Blood-Brain Barrier Disruption in Preclinical Mouse Models of Stroke Can Be an Experimental Artifact Caused by Craniectomy.

The pathophysiological features of ischemia-related blood-brain barrier (BBB) disruption are widely studied using preclinical stroke models. However, in many of these models, craniectomy is required to confirm arterial occlusion via laser Doppler flowmetry or to enable direct ligation of the cerebral artery. In the present study, mice were used to construct a distal middle cerebral artery occlusion (dMCAO) model, a preclinical stroke model that requires craniectomy to enable direct ligation of the cerebral artery, or were subjected to craniectomy alone. dMCAO but not craniectomy caused neurodegeneration and cerebral infarction, but both procedures induced an appreciable increase in BBB permeability to Evans blue dye, fluorescein, and endogenous albumin but not to 10 kDa dextran-FITC, leading to cerebral edema. Using rats, we further showed that BBB disruption induced by craniectomy with no evidence of dural tearing was comparable to that induced by craniectomy involving tearing of the dura. In conclusion, our data demonstrated that craniectomy can be a major contributor to BBB disruption and cerebral edema in preclinical stroke models. The implications of this experimental artifact for translational stroke research and preclinical data interpretation are discussed.

Perioperative hemodynamic optimization in laparoscopic sleeve gastrectomy using stroke volume variation to reduce postoperative nausea and vomiting.

BACKGROUND: Risk of postoperative nausea and vomiting (PONV) is usually high among patients undergoing laparoscopic sleeve gastrectomy (LSG). Perioperative hemodynamic optimization using goal-directed fluid therapy (GDFT) based on stroke volume variation (SVV) has been suggested to reduce PONV. OBJECTIVES: This study aimed to investigate the effectiveness of GDFT on reducing PONV. SETTING: The operating rooms in China Medical University Hospital. METHODS: This prospective cohort study included 75 patients undergoing LSG. Patients were randomized into 3 groups: controls (conventional fluid therapy), GDFT-hydroxyethyl starch (GH), and GDFT-lactated Ringer's (GL) groups. In both GDFT groups, optimization of fluid administration was achieved by continuous monitoring and adjusting of SVV. Severity of PONV was evaluated using a standardized questionnaire. Other clinically relevant events, including in-hospital surgical site infections and length of hospital stay were also investigated. RESULTS: In the GH group, the total volume of fluid administered intraoperatively was significantly lower than that in the GL and control groups (P < .001). Assessment of PONV severity showed a significantly higher score at postoperative 24 hours in the GH group (P < .05), while no significant differences were found between the 3 groups at postoperative 48 hours. No significant differences were observed between the 3 groups in surgical site infections and length of hospital stay. CONCLUSION: No significant benefit is found in reducing PONV by using GDFT in patients undergoing LSG, although GDFT effectively avoids excessive volume of fluid administration. PONV incidence appears to be higher with intraoperative colloid infusion for GDFT during LSG. Further investigation is warranted to elucidate the mechanism underlying PONV in postoperative LSG.

Stroke injury induced by distal middle cerebral artery occlusion is resistant to N-methyl-d-aspartate receptor antagonism in FVB/NJ mice.

Although N-methyl-d-aspartate receptor (NMDAR) antagonism has been shown to have a neuroprotective effect in many preclinical stroke models, the efficacy of this antiexcitotoxicity strategy in clinical trials in stroke patients has been disappointing. Interestingly, it has been reported that NMDAR antagonism is not neuroprotective in C57BL/6 mice subjected to distal middle cerebral artery occlusion (dMCAO), supporting the notion that whether these treatments are neuroprotective depends on the type of cerebral ischemia. However, because C57BL/6 mice are inherently resistant to excitotoxicity, the reported lack of neuroprotection could also be explained by the difference in the mouse strain studied rather than the stroke model used. Here we examined the neuroprotective efficacy of NMDAR antagonism in FVB/NJ mice, an excitotoxicity-prone mouse strain, subjected to dMCAO. Although C57BL/6 mice are known to have an excitotoxicity-resistant genetic background and FVB/NJ mice are known to have an excitotoxicity-prone genetic background, the infarct volume and density of neurodegenerating neurons were similar in the two mouse strains following dMCAO. In addition, none of the antiexcitotoxicity agents studied, including the canonical NMDAR antagonist MK801 and the therapeutic peptides Tat-NR2B9c and L-JNKI-1, protected the FVB/NJ mouse brain against ischemic damage induced by dMCAO. In conclusion, our data demonstrated that FVB/NJ mice are no more susceptible to cerebral ischemia than C57BL/6 mice and that NMDAR antagonism is ineffective in mice, even in an excitotoxicity-prone strain, subjected to dMCAO.

Hypothermia but not NMDA receptor antagonism protects against stroke induced by distal middle cerebral arterial occlusion in mice.

Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3-72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24-48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials.

Isoflurane attenuates carbogen-induced blood-brain barrier disruption independent of body temperature in mice and rats.

Isoflurane protects the blood-brain barrier (BBB) against cerebral extravasation of Evans blue dye (EBD), a commonly used serum protein tracer, in animals subjected to BBB disruption. As such, it has been implicated as a therapeutic agent that can prevent brain edema and damage caused by a number of brain insults, including focal ischemia and subarachnoid hemorrhage. Recently, it has been shown that isoflurane inhibits the cerebral extravasation of EBD following ischemic stroke chiefly by inducing hypothermia, raising the intriguing possibility that isoflurane protected against other causes of BBB disruption also through hypothermia. To test this hypothesis, we subjected mice and rats to inhalation of 20-30% carbogen, an inducer of BBB disruption, in the presence or absence of isoflurane while measuring their rectal temperature. In mice, carbogen inhalation on its own decreased rectal temperature from 36.4 ± 0.4 to 26.2 ± 0.6°C over a period of 60 minutes, and under this condition, isoflurane had no additional effect on body temperature. Nevertheless, isoflurane protected against carbogen-induced cerebral extravasation of EBD. In addition, when the body temperature was maintained in the normothermic range using an automated heating pad, isoflurane remained protective against cerebral extravasation of EBD. In rats, isoflurane also protected against cerebral extravasation of EBD, while having no effect on plasma pH, electrolyte concentrations, or osmolarity. In conclusion, isoflurane protected against BBB disruption caused by carbogen inhalation in mice and rats, but unlike isoflurane-mediated protection against ischemic BBB disruption, the effect could not be explained by anesthesia-induced hypothermia.

Carbogen inhalation opens the blood-brain barrier in rats without causing long-term metabolic or neurological deficit.

The blood-brain barrier (BBB) prevents many drugs from entering the brain. Yet, conventional methods that open the BBB are technically demanding, poorly reversible, and can be associated with long-term adverse effects. In comparison, carbogen, which is introduced nearly a century ago as a treatment for psychiatric disorders, is easy to administer and readily available to many labs and hospitals. Here, we show that carbogen inhalation opened the BBB in rats, as indicated by the extravasation of an intravenous protein tracer. When the tracer was injected immediately or hours after carbogen inhalation, less tracer was detected in the rat brains, suggesting at least partial reversibility of this response after carbogen exhalation. Despite marked increase in BBB permeability, inhalation of carbogen for 30-90 min had no acute effect on the level of neuroinflammation or apoptosis in the brain, and had no long-term effect on body weight, food intake, locomotor activity, or learning and memory performance. Our study demonstrated that carbogen inhalation is a safe method to open the BBB.

Rescue patient from tracheal obstruction by dislocated bronchial stent during tracheostomy surgery with readily available tools: A case report.

RATIONALE: Airway stenting is a well-established method that relieves symptoms and maintains airway patency in patients with airway obstruction. Serious complications caused by airway stents such as stent dislocation and airway obstruction during surgery are life-threatening. PATIENT CONCERNS: An 80-year-old man was treated with bronchial stent for left bronchus obstruction caused by metastatic esophageal cancer. During tracheostomy surgery, he suffered from acute tracheal obstruction caused by dislocated bronchial stent. DIAGNOSES: Esophageal cancer, left bronchus obstruction, respiratory failure, tracheal obstruction. INTERVENTIONS: Threading a 5.0-sized endotracheal tube combined with an Eschmann tracheal tube introducer to prop up the collapsed stent. OUTCOMES: The bronchial stent was re-expanded and threaded into right main bronchus and ventilation restored. LESSONS: Patient with airway stent undergoing surgery with airway involved should be performed under the support of a backup physician and equipment that are capable of handling potentially life-threatening complications of airway stent. If not, in the emergent situation of tracheal obstruction due to tracheal/bronchial stent, protruding through the stent with a suitable, small-sized endotracheal tube with Eschmann tracheal tube introducer may be an alternative skill for saving life weighted with possible complications.

Tension pneumothorax during peroral endoscopic myotomy for treatment of esophageal achalasia under general anesthesia / Pneumotórax de tensão durante miotomia endoscópica por via oral para tratamento de megaesôfago sob anestesia geral

Abstract More and more endoscopically gastrointestinal procedures require anesthesiologists to perform general anesthesia, such as "peroral endoscopic myotomy". Peroral endoscopic myotomy is a novel invasive treatment for the primary motility disorder of esophagus, called esophageal achalasia. Despite of its minimally invasive feature, there are still complications during the procedure which develop to critical conditions and threat patients' lives. Herein we describe a case about tension pneumothorax subsequent to esophageal rupture during peroral endoscopic myotomy. The emergent management of the complication is stated in detail. The pivotal points of general anesthesia for patients undergoing peroral endoscopic myotomy are emphasized and discussed. Also, intraoperative and post-operative complications mentioned by literature are integrated.

Resumo Cada vez mais os procedimentos gastrointestinais feitos por endoscopia, tais como a miotomia endoscópica por via oral (MEVO), exigem anestesiologistas para administrar anestesia geral. A MEVO é um novo tratamento invasivo para o distúrbio de motilidade primária do esôfago, denominado acalasia esofágica (AE). Apesar de sua característica minimamente invasiva, existem complicações durante o procedimento que evoluem para condições críticas e de risco à vida. Descrevemos aqui um caso de pneumotórax hipertensivo após a ruptura do esôfago durante uma MEVO. O tratamento de emergência da complicação é relatado em detalhes. Os pontos cruciais da anestesia geral para pacientes submetidos à MEVO são enfatizados e discutidos. Além disso, as complicações mencionadas pela literatura nos períodos intraoperatório e pós-operatório são integradas ao texto.

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison to the inhibitors of the neuronal death signaling cascade; these, in fact, can attenuate the infarct volume measured at 24 h post-ischemia when administered at 6 h in our same stroke model.

[Tension pneumothorax during peroral endoscopic myotomy for treatment of esophageal achalasia under general anesthesia]. / Pneumotórax de tensão durante miotomia endoscópica por via oral para tratamento de megaesôfago sob anestesia geral.

More and more endoscopically gastrointestinal procedures require anesthesiologists to perform general anesthesia, such as "peroral endoscopic myotomy". Peroral endoscopic myotomy is a novel invasive treatment for the primary motility disorder of esophagus, called esophageal achalasia. Despite of its minimally invasive feature, there are still complications during the procedure which develop to critical conditions and threat patients' lives. Herein we describe a case about tension pneumothorax subsequent to esophageal rupture during peroral endoscopic myotomy. The emergent management of the complication is stated in detail. The pivotal points of general anesthesia for patients undergoing peroral endoscopic myotomy are emphasized and discussed. Also, intraoperative and post-operative complications mentioned by literature are integrated.

Adenosine receptor agonist NECA increases cerebral extravasation of fluorescein and low molecular weight dextran independent of blood-brain barrier modulation.

Conventional methods for therapeutic blood-brain barrier (BBB) disruption facilitate drug delivery but are cumbersome to perform. A previous study demonstrated that adenosine receptor (AR) stimulation by 5'-N-ethylcarboxamide adenosine (NECA) increased the extravasation of intravascular tracers into the brain and proposed that AR agonism may be an effective method for therapeutic BBB disruption. We attempted to confirm the extravasation of tracers into the brain and also investigated tracer extravasation into peripheral organs and tracer retention in the blood. We found that NECA not only increased the extravasation of intravascular fluorescein and low molecular weight dextran into the brain of mice but also increased the concentrations of these tracers in the blood. In fact, the brain:blood ratio-normalized BBB permeability for either tracer is actually decreased by NECA administration. Elevated blood urea nitrogen levels in mice following NECA treatment suggested that renal function impairment was a probable cause of tracer retention. Therefore, NECA has almost no effect on the extravasation of intravascular Evans blue dye (EBD), an albumin-binding tracer with little renal clearance. Rather than inducing BBB disruption, our study demonstrated that NECA increased tracer extravasation into the brain by increasing the concentration gradient of the tracer across the BBB.