reactions, whereas its role in acute lung injury (ALI) remains unclear. Here, we report that notch signal activity is upregulated in lung tissue harvested from an ALI mouse model (induced by zymosan). We showed that notch signal activity in lung tissue was increased 6 h after zymosan injection and peaked at 24 h. Inhibition of notch signaling by either pre- or post-zymosan treatment with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) significantly reduced lung injury, characterized by improvement in lung histopathology, lung permeability (protein concentration in bronchoalveolar lavage fluid and lung wet-to-dry weight ratio), lung inflammation (bronchoalveolar lavage fluid cell count, lung myeloperoxidase, and tumor necrosis factor α), and also alleviated systemic inflammation and tissue damage, thus increasing the 7-day survival rate in zymosan-challenged mice. In conclusion, the role of notch signaling is functionally significant in the development of ALI. Inhibition of notch signaling by pretreatment or posttreatment with DAPT likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment. These results also imply that notch inhibitors may help attenuate local inflammatory lung damage.

Background: Medical therapy, the cornerstone of managing epilepsy, still fails a substantial portion of patients. Little information is available regarding the potential impact of different bispectral index (BIS) levels on electrocorticographic spike identification for surgical epileptic foci resection. Methods: Twenty-two intractable epilepsy subjects were randomly allocated to the propofol–remifentanil or sevoflurane–remifentanil groups, and were further randomized to four BIS85 (BIS 71–85), BIS70 (BIS 56–70), BIS55 (BIS 41–55), and BIS40 (BIS ≤40) sequence order. Results: Two-way ANOVA revealed no differences between groups in spike frequency (P = 0.720), spike amplitude (P = 0.647), or number of spiking leads (P = 0.653). In the propofol and sevoflurane groups, decreasing BIS levels increased mean ± SD spike/min frequency (P < 0.001 and P < 0.001) at BIS85 (10 ± 12 and 10 ± 8), BIS70 (19 ± 17 and 17 ± 15), BIS55 (22 ± 17 and 18 ± 8), and BIS40 (25 ± 15 and 23 ± 17). Furthermore, in the propofol and sevoflurane groups, decreasing BIS levels increased spike microvolt amplitude (P = 0.006 and P = 0.009) at BIS85 (1,100 ± 400 and 750 ± 400), BIS70 (1,200 ± 460 and 850 ± 490), BIS55 (1,300 ± 560 and 940 ± 700), and BIS40 (1,400 ± 570 and 1,300 ± 700). Whereas, in the propofol and sevoflurane groups, there was no difference in the location or number of spiking leads (P = 0.057 and P = 0.109) at the four BIS levels. Compared with BIS85, spike frequency in the propofol and sevoflurane groups increased 100 and 170% at BIS70, 116 and 180% at BIS55, and 132 and 230% at BIS40. Compared with BIS85, spike amplitude increased 108 and 113% at BIS70, 121 and 125% at BIS55, and 128 and 170% at BIS40. Conclusion: Decreasing BIS levels in the propofol and sevoflurane groups enhanced epileptogenic spike frequency and amplitude with the same location and number of spiking leads.

Background A wealth of evidence has demonstrated that sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly understood. This study was designed to investigate the role of canonical Notch signaling in the neuroprotection induced by sevoflurane preconditioning in a mouse model. Methods C57BL/6 mice were pretreated with 1-h sevoflurane exposure at a dose of 2.5% for 5 consecutive days. Twenty-four hours after the last exposure, all mice were subjected to focal cerebral ischemia by right middle cerebral artery occlusion for 60 min. Neurobehavioral scores, brain infarct volumes, and cellular apoptosis were determined at 72 h after reperfusion (n = 10 per group). The activation of Notch signaling was evaluated (n = 5 per group), and its role in ischemic tolerance was assessed by intraperitoneal administration of γ-secretase inhibitor DAPT (100 mg/kg, n = 10 per group) and conditional Notch-RBP-J knockout technique (n = 8 per group). Results Sevoflurane preconditioning reduced brain infarct volumes (42.5%), improved neurologic outcomes (P < 0.01 vs. control), and attenuated neuronal cell apoptosis (cells positive for terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling reduced to 21.2%). The expression of Notch1 intracellular domain (1.35 folds) and the transcriptions of Hes1 (1.95 times) and Hes5 (1.48 times) were up-regulated. DAPT augmented the brain infarcts (1.64-fold) and decreased neurologic scores (P = 0.43 vs. sevoflurane) in sevoflurane-preconditioned mice. Brain infarct volumes, neurobehavioral scores, and apoptotic cell numbers showed no significance between Notch knockout mice with sevoflurane preconditioning and wild-type mice without preconditioning. Conclusions Sevoflurane preconditioning-induced protective effects against transient cerebral ischemic injuries are mediated by the activation of canonical Notch signaling pathway in mice.

