Remimazolam anaphylaxis in a patient not allergic to brotizolam: a case report and literature review.

BACKGROUND: Remimazolam is a recently developed, ultrashort-acting benzodiazepine that is used as a general anesthetic. Some cases of remimazolam anaphylaxis have been reported, but its characteristics are not fully understood. We present an interesting case report and review of the literature to better understand remimazolam anaphylaxis. CASE PRESENTATION: A 75-year-old man scheduled for robot-assisted gastrectomy was administered remimazolam for the induction of general anesthesia. After intubation, low end-expiratory CO2, high airway pressure and concurrent circulatory collapse were observed. Bronchoscopy revealed marked tracheal and bronchial edema, which we diagnosed as anaphylaxis. The patient suffered cardiac arrest after bronchoscopy but recovered immediately with intravenous adrenaline administration and chest compressions. We performed skin prick tests for the drugs used during induction except for remimazolam, considering the high risk of systemic adverse reactions to remimazolam. We diagnosed remimazolam anaphylaxis because the skin prick test results for the other drugs used during anesthesia were negative, and these drugs could have been used without allergic reactions during the subsequent surgery. Furthermore, this patient had experienced severe anaphylactic-like reactions when he underwent cardiac surgery a year earlier, in which midazolam had been used, but it was not thought to be the allergen at that time. Based on these findings, cross-reactivity to remimazolam and midazolam was suspected. However, the patient had previously received another benzodiazepine, brotizolam, to which he was not allergic, suggesting that cross-reactivity of remimazolam may vary among benzodiazepines. In this article, we reviewed the 11 cases of remimazolam anaphylaxis that have been described in the literature. CONCLUSIONS: Remimazolam is an ultrashort-acting sedative; however, it can cause life-threatening anaphylaxis. In addition, its cross-reactivity with other benzodiazepines is not fully understood. To increase the safety of this drug, further research and more experience in its use are needed.

Incidence and factors associated with newly implemented do-not-attempt-resuscitation orders among deteriorating patients after rapid response system activation: A retrospective observational study using a Japanese multicenter database.

Aim: The rapid response system (RRS) was initially aimed to improve patient outcomes. Recently, some studies have implicated that RRS might facilitate do-not-attempt-resuscitation (DNAR) orders among patients, their families, and healthcare providers. This study aimed to examine the incidence and factors independently associated with DNAR orders newly implemented after RRS activation among deteriorating patients. Methods: This observational study assessed patients who required RRS activation between 2012 and 2021 in Japan. We investigated patients' characteristics and the incidence of new DNAR orders after RRS activation. Furthermore, we used multivariable hierarchical logistic regression models to explore independent predictors of new DNAR orders. Results: We identified 7904 patients (median age, 72 years; 59% male) who required RRS activation at 29 facilities. Of the 7066 patients without pre-existing DNAR orders before RRS activation, 394 (5.6%) had new DNAR orders. Multivariable hierarchical logistic regression analyses revealed that new DNAR orders were associated with age category (adjusted odds ratio [aOR], 1.56; 95% confidence interval, 1.12-2.17 [65-74 years old reference to 20-64 years old], aOR, 2.56; 1.92-3.42 [75-89 years old], and aOR, 6.58; 4.17-10.4 [90 years old]), malignancy (aOR, 1.82; 1.42-2.32), postoperative status (aOR, 0.45; 0.30-0.71), and National Early Warning Score 2 (aOR, 1.07; 1.02-1.12 [per 1 score]). Conclusion: The incidence of new DNAR orders was one in 18 patients after RRS activation. The factors associated with new DNAR orders were age, malignancy, postoperative status, and National Early Warning Score 2.

Malposition of a pulmonary artery catheter in the left ventricle: a case report.

