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Background: Although pharmacokinetic and pharmacodynamic models of remimazolam have been developed, their clinical application remains limited. This study aimed to administer a target-controlled infusion (TCI) of remimazolam at the effect-site concentration (Ce) in patients undergoing general anesthesia and to investigate the relationship of the remimazolam Ce with sedative effects and with recovery from general anesthesia. Methods: Fifty patients aged 20-75 years, scheduled for minimally invasive surgery under general anesthesia for less than 2 h, were enrolled. Anesthesia was induced and maintained using Schüttler's model for effect-site TCI of remimazolam. During induction, the remimazolam Ce was increased stepwise, and sedation levels were assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and bispectral index (BIS). Following attainment of MOAA/S scale 1, continuous infusion of remifentanil was commenced, and rocuronium (0.6 mg/kg) was administered for endotracheal intubation. The target Ce of remimazolam and the remifentanil infusion rate were adjusted to maintain a BIS between 40 and 70 and a heart rate within 20% of the baseline value. Approximately 5 min before surgery completion, the target Ce of remimazolam was reduced by 20-30%, and anesthetic infusion ceased at the end of surgery. Nonlinear mixed-effects modeling was employed to develop pharmacodynamic models for each sedation level as well as emergence from anesthesia. Results: The remimazolam Ces associated with 50% probability (Ce50) of reaching MOAA/S scale ≤4, 3, 2, and 1 were 0.302, 0.397, 0.483, and 0.654 µg/mL, respectively. The Ce50 values for recovery of responsiveness (ROR) and endotracheal extubation were 0.368 and 0.345 µg/mL, respectively. The prediction probabilities of Ce and BIS for detecting changes in sedation level were 0.797 and 0.756, respectively. The sedation scale significantly correlated with remimazolam Ce (r = -0.793, P < 0.0001) and BIS (r = 0.914, P < 0.0001). Age significantly correlated with Ce at MOAA/S1 and ROR. Conclusion: Effect-site TCI of remimazolam was successfully performed in patients undergoing general anesthesia. The remimazolam Ce significantly correlated with sedation depth. The Ce50 for MOAA/S scale ≤1 and ROR were determined to be 0.654 and 0.368 µg/mL, respectively.

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BACKGROUND: Propofol-based total intravenous anesthesia (TIVA) improves long-term outcomes after cancer surgery compared with inhalation anesthesia. However, its effect on patients undergoing non-small cell lung cancer (NSCLC) surgery remains unclear. We aimed to compare the oncological outcomes of TIVA and inhalation anesthesia after curative resection of early-stage NSCLC. METHODS: We analyzed the medical records of patients diagnosed with stage I or II NSCLC who underwent curative resection at a tertiary university hospital between January 2010 and December 2017. The primary outcomes were recurrence-free survival (RFS) and overall survival (OS) according to anesthesia type. RESULTS: We included 1,508 patients with stage I/II NSCLC. The patients were divided into the TIVA (n = 980) and Inhalation (n = 528) groups. The two groups were well-balanced in terms of baseline clinical characteristics. The TIVA group demonstrated significantly improved RFS (7.7 years, 95% CI [7.37, 8.02]) compared with the Inhalation group (6.8 years, 95% CI [6.30, 7.22], P = 0.003). Similarly, TIVA was superior to inhalation agents with respect to OS (median OS; 8.4 years, 95% CI [8.08, 8.69] vs. 7.3 years, 95% CI [6.81, 7.71]; P < 0.001). Multivariable Cox regression analysis revealed that TIVA was an independent prognostic factor related to recurrence (hazard ratio [HR]: 1.24, 95% CI [1.04, 1.47], P = 0.014) and OS (HR: 1.39, 95% CI [1.12, 1.72], P = 0.002). CONCLUSIONS: Propofol-based TIVA was associated with better RFS and OS than inhalation anesthesia in patients with stage I/II NSCLC who underwent curative resection.

