Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).

Mutations in the nonstructural proteins of SARS-CoV-2 may contribute to adverse clinical outcome in patients with COVID-19.

BACKGROUND: From late March through April 2021, we experienced a cluster of patients with COVID-19, named "Cluster K", with rapid severe illness compared with those who were infected before. METHODS: Patients with COVID-19 who were enrolled in this study were divided into two groups: 66 patients from November 2020 to March 2021 (group A) and 37 patients whose infection links were traced from Cluster K (group B). The primary outcome was mortality rate, and the secondary outcome was maximal oxygen flow rate as the severity of the disease. Viral genome sequences were compared between the two groups. RESULTS: Mortality rates were 6.1% in group A and 16.2% in group B (odds ratio: 2.97, 95% confidence interval: 0.65-15.38). The patients in group B required high oxygen flow rate (O2 ≥10 l/min) in the earlier clinical course (P = 0.029). Viral genome sequences revealed five amino acid mutations; of these, four were found on three nonstructural proteins (NSPs): one in nsp3 and nsp15, two in nsp6 (one of them is near the potential sites under positive selective pressure). Another one was on the S protein. CONCLUSION: This study suggests that mutations in NSPs, especially nsp6, are associated with adverse clinical outcome in patients with COVID-19.

Ability of CP-532,903 to protect mouse hearts from ischemia/reperfusion injury is dependent on expression of A3 adenosine receptors in cardiomyoyctes.

A3 adenosine receptor (A3AR) agonists are effective at limiting injury caused by ischemia/reperfusion injury of the heart in experimental animal models. However, understanding of their mechanism of action, which is likely multifactorial, remains incomplete. In prior studies, it has been demonstrated that A3AR-mediated ischemic protection is blocked by glibenclamide and is absent in Kir6.2 gene ablated mice that lack the pore-forming subunit of the ATP-sensitive potassium (KATP) channel, suggesting one contributing mechanism may involve accelerated activation of KATP channels. However, presence of A3ARs in the myocardium has yet to be established. Utilizing a whole-cell recording technique, in this study we confirm functional expression of the A3AR in adult mouse ventricular cardiomyocytes, coupled to activation of ATP-dependent potassium (KATP) channels via Gi inhibitory proteins. We further show that ischemic protection provided by the selective A3AR agonist CP-532,903 in an isolated, buffer-perfused heart model is lost completely in Adora3LoxP/LoxP;Myh6-Cre mice, which is a newly developed model developed and comprehensively described herein whereby the A3AR gene (Adora3) is deleted exclusively in cardiomyocytes. Our findings, taken together with previously published work, are consistent with the hypothesis that A3AR agonists provide ischemic tolerance, at least in part, by facilitating opening of myocardial KATP channels.

Three-step procedure for safe internal jugular vein catheterization under ultrasound guidance.

Real-time ultrasound guidance for central venous catheterization has become a standard technique. This technique has been reported to yield high success rates and fewer complications compared with landmark techniques. However, it can be risky when the practitioner does not possess proper knowledge and skills. Lose sight of the needle tip can lead to severe complications such as arterial puncture or pneumothorax. Also, posterior wall penetration of the target vessels must be avoided. Misplacement of the catheter to other vessels can sometimes occur, and may only be discovered after the catheterization procedure. To avoid these complications, we perform a three-step procedure to place an internal jugular vein catheter under ultrasound guidance. The three steps are: (a) advance the needle tip to the internal jugular vein with a short-axis image with an out-of-plane technique, (b) rupture the anterior wall by using a long-axis image with an in-plane technique, and (c) confirm the guidewire position from the internal jugular vein to the brachiocephalic vein using a short-axis image, and a coronal image from the supraclavicular fossa. For safe needle advancement and penetration of the anterior wall of the vein, combined use of short-axis and long-axis images is helpful, and guidewire placement should be confirmed by scanning with the short-axis image and the coronal image.

Low-dose immunoglobulin G is not associated with mortality in patients with sepsis and septic shock.

BACKGROUND: The administration of low-dose intravenous immunoglobulin G (IVIgG) (5 g/day for 3 days; approximate total 0.3 g/kg) is widely used as an adjunctive treatment for patients with sepsis in Japan, but its efficacy in the reduction of mortality has not been evaluated. We investigated whether the administration of low-dose IVIgG is associated with clinically important outcomes including intensive care unit (ICU) and in-hospital mortality. METHODS: This is a post-hoc subgroup analysis of data from a retrospective cohort study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study. The JSEPTIC DIC study was conducted in 42 ICUs in 40 institutions throughout Japan, and it investigated associations between sepsis-related coagulopathy, anticoagulation therapies, and clinical outcomes of 3195 adult patients with sepsis and septic shock admitted to ICUs from January 2011 through December 2013. To investigate associations between low-dose IVIgG administration and mortalities, propensity score-based matching analysis was used. RESULTS: IVIgG was administered to 960 patients (30.8%). Patients who received IVIgG were more severely ill than those who did not (Acute Physiology and Chronic Health Evaluation (APACHE) II score 24.2 ± 8.8 vs 22.6 ± 8.7, p < 0.001). They had higher ICU mortality (22.8% vs 17.4%, p < 0.001), but similar in-hospital mortality (34.4% vs 31.0%, p = 0.066). In propensity score-matched analysis, 653 pairs were created. Both ICU mortality and in-hospital mortality were similar between the two groups (21.0% vs 18.1%, p = 0.185, and 32.9% vs 28.6%, p = 0.093, respectively) using generalized estimating equations fitted with logistic regression models adjusted for other therapeutic interventions. The administration of IVIgG was not associated with ICU or in-hospital mortality (odds ratio (OR) 0.883; 95% confidence interval (CI) 0.655-1.192, p = 0.417, and OR 0.957, 95% CI, 0.724-1.265, p = 0.758, respectively). CONCLUSIONS: In this analysis of a large cohort of patients with sepsis and septic shock, the administration of low-dose IVIgG as an adjunctive therapy was not associated with a decrease in ICU or in-hospital mortality. TRIAL REGISTRATION: University Hospital Medical Information Network Individual Clinical Trials Registry, UMIN-CTR000012543 . Registered on 10 December 2013.

Antithrombin Supplementation and Mortality in Sepsis-Induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study.

Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of AT supplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n = 715, AT group; n = 1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (n = 1,784, odds ratio [95% confidence intervals]: 0.748 [0.572-0.978], P = 0.034). