Safety of intranasal insulin administration in patients undergoing cardiovascular surgery: An open-label, nonrandomized, dose-escalation study.

Objective: This study aimed to determine the maximum safe dose of intranasal insulin administration during cardiac surgery. Methods: This open-label, Phase 1, single-center, dose-escalation clinical trial recruited patients scheduled to undergo elective cardiac surgery or major vascular surgery requiring cardiopulmonary bypass between February and September 2021. They were grouped into 5 dose-escalation cohorts and administered 0, 40, 80, 160, and 240 IU insulin (n = 6 in each group) via a metered nasal dispenser after the induction of general anesthesia. Blood samples were collected at 10-minute intervals for the first 60 minutes and at 30-minute intervals thereafter. Hypoglycemia was defined as a blood glucose level <70 mg/dL. Patient recruitment was terminated after hypoglycemia was observed in 2 patients in any of the groups. Results: In total, 27 of 29 enrolled patients were administered intranasal insulin or saline. Hypoglycemia was not observed after the administration of intranasal insulin in the 0, 40, 80, or 160 IU groups; however, it was observed in 2 of 3 patients in the 240 IU group. The serum insulin concentration was elevated in the 160-IU group, but the C-peptide concentration was not elevated in any of the groups. Conclusions: The administration of up to 160 IU intranasal insulin did not induce clinically significant hypoglycemia. However, 160 IU intranasal insulin should be administered cautiously because insulin can enter the systemic circulation in a dose-dependent manner.

Rare Co-occurrence of Spinal Cord Hemorrhage from Radiation-induced Cavernous Hemangioma and Classical Hodgkin Lymphoma Post-transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.

Role of the protein kinase A signaling pathway and identification of mediators in the cardioprotective effects of enteral lactoferrin for ischemia-reperfusion injury in an isolated rat heart model.

OBJECTIVE: Lactoferrin is an iron-binding glycoprotein. Enteral lactoferrin attenuates myocardial ischemia-reperfusion (IR) injury, but the underlying mechanism remains unknown. The aim of this study was to investigate protein kinase A (PKA) signaling pathway activation and levels of serum glucagonlike peptide-1 (GLP-1), secreted by intestinal endocrine L cells, and adiponectin, secreted by adipose tissue, after enteral lactoferrin administration. METHODS: Hearts (N = 32) were excised from Wistar rats and perfused using a Langendorff system. To assess the role of the PKA pathway in the cardioprotective effects of lactoferrin, an inhibitor of PKA (H89) was applied before no-flow ischemia. Rats were randomly divided into four groups: control, lactoferrin (LF), control+H89, and LF+H89. The control and control+H89 groups were administered normal saline by gavage, and the LF and L +H89 groups were administered bovine lactoferrin (1000 mg/kg) by gavage 15 min before intraperitoneal pentobarbital injection. Muscle sampling was performed at the end of reperfusion. When rats were sacrificed, blood was sampled to measure hormone levels. The primary outcome was maximum left ventricular pressure derivative (LV dP/dt max) 15 min after reperfusion. RESULTS: LV dP/dt max at 10 and 15 min after reperfusion was significantly higher in the LF group than in the control group (P < 0.05), and the effect was diminished by H89. The PKA pathway was significantly activated in the LF group. Enteral lactoferrin increased serum GLP-1 but not serum adiponectin levels. CONCLUSIONS: Enteral lactoferrin induces cardioprotective effects against myocardial IR injury via the PKA signaling pathway and increases serum GLP-1 levels.

Epidural Hematoma related to lower limb pain and massive liver bleeding in Gorham-Stout disease: A case report.

