Suppression of ERK phosphorylation through oxidative stress is involved in the mechanism underlying sevoflurane-induced toxicity in the developing brain.

In animal models, neonatal exposure to general anesthetics significantly increased neuronal apoptosis with subsequent behavioral deficits in adulthood. Although the underlying mechanism is largely unknown, involvement of extracellular signal-regulated kinases (ERKs) is speculated since ERK phosphorylation is decreased by neonatal anesthetic exposure. Importance of ERK phosphorylation for neuronal development is underscored by our recent finding that transient suppression of ERK phosphorylation during the neonatal period significantly increased neuronal apoptosis and induced behavioral deficits. However, it is still unknown as to what extent decreased ERK phosphorylation contributes to the mechanism underlying anesthetic-induced toxicity. Here we investigated the causal relationship of decreased ERK phosphorylation and anesthetic-induced toxicity in the developing brain. At postnatal day 6 (P6), mice were exposed to sevoflurane (2%) or the blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) (50 mg/kg). Transient suppression of ERK phosphorylation by an intraperitoneal injection of SL327 at P6 significantly increased apoptosis similar to sevoflurane-induced apoptosis. Conversely, SL327 administration at P14 or P21 did not induce apoptosis, even though ERK phosphorylation was inhibited. Restoring ERK phosphorylation by administration of molecular hydrogen ameliorated sevoflurane-induced apoptosis. Together, our results strongly suggests that suppressed ERK phosphorylation is critically involved in the mechanism underlying anesthetic-induced toxicity in the developing brain.

Anesthetic management using peripheral nerve block in patients with factor XI deficiency: a case report.

Factor XI deficiency is rare but may cause life-threatening bleeding during the perioperative period. The clinical manifestation of factor XI deficiency is characterized by bleeding tendency. This unpredictable bleeding tendency makes anesthetic management difficult. We report a case of a partial duodenectomy in a patient with factor XI deficiency. The patient was scheduled for duodenectomy because of a duodenal tumor. When checked for coagulation before surgery, the patient was found to have a remarkably prolonged activated partial thrombin time, and further investigation revealed factor XI deficiency. Fresh frozen plasma was transfused before surgery, and general anesthesia and peripheral nerve block were performed. In the present case of factor XI deficiency, supplementation with clotting factor and proper anesthetic management were important to prevent severe complications.

Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice.

The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.

Successful resuscitation of amniotic fluid embolism applying a new classification and management strategy.

Amniotic fluid embolism (AFE) is a rare but life-threatening maternal emergency caused by the entry of amniotic fluid contents into the maternal circulation. The clinical manifestations of AFE are heterogeneous, leading to misdiagnosis or treatment delay. Kanayama and colleagues distinguished the cardiopulmonary collapse type (or classic type) from the disseminated intravascular coagulation (DIC) type of AFE on the basis of the presence of uterine atony and DIC in the latter prior to cardiopulmonary failure. We report a case of DIC-type AFE successfully treated by blood volume replacement and coagulation therapy. The patient was scheduled for elective cesarean delivery because of a previous cesarean section and moyamoya disease. Delivery was uneventful, but massive vaginal bleeding without clotting and ensuing hypovolemic shock occurred 4 h later. She was transferred to the operating room for emergency laparotomy, but sustained a cardiac arrest. The patient was successfully resuscitated and a hysterectomy performed. During surgery, the patient received fresh frozen plasma, platelets, fibrinogen, and antithrombin concentrate. In cardiopulmonary collapse type AFE, cardiopulmonary resuscitation without delay is important. In the present case of DIC-type AFE, however, early supplementation of clotting factors and platelets was critical for patient survival.

Acute transverse myelitis arising after combined general and thoracic epidural anesthesia.

Acute transverse myelitis after surgery is a rare condition, but this complication is devastating. The relationship between anesthetic procedures and acute transverse myelitis is controversial. A 46-year-old woman was scheduled a colostomy closure, and general anesthesia with thoracic epidural anesthesia was performed. Epidural catheter was inserted at the T10-11 interspace, and insertion was smooth, and no blood or cerebrospinal fluid leakage was seen. However, 28 h after the surgery, the patient complained motor, sensory, and autonomic dysfunction. Two days after onset, a magnetic resonance imaging study demonstrated intramedullary hyperintensity, particularly in the gray matter, extending from T5-T9 and then diagnosed with acute transverse myelitis followed by the several examinations. High-dose IV methylprednisolone treatment was initiated and neurologic function restored 2 months after onset. Transverse myelitis may unpredictably occur following surgery. We are not able to determine the pathogenic relationship between anesthesia and myelitis with certainty, but proper diagnostic approach to myelitis may improve the prognosis.

Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood.

BACKGROUND: In animal models, exposure to general anesthetics induces widespread increases in neuronal apoptosis in the developing brain. Subsequently, abnormalities in brain functioning are found in adulthood, long after the anesthetic exposure. These abnormalities include not only reduced learning abilities but also impaired social behaviors, suggesting pervasive deficits in brain functioning. But the underlying features of these deficits are still largely unknown. METHODS: Six-day-old C57BL/6 female mice were exposed to 3% sevoflurane for 6 h with or without hydrogen (1.3%) as part of the carrier gas mixture. At 7-9 weeks of age, they were mated with healthy males. The first day after parturition, the maternal behaviors of dams were evaluated. The survival rate of newborn pups was recorded for 6 days after birth. RESULTS: Female mice that received neonatal exposure to sevoflurane could mate normally and deliver healthy pups similar to controls. But these dams often left the pups scattered in the cage and nurtured them very little, so that about half of the pups died within a couple of days. Yet, these dams did not show any deficits in olfactory or exploratory behaviors. Notably, pups born to sevoflurane-treated dams were successfully fostered when nursed by control dams. Mice coadministered of hydrogen gas with sevoflurane did not exhibit the deficits of maternal behaviors. CONCLUSION: In an animal model, sevoflurane exposure in the developing brain caused serious impairment of maternal behaviors when fostering their pups, suggesting pervasive impairment of brain functions including innate behavior essential to species survival.