Asunto(s)

Anestésicos por Inhalación , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Propofol , Humanos , Propofol/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/etiología , Anestésicos Intravenosos/efectos adversos , Estudios Retrospectivos , Anestésicos por Inhalación/efectos adversos , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/etiología , Anestesia por Inhalación/efectos adversos

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BACKGROUND: Neuroleukemiosis is a rare complication of leukemia. The diagnosis may be delayed owing to non-specific symptoms and the need for special diagnostic modalities. CASE: A 70-year-old man in his sixth year of remission from acute myeloid leukemia was referred to the pain clinic for shooting and radiating pain in the left posterior leg. A lumbar spine magnetic resonance imaging showed mild disc bulging of the L2-3, which was insufficient to explain the patient's symptoms. With insufficient pain response to lumbar epidural block and piriformis injection, we examined both sciatic nerves using an ultrasound and identified an enlarged hypoechoic mass on the left sciatic nerve at mid-thigh level. After that, we biopsied the mass under general anesthesia, and histology confirmed it to be neuroleukemiosis. CONCLUSIONS: Ultrasound is an inexpensive, non-invasive, simple, and quick diagnostic modality that can be used as a screening tool in the diagnosis of neuroleukemiosis.

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Medios de Contraste , Tomografía Computarizada por Tomografía de Emisión de Positrones , Anciano , Gadolinio , Humanos , Imagen por Resonancia Magnética , Masculino , Ultrasonografía

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PURPOSE: Endocrinological complications of an epidural steroid injection (ESI) are rare but dangerous. Nevertheless, despite the associated risks, repeated long-term ESIs are indispensable in some clinical situations. However, only a few reports to date have assessed the safety of this procedure. In this study, we evaluate the incidence of adrenal insufficiency (AI) and Cushing's syndrome after long-term ESIs. METHODS: This clinical observational study enrolled herniated nucleus pulposus or spinal stenosis patients who had received ESIs over a period of six months or longer. The adrenocorticotropic hormone (ACTH) stimulation test was performed to confirm AI and the late-night salivary cortisol (LNSC) test was performed to diagnose Cushing's syndrome. To evaluate the hypothalamus pituitary adrenal axis suppression, salivary cortisol (SC) levels were measured on days 0, 1, 7, 21, 28, 35, and 42. RESULTS: This study included 17 patients. Among these, two patients (11.8%) developed AI, but no cases of Cushing's syndrome were reported. There was no predictor for the development of AI. The SC levels tended to increase with time after an ESI (ß = 0.003). The slope of the mixed effect model between the AI and non-AI groups showed a significant difference (p value = 0.015). However, the differences in mean SC levels at each time point between the two groups were not significant (adjusted p value = 0.053). CONCLUSION: Long-term ESI use may be associated with AI development. An unexpected adrenal crisis due to AI could be life threatening. Therefore, regular monitoring of adrenal function in patients who have received long-term ESIs may be prudent.

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RATIONALE: Hepatectomy is a treatment to increase survival and curability of patients with intrahepatic lesions or malignant tumors. However, posthepatectomy liver failure (PHLF) can occur. This case is a patient showing acute mental change in postanesthetic care unit (PACU) as an uncommon symptom of PHLF after extended right hepatectomy. PATIENT CONCERNS: A 68-year-old male patient was admitted for surgery of Klatskin tumor. He had hypertension and atrial fibrillation. His model for end-stage liver disease score was 16 pts. His serum bilirubin and ammonia levels were 4.75 mg/dL and 132.8 mcg/dL, respectively. Other laboratory data were nonspecific. He underwent extended right hepatic lobectomy including segments IV-VIII for 9 hours. Weight of liver specimen was 1028 g which was about 58% of total liver volume based on computed tomographic volumetry. The patient was extubated and moved to the PACU with stable vital sign and regular self-breathing. He could obey verbal commands. Fifteen minutes after admission to the PACU, the patient showed abruptly decreasing mental status and self-breathing. DIAGNOSES: Brain computed tomography, blood culture, and sputum culture were performed to diagnose brain lesions and sepsis for evaluating the sudden onset comatous mental status. Results showed nonspecific finding. INTERVENTIONS: He was intubated for securing airway and applying ventilatory care. The patient was moved to the intensive care unit. He received intensive conservative therapy including continuous renal replacement therapy and broad-spectrum antibiotics. OUTCOMES: The patient's condition was worsened. He expired on postoperative day 3. LESSONS: Acute mental change is uncommon and rare as initial symptoms of PHLF. Therefore, clinician may overlook the diagnosis of PHLF in patients with acute mental change after hepatectomy. Thus, clinician should plan an aggressive treatment for PHLF including liver transplantation by recognizing any suspicious symptom, although such symptom is rare.