RATIONALE: Gorham-Stout disease (GSD) is a rare disease that causes massive osteolysis and proliferation of abnormal lymphangiomatous tissues. Patients with GSD often experience pain associated with bone fractures and chylothorax. However, bleeding caused by abnormal lymphangiomatous tissue or hematological dysfunction rarely occurs. PATIENT CONCERNS: A 22-year-old female patient with GSD presented with severe left hip and lower limb pain. The GSD had disappeared her right pelvic bone and femur, but no abnormalities were found in the bones at the site of the pain. DIAGNOSES: The patient presented with a chylothorax and cerebrospinal fluid leakage. She was treated with sirolimus and an epidural blood patch, and her symptoms resolved. Computed tomography and magnetic resonance imaging revealed an epidural hematoma extending from L3 to the caudal region, and blood results revealed a consumption coagulopathy. INTERVENTIONS: We presumed that the hematoma caused pain and prescribed pregabalin and morphine. The pain gradually subsided. OUTCOMES: An unexpected liver subcapsular hemorrhage occurred 4 months later, and the patient went into hemorrhagic shock. Transcatheter arterial embolization was promptly performed, and the patient recovered. LESSONS: GSD infrequently causes bleeding related to abnormal lymphangiomatous tissues and coagulopathy, yet it can lead to serious events if it occurs.

Neurofilament light chain levels in cerebrospinal fluid as a sensitive biomarker for cerebral adrenoleukodystrophy.

OBJECTIVE: Adrenoleukodystrophy (ALD) has a poor prognosis when it progresses to the cerebral form (CALD). The aim of this study is to investigate whether cerebrospinal fluid (CSF) neurofilament light chain (cNfL) is a sensitive biomarker for detecting CALD and assessing response to hematopoietic stem cell transplantation (HSCT). METHODS: We conducted a cross-sectional study of 41 male ALD patients. The cNfL levels in patients with the cerebral form of ALD (CALD) or the cerebello-brainstem form of ALD were compared with those in patients with adrenomyeloneuropathy (AMN). The correlation between cNfL levels and MRI-based Loes severity scores was investigated. A longitudinal analysis was performed on patients who underwent multiple CSF examinations. RESULTS: The cNfL levels in 22 patients with CALD were significantly higher than those in 14 patients with AMN (median, 5545 vs. 1490 pg/mL; p < 0.001). The cutoff cNfL level of 1930 pg/mL showed good sensitivity (95.5%) and specificity (85.7%) for distinguishing CALD from AMN. The cNfL levels were positively correlated with Loes scores (p < 0.001). The cNfL levels in three AMN patients who later converted to CALD increased above the cutoff level during the conversion period, while the cNfL levels in four patients who remained in AMN were consistently below the cutoff. In 10 ALD patients who underwent HSCT, their cNfL levels decreased 3-24 months after HSCT. Two patients whose cNfL increased after HSCT showed deterioration in cognitive functions. INTERPRETATION: The cNfL level is useful for evaluating the disease activities of ALD and the response to HSCT.

Role of macrophage autophagy in postoperative pain and inflammation in mice.

BACKGROUND: Postoperative pain and inflammation are significant complications following surgery. Strategies that aim to prevent excessive inflammation without hampering natural wound-healing are required for the management of postoperative pain and inflammation. However, the knowledge of the mechanisms and target pathways involved in these processes is lacking. Recent studies have revealed that autophagy in macrophages sequesters pro-inflammatory mediators, and it is therefore being recognized as a crucial process involved in regulating inflammation. In this study, we tested the hypothesis that autophagy in macrophages plays protective roles against postoperative pain and inflammation and investigated the underlying mechanisms. METHODS: Postoperative pain was induced by plantar incision under isoflurane anesthesia in mice lacking macrophage autophagy (Atg5flox/flox LysMCre +) and their control littermates (Atg5flox/flox). Mechanical and thermal pain sensitivity, changes in weight distribution, spontaneous locomotor activity, tissue inflammation, and body weight were assessed at baseline and 1, 3, and 7 days after surgery. Monocyte/macrophage infiltration at the surgical site and inflammatory mediator expression levels were evaluated. RESULTS: Atg5flox/flox LysMCre + mice compared with the control mice exhibited lower mechanical and thermal pain thresholds and surgical/non-surgical hindlimb weight-bearing ratios. The augmented neurobehavioral symptoms observed in the Atg5flox/flox LysMCre + mice were associated with more severe paw inflammation, higher pro-inflammatory mediator mRNA expression, and more monocytes/macrophages at the surgical site. CONCLUSION: The lack of macrophage autophagy augmented postoperative pain and inflammation, which were accompanied by enhanced pro-inflammatory cytokine secretion and surgical-site monocyte/macrophage infiltration. Macrophage autophagy plays a protective role in postoperative pain and inflammation and can be a novel therapeutic target.

Favorable outcome of hematopoietic stem cell transplantation in late-onset Krabbe disease.

BACKGROUND: Late-onset Krabbe disease is a disorder with autosomal recessive inheritance caused by a deficiency in galactocerebrosidase (GALC) activity. Its late-onset form usually shows slow disease progression with atypical symptoms including spastic paresis. The efficacy of hematopoietic stem cell transplantation (HSCT) in late-onset Krabbe disease has not been fully established. CASE REPORT: We describe the case of a patient with late-onset Krabbe disease showing progressive spastic paraparesis. At the age of 18, one and a half years after the development of symptoms, the patient underwent HSCT. After HSCT, the patient's GALC activity returned to a normal level and the lesions in the brain and spinal cord became faint on images. Over two and a half years after the HSCT, the patient's gait remained spastic, however, an improvement in gait speed and modified Rankin Scale score was observed. No severe adverse events occurred during this period. CONCLUSION: Our experience reported herein provides additional evidence for a favorable course in HSCT conducted in the early course of late-onset Krabbe disease.

Risk factors for postoperative complications in patients with Parkinson disease: A single center retrospective cohort study.

Surgical treatment for patients with Parkinson disease (PD) under general anesthesia has become frequent. PD is a significant predictor of postoperative complications. However, the factors that predict complications in patients with PD remain unknown. We retrospectively recruited patients with PD who underwent surgery between April 2015 and March 2019. The prevalence of postoperative complications was analyzed. We compared the patient characteristics, medical data, and surgical data between patients with and without postoperative complications. We also estimated the odds ratios (OR) for postoperative complications in patients with PD who underwent surgery. Sixty-five patients were enrolled. Eighteen patients presented with 22 complications, including urinary tract infections (UTI) (n = 3; 5%), pneumonia (n = 1; 2%), surgical site infections (SSI) (n = 3; 5%), postoperative delirium (POD) (n = 7; 10%), and others (n = 8; 12%). Four patients presented with 2 complications each. The operation time, the red blood cell transfusion and the rate of rotigotine usage were higher in patients with complications than those without (314 ± 197 min vs 173 ± 145 min, P = .006; 0 [0-560] mL vs 0 [0-0] mL, P = .02; 39% vs 6%, P = .003, respectively) (mean ± standard deviation or median [interquartile range]). Preoperative rotigotine usage (OR: 9.33; 95% confidential interval [CI]: 2.07-42.07; P = .004) was an independent risk factors for postoperative complications. The findings indicate that clinicians should closely monitor postoperative complications when patients with PD who have received transdermal dopamine agonists undergone longer time surgery.

Cardioprotective effects of enteral vs. parenteral lactoferrin administration on myocardial ischemia-reperfusion injury in a rat model of stunned myocardium.

BACKGROUND: Lactoferrin, an iron-binding glycoprotein, is known to have protective effects against intestinal and cerebral ischemia-reperfusion (IR) injuries; however, its cardioprotective effects against the stunned myocardium are unknown. This study aimed to test the hypothesis that lactoferrin has cardioprotective effects against stunned myocardium. METHODS: Using isolated rat hearts (Langendorff system), we determined the effects of lactoferrin administered enterally and by direct cardiac perfusion. Rat hearts were perfused using the Langendorff system, and two experiments were performed. In experiment 1, the hearts were divided into the enteral lactoferrin (E-LF) 7.5 m, 15 m, 30 m, and 60 m groups, where lactoferrin (1000 mg/kg) was administered enterally 7.5, 15, 30, and 60 min, respectively, before perfusion; and a control group, where saline was administered 30 min before perfusion. In experiment 2, hearts were allocated to the perfusate lactoferrin (P-LF) 15 and 100 groups, where 15 mg/L and 100 mg/L lactoferrin were respectively added to the perfusate, and a control group. Each group was perfused for 20 min prior to 15 min of no-flow ischemia with pacing, followed by 20 min of reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (LV dP/dt max) 15 min after reperfusion. Myocardial phospho-protein kinase B (p-Akt) was assayed using western blotting. RESULTS: The LV dP/dt max 15 min after reperfusion in the E-LF 15 and 30 m groups was significantly higher than that in the control group. However, the effects disappeared in the E-LF 60 m group. In the second experiment, there were no significant differences in LV dP/dt max. Myocardial p-Akt was not significantly activated in any lactoferrin group. CONCLUSION: Cardioprotection was observed 15-30 min after enteral lactoferrin but not by direct cardiac perfusion with lactoferrin. Myocardial p-Akt was not associated with the cardioprotective effect. The cardioprotective effect may be induced by enteral lactoferrin-induced substances.

Novel ultrashort-acting benzodiazepine remimazolam lowers shivering threshold in rabbits.

Shivering after surgery or during therapeutic hypothermia can lead to serious complications, such as myocardial infarction and respiratory failure. Although several anesthetics and opioids are shown to have anti-shivering effects, their sedative and respiratory side effects dampen the usefulness of these drugs for the prevention of shivering. In the present study, we explored the potential of a novel ultrashort-acting benzodiazepine, remimazolam, in the prevention of shivering using a rabbit model of hypothermia. Adult male Japanese white rabbits were anesthetized with isoflurane. The rabbits received saline (control), remimazolam (either 0.1 or 1 mg/kg/h), or remimazolam + flumazenil, a selective γ-aminobutyric acid (GABA) type A receptor antagonist (n = 6 each). Thirty minutes after discontinuation of the drugs, cooling was initiated by perfusing 10°C water via a plastic tube positioned in the colon until the animal shivered. Core body temperature and hemodynamic and physiological parameters were recorded. Remimazolam at 1 mg/kg/h significantly lowered the core temperature change during shivering (-2.50 ± 0.20°C vs. control: -1.00 ± 0.12°C, p = 0.0009). The effect of 1 mg/kg/h remimazolam on the core temperature change was abolished by flumazenil administration (-0.94 ± 0.16°C vs. control: -1.00 ± 0.12°C, p = 0.996). Most of the hemodynamic and physiological parameters did not differ significantly among groups during cooling. Remimazolam at a clinically relevant dose successfully suppressed shivering in rabbits via the GABA pathway even after its anesthetic effects likely disappeared. Remimazolam may have the potential to prevent shivering in patients undergoing surgery or therapeutic hypothermia.

PI3K/Akt pathway mediates the positive inotropic effects of insulin in Langendorff-perfused rat hearts.

Insulin exerts positive inotropic effects on cardiac muscle; however, the relationship between cardiac contractility and phosphoinositol-3-kinase/Akt (PI3K/Akt) activation remains unclear. We hypothesized that the positive inotropic effects of insulin are dose-dependent and mediated via the PI3K/Akt pathway in isolated normal rat hearts. The Institutional Animal Investigation Committee approved the use of hearts excised from rats under pentobarbital anesthesia. The hearts were perfused at a constant pressure using the Langendorff technique. After stabilization (baseline), the hearts were randomly divided into the following four insulin (Ins) groups: 1) Ins0 (0 IU/L), 2) Ins0.5 (0.5 IU/L), 3) Ins5 (5 IU/L), and 4) Ins50 (50 IU/L) (n = 8 in each group). To clarify the role of the PI3K/Akt pathway in insulin-dependent inotropic effects, we also treated the insulin groups with the PI3K inhibitor wortmannin (InsW): 5) InsW0 (0 IU/L), 6) InsW0.5 (0.5 IU/L), 7) InsW5 (5 IU/L), and 8) InsW50 (50 IU/L). Hearts were perfused with Krebs-Henseleit buffer solution with or without wortmannin for 10 min, followed by 20 min perfusion with the solution containing each concentration of insulin. The data were recorded as the maximum left ventricular derivative of pressure development (LV dP/dt max). Myocardial p-Akt levels were measured at 3 min, 5 min, and at the end of the perfusion. In the Ins groups, LV dP/dt max in Ins5 and Ins50 increased by 14% and 48%, respectively, 3 min after insulin perfusion compared with the baseline. Tachyphylaxis was observed after 10 min in the Ins5 and Ins50 treatment groups. Wortmannin partially inhibited the positive inotropic effect of insulin; although insulin enhanced p-Akt levels at all time points compared with the control group, this increase was suppressed in the presence of wortmannin. The positive inotropic effect of insulin is dose-dependent and consistent with Akt activation. This effect mediated by high doses of insulin on cardiac tissue was temporary and caused tachyphylaxis, potentially triggered by Akt overactivation, which leads beta 1 deactivation.

Intranasal administration of 40 and 80 units of insulin does not cause hypoglycemia during cardiac surgery: a randomized controlled trial.

PURPOSE: Intranasal insulin administration may improve cognitive function in patients with dementia and may prevent cognitive problems after surgery. Although the metabolic effects of intranasal insulin in non-surgical patients have been studied, its influence on glucose concentration during surgery is unknown. METHODS: We conducted a randomized, double-blind, placebo-contolled trial in patients scheduled for elective cardiac surgery. Patients with type 2 diabetes mellitus (T2DM) and non-T2DM patients were randomly allocated to one of three groups (normal saline, 40 international units [IU] of intranasal insulin, and 80 IU intranasal insulin). Insulin was given after the induction of general anesthesia. Glucose and plasma insulin concentrations were measured in ten-minute intervals during the first hour and every 30 min thereafter. The primary outcome was the change in glucose concentration 30 min after intranasal insulin administration. RESULTS: A total of 115 patients were studied, 43 of whom had T2DM. In non-T2DM patients, 40 IU intranasal insulin did not affect glucose concentration, while 80 IU intranasal insulin led to a statistically significant but not clinically important decrease in blood glucose levels (mean difference, 0.4 mMol·L-1; 95% confidence interval, 0.1 to 0.7). In T2DM patients, neither 40 IU nor 80 IU of insulin affected glucose concentration. No hypoglycemia (< 4.0 mMol·L-1) was observed after intranasal insulin administration in any patients. In non-T2DM patients, changes in plasma insulin were similar in the three groups. In T2DM patients, there was an increase in plasma insulin concentrations ten minutes after administration of 80 IU of intranasal insulin compared with saline. CONCLUSIONS: In patients with and without T2DM undergoing elective cardiac surgery, intranasal insulin administration at doses as high as 80 IU did not cause clinically important hypoglycemia. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT02729064); registered 5 April 2016.

RéSUMé: OBJECTIF: L'administration intranasale d'insuline pourrait améliorer la fonction cognitive des patients souffrant de démence et pourrait prévenir les problèmes cognitifs après une chirurgie. Bien que les effets métaboliques de l'insuline intranasale chez les patients non chirurgicaux aient été étudiés, son influence sur la glycémie pendant une chirurgie est inconnue. MéTHODE: Nous avons réalisé une étude randomisée, à double insu, contrôlée par placebo auprès de patients devant subir une chirurgie cardiaque non urgente. Des patients atteints de diabète de type 2 et des patients non diabétiques ont été randomisés dans l'un de trois groupes (solution physiologique salée, 40 unités internationales [UI] d'insuline intranasale et 80 UI d'insuline intranasale). La solution intranasale a été administrée après l'induction de l'anesthésie générale. Les concentrations de glucose et d'insuline plasmatique ont été mesurées à des intervalles de dix minutes pendant la première heure et toutes les 30 minutes par la suite. Le critère d'évaluation principal était le changement de glycémie 30 min après l'administration intranasale d'insuline. RéSULTATS: Un total de 115 patients ont été étudiés, dont 43 souffraient de diabète de type 2. Chez les patients non diabétiques, 40 UI d'insuline intranasale n'ont pas affecté la glycémie, alors que 80 UI d'insuline intranasale ont entraîné une réduction statistiquement significative mais non cliniquement importante de la glycémie (différence moyenne, 0,4 mMol·L−1; intervalle de confiance de 95 %, 0,1 à 0,7). Chez les patients diabétiques, ni 40 UI ni 80 UI d'insuline n'ont affecté la glycémie. Aucune hypoglycémie (< 4,0 mMol·L−1) n'a été observée après administration intranasale d'insuline chez les patients diabétiques ou non diabétiques. Chez les patients non diabétiques, les changements de l'insuline plasmatique étaient semblables dans les trois groupes. Chez les patients diabétiques, une augmentation des concentrations d'insuline plasmatique a été observée dix minutes après l'administration de 80 UI d'insuline intranasale comparée à la solution saline. CONCLUSION: Chez les patients diabétiques et non diabétiques subissant une chirurgie cardiaque non urgente, l'administration intranasale d'insuline à des doses allant jusqu'à 80 UI n'a pas causé d'hypoglycémie cliniquement importante. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.