Anesthetic preconditioning appears to be a viable strategy to treat ischemic cerebral injury. Here we investigated 1) whether the protection conferred by sevoflurane preconditioning sustains in time; 2) whether sevoflurane preconditioning diminishes mitochondrial dysfunction following cerebral ischemia; and 3) whether mitochondrial permeability transition pore plays a crucial role in the sevoflurane preconditioning.Laboratory investigation.University research laboratory.: Sprague-Dawley rats.Rats underwent 2 hrs of focal cerebral ischemia induced by middle cerebral artery occlusion. Preconditioning was elicited with sevoflurane (2.3%) for 60 mins at 24 hrs before ischemia. The involvement of mitochondrial permeability transition pore was determined with a mitochondrial permeability transition pore opener atractyloside and a specific mitochondrial permeability transition pore inhibitor cyclosporin A. In vitro study was performed on acutely isolated mitochondria subjected to calcium overload.Sevoflurane preconditioning significantly decreased the infarct size by 35.9% (95% confidence interval 6.5-28.4, p.001). This reduction of injury volume was associated with a long-term improvement of neurological function according to modified neurological severity score (F = 13.6, p = .001) and sticky-tape test (F = 29.1, p.001) for 42 days after ischemia. Furthermore, sevoflurane preconditioning markedly protected mitochondria, as indicated by preserved respiratory chain complex activities and membrane potential, lowered mitochondrial hydrogen-peroxide production, and attenuated mitochondrial permeability transition pore opening. Isolated mitochondria also demonstrated a reduced sensitivity to Ca-induced mitochondrial permeability transition pore opening after pre-exposure to sevoflurane in vitro (95% confidence interval 24.2-196.5,p = .006). Inhibiting mitochondrial permeability transition pore using cyclosporin A resulted in protective effects similar to those seen with sevoflurane preconditioning, whereas pharmacologically opening the mitochondrial permeability transition pore with atractyloside abrogated all the positive effects of sevoflurane preconditioning and cyclosporin A, including suppression of mitochondrial permeability transition pore opening, counteraction of mitochondria-dependent apoptotic pathway, and subsequent histological and behavioral improvements.Sevoflurane preconditioning protects mitochondria from cerebral ischemia/reperfusion injury and ameliorates long-term neurological deficits. Inhibition of mitochondrial permeability transition pore opening is a crucial step in mediating the neuroprotection of sevoflurane preconditioning.

Sepsis/multiple organ dysfunction syndrome is the leading cause of death in critically ill patients. Recently, it has been suggested that hydrogen gas (H2) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical (•OH, the most cytotoxic reactive oxygen species). We have found that H2 inhalation significantly improved the survival rate and organ damage of septic mice with moderate or severe cecal ligation and puncture. In the present study, we investigated the effects of 2% H2 treatment on survival rate and organ damage in zymosan (ZY)-induced generalized inflammation model. Here, we found that 2% H2 inhalation for 60 min starting at 1 and 6 h after ZY injection, respectively, significantly improved the 14-day survival rate of ZY-challenged mice from 10% to 70%. Furthermore, ZY-challenged mice showed significant multiple organ damage characterized by the increase in serum biochemical parameters (aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine), as well as lung, liver, and kidney histopathological scores at 24 h after ZY injection, which was significantly attenuated by 2% H2 treatment. In addition, we found that the beneficial effects of H2 treatment on ZY-induced organ damage were associated with the decreased levels of oxidative product, increased activities of antioxidant enzyme, and reduced levels of early and late proinflammatory cytokines in serum and tissues. In conclusion, this study provides evidence that H2 treatment protects against multiple organ damages in ZY-induced generalized inflammation model, suggesting the potential use of H2 as a therapeutic agent in the therapy of conditions associated with inflammation-related multiple organ dysfunction syndrome.