Asunto(s)

Neoplasias de los Conductos Biliares/cirugía , Hepatectomía , Encefalopatía Hepática , Tumor de Klatskin/cirugía , Fallo Hepático , Hígado , Complicaciones Posoperatorias , Anciano , Neoplasias de los Conductos Biliares/patología , Tomografía Computarizada de Haz Cónico/métodos , Tratamiento Conservador/métodos , Resultado Fatal , Hepatectomía/efectos adversos , Hepatectomía/métodos , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/etiología , Encefalopatía Hepática/fisiopatología , Humanos , Tumor de Klatskin/patología , Hígado/diagnóstico por imagen , Hígado/patología , Hígado/cirugía , Fallo Hepático/diagnóstico , Fallo Hepático/etiología , Fallo Hepático/psicología , Pruebas de Función Hepática/métodos , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/fisiopatología , Complicaciones Posoperatorias/psicología

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Recipient's immune responses are an important factor in allograft survival in transplantation. Cytokines are reflected with immune responses. In the present study, we aimed to evaluate potential affecting factors of liver allograft survival and their possible correlation with seroum cytokine levels in living donor liver transplantation (LDLT). One hundred and seventy-one adult patients' data were collected retrospectively. Five cytokines were collected: interferon (IFN)-γ, interleukin (IL)-2, IL-10, IL-6, and IL-17. Ischemic time of liver grafts was divided into two periods: cold and warm ischemic times (CIT and WIT, respectively). CIT had no statically significant correlation, but WIT showed a significant correlation with IFN-γ, IL-2, and IL-17 serum levels (r = 0.0252, 0.282, 0.178, respectively; P < 0.05). WIT was dichotomized as T1 (<22 min), T2 (22-70 min), and T3 (>70 min). IFN-γ was significantly increased in T2 and T3 as compared to T1. IL-6 was in T3 compared to T1 and T2. IL-17 was in T3 compared to T1. For the Th1-to-Th2 ratio, IFN-γ/IL-10, IFN-γ/IL-6, and IL-2/IL-10 were significantly different in T2 and T3 as compared to T1, and also in T3 as compared to T2. Th1 cell activities were enhanced with increased WIT. In conclusion, the longer WIT (>70 min) in LDLT is more likely to induce immunological reactions of recipients by leading to a deleterious cytokine balances in favor of an reinforced production of Th1 cytokines.

Asunto(s)

Citocinas/sangre , Trasplante de Hígado/métodos , Células TH1/inmunología , Balance Th1 - Th2/fisiología , Células Th2/inmunología , Isquemia Tibia , Femenino , Supervivencia de Injerto/fisiología , Humanos , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-17/sangre , Interleucina-2/sangre , Interleucina-6/sangre , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tolerancia al Trasplante/inmunología , Trasplante Homólogo

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This corrects the article on p. 80 in vol. 81, PMID: 29332324.

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Peripheral nerve stimulation (PNS) is a useful treatment for chronic pain, but it can cause damage depending on its application site. Here, we describe the case of a 54-year-old man who underwent PNS for brachial plexopathy in 2015. One lead was implanted on the left medial cord to stimulate the medial antebrachial cutaneous nerve, and the other was implanted on the radial nerve to stimulate the posterior antebrachial cutaneous nerve. Both leads were inserted near the shoulder joint but did not cross it. Before PNS, the patient did not move his shoulder and elbow because of severe pain, but the treatment greatly alleviated this pain. Twenty months after the operation, both leads were fractured, and the severe pain returned. Repetitive motion near the joint was closely related to the lead fractures. In conclusion, large joints as the insertion sites of PNS leads should be avoided to prevent lead fractures.

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BACKGROUND: The beach-chair position (BCP) results in decreases in venous return, cardiac output, and cerebral perfusion pressure. In this randomized, prospective study, we investigated whether applying thigh-high compression stockings affected the maintenance of regional cerebral tissue oxygen saturation (rSO2) in the BCP. METHODS: Patients undergoing orthopedic surgery in the BCP under general anesthesia were included and assigned randomly to the control or the compression stocking group. Appropriately sized thigh-high compression stockings were applied to the patients in the stockings group. All patients were tilted, up to 45°, throughout the operation. Non-invasive blood pressure, invasive arterial blood pressure zeroed at the external auditory meatus, and rSO2 were recorded. RESULTS: Data were analyzed from 19 patients per group. In the BCP, the values of rSO2 and blood pressure decreased significantly compared with those at baseline, with no significant difference between the groups. The incidences of cerebral desaturation events (CDEs) were similar between the groups; however, that of hypotension was significantly lower in the compression stocking group. During 36 CDEs, the levels of rSO2 and blood pressure decreased significantly compared with those at baseline in both groups. No significant correlation was found between rSO2 and blood pressure. CONCLUSIONS: Thigh-high compression stockings reduced the incidence of hypotension but not that of CDEs. Our results suggest that other factors, beyond hypotension itself, contribute to CDEs and in other words, efforts just to reduce the incidence of hypotension may not mainly contribute to a reduction of CDEs occurrence in the BCP under general anesthesia.

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BACKGROUND: Asthma is a disease of chronic airway inflammation with heterogeneous features. Neutrophilic asthma is corticosteroid-insensitive asthma related to absence or suppression of TH2 process and increased TH1 and/or TH17 process. Macrolides are immunomodulatory drug that reduce airway inflammation, but their role in asthma is not fully known. The purpose of this study was to evaluate the role of macrolides in neutrophilic asthma and compare their effects with those of corticosteroids. METHODS: C57BL/6 female mice were sensitized with ovalbumin (OVA) and lipopolysaccharides (LPS). Clarithromycin (CAM) and/or dexamethasone (DXM) were administered at days 14, 15, 21, 22, and 23. At day 24, the mice were sacrificed. RESULTS: Airway resistance in the OVA+LPS exposed mice was elevated but was more attenuated after treatment with CAM+DXM compared with the monotherapy group (p<0.05 and p<0.01). In bronchoalveolar lavage fluid study, total cells and neutrophil counts in OVA+LPS mice were elevated but decreased after CAM+DXM treatment. In hematoxylin and eosin stain, the CAM+DXM-treated group showed less inflammation additively than the monotherapy group. There was less total protein, interleukin 17 (IL-17), interferon γ, and tumor necrosis factor α in the CAM+DXM group than in the monotherapy group (p<0.001, p<0.05, and p<0.001). More histone deacetylase 2 (HDAC2) activity was recovered in the DXM and CAM+DXM challenged groups than in the control group (p<0.05). CONCLUSION: Decreased IL-17 and recovered relative HDAC2 activity correlated with airway resistance and inflammation in a neutrophilic asthma mouse model. This result suggests macrolides as a potential corticosteroid-sparing agent in neutrophilic asthma.

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Brachial plexus injury (BPI) often causes severe neuropathic pain that becomes chronic and difficult to treat pharmacologically or surgically. Here, we describe two cases of successful treatment of BPI with peripheral nerve stimulation (PNS). Both patients had experienced severe neuropathic pain after incomplete BPI for a long time (32 and 17 years) and did not response to medication, radiofrequency neuroablation, or spinal cord stimulation. After PNS using ultrasound, their pain was relieved by more than 50% over the course of 1 year. Both patients were satisfied with their improved sleep and quality of life. We conclude that PNS could be an alternative therapeutic modality for neuropathic pain after BPI as it provides direct nerve stimulation, has few complications, and is easy to perform.

