Impact of preoperative bloodstream infection on outcomes of pediatric liver transplant recipients treated for acute liver failure.

BACKGROUND: Acute liver failure (ALF) is a component of multisystem organ failure that causes severe liver dysfunction in patients without underlying chronic liver disease. The patients with ALF are prone to have infections, including bacteremia. However, studies of the infectious impact for post liver transplantation (LT) in pediatric ALF are limited. We aimed to evaluate our current practice for pediatric LT cases of ALF with preoperative bacteremia. METHODS: The records of all patients under 18 years old undergoing LT for ALF in our center from November 2005 to December 2021 were collected. They were divided into two groups: those with a preoperative bloodstream infection (BSI) and those without (NBSI). We compared the preoperative status and also reviewed the details of the BSI group. Intraoperative course and postoperative outcomes were also compared. RESULTS: There were 19 BSI patients and 66 NBSI patients. One BSI case was detected on the day of LT. This patient had no changes in vital signs and general condition. After evaluation and therapeutic intervention by pediatric infectious disease specialists, LT was performed on the same day. Five cases developed septic shock at the time of detection of BSI. All BSI patients were in stable condition on the operation day with proper interventions. There were no significant differences in mortality and hospital stay between both groups. CONCLUSIONS: LT might be able to be performed for pediatric ALF even with positive blood cultures. In addition, appropriate therapeutic intervention by specialists and patient's stable condition before LT are essential.

Criteria for immediate extubation after pediatric liver transplantation in a single pediatric liver transplant center in Japan.

Immediate extubation (IE) following liver transplantation (LT) has become the standard practice, even for pediatric patients. However, no preoperative or postoperative case selection protocols for IE are currently available. We have developed selection criteria for IE following pediatric LT. The aim of this study is to assess the safety and effectiveness of these selection criteria and anesthetic management protocol implemented in our hospital for IE after pediatric LT. METHOD: This was a retrospective study. The records of all cases undergoing LT in our center from January 2016 to December 2020 were collected. We excluded cases > 18 years old at the time of LT. Enrolled cases were divided into two groups: cases with immediate extubation (IE) or without immediate extubation (NIE). We compared preoperative conditions, intraoperative management, and postoperative courses. Finally, we classified NIE group patients into cases extubated at postoperative day 1 (early; E-NIE) and others (delayed; D-NIE) and compared their underlying diseases and postoperative courses. RESULTS: In the IE group, there were 81 cases, while the NIE group consisted of 185 cases. All patients in the IE group were successfully extubated without any instances of re-intubation due to respiratory failure. Within the E-NIE group, comprising 130 cases, all patients were ultimately extubated without the need for tracheostomy. However, in the D-NIE group, which encompassed 53 cases, seven patients required tracheostomy. CONCLUSION: In our center, the implementation of our anesthesia management protocol and the use of pre/postoperative case selection criteria have allowed for the safe practice of IE following pediatric LT. However, it should be noted that patients who cannot be extubated by Postoperative Day 1 (POD1) may be at an increased risk of requiring a tracheostomy. When contemplating IE, it is crucial to take into account the disease-specific physiological aspects and surgical site situations.

Protocol for a randomized controlled trial to reduce pediatric anesthesia emergence delirium by titration of sevoflurane anesthesia using brain function monitoring.

BACKGROUND: Emergence agitation or emergence delirium is a common complication of unknown etiology in pediatric anesthesia. Pediatric anesthesia emergence delirium (PAED) has been reported most commonly in younger children and may occur in about 30% of children up to 5-6 years old. Exposure to anesthetic agents may contribute to PAED, and we hypothesized that a management strategy to minimize exposure to volatile anesthetics may reduce PAED. Electroencephalography (EEG) signatures captured and displayed by brain function monitors during anesthesia change with concentration of sevoflurane and level of unconsciousness, and these EEG signatures may be used to inform titration of anesthetics. METHODS: A single-center, parallel-group, two-arm, superiority trial with a 1:1 allocation ratio will be performed to compare the incidence of PAED following standard sevoflurane anesthesia (maintained at 1.0MAC) and EEG-guided anesthesia (minimum concentration to sustain surgical anesthesia as determined by monitoring of EEG signatures). Participants between 1 and 6 years of age undergoing surgical procedures involving minimal postoperative pain will be randomly assigned to receive standard (n = 90) or EEG-guided (n = 90) anesthesia. PAED score will be assessed by a blinded observer in the PACU on arrival and after 5, 10, 15, and 30 min. DISCUSSION: Anesthesia management with proactive use of brain function monitoring is expected to reduce exposure to sevoflurane without compromising surgical anesthesia. We expect this reduced exposure should help prevent PAED. Routinely administering what may be considered standard levels of anesthetic such as 1.0 MAC sevoflurane may be excessive and potentially associated with unfavorable sequelae such as PAED. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs032210248. Prospectively registered on 17 August 2021.

Physical and psychological recovery after vaginal childbirth with and without epidural analgesia: A prospective cohort study.

BACKGROUND: Enhanced recovery is the gold standard in modern perioperative management, including that for cesarean deliveries. However, qualitative and quantitative data on the physical and psychological recovery of women after vaginal childbirth are limited. Whether neuraxial labor analgesia influences postpartum recovery is unknown. METHODS: Primiparous women anticipating a vaginal childbirth between January 2020 and May 2021 were enrolled. Women with major comorbidities or postpartum complications and those who underwent a cesarean delivery were excluded. Daily step count was measured using a wrist-worn activity tracker (FitbitTM Inspire HR) for 120 hours after vaginal childbirth. Subjective fatigue levels and health-related quality of life were assessed using the Multidimensional Fatigue Inventory (MFI) and EuroQol 5 Dimension 5 Level (EQ-5D-5L), respectively, at the 3rd trimester antenatal visit, on postpartum day 1 and 3, and at the one-month postpartum visit. Rest and dynamic pain scores and the location of pain were documented by participants during postpartum hospitalization. RESULTS: Among 300 women who were enrolled antenatally, 95 and 116 had a vaginal delivery without (NCB group) and with (EPL group) epidural analgesia, respectively. The median number of steps per 24 hours increased daily in both groups, and no significant difference was detected between the groups. Postpartum pain was mild overall, with median rest and dynamic pain scores being less than 4 and similar between the groups. MFI and EQ-5D-5L scores were the worst on postpartum day 1 in both groups and gradually improved to antepartum level by the one-month postpartum visit. Higher MFI score on postpartum day 1, but not the use of epidural analgesia, was associated with lower odds of achieving adequate postpartum ambulation (defined as >3500 steps between 48 and 72 hours postpartum). CONCLUSION: The use of epidural analgesia was not associated with worse recovery outcomes during postpartum hospitalization. TRIAL REGISTRATION: UMIN-CTR, #UMIN000039343, registered on January 31, 2020.

Anesthesia management protocol for liver transplantation as treatment for ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase deficiency is an X-linked genetic disorder that induces accumulation of ammonia in the liver and is the most common urea cycle disorder. The clinical manifestation of ornithine transcarbamylase deficiency is hyperammonemia that causes irreversible neurological damage. Liver transplantation is a curative therapy for ornithine transcarbamylase deficiency. The aim of this study is to suggest, from our previous experience, an anesthesia management protocol of liver transplantation for ornithine transcarbamylase deficiency, particularly focused on liver transplantation for cases with uncontrolled hyperammonemia. METHOD: We retrospectively reviewed our anesthesia-related experience in all cases of liver transplantation for ornithine transcarbamylase deficiency in our center. RESULTS: Twenty-nine liver transplantation cases for ornithine transcarbamylase deficiency were found between November 2005 and March 2021 in our center. Of these, 25 cases were stable through the perioperative period. However, 2 cases with carrier donor graft had hyperammonemia after liver transplantation. Another two cases had uncontrolled hyperammonemia before liver transplantation, even with continuous hemodialysis. They underwent life-saving liver transplantation. Their metabolic status stabilized after the anhepatic phase. CONCLUSION: Liver transplantation for cases with uncontrolled hyperammonemia can be performed with proper management. Second, liver transplantation with carrier donors should be avoided because of the risk of postoperative recurrence.

Acute pain and analgesic requirement after vaginal childbirth with and without neuraxial labor analgesia-Retrospective cohort study.

BACKGROUND: Few data are available on the intensity of pain that women experience during the first five days after vaginal childbirth. Moreover, it is unknown if the use of neuraxial labor analgesia has any impact on the level of postpartum pain. METHODS: We performed a retrospective cohort study based on chart review of all women who delivered vaginally at an urban teaching hospital between April 2017 and April 2019. The primary outcome was the area under the curve of pain score on numeric rating scale (NRS) documented in electronic medical records for five days postpartum (NRS-AUC5days). Secondary outcomes included peak NRS score, doses of oral and intravenous analgesics consumed during the first five days postpartum, and relevant obstetric outcomes. Logistic regression was used to examine the associations between the use of neuraxial labor analgesia and pain-related outcomes adjusting for potential confounders. RESULTS: During the study period, 778 women (38.6%) underwent vaginal delivery with neuraxial analgesia and 1240 women (61.4%) delivered without neuraxial analgesia. Median (Interquartile range) of NRS-AUC5days was 0.17 (0.12-0.24) among women who received neuraxial analgesia and 0.13 (0.08-0.19) among women who did not (p<0.001). Women who received neuraxial analgesia were more likely to require the first- and second-line analgesics postpartum than women who did not: diclofenac (87.9% vs. 73.0%, p< 0.001, respectively); acetaminophen (40.7% vs. 21.0%, p< 0.001, respectively). The use of neuraxial labor analgesia was independently associated with increased odds of having NRS-AUC5days in the highest 20 percentile (adjusted odds ratio [aOR] 2.03; 95% confidence interval [CI] 1.55-2.65), having peak NRS ≥ 4 (aOR 1.54; 95% CI 1.25-1.91) and developing hemorrhoids during the postpartum hospitalization (aOR 2.13; 95% CI 1.41-3.21) after adjusting for relevant confounders. CONCLUSION: Although women who used neuraxial labor analgesia had slightly higher pain scores and increased analgesic requirement during postpartum hospitalization, pain after vaginal childbirth was overall mild. The small elevation in the pain burden in neuraxial group does not seem to be clinically relevant and should not influence women's choice to receive labor analgesia.

Hemolysis Precedes Urine Color Change in Patients Undergoing Open-Heart Surgery on Cardiopulmonary Bypass.

PURPOSE: Red-colored urine often occurs in patients in the perioperative period who undergo cardiac surgery using cardiopulmonary bypass (CPB). This urine color change has been utilized for approximating hemolysis during CPB without a proven relationship for ongoing hemolysis. This case series study aimed to examine the relationship between plasma free hemoglobin (Hb) levels and quantified measures of urine color. METHODS: Ten patients were enrolled in this study. Blood and urine were collected for analyses for the following time points: before surgery, two hours after the initiation of CPB, every 30 min during CPB thereafter, and 0, 2, 4, 12, and 24 hours after the completion of CPB. We measured free Hb in plasma and urine using the azide-methemoglobin method. Photographs of urine were obtained, and the luminance of the three basic colors (red/green/blue) was analyzed by quantitative luminance contrast analysis to find a correlation for hemolysis. RESULTS: Median levels of plasma free Hb were 0.015 (0.010-0.080, n = 10) g/dL at baseline. During the CPB, increases in plasma free Hb levels were measured: median plasma free Hb levels were increased to 0.100 g/dL (0.020-0.240, p = 0.039, vs. baseline, n = 9) at two hours into CPB, median and range, respectively. In contrast, increases in urinary free Hb levels and/or urine color changes were measured only after cessation of CPB in nine patients. CONCLUSION: Urine color change or elevation of urinary free Hb levels followed the elevation of plasma free Hb levels with considerable delay.

A Novel Magnetic Resonance Imaging-Compatible Titanium Alloy Wire-Reinforced Endotracheal Tube.