BACKGROUND: In this study, we sought to clarify the role of inhibiting ubiquitin-conjugated protein aggregation in the formation of a neuroprotective effect after isoflurane preconditioning using a transient global cerebral ischemia-reperfusion injury mouse model. METHODS: C57BL/6 mice were randomly assigned to 3 groups (isoflurane preconditioning [IsoPC] group, control [Con] group, and sham group, n = 24 in each group). Mice in the IsoPC group and sham group were placed in a chamber and pretreated with isoflurane (1.2% isoflurane, 98% O 2 , 1 hour/day) for 5 days. Mice in the Con group were placed in the same chamber but pretreated with oxygen only (98% O 2 , 2% N 2 , 1 hour/day) for 5 days. Twenty-four hours after the last preconditioning day, bilateral common carotid artery occlusion was performed as a model of global cerebral ischemia for 20 minutes in the IsoPC group and Con group. The total motor scores, number of viable neurons in the CA1 region of the hippocampus, and expression levels of conjugated ubiquitin or free ubiquitin were assessed by neurological assessment, immuno-histochemistry, and Western blotting (at 24 and 72 hours) after reperfusion, respectively. RESULTS: The total motor scores in the IsoPC group were better than the Con group (P < 0.05). Morphological observations showed that the IsoPC group had better neuron structure than in the Con group. The numbers of viable neurons in the CA1 region were significantly increased by isoflurane preconditioning compared with those in the Con group (P < 0.05). The numbers of TUNEL-positive neurons in the CA1 region were significantly decreased after isoflurane preconditioning. The density of conjugated ubiquitin staining in the CA1 region of the IsoPC group was significantly lower than in the Con group (P < 0.05) and the expression of conjugated ubiquitin in the IsoPC group was lower than in the Con group (P < 0.05). CONCLUSION: Inhibition of ubiquitin-conjugated protein aggregation may have an essential role in inducing cerebral ischemic tolerance by isoflurane preconditioning in a transient global cerebral ischemia-reperfusion injury mouse model.

Background It remains to be established whether spinal cord ischemic tolerance can be induced by limb remote ischemic preconditioning (RIPC), and the mechanisms underlying the neuroprotective effects of RIPC on the spinal cord need to be clarified. Methods Spinal cord ischemia was studied in New Zealand White rabbits. In experiment 1, all rabbits were subjected to 20-min spinal cord ischemia by aortic occlusion. Thirty minutes before ischemia, rabbits were subjected to sham intervention or RIPC achieved by bilateral femoral artery occlusion (10 min ischemia/10 min reperfusion, two cycles). Dimethylthiourea (500 mg/kg, intravenously), a hydroxyl radical scavenger, or vehicle was given 1 h before RIPC. Antioxidant enzyme activity was measured along with spinal cord histology and neurologic function. In experiment 2, rabbits were subjected to spinal cord ischemia, with or without RIPC. In addition, rabbits were pretreated with various doses of hexamethonium. Results RIPC improved neurologic function and reduced histologic damage. This was associated with increased endogenous antioxidant activity. Dimethylthiourea inhibited the protective effects of RIPC. In contrast, there was no effect of hexamethonium on the protective effect of RIPC. Conclusions An initial oxidative stress acts as a trigger to upregulate antioxidant enzyme activity, rather than the neural pathway, and plays an important role in the formation of the tolerance against spinal cord ischemia by limb RIPC.

Sepsis is a leading cause of death in patients with critical illness. However, there is no effective therapy available. Recent studies have suggested that ventilation with 100% oxygen (Oxy) can improve the survival rate and organ function in several shock models. However, a lot of work is necessary to be done before its clinical application, and its detailed mechanism remains to be clarified. In the present study, we showed that 100% Oxy inhalation for 2 or 3 h starting at 4 and 12 h after zymosan (ZY) injection, respectively, prevented the abnormal changes of serum biochemical parameters, tissue oxygenation, and organ histopathology, and improved the 14-day survival rate from 10% to 60% to 80% in mice. However, 100% Oxy inhalation for 1 or 4 h starting at the same time points has little preventive effects. We also showed that twice 100% Oxy inhalation for 2 or 3 h attenuated the increase of inflammatory cytokines and precluded the downregulation of antioxidant enzymatic activities. We further showed that the therapeutic time window of Oxy treatment against sterile sepsis was less than 12 h after ZY injection. We conclude that 100% Oxy inhalation for 2 or 3 h starting 4 and 12 h after ZY injection, respectively, protects against ZY-induced sterile sepsis via regulating inflammatory cytokines and antioxidant system in mice. The present results may provide a potential cue for developing more effective therapeutic strategies for patients with sepsis.

Background: Voluven (hydroxyethyl starch [HES] 130/0.4), a new generation of HES product with low molecular weight, has been widely used for the treatment of traumatic and hemorrhagic shock in clinics. However, no data are available whether it affects the balance of cerebral oxygen supply and consumption when applied to resuscitate hemorrhagic shock. The purpose of this study was to address this question in rabbits subjected to a severe hemorrhagic shock. Methods: In New Zealand rabbits, an acute hemorrhagic shock was induced by withdrawing 45% to 50% of total blood volume from the femoral vein in 10 minutes when the mean arterial pressure was reduced to 60% of the baseline level. Thirty minutes after the hemorrhage, animals were infused with either an equal amount of Voluven (group V) or a tripled amount of lactated Ringer's solution (group R). The saturation of oxygen was obtained in arterial (Sao 2 ) and venous (SjvO 2 ) blood samples from the femoral artery and jugular bulb, respectively. Arterial oxygen content (Cao 2 ), jugular oxygen content (CjvO 2 ), arteriovenous oxygen difference (AVDO 2 ), and cerebral oxygen extraction rate (CERO 2 ) were calculated accordingly to evaluate the oxygenation state in the brain. Results: Levels of SjvO 2 and CjvO 2 were decreased after hemorrhagic shock, and there were increases in AVDO 2 and CERO 2 values. After resuscitation, the SjvO 2 , AVDO 2 , and CERO 2 levels in group V were quickly recovered to the basal levels, whereas the values in group R remained in the abnormal levels (p < 0.05). There were significant differences between the groups in their SjvO 2 and CERO 2 levels at 30 minutes after resuscitation. In addition, the mean arterial pressure was restored to the basal levels in group V but not in group R after resuscitation (p < 0.05). Conclusion: We conclude that early infusion of Voluven is beneficial for maintenance of the hemodynamic stability and for the balance of cerebral oxygen supply and consumption during the resuscitation of acute hemorrhagic shock.

BACKGROUND: The neuroprotective effect of the cyclooxygenase (COX) inhibitor has been demonstrated in acute and chronic neurodegenerative processes. But its function under cerebral ischemic conditions is unclear. This study was designed to evaluate the neuroprotective efficacy of emulsified flurbiprofen axetil (FA, COX inhibitor) and its therapeutic time window in a model of transient middle cerebral artery occlusion (MCAO) in rats. METHODS: Forty-eight male SD rats were randomly assigned into six groups (n = 8 in each group); three FA groups, vehicle, sham and ischemia/reperfusion (I/R) groups. Three doses of FA (5, 10 or 20 mg/kg, intravenous infusion) were administered just after cerebral ischemia/reperfusion (I/R). The degree of neurological outcome was measured by the neurologic deficit score (NDS) at 24, 48 and 72 hours after I/R. Mean brain infarct volume percentage (MBIVP) was determined with 2, 3, 5-triphenyltetrazolium chloride (TTC) staining at 72 hours after I/R. In three other groups (n = 8 in each group), the selected dosage of 10 mg/kg was administrated intravenously at 6, 12 and 24 hours after I/R. RESULTS: The three different doses of FA improved NDS at 24, 48 and 72 hours after I/R and significantly reduced MBIVP. However, the degree of MBIVP in the FA 20 mg/kg group differed from that in FA 10 mg/kg group. Of interest is the finding that the neuroprotective effect conferred by 10 mg/kg of FA was also observed when treatment was delayed until 12 - 24 hours after ischemia reperfusion. CONCLUSION: COX inhibitor FA is a promising therapeutic strategy for cerebral ischemia and its therapeutic time window could last for 12 - 24 hours after cerebral ischemia reperfusion, which would help in lessening the initial ischemic brain damage.

BACKGROUND Our previous in vivo study in the rat demonstrates that Shenfu injection, a clinically used extract preparation from Chinese herbs, attenuates neural and cardiac toxicity induced by intravenous infusion of bupivacaine, a local anesthetic. This study was designed to investigate whether bupivacaine could induce a toxic effect in primary cultured mouse spinal cord neuron and if so, whether the Shenfu injection had a similar neuroprotective effect in the cell model. METHODS The spinal cords from 11- to 14-day-old fetal mice were minced and incubated. Cytarabine was added into the medium to inhibit the proliferation of non-neuronal cells. The immunocytochemical staining of beta-tubulin was used to determine the identity of cultured cells. The cultured neurons were randomly assigned into three sets treated with various doses of bupivacaine, Shenfu and bupivacaine + Shenfu, for 48 hours respectively. Cell viability in each group was analyzed by methyl thiazoleterazolium (MTT) assay. RESULTS The viability of the cultured neurons treated with bupivacaine at concentrations of 0.01%, 0.02%, 0.04% and 0.08% was decreased in a dose-dependent manner. Although the Shenfu injection at concentrations ranging from 1/50 to 1/12.5 (V/V) had no significant influence on the viability of cultured neurons (P < 0.05 vs control), the injection significantly increased the cellular viability of cultured neurons pretreated with 0.03% bupivacaine (P < 0.05). CONCLUSION Although Shenfu injection itself has no effect on spinal neurons, it was able to reduce the bupivacaine-induced neurotoxicity in vitro.

Background Vasoactive drugs are often necessary for reversing hypotension in patients with severe infection. The standard for evaluating effects of vasoactive drugs should not only be based on the increase of arterial blood pressure, but also on the blood flow perfusion of internal organs. The effects of dopamine and metaraminol on the renal function of the patients with septic shock were investigated retrospectively in this study. Methods Ninety-eight patients with septic shock were divided into three groups according to the highest infusing rate of metaraminol, with the lightest infusing rate of (0.1 - 0.5, 0.6 - 1.0, > 1.0) microgxkg(-1)xmin(-1) in group A, B and C respectively. Urine output, mean arterial blood pressure (MAP), heart rate (HR), urine output, blood urea nitrogen (BUN), creatinine (CRE), urine albumin (U-ALB), urine beta(2)-microglubulin (Ubeta(2)-MG) and Apache III scores were recorded. Results Before antishock therapy, hypotension, tachycardia and oliguria occurred to all the 98 patients with septic shock and CRE, BUN, U-ALB, Ubeta(2)-MG and Apache III scoring were abnormal in most cases. With the antishock therapy, MAP, HR, urine output, BUN and CRE in all patients returned gradually to normal (P 0.05). Conclusion Dopamine and metaraminol when applied to the patients with septic shock could effectively maintain the circulatory stability and promote restoration of renal function.

BACKGROUND Preconditioning with repeated electroacupuncture (EA) could mimic ischemic preconditioning to induce cerebral ischemic tolerance in rats. The present study was designed to investigate whether mu (micro)-, delta (delta)- or kappa (kappa)-opioid receptors are involved in the neuroprotection induced by repeated EA preconditioning. METHODS The rats were pretreated with naltrindole (NTI), nor-binaltorphimine (nor-BNI) or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), which is a highly selective delta-, kappa- or micro-opioid receptor antagonist respectively, before each EA preconditioning (30 minutes per day, 5 days). Twenty-four hours after the last EA treatment, the middle cerebral artery occlusion (MCAO) was induced for 120 minutes. The brain infarct volume was determined with 2, 3, 5-triphenyltetrazolium chloride staining at 24 hours after MCAO and compared with that in rats which only received EA preconditioning. In another experiment, the met-enkephalin-like immunoreactivity in rat brain was investigated by immunohistochemistry in both EA preconditioning and control rats. RESULTS The EA preconditioning reduced brain infarct volume compared with the control rats (P = 0.000). Administration of both NTI and CTOP attenuated the brain infarct volume reduction induced by EA preconditioning, presenting with larger infarct volume than that in the EA preconditioning rats (P < 0.001). But nor-BNI administration did not block the infarct volume reduction induced by EA preconditioning, presenting with smaller infarct volume than the control group rats (P = 0.000). The number of met-enkephalin-like immunoreactivity positive neurons in the EA preconditioning rats was more than that of the control rats (P = 0.000). CONCLUSION Repeated EA preconditioning stimulates the release of enkephalins, which may bind delta- and micro-opioid receptors to induce the tolerance against focal cerebral ischemia.