Asunto(s)

Neuropatías del Plexo Braquial/terapia , Estimulación Eléctrica/métodos , Neuralgia/terapia , Adulto , Plexo Braquial , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Calidad de Vida , Ultrasonografía/métodos

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OBJECTIVE: The purpose of this study was to present the outcome of the microsurgical foraminotomy via Wiltse paraspinal approach for foraminal or extraforaminal (FEF) stenosis at L5-S1 level. We investigated risk factors associated with poor outcome of microsurgical foraminotomy at L5-S1 level. METHODS: We analyzed 21 patients who underwent the microsurgical foraminotomy for FEF stenosis at L5-S1 level. To investigate risk factors associated with poor outcome, patients were classified into two groups (success and failure in foraminotomy). Clinical outcomes were assessed by the visual analogue scale (VAS) scores of back and leg pain and Oswestry disability index (ODI). Radiographic parameters including existence of spondylolisthesis, existence and degree of coronal wedging, disc height, foramen height, segmental lordotic angle (SLA) on neutral and dynamic view, segmental range of motion, and global lumbar lordotic angle were investigated. RESULTS: Postoperative VAS score and ODI improved after foraminotomy. However, there were 7 patients (33%) who had persistent or recurrent leg pain. SLA on neutral and extension radiographic films were significantly associated with the failure in foraminotomy (p<0.05). Receiver-operating characteristics curve analysis revealed the optimal cut-off values of SLA on neutral and extension radiographic films for predicting failure in foraminotomy were 17.3° and 24°s, respectively. CONCLUSION: Microsurgical foraminotomy for FEF stenosis at L5-S1 level can provide good clinical outcomes in selected patients. Poor outcomes were associated with large SLA on preoperative neutral (>17.3°) and extension radiographic films (>24°).

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Brachial plexopathy usually results from an iatrogenic brachial plexus injury and can sometimes cause severe chronic pain and disability. There are a number of possible treatments for this condition, including medication, physical therapy, nerve blocks, and neuromodulation, but they are not always successful. Recently, combined spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) have been tried for various chronic pain diseases because of their different mechanisms of action.Here, we describe the case of a 54-year-old man who was diagnosed with brachial plexopathy 8 years ago. He underwent video-assisted thoracoscopic surgery to remove a superior mediastinal mass. However, his brachial plexus was damaged during the surgery. Although he had received various treatments, the pain did not improve. For the management of intractable severe pain, he underwent SCS 2 years ago, which initially reduced his pain from numeric rating scale (NRS) 10/10 to NRS 4 - 5/10, but the pain then gradually increased, reaching NRS 8/10, 6 months ago. At that time, he was refractory to other treatments, and we therefore applied PNS in combination with SCS. The PNS electrode was positioned on the radial nerve under ultrasound guidance. After combined PNS and SCS, his background pain disappeared, although a breakthrough pain (NRS 3 - 4/10) was caused intermittently by light touch. Furthermore, the patient's need for analgesics decreased, and he was satisfied with the outcome of this combined treatment. We concluded that combined SCS and PNS is a very useful treatment modality, which can stimulate the target nerve both directly and indirectly, and hence, relieve pain from brachial plexopathy.

Asunto(s)

Neuropatías del Plexo Braquial/terapia , Terapia por Estimulación Eléctrica/métodos , Nervios Periféricos , Estimulación de la Médula Espinal/métodos , Plexo Braquial/diagnóstico por imagen , Plexo Braquial/lesiones , Neuropatías del Plexo Braquial/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Dolor Intratable/terapia , Complicaciones Posoperatorias , Nervio Radial , Ultrasonografía Intervencional

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Lead migration is the most common complication of spinal cord stimulation (SCS). However, the only corrective method for lead migration is revision surgery, which may cause additional complications. Here, we describe a new technique for adjusting a transversely migrated SCS lead. The medical records of four patients diagnosed with complex regional pain syndrome (n = 3) or failed back surgery syndrome (n = 1) who underwent implantation of percutaneous leads for SCS were retrospectively reviewed. Transverse lead migration was diagnosed radiographically after patients reported recurrence of pain or numbness in treated sites. The guide wire from the SCS implant kit was bent and inserted into the target epidural space using a 14-gauge Tuohy needle. When the guide wire contacted the migrated SCS lead, they were advanced to the correct location under C-arm guidance. After re-adjustment of the SCS lead, good coverage of the electrical stimulation was confirmed. Patients were followed for 9-19 months and they reported satisfactory pain relief and good electrical coverage after adjusting the SCS lead. Here, we describe a new technique for adjusting a transversely migrated SCS lead using a percutaneous epidural approach as a simple, safe, and cost-effective alternative to revision surgery.

Asunto(s)

Electrodos Implantados/efectos adversos , Síndrome de Fracaso de la Cirugía Espinal Lumbar/etiología , Estimulación de la Médula Espinal/efectos adversos , Adulto , Espacio Epidural/patología , Femenino , Migración de Cuerpo Extraño/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Médula Espinal/cirugía

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Tarsal tunnel syndrome (TTS) is a compression neuropathy that results from entrapment of the posterior tibial nerve or its branches. TTS may be treated either by conservative measures, including physical therapy, medications, and steroid injections, or by surgical decompression. Despite a variety of treatments, a few cases of TTS will relapse, and many cases of recurrent TTS will require re-operation. Pulsed radiofrequency (PRF) is known to have a number of advantages for pain management, particularly as this technique does not cause neural compromise such as motor weakness. Here, we report a new application of ultrasound-guided PRF in two cases of intractable TTS. Both patients had a long duration of severe foot pain and had been treated with various therapeutic modalities without lasting relief. We applied ultrasound-guided PRF to the affected posterior tibial nerve in each patient, and both had significantly reduced pain intensity scores and analgesic requirements without any complications. Ultrasound-guided PRF for intractable TTS relieved severe foot pain. It may supersede surgery as a reliable treatment for intractable TTS.

Asunto(s)

Tratamiento de Radiofrecuencia Pulsada/métodos , Síndrome del Túnel Tarsiano/terapia , Nervio Tibial/patología , Anciano , Femenino , Pie , Humanos , Masculino , Persona de Mediana Edad , Dolor/etiología , Síndrome del Túnel Tarsiano/fisiopatología

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Subdural injection of epidural anesthesia is rare and is usually undiagnosed during epidural anesthesia causing severely delayed maternal hypotension, hypoxia, and fetal distress. A 38-year-old primiparous woman was administered epidural labor analgesia at 40(+6) weeks' gestation, and developed progressive maternal respiratory depression, bradycardia, and hypotension after accidental subdural administration of the anesthetic agent. Furthermore, fetal distress occurred soon after administration. The patient was managed with oxygen, position changes, fluid resuscitation, and ephedrine. Intrauterine fetal resuscitation was successfully performed with atropine before cesarean section, and a healthy baby was delivered. Although subdural injection is uncommon, this case emphasizes the importance of anesthesiologists monitoring patients for a sufficient period after epidural labor analgesia, and being prepared to perform maternal or fetal resuscitation.

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We present successful epidural anesthesia and assisted mechanical ventilation in a parturient woman with respiratory failure. A 41-year-old woman at 35 weeks' of gestation was entering labor. She was pneumonectomized on the left, had bronchiectasis on the remnant lung, and was under assisted mechanical ventilation by continuous positive airway pressure (CPAP) because of severely restricted lung function and superimposed pneumonia. We administered continuous epidural analgesia for vaginal delivery, and extended it for cesarean section after failure of vaginal delivery. During the procedure, her ventilation was continuously assisted by CPAP. The maternal and fetal outcomes were successful.

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Sugammadex is a modified gamma-cyclodextrin which is showing favorable outcomes regarding reversal of neuromuscular blockade, especially by rocuronium. It is designed to encapsulate rocuronium and being considered a new class of drugs as selective relaxant binding agents. It has given countless benefits to the patients at risk of incomplete or delayed recovery after neuromuscular block and has renown for another milestone in anesthesia practice. Recurrence of neuromuscular block has not been reported to be associated with the provided doses of sugammadex that are adequate for selected for reversal. Acceptable profiles are brought to light telling safety of sugammadex. However, some questions related to the twitch characteristics those resembled succinylcholine when reversal, the application for rocuronium anaphylaxis, and the hypersensitivity or anaphylaxis to sugammadex remain and are need of further investigation. It is imperative that potential problems that we need attention may include the patient's history of pulmonary disease and allergic disease for using sugammadex.