Reinforced endotracheal tubes (ET) are advantageous in preventing tube obstruction and kinking by procedural compression during neurosurgeries. However, the standard reinforced ET contains an embedded stainless steel (SS) helical wire, which produces artifacts and heat during magnetic resonance imaging (MRI). Therefore, MRI is not indicated in the presence of a reinforced ET containing SS. To overcome this challenge, we developed an MRI-compatible titanium (Ti) reinforced ET. A newly developed Ti alloy helical wire was inserted in a reinforced ET. Here, we report our first clinical experience with six patients who underwent neurosurgery intubated with this Ti-alloy-reinforced ET. The Ti-alloy-reinforced ET was used in six patients requiring reinforced ET intubation. It was clearly delineated on radiography, and metal artifacts were small on computed tomography. Patients intubated with the Ti-alloy-reinforced ET could safely undergo MRI under sedation. MR images without remarkable susceptibility artifacts were obtained without noted adverse effects. We invented a novel Ti-alloy-reinforced ET. This device allows clinical use during MRI because it is less susceptible to artifacts in high magnetic fields.

Antihypertensive Mechanism of Orally Administered Acetylcholine in Spontaneously Hypertensive Rats.

Acetylcholine (ACh) acts as a neurotransmitter and neuromodulator. A small dose of eggplant powder rich in ACh (equivalent to 22 g fresh eggplant/d) has been shown to reduce blood pressure (BP) in individuals with higher BP. Here, we investigated the mechanisms underlying the antihypertensive effects of low-dose orally administered ACh in spontaneously hypertensive rats (SHRs). The effects of ACh on BP and sympathetic nervous activity (SNA), including lumbar SNA (LSNA) and renal SNA (RSNA), were evaluated by subjecting conscious SHRs to a telemetry method. Single oral administration of ACh decreased LSNA and lowered BP. Repeated oral administration of ACh for 30 d decreased RSNA and suppressed the elevated BP. Noradrenaline levels in the urine also decreased. However, vagotomy and co-administration of M3 muscarinic ACh receptor antagonist reversed the BP-lowering effect; the dynamics of non-absorbable orally administered ACh was revealed using stable isotope-labeled ACh. In conclusion, ACh acts on the gastrointestinal M3 muscarinic ACh receptor to increase afferent vagal nerve activity, which decreases SNA by autonomic reflex, suppressing noradrenaline release and lowering BP. This study suggests the use of exogenous ACh as an antihypertensive food supplement for controlling the autonomic nervous system, without absorption into the blood.

Right ventricular perforation, pneumothorax, and a pneumatocele by a pacemaker lead: a case report.

BACKGROUND: Perforation of the right ventricle by a pacemaker lead is a rare and potentially life-threatening complication. We present a patient who developed right ventricular perforation, pneumothorax, and a cyst and underwent partial lung resection. CASE PRESENTATION: A 94-year-old woman was diagnosed with sick sinus syndrome and underwent a dual-chamber permanent pacemaker implantation. The next day, pacing failed and chest radiography showed that the right ventricular lead was outside the cardiac silhouette. Computed tomography revealed that the lead had perforated the right ventricular apex, causing a left-sided pneumothorax and a cystic lesion at the site of pulmonary injury by the pacemaker lead. The patient underwent lung resection and a right ventricular lead extraction. Pathological analysis revealed the cystic lesion to be an acute pneumatocele. CONCLUSIONS: Pneumothorax and pneumatocele associated with right ventricular pacemaker lead perforation is extremely rare. In our case, a radical surgical intervention provided an excellent outcome.

Cerebral oximetry-guided pulmonary artery banding for end-stage heart failure in a child with left ventricular noncompaction cardiomyopathy: a case report.

Pulmonary artery banding (PAB) may reduce the need for left ventricular assist devices and heart transplantation in children with end-stage heart failure. However, excessive banding may increase the right ventricular afterload, leading to worsening of heart failure. The estimated right ventricular pressure and the shifting of the interventricular septum by transesophageal echocardiography (TEE), pulmonary artery pressure, right atrial and ventricular pressure, percutaneous oxygen saturation, and mixed venous oxygen saturation are utilized to determine the optimal circumference for PAB. Here, we report the case of a 5-month-old patient with end-stage heart failure due to left ventricular noncompaction cardiomyopathy (LVNC), with a gene mutation of MYH7, who underwent successful PAB. The exact PAB placement was additionally guided by using cerebral regional oxygen saturation (rSO2) measurement to achieve a tolerable and optimal PAB effect. We monitored rSO2 and other hemodynamic parameters while surgeons banded the pulmonary artery to achieve both highest rSO2 levels and stable hemodynamics. rSO2 was 68% before banding, and increased and remained at over 90% after the banding at same FiO2. Patient's heart failure improved gradually, and the child was discharged home at 6 months after PAB. The rSO2 is a simple and non-invasive monitor for the measurement of oxygen delivery to the brain tissue. rSO2 alone would not be able to guide PAB placement in the vulnerable DCM patients, but it may be of one further monitoring value for the optimal pulmonary artery circumference while patients are undergoing PAB.

Challenges and hurdles for patient safety in obstetric anesthesia in Japan.

The use of pain relief for labor has gained popularity in Japan. However, its acceptance is still low among laboring women: only 6.1% of Japanese parturients receive labor analgesia, in contrast with the United States, where approximately 70% receive labor analgesia. Unfortunately, several maternal deaths associated with labor analgesia have been reported in recent years in Japan and how to achieve safer obstetric care is a pressing concern. In this review, we focus on current approaches to labor analgesia in the United States as they compare to existing practices in Japan. We discuss challenges for the introduction and implementation of standard anesthesia practice into the Labor and Delivery Room (LDR; i.e., labor and delivery ward), aiming to secure safety for both mothers and fetus in every part of Japan in the near future.

Pharmacological preconditioning with inhaled nitric oxide (NO): Organ-specific differences in the lifetime of blood and tissue NO metabolites.

BACKGROUND: Endogenous nitric oxide (NO) may contribute to ischemic and anesthetic preconditioning while exogenous NO protects against ischemia-reperfusion (I/R) injury in the heart and other organs. Why those beneficial effects observed in animal models do not always translate into clinical effectiveness remains unclear. To mitigate reperfusion damage a source of NO is required. NO inhalation is known to increase tissue NO metabolites, but little information exists about the lifetime of these species. We therefore sought to investigate the fate of major NO metabolite classes following NO inhalation in mice in vivo. METHODS: C57BL/6J mice were exposed to 80 ppm NO for 1 h. NO metabolites were measured in blood (plasma and erythrocytes) and tissues (heart, liver, lung, kidney and brain) immediately after NO exposure and up to 48 h thereafter. Concentrations of S-nitrosothiols, N-nitrosamines and NO-heme products as well as nitrite and nitrate were quantified by gas-phase chemiluminescence and ion chromatography. In separate experiments, mice breathed 80 ppm NO for 1 h prior to cardiac I/R injury (induced by coronary arterial ligation for 1 h, followed by recovery). After sacrifice, the size of the myocardial infarction (MI) and the area at risk (AAR) were measured. RESULTS: After NO inhalation, elevated nitroso/nitrosyl levels returned to baseline over the next 24 h, with distinct multi-phasic decay profiles in each compartment. S/N-nitroso compounds and NO-hemoglobin in blood decreased exponentially, but remained above baseline for up to 30min, whereas nitrate was elevated for up to 3hrs after discontinuing NO breathing. Hepatic S/N-nitroso species concentrations remained steady for 30min before dropping exponentially. Nitrate only rose in blood, liver and kidney; nitrite tended to be lower in all organs immediately after NO inhalation but fluctuated considerably in concentration thereafter. NO inhalation before myocardial ischemia decreased the ratio of MI/AAR by 30% vs controls (p = 0.002); only cardiac S-nitrosothiols and NO-hemes were elevated at time of reperfusion onset. CONCLUSIONS: Metabolites in blood do not reflect NO metabolite status of any organ. Although NO is rapidly inactivated by hemoglobin-mediated oxidation in the circulation, long-lived tissue metabolites may account for the myocardial preconditioning effects of inhaled NO. NO inhalation may afford similar protection in other organs.

Sensitivity to Sevoflurane anesthesia is decreased in mice with a congenital deletion of Guanylyl Cyclase-1 alpha.

BACKGROUND: Volatile anesthetics increase levels of the neurotransmitter nitric oxide (NO) and the secondary messenger molecule cyclic guanosine monophosphate (cGMP) in the brain. NO activates the enzyme guanylyl cyclase (GC) to produce cGMP. We hypothesized that the NO-GC-cGMP pathway contributes to anesthesia-induced unconsciousness. METHODS: Sevoflurane-induced loss and return of righting reflex (LORR and RORR, respectively) were studied in wild-type mice (WT) and in mice congenitally deficient in the GC-1α subunit (GC-1-/- mice). Spatial distributions of GC-1α and the GC-2α subunit in the brain were visualized by in situ hybridization. Brain cGMP levels were measured in WT and GC-1-/- mice after inhaling oxygen with or without 1.2% sevoflurane for 20 min. RESULTS: Higher concentrations of sevoflurane were required to induce LORR in GC-1-/- mice than in WT mice (1.5 ± 0.1 vs. 1.1 ± 0.2%, respectively, n = 14 and 14, P < 0.0001). Similarly, RORR occurred at higher concentrations of sevoflurane in GC-1-/- mice than in WT mice (1.0 ± 0.1 vs. 0.8 ± 0.1%, respectively, n = 14 and 14, P < 0.0001). Abundant GC-1α and GC-2α mRNA expression was detected in the cerebral cortex, medial habenula, hippocampus, and cerebellum. Inhaling 1.2% sevoflurane for 20 min increased cGMP levels in the brains of WT mice from 2.6 ± 2.0 to 5.5 ± 3.7 pmol/mg protein (n = 13 and 10, respectively, P = 0.0355) but not in GC-1-/- mice. CONCLUSION: Congenital deficiency of GC-1α abolished the ability of sevoflurane anesthesia to increase cGMP levels in the whole brain, and increased the concentration of sevoflurane required to induce LORR. Impaired NO-cGMP signaling raises the threshold for producing sevoflurane-induced unconsciousness in mice.

Harlequin Syndrome After Thoracic Paravertebral Block.

Harlequin syndrome is characterized by the sudden onset of unilateral facial flushing and sweating, often preceded by exercise, excessive heat, or, rarely, regional anesthesia. Although the exact mechanism remains unclear, it is often referred to as transient or permanent interruption of the sympathetic nervous system. We present a case of Harlequin syndrome without Horner syndrome in a patient with unilateral right-sided facial flushing that started shortly after a left-sided thoracic paravertebral nerve block for a mastectomy. We discuss the interruption of the sympathetic and parasympathetic nervous system and the levels of spinal nerve block associated with a thoracic paravertebral nerve block.

Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy.

Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1(-/-)) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1(-/-) mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1(-/-) mice. UCP1(-/-) mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1(-/-) mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1(-/-) BAT transplanted to either UCP1(-/-) or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1(-/-) mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1(-/-) mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy.

Elevated upper body position improves pregnancy-related OSA without impairing sleep quality or sleep architecture early after delivery.

BACKGROUND: During pregnancy, upper airway resistance is increased, predisposing vulnerable women to pregnancy-related OSA. Elevation of the upper body increases upper airway cross-sectional area (CSA) and improves severity of OSA in a subgroup of nonpregnant patients (positional-dependent sleep apnea). We tested the hypothesis that elevated position of the upper body improves OSA early after delivery. METHODS: Following institutional review board approval, we conducted a randomized, crossover study on two postpartum units of Massachusetts General Hospital. Women during the first 48 h after delivery were included. Polysomnography was performed in nonelevated and 45° elevated upper body position. Upper airway CSA was measured by acoustic pharyngometry in nonelevated, 45° elevated, and sitting body position. RESULTS: Fifty-five patients were enrolled, and measurements of airway CSA obtained. Thirty patients completed polysomnography in both body positions. Elevation of the upper body significantly reduced apnea-hypopnea index (AHI) from 7.7 ± 2.2/h in nonelevated to 4.5 ± 1.4/h in 45° elevated upper body position (P = .031) during sleep. Moderate to severe OSA (AHI > 15/h) was diagnosed in 20% of postpartum patients and successfully treated by elevated body position in one-half of them. Total sleep time and sleep architecture were not affected by upper body elevation. Change from nonelevated to sitting position increased inspiratory upper airway CSA from 1.35 ± 0.1 cm2 to 1.54 ± 0.1 cm2 during wakefulness. Position-dependent increase in CSA and decrease in AHI were correlated (r = 0.42, P = .022). CONCLUSIONS: Among early postpartum women, 45° upper body elevation increased upper airway CSA and mitigated sleep apnea. Elevated body position might improve respiratory safety in women early after delivery. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01719224; URL: www.clinicaltrials.gov.

Nitric oxide regulates pulmonary vascular smooth muscle cell expression of the inducible cAMP early repressor gene.

Nitric oxide (NO) regulates vascular smooth muscle cell (VSMC) structure and function, in part by activating soluble guanylate cyclase (sGC) to synthesize cGMP. The objective of this study was to further characterize the signaling mechanisms by which NO regulates VSMC gene expression using transcription profiling. DNA microarrays were hybridized with RNA extracted from rat pulmonary artery smooth muscle cells (RPaSMC) exposed to the NO donor compound, S-nitroso-glutathione (GSNO). Many of the genes, whose expression was induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER). sGC and cAMP-dependent protein kinase, but not cGMP-dependent protein kinase, were required for NO-mediated phosphorylation of CRE-binding protein (CREB) and induction of ICER gene expression. Expression of a dominant-negative CREB in RPaSMC prevented the NO-mediated induction of CRE-dependent gene transcription and ICER gene expression. Pre-treatment of RPaSMC with the intracellular calcium (Ca(2+)) chelator, BAPTA-AM, blocked the induction of ICER gene expression by GSNO. The store-operated Ca(2+) channel inhibitors, 2-ABP, and SKF-96365, reduced the GSNO-mediated increase in ICER mRNA levels, while 2-ABP did not inhibit GSNO-induced CREB phosphorylation. Our results suggest that induction of ICER gene expression by NO requires both CREB phosphorylation and Ca(2+) signaling. Transcription profiling of RPaSMC exposed to GSNO revealed important roles for sGC, PKA, CREB, and Ca(2+) in the regulation of gene expression by NO. The induction of ICER in GSNO-treated RPaSMC highlights a novel cross-talk mechanism between cGMP and cAMP signaling pathways.

Soluble guanylate cyclase-α1 is required for the cardioprotective effects of inhaled nitric oxide.

Reperfusion injury limits the benefits of revascularization in the treatment of myocardial infarction (MI). Breathing nitric oxide (NO) reduces cardiac ischemia-reperfusion injury in animal models; however, the signaling pathways by which inhaled NO confers cardioprotection remain uncertain. The objective of this study was to learn whether inhaled NO reduces cardiac ischemia-reperfusion injury by activating the cGMP-generating enzyme, soluble guanylate cyclase (sGC), and to investigate whether bone marrow (BM)-derived cells participate in the sGC-mediated cardioprotective effects of inhaled NO. Wild-type (WT) mice and mice deficient in the sGC α(1)-subunit (sGCα(1)(-/-) mice) were subjected to cardiac ischemia for 1 h, followed by 24 h of reperfusion. During ischemia and for the first 10 min of reperfusion, mice were ventilated with oxygen or with oxygen supplemented with NO (80 parts per million). The ratio of MI size to area at risk (MI/AAR) did not differ in WT and sGCα(1)(-/-) mice that did not breathe NO. Breathing NO decreased MI/AAR in WT mice (41%, P = 0.002) but not in sGCα(1)(-/-) mice (7%, P = not significant). BM transplantation was performed to restore WT BM-derived cells to sGCα(1)(-/-) mice. Breathing NO decreased MI/AAR in sGCα(1)(-/-) mice carrying WT BM (39%, P = 0.031). In conclusion, these results demonstrate that a global deficiency of sGCα(1) does not alter the degree of cardiac ischemia-reperfusion injury in mice. The cardioprotective effects of inhaled NO require the presence of sGCα(1). Moreover, our studies suggest that BM-derived cells are key mediators of the ability of NO to reduce cardiac ischemia-reperfusion injury.