UNLABELLED In this study, we determined whether repeated brief isoflurane (Iso) anesthesia induces ischemic tolerance to focal cerebral ischemia in a dose-response manner and whether the effect is dependent on adenosine triphosphate-regulated potassium channels. In Experiment 1, 40 rats were randomly assigned to 4 groups: control animals received 100% oxygen 1 h/d for 5 days, whereas the isoflurane (Iso)1, Iso2, and Iso3 groups received 0.75%, 1.5%, or 2.25% Iso in oxygen 1 h/d for 5 days. In Experiment 2, 36 rats were randomly assigned to 4 groups: controls received 100% oxygen 1 h/d for 5 days; animals in the Iso and I+G (Iso+glibenclamide) groups received 2% Iso in oxygen 1 h/d for 5 days, and the I+G group received glibenclamide (GLB) (5 mg/kg intraperitoneally) before each Iso pretreatment. Animals in the GLB group received GLB (5 mg/kg intraperitoneally) once a day for 5 days. Twenty-four hours after the last pretreatment, the right middle cerebral artery was occluded for 120 min. Neurologic deficit scores (NDS) and brain infarct volumes were evaluated at 24 h. The NDS and infarct volumes of Iso2 and Iso3 were less than those of the controls (P < 0.05). The infarct volume in Iso3 was smaller than in Iso2 (P < 0.05). The NDS and infarct volume in the Iso group were less than in the control and I+G groups (P < 0.05). There was no statistical difference among the control, I+G, and GLB groups. The study demonstrated that repeated Iso anesthesia induces ischemic tolerance in rats in a dose-response manner. GLB, an adenosine triphosphate-regulated potassium channel blocker, abolished the tolerance induced by Iso. IMPLICATIONS Brief isoflurane anesthesia induces ischemic tolerance in the brain. The effect was found to be dose dependent in a rat focal cerebral ischemia model. Ischemic tolerance induced by isoflurane preconditioning is dependent on activation of adenosine triphosphate-regulated potassium channels.

Background The aim of this study was to determine if the ischemic tolerance could be induced in the spinal cord by pretreatment with hyperbaric oxygen (HBO) and what components of HBO (hyperoxia, hyperbaricity, and combination of these two) were critical in the induction of tolerance against ischemic injury. Methods In experiment 1, 21 rabbits were randomly assigned to one of three groups (n = 7 each): animals in the control group received no HBO before spinal cord ischemia; animals in the HBO-1 and HBO-2 groups received HBO (2.5 atmosphere absolute [ATA], 100% O2) pretreatment 1 h/day for 3 and 5 days before ischemia, respectively. In experiment 2, 48 rabbits were randomly assigned to one of four groups (n = 12 each): the control group received no HBO (21% O2, 1 ATA, 1 h/day, 5 days) before spinal cord ischemia; the HB group received 1-h treatment in 21% O2 at 2.5 ATA each day for 5 days; the HO group received 1-h treatment in 100% oxygen at 1 ATA each day for 5 days; and the HBO group received HBO (2.5 ATA, 100% O2) treatment 1 h/day for 5 days. Twenty-four hours after the last treatment, spinal cord ischemia was induced by an infrarenal aorta clamping for 20 min. Forty-eight hours after reperfusion, hind-limb motor function and histopathology of the spinal cord were examined in a blinded fashion. Results In experiment 1, the neurologic outcome in the HBO-2 group was better than that of the control group (P = 0.004). The number of normal neurons in the anterior spinal cord in the HBO-2 group was more than that of the control group (P = 0.021). In experiment 2, the neurologic and histopathologic outcomes in the HBO group were better than that of the control group (P < 0.01). The histopathologic outcome in the HO group was better than that in the control group (P < 0.05). Conclusions Serial exposure to high oxygen tension induced ischemic tolerance in spinal cord of rabbits. Simple hyperbaricity (2.5 ATA, 21% O2) did not induce ischemic tolerance.