BACKGROUND: Placement of pulmonary artery catheters may be associated with a variety of complications. We present a case where a pulmonary artery catheter was accidentally advanced into the left ventricle by perforating the intraventricular septum. CASE PRESENTATION: A 73-year-old woman underwent mitral valve dysfunction. A pulmonary artery catheter could not pass the tricuspid valve under general anesthesia, which was manually advanced via the right ventricle during surgery. After valve replacement, systolic pulmonary artery pressure was higher than radial arterial blood pressure. Transesophageal echocardiography (TEE) revealed the tip of the catheter in the left ventricle. The catheter was withdrawn and then advanced to the pulmonary artery under monitoring of TEE. Transseptal shunt flow gradually decreased and finally disappeared. The surgery was completed without additional procedures. CONCLUSIONS: Although ventricular septal perforation is rare, it should be recognized as a potential complication of pulmonary artery catheter insertion.

3M microfoam™ surgical tape prevents nasal pressure injury associated with nasotracheal intubation: A randomized double-blind trial.

BACKGROUND: 3M microfoam™ surgical tape (3ST: 3M Japan Limited) is used for pressure wound control of medical equipment. It is cushioned and can be fitted to any body part. Here we investigated whether 3ST prevents nasal pressure injury associated with nasotracheal intubation (NTI). METHODS: We conducted a prospective, randomized double-blind study, enrolling 63 patients aged 20 to 70 years, who underwent general anesthesia with NTI. They were divided into 2 groups; those treated with 3ST (group S; n = 31) and control (group C; n = 31). After NTI and before securing the nasotracheal tube, a 35 × 25 mm 3ST was used to protect the nasal wing in group S, and the nasotracheal tube was fixed in place after NTI without protection in group C. The primary outcome was the presence or absence of nasal pressure injury after extubation. The Chi-Square test was used to assess the association between the 2 categorical variables. RESULTS: Nasal pressure injury was observed in 7 and 19 patients from groups S and C, respectively, representing a significant difference between the 2 groups (24.1% vs 67.8%, P = .001). Remarkably, none of the patients developed ulcers. CONCLUSION: 3ST prevents nasal pressure injury associated with NTI.

Remimazolam for induction of anesthesia in elderly patients with severe aortic stenosis: a prospective, observational pilot study.

BACKGROUND: Remimazolam, a novel benzodiazepine, has been reported to cause less hypotension than propofol during induction of anesthesia. Therefore, remimazolam might be a valuable option in elderly patients with severe aortic stenosis who are considered to be the most vulnerable to hemodynamic instability. We aimed to evaluate the feasibility and hemodynamic effects of remimazolam as an induction agent in elderly patients with severe aortic stenosis. METHODS: This prospective, open-label, single-arm, observational pilot study was conducted in a university hospital between November 2020 and April 2021. We included 20 patients aged 65 years or older scheduled for transcatheter or surgical aortic valve replacement for severe aortic stenosis under general anesthesia. Patients were administered intravenous remimazolam infusion at 6 mg/kg/h combined with 0.25 µg/kg/min of remifentanil infusion. The primary outcome was the vasopressor dosage between the induction of anesthesia and the completion of tracheal intubation. The secondary outcomes included hemodynamic changes, bispectral index changes, and the time from the start of remimazolam infusion to loss of consciousness. We also recorded awareness during anesthesia induction and serious adverse events related to death, life-threatening events, prolonged hospitalizations, and disability due to permanent damage. RESULTS: Twenty patients aged 84 [79-86] (median [interquartile range]) with American Society of Anesthesiologists physical status 4 were analyzed. Ephedrine 0 [0-4] mg and phenylephrine 0.1 [0-0.1] mg were administered to 14/20 patients (3 doses in 1 patient, 2 doses in 4 patients, and one dose in 9 patients). Loss of consciousness was achieved at 80 [69-86] s after the remimazolam infusion was started. The mean arterial pressure decreased gradually after loss of consciousness but recovered immediately after tracheal intubation. The bispectral index values gradually decreased and reached < 60 at 120 s after loss of consciousness. Neither awareness during induction of anesthesia nor serious adverse events, such as severe bradycardia (< 40 bpm), life-threatening arrhythmia, myocardial ischemia, or anaphylactic reactions were observed. CONCLUSIONS: Remimazolam could be used as an induction agent with timely bolus vasopressors in elderly patients with severe aortic stenosis. TRIAL REGISTRATION: UMIN Clinical Trials Registry, identifier UMIN000042318 .

Comparison of hemostatic effect and safety between epinephrine and tramazoline during nasotracheal intubation: a double-blind randomized trial.

BACKGROUND: Nasal bleeding is the most common complication during nasotracheal intubation (NTI). To reduce nasal bleeding, the nasal mucosa is treated with vasoconstrictors (epinephrine [E] or tramazoline [T]) prior to NTI. This study aimed to determine whether E or T is more effective and safe for reducing nasal bleeding during NTI. METHODS: This study was preregistered on UMIN-CTR after being approved by the IRB of the School of Dentistry at Aichi Gakuin University. Written consent was received from all the patients. Total 206 patients aged 20-70 years and classified as 1-2 on American Society of Anesthesiologists-physical status were scheduled to undergo general anesthesia with NTI. At last, 197 patients were randomly divided into two groups and treated with either E (n = 99; 3 patients were discontinued) or T (n = 98; 2 patient were discontinued). After induction of general anesthesia, each patient's nasal mucosa was treated using either E or T. The E used in this study was BOSMIN® SOLUTION 0.1% (Daiichi-Sankyo Co., Ltd., Tokyo), and the T used in this study was TRAMAZOLIN Nasal Solution 0.118% AFP, (Alfresa Pharma Corporation, Osaka). E was diluted five times according to the package insert (final concentration of E = 0.02%), and T was used in its original solution. After 2 min, NTI was performed via the right nostril. Primary outcome were the presence of nasal bleeding (if bleeding was recognized at the posterior pharyngeal wall via nasal cavity during intubation, it was defined as bleeding) and the degree of bleeding (classified as none, mild, moderate, or severe). Secondary outcomes were arrhythmia, and hemodynamic (mean atrial pressure and heart rate) changes associated with vasoconstrictors. RESULTS: The presence of bleeding was comparable in both groups (12.5%, E; 14.5%, T; P = 0.63). No significant difference between the groups regarding the degree of bleeding (P = 0.78) was observed, with most patients having no bleeding (n = 84, E; n = 82, T). No severe bleeding and no arrhythmias induced by vasoconstrictor were observed in the two groups. CONCLUSIONS: Nasal treatment with E or T shows no difference in nasal bleeding during NTI. Although no arrhythmia associated with E was observed in this study, it has been reported in literature. Therefore, as frequency and degree of nasal bleeding were comparable, nasal treatment with T could reduce the risk of NTI. TRIAL REGISTRATION: UMIN-CTR (Registration No. UMIN000037907 ). Registered (05/09/2019).

Anesthetic management of a patient with Freeman-Sheldon syndrome undergoing oral surgery: A case report.

In the anesthetic management in this case was how to manage the patient without causing respiratory depression and respiratory muscle fatigue.

Anesthetic considerations for cesarean delivery in a parturient with hereditary hemorrhagic telangiectasia: a case report.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant disorder characterized by mucocutaneous telangiectasia and arteriovenous malformations (AVMs). There are some anesthetic considerations for cesarean delivery in a parturient with HHT. CASE PRESENTATION: A 27-year-old parturient with pulmonary hemorrhage was admitted to our tertiary perinatal center. She was first diagnosed with HHT and a cesarean delivery using spinal anesthesia at 37 weeks of gestation was initially planned. However, magnetic resonance imaging (MRI) at 32 weeks of gestation revealed spinal AVM ranging from the thoracic to the lumbar levels. Thus, elective cesarean delivery under general anesthesia was planned. The parturient had an uneventful perioperative course. CONCLUSIONS: HHT should be considered as a differential diagnosis when parturients develop pulmonary hemorrhage. In a cesarean delivery of parturients with HHT, spinal MRI during pregnancy can help in deciding the anesthetic procedure to be used.

Perioperative management of thyroglossal duct cystectomy in a pediatric patient: A case report.

Thyroglossal duct on the dorsum of the tongue in the pediatric patient can cause a difficult airway due to the large mass and risk of airway obstruction associated with a swollen tongue after surgery.

Effects of the anesthesiologist's experience on postoperative hoarseness after double-lumen endotracheal tube intubation: a single-center propensity score-matched analysis.

BACKGROUND: Postoperative hoarseness after general anesthesia is associated with patient discomfort and dissatisfaction. A recent large retrospective study showed that single-lumen endotracheal tube intubation by a trainee did not alter the incidence of postoperative pharyngeal symptoms compared with intubation by a senior anesthesiologist. However, there is limited information about the relationship between the anesthesiologist's experience and hoarseness after double-lumen endotracheal tube intubation. We tested the hypothesis that double-lumen endotracheal tube intubation performed by a trainee increases the incidence of postoperative hoarseness compared to intubation by a senior anesthesiologist. METHODS: This retrospective observational study included patients who underwent lung resection between April 2015 and March 2018 at a university hospital. Double-lumen endotracheal tube intubation was carried out with a Macintosh laryngoscope. We divided the patients into 2 groups - one group comprised of patients who were intubated by a trainee anesthesiologist with < 2 years of experience, and the other group comprised of those who underwent intubation by a senior anesthesiologist with ≥2 years of experience. The primary outcome was the incidence of postoperative hoarseness 24 h after surgery and we collected data on postoperative hoarseness using a checklist of postanesthetic adverse events. One-to-one propensity score matching was conducted and P values < 0.05 were considered statistically significant. RESULTS: There was a total of 256 eligible patients, of which 153 underwent intubation by trainee anesthesiologists, and the remaining 103 patients were intubated by a senior anesthesiologist. The one-to-one propensity score matching resulted in 96 pairs of patients for the groups. The incidence of postoperative hoarseness 24 h after surgery was significantly higher in patients who were intubated by a trainee anesthesiologist than in patients who were intubated by a senior anesthesiologist (9.4% vs. 2.1%, respectively; P = 0.03). CONCLUSIONS: Double-lumen endotracheal tube intubation by trainee anesthesiologists with < 2 years of experience increased the incidence of postoperative hoarseness 24 h after surgery compared to intubation by senior anesthesiologists with ≥2 years of experience.

Comparison of disinfection effect between benzalkonium chloride and povidone iodine in nasotracheal intubation: a randomized trial.

BACKGROUND: Nasotracheal intubation can potentially result in microbial contamination from the upper respiratory tract to the lower respiratory tracts. However, an ideal nasotracheal disinfection method is yet to be determined. Therefore, we compared the disinfection effects between benzalkonium chloride and povidone iodine in nasotracheal intubation. METHODS: Overall, this study enrolled 53 patients aged 20-70 years who were classified into classes 1 and 2 as per American Society of Anesthesiologists-physical status and were scheduled to undergo general anesthesia with NTI. Patients who did not give consent (n = 2) and who has an allergy for BZK or PVI were excluded from the study. The patients were randomly divided into two groups on the basis of the disinfection method: BZK (n = 26, one patient was discontinued intervention) and PVI (n = 25). 50 patients were assessed finally. The subjects' nasal cavities were swabbed both before (A) and after disinfection (B), and the internal surface of the endotracheal tube was swabbed after extubation (C). The swabs were cultured on Brain heart infusion agar and Mannitol salt agar. The number of bacteria per swab was determined and the rates of change in bacterial count (B/A, C/B) were calculated. The growth inhibitory activity of the disinfectants on Staphylococcus aureus were also investigated in vitro. RESULTS: Although the initial disinfection effects (B/A) were inferior for benzalkonium chloride compared with those for povidone iodine, the effects were sustained for benzalkonium chloride (C/B). In the in vitro growth inhibitory assay against S. aureus, benzalkonium chloride showed higher inhibitory activity than povidone iodine. CONCLUSION: Although both disinfectants were inactivated or diffused/diluted over time, benzalkonium chloride maintained the threshold concentration and displayed antimicrobial effects longer than povidone iodine; therefore, benzalkonium chloride appeared to show a better sustained effect. Benzalkonium chloride can be used for creating a hygienic nasotracheal intubation environment with sustained sterilizing effects. TRIAL REGISTRATION: UMIN-CTR (Registration No. UMIN000029645 ). Registered 21 Oct 2017.

Necrotizing fasciitis following primary peritonitis caused by Streptococcus pyogenes with covS mutation in a healthy woman: a case report.

BACKGROUND: Primary peritonitis due to Streptococcus pyogenes (S. pyogenes) is uncommon in patients without comorbid conditions such as immunosuppression, nephritic disease, or liver cirrhosis. Furthermore, it does not cause another infection at the same time in a healthy person. However, several S. pyogenes mutants have been reported, and some of them exhibit strong virulence. Mutation of the control of virulence (cov) S gene of Streptococcus enhances bacterium survival by repressing negative regulators of virulence, which causes bacterial invasion of aseptic tissues, such as the parenteral space. We report a case of primary peritonitis and subsequent necrotizing fasciitis by the same S. pyogenes species with mutated covS in a previously healthy woman. CASE PRESENTATION: We present the case of a 55-year-old woman admitted to the hospital due to abdominal pain and nausea. She was treated for peritonitis. A few days later, she became hypotensive and tachycardic and was transferred to the intensive care unit (ICU) for the treatment of septic shock with primary peritonitis. On the second day of her ICU stay, both of her forearms developed swelling and redness around the peripheral injection site. The patient had developed necrotizing fasciitis. Since her skin symptoms spread rapidly, urgent debridement was performed. Her condition improved with antibiotic treatment and multiple episodes of debridement. S. pyogenes was detected in cultures of the patient's blood, ascites, and skin. The identified strain was emm89 genotype and had a genetic mutation of covS. CONCLUSIONS: S. pyogenes with covS mutation may spread from a portal, such as the upper respiratory tract or digestive system, to all organs immediately, causing septic shock. Infection with S. pyogenes with mutated genes should be considered in the differential diagnosis of gastrointestinal symptoms, even in a previously healthy patient.

General anesthetic management of a patient with multiple chemical sensitivity for oral surgery: a case report.

BACKGROUND: Multiple chemical sensitivity (MCS) was first described in 1987. It is said that MCS is caused by neurological and immunological mechanisms in addition to psychosomatic mechanisms. When performing general anesthesia in patients with MCS, careful perioperative management is necessary. CASE PRESENTATION: The patient was a 32-year-old man. Wisdom teeth extraction under general anesthesia was scheduled under the diagnosis of pericoronitis. In 2015, he was diagnosed with MCS. Since then, he experienced sweating and urticaria when exposed to artificial fragrances. We prepared the surgical surroundings by letting the patient touch every possible equipment. In selecting the anesthetic drugs, a completely intravenous route was selected because of the possibility that artificial fragrance of inhalation anesthesia could induce symptoms. There was no allergic reaction during the preoperative period. CONCLUSIONS: It is important to reduce psychological burden of patient and to eliminate all possible reactive substances to prevent symptom onset.

Peripheral Nerve Block Provides Effective Analgesia for a Patient With Peripheral Nerve Hyperexcitability Syndrome: Isaacs Syndrome Case Report.

Isaacs syndrome is a rare peripheral nerve hyperexcitability syndrome. The painful discharges in Isaacs syndrome are abolished by the blockade of the neuromuscular junction but not by peripheral nerve blocks (PNB). However, the efficacy of PNB for intraoperative and postoperative analgesia among those with Isaacs syndrome is unknown. A 41-year-old woman with Isaacs syndrome underwent open reduction and internal fixation of radius fractures. Ultrasound-guided bilateral axillary brachial plexus blocks were performed, followed by general anesthesia. The patient required only a single low dose of rocuronium for intubation and surgery. On emergence from anesthesia, the patient was pain free for 6 hours and did not return to her preoperative pain state for 36 hours. PNB can be an effective means of postoperative pain control for patients with Isaacs syndrome.