Delayed awakening with apnea as a sign of cerebellar hemorrhage after vestibular schwannoma surgery: A case report.

Cerebellar hemorrhage after surgery is a rare but critical complication requiring prompt diagnosis and intervention. However, anesthetics can mask most brain compression signs. Prolonged coma with apnea after tumor resection under general anesthesia may indicate the need for prompt imaging to detect or exclude cerebellar lesions.

Short Sleep Duration on the Night Before Surgery Is Associated With Postoperative Cognitive Decline in Elderly Patients: A Prospective Cohort Study.

As the world is rapidly aging, and the number of elderly patients who undergo surgery is rising, postoperative cognitive decline among those patients has become an increasing healthcare problem. Although understanding the risk factors and mechanisms underlying the pathogenesis of postoperative cognitive decline is critically important from a preventative viewpoint, such knowledge and evidence are lacking. A growing body of evidence suggest an association between cognitive function and sleep duration. The purpose of this study was to investigate the association between postoperative cognitive function and sleep duration on the night before surgery using a wearable sleep tracker. In this 6-month prospective cohort study, we analyzed data from 194 patients aged ≥ 65 years who underwent elective non-cardiac and non-cranial surgery under general anesthesia. According to the sleep duration on the night before surgery, patients were categorized into following four groups: <5, 5-7, 7-9, and >9 h. Perioperative cognitive function and domains were assessed using a neuropsychological test battery, and the incidence and prevalence of cognitive decline over 6 months after surgery were analyzed using the multiple logistic regression analysis. During the 6-month follow-up period, 41 patients (21%) developed cognitive decline. The incidence of cognitive decline was significantly elevated for the patients with sleep duration < 5 h (vs. 7-9 h; surgical duration-adjusted odds ratio, 3.50; 95% confidence interval, 1.20-10.2; P < 0.05). The association between sleep duration and prevalence of cognitive decline was limited to the early postoperative period (at 1 week and 1 month). Among the cognitive domains assessed, attentional function was significantly impaired in patients with a sleep duration < 5 h [vs. 7-9 h at 1 week; 4/37 (10.8%) vs. 0/73 (0%); P < 0.05]. In conclusion, sleep duration < 5 h on the night before surgery was significantly associated with worse attentional function after surgery and higher incidence of cognitive decline. The present results indicate that sleep deprivation on the night before surgery may have a temporary but significantly negative influence on the patient's postoperative cognitive function and is a potential target for preventing cognitive decline.

Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

Adrenoleukodystrophy siblings with a novel ABCD1 missense variant presenting with phenotypic differences: a case report and literature review.

Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

Effects of spinal anesthesia and sedation with dexmedetomidine or propofol on cerebral regional oxygen saturation and systemic oxygenation a period after spinal injection.

PURPOSE: To evaluate changes in cerebral regional oxygen saturation (rSO2) after spinal anesthesia and compare the changes in rSO2 and systemic oxygenation between dexmedetomidine sedation and propofol sedation. METHODS: Thirty-six patients scheduled to undergo transurethral surgery under spinal anesthesia were randomly assigned to the dexmedetomidine (n = 18) and propofol groups (n = 18). We used near-infrared spectroscopy sensors to measure rSO2, and obtained data from each side were averaged. After oxygen insufflation, baseline measurements of mean arterial blood pressure (MAP), heart rate, rSO2, pulse oximetry saturation (SpO2), bispectral index, and body temperature were made. After spinal anesthesia, we measured these parameters every 5 min. Twenty minutes after spinal injection, dexmedetomidine or propofol administration was started. We measured each parameter at 10, 25, and 40 min after the administration of dexmedetomidine or propofol. RESULTS: The baseline rSO2 in the dexmedetomidine group was 71.3 ± 7.3%, and that in the propofol group was 71.8 ± 5.6%. After spinal anesthesia, rSO2 in both groups decreased significantly (dexmedetomidine group: 65.4 ± 6.9%; propofol group: 64.3 ± 7.4%). After administering sedatives, rSO2 was equivalent after spinal anesthesia. rSO2 was comparable between the two groups. MAP and SpO2 were significantly higher in the dexmedetomidine group than in the propofol group. CONCLUSION: Spinal anesthesia decreased rSO2; however, the decline was not severe. Dexmedetomidine and propofol did not compromise cerebral oxygenation under spinal anesthesia. Nevertheless, MAP and SpO2 were more stable in dexmedetomidine sedation than in propofol sedation. Dexmedetomidine may be suitable for spinal anesthesia.

Changes of cerebral regional oxygen saturation during pneumoperitoneum and Trendelenburg position under propofol anesthesia: a prospective observational study.

BACKGROUND: We evaluated the change of cerebral regional tissue oxygen saturation (rSO2) along with the pneumoperitoneum and the Trendelenburg position. We also assessed the relationship between the change of rSO2 and the changes of mean arterial blood pressure (MAP), heart rate (HR), arterial carbon dioxide tension (PaCO2), arterial oxygen tension (PaO2), or arterial oxygen saturation (SaO2). METHODS: Forty-one adult patients who underwent a robotic assisted endoscopic prostatic surgery under propofol and remifentanil anesthesia were involved in this study. During the surgery, a pneumoperitoneum was established using carbon dioxide. Measurements of rSO2, MAP, HR, PaCO2, PaO2, and SaO2 were performed before the pneumoperitoneum (baseline), every 5 min after the onset of pneumoperitoneum, before the Trendelenburg position. After the onset of the Trendelenburg position, rSO2, MAP, HR were recorded at 5, 10, 20, 30, 45, and 60 min, and PaCO2, PaO2, and SaO2 were measured at 10, 30, and 60 min. RESULTS: Before the pneumoperitoneum, left and right rSO2 were 67.9 ± 6.3% and 68.5 ± 7.0%. Ten minutes after the onset of pneumoperitoneum, significant increase in the rSO2 was observed (left: 69.6 ± 5.9%, right: 70.6 ± 7.4%). During the Trendelenburg position, the rSO2 increased initially and peaked at 5 min (left: 72.2 ± 6.5%, right: 73.1 ± 7.6%), then decreased. Multiple regression analysis showed that change of rSO2 correlated with MAP and PaCO2. CONCLUSIONS: Pneumoperitoneum and the Trendelenburg position in robotic-assisted endoscopic prostatic surgery did not worsen cerebral oxygenation. Arterial blood pressure is the critical factor in cerebral oxygenation. TRIAL REGISTRATION: Japan Primary Registries Network (JPRN); UMIN-CTR ID; UMIN000026227 (retrospectively registered).

Accuracy of blood glucose measurements using the NOVA StatStrip® glucometer during cardiac surgery: a prospective observational study.

PURPOSE: The Nova StatStrip® Glucose Hospital Meter System (Nova Biomedical, Waltham, MA, USA) is United States Food and Drug Administration approved for point-of-care use in critically ill patients, but its use during cardiac surgery has not been evaluated. In this study, we compare glucose values obtained during cardiac surgery by StatStrip® with values obtained by a blood gas analyzer. METHODS: Blood glucose concentrations were analyzed in 121 patients by the StatStrip point- of-care test (POCT) glucose monitor and the GEM® Premier™ 3000 blood gas analyzer (Instrumentation Laboratory Company, Bedford MA, USA). Arterial blood samples were taken at baseline (before surgery), before cardiopulmonary bypass (CPB), during early and late CPB, and 30 min after CPB. Accuracy of the StatStrip glucometer was analyzed using the Clinical and Laboratory Standards Institute (CLSI) POCT12-A3 criteria (criterion 1; 95% of samples should be ± 0.66 mMol·L-1 of reference glucose values < 5.5 mMol·L-1 and ± 12.5% for reference glucose values > 5.5 mMol·L-1, criterion 2; 98% of samples should be ± 0.83 mMol·L-1 of reference glucose values < 4.1 mMol·L-1 or 20% of the reference glucose for values > 4.1 mMol·L-1). RESULTS: The accuracy of StatStrip glucose measurements at baseline (99%, 100%) and before CPB (95%, 98%), but not during (early: 84%, 97%; late: 83%, 96%) and after (92%, 100%) CPB, satisfied the CLSI POCT12-A3 criteria. CONCLUSION: Arterial blood glucose measurement by StatStrip was accurate before CPB, but lacked accuracy during and after CPB. Glucose values should be interpreted with caution when intensive glucose control protocols are being used during cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02729064); registered 5 April, 2016.

RéSUMé: OBJECTIF: Le glucomètre hospitalier StatStrip® de Nova (Nova Biomedical, Waltham, MA, É.-U.) est approuvé par la FDA (Food and Drug Administration) américaine pour une utilisation au chevet chez les patients en état critique, mais son utilisation n'a pas été évaluée en chirurgie cardiaque. Dans cette étude, nous avons comparé les valeurs glycémiques obtenues par le lecteur StatStrip® et les valeurs obtenues par un analyseur des gaz du sang pendant une chirurgie cardiaque. MéTHODE: Les concentrations glycémiques de 121 patients ont été analysées en utilisant le moniteur glycémique StatStrip et l'analyseur de gaz sanguins GEM® Premier™ 3000 (Instrumentation Laboratory Company, Bedford, MA, É.-U.). Des échantillons de sang artériel ont été prélevés avant la chirurgie, avant la circulation extracorporelle (CEC), au début et à la fin de la CEC et 30 min après la CEC. La précision du glucomètre StatStrip a été analysée à l'aide des critères de l'Institut des normes cliniques et de laboratoire (Clinical and Laboratory Standards Institute (CLSI)) POCT12-A3 (1er critère; 95 % des échantillons doivent être à l'intérieur de ± 0,66 mMol·L−1 des valeurs glycémiques de référence < 5,5 mMol·L−1 et ± 12,5 % pour les valeurs glycémiques de référence > 5,5 mMol·L−1, 2ème critère; 98 % des échantillons doivent être à l'intérieur de ± 0,83 mMol·L−1 des valeurs glycémiques de référence < 4,1 mMol·L−1 ou 20 % du taux glycémique de référence pour les valeurs > 4,1 mMol·L−1). RéSULTATS: La précision des mesures glycémiques prises par le StatStrip avant l'opération (99 %, 100 %) et avant la CEC (95 %, 98 %), mais non durant (début : 84 %, 97 %; fin : 83 %, 96 %) et après (92 %,100 %) la CEC, respectait les critères POCT12-A3 du CLSI. <0} CONCLUSION: La mesure de la glycémie artérielle réalisée avec le StatStrip était précise avant la CEC mais a manqué de précision pendant et après la CEC. Les valeurs glycémiques devraient donc être interprétées avec prudence lorsque des protocoles intensifs de contrôle glycémique sont utilisés pendant une chirurgie cardiaque. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.