General Anesthetic Management of a Child With Horseshoe Lung and Left Lung Hypoplasia for Cheiloplasty: A Case Report.

Horseshoe lung is an extremely rare congenital malformation in which the right and left lungs are fused due to stenosis of the lung parenchyma. In anesthetic management, it is important to avoid hypoxemia and hypercapnia caused by a decline in lung capacity and functional residual capacity. A 3-year-old boy with horseshoe lung and left lung hypoplasia was scheduled to undergo cheiloplasty. Regarding respiratory management, to prevent hypoxemia and hypercapnia, we avoided intraoperative peripheral airway obstruction with positive end-expiratory pressure, set a long inspiratory phase time for sufficient alveolar expansion, and maintained sufficient gas exchange in lungs with low reserve capacity.

The usefulness of the McGrath MAC laryngoscope in comparison with Airwayscope and Macintosh laryngoscope during routine nasotracheal intubation: a randomaized controlled trial.

BACKGROUND: McGrath MAC video laryngoscope offers excellent laryngosopic views and increases the success rate of orotracheal intubation in some cases. The aim of this study was to determine the usefulness of McGrath MAC for routine nasotracheal intubation by comparing McGrath MAC with Airway scope and Macintosh laryngoscope. METHODS: A total of 60 adult patients with ASA physical status class 1 or 2, aged 20-70 years were enrolled in this study. Patients were scheduled for elective oral surgery under general anesthesia with nasotracheal intubation. Exclusion criteria included lack of consent and expected difficult airway. Patients were randomly allocated to three groups: McGrath MAC (n = 20), Airway scope (n = 20), and Macintosh laryngoscope (n = 20). After induction, nasotracheal intubation was performed by six expert anesthesiologists with more than 6 years of experience. RESULTS: There were no significant differences in preoperative airway assessment among the three groups. Successful tracheal intubation time was 26.8 ± 5.7 (mean ± standard deviation) s for McGrath MAC, 36.4 ± 11.0 s for Airway scope, and 36.5 ± 8.9 s for Macintosh laryngoscope groups. The time for successful tracheal intubation for McGrath MAC group was significantly shorter than that for Airway scope and Macintosh laryngoscope (p < 0.01). McGrath MAC significantly improved the Cormack Lehane grade for nasotracheal intubation compared with Macintosh laryngoscope (p < 0.05). CONCLUSION: McGrath MAC significantly facilitates routine nasotracheal intubation compared with Airwayscope and Macintosh laryngoscope by shortening the tracheal intubation time and improving the Cormack Lehane grade. TRIAL REGISTRATION: UMINCTR Registration number UMIN000023506 . Registered 5 Aug 2016.

Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives.

In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells throughout life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain areas in response to several types of insult, including ischemia and demyelinating diseases. However, this spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. Erythropoietin (EPO), a clinically applied erythropoietic factor, is reported to have cytoprotective effects in various kinds of insult in the central nervous system. Moreover, recent studies suggest that EPO promotes the V-SVZ-derived neurogenesis and oligodendrogenesis. EPO increases the proliferation of progenitors in the V-SVZ and/or the migration and differentiation of their progenies in and around injured areas, depending on the dosage, timing, and duration of treatment, as well as the type of animal model used. On the other hand, EPO has undesirable side effects, including thrombotic complications. We recently demonstrated that a 2-week treatment with the EPO derivative asialo-EPO promotes the differentiation of V-SVZ-derived OPCs into myelin-forming mature oligodendrocytes in the injured white matter of neonatal mice without causing erythropoiesis. Here we present an overview of the multifaceted effects of EPO and its derivatives in the V-SVZ and discuss the possible applications of these molecules in regenerative medicine.

Age-related requisite concentration of sevoflurane for adequate sedation with combined epidural-general anesthesia.

BACKGROUND: The requisite anesthetic concentration of sevoflurane required to obtain adequate sedation when sufficient analgesics are supplied has not been determined. The purpose of this study was to determine the requisite age-associated concentration of sevoflurane to obtain an adequate level of anesthesia during combined epidural-general anesthesia by bispectral index (BIS) monitoring. METHODS: Twenty-seven elective abdominal surgery patients (American Society of Anesthesiologists physical status I-II) were enrolled. The patients were divided into two groups of more or less than 60 years of age. We investigated the concentration of sevoflurane required to obtain an adequate sedation level during combined epidural-general anesthesia, maintaining the BIS value between 40 and 60. RESULTS: The requisite sevoflurane concentration required to keep the BIS value at 40-60 was not stable during surgery. In the younger group, the maximum concentration of sevoflurane needed during surgery was 1.95 ± 0.14 (95% confidence interval: 1.87-2.10) vol%, while it was 1.54 ± 0.44 (95% confidence interval: 1.27-1.80) vol% in the older group (P < 0.01). CONCLUSIONS: The requisite concentration of sevoflurane required with combined epidural-general anesthesia was 2.5 vol% for the younger group and 2.0 vol% for the older group as determined by BIS monitoring. We believe that these percentages are sufficient to avoid awareness during surgery with adequate analgesia.

Human dental pulp-derived stem cells protect against hypoxic-ischemic brain injury in neonatal mice.

BACKGROUND AND PURPOSE: Perinatal hypoxia-ischemia (HI) has high rates of neurological deficits and mortality. So far, no effective treatment for HI brain injury has been developed. In this study, we investigated the therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) for the treatment of neonatal HI brain injury. METHODS: Unilateral HI was induced in postnatal day 5 (P5) mice. Twenty-four hours later, SHED, human skin fibroblasts, or serum-free conditioned medium derived from these cells was injected into the injured brain. The effects of cell transplantation or conditioned medium injection on the animals' neurological and pathophysiological recovery were evaluated. RESULTS: Transplanted SHED, but not fibroblasts, significantly reduced the HI-induced brain-tissue loss and improved neurological function. SHED also improved the survival of the HI mice. The engrafted SHED rarely differentiated into neural lineages; however, their transplantation inhibited the expression of proinflammatory cytokines, increased the expression of anti-inflammatory ones, and significantly reduced apoptosis. Notably, the intracerebral administration of SHED-conditioned medium also significantly improved the neurological outcome, inhibited apoptosis, and reduced tissue loss. CONCLUSIONS: SHED transplantation into the HI-injured brain resulted in remarkable neurological and pathophysiological recovery. Our findings indicate that paracrine factors derived from SHED support a neuroprotective microenvironment in the HI brain. SHED graft and SHED-conditioned medium may provide a novel neuroprotective therapy for HI.

Subventricular zone-derived oligodendrogenesis in injured neonatal white matter in mice enhanced by a nonerythropoietic erythropoietin derivative.

Perinatal hypoxia-ischemia (HI) frequently causes white-matter injury, leading to severe neurological deficits and mortality, and only limited therapeutic options exist. The white matter of animal models and human patients with HI-induced brain injury contains increased numbers of oligodendrocyte progenitor cells (OPCs). However, the origin and fates of these OPCs and their potential to repair injured white matter remain unclear. Here, using cell-type- and region-specific genetic labeling methods in a mouse HI model, we characterized the Olig2-expressing OPCs. We found that after HI, Olig2+ cells increased in the posterior part of the subventricular zone (pSVZ) and migrated into the injured white matter. However, their oligodendrocytic differentiation efficiency was severely compromised compared with the OPCs in normal tissue, indicating the need for an intervention to promote their differentiation. Erythropoietin (EPO) treatment is a promising candidate, but it has detrimental effects that preclude its clinical use for brain injury. We found that long-term postinjury treatment with a nonerythropoietic derivative of EPO, asialo-erythropoietin, promoted the maturation of pSVZ-derived OPCs and the recovery of neurological function, without affecting hematopoiesis. These results demonstrate the limitation and potential of endogenous OPCs in the pSVZ as a therapeutic target for treating neonatal white-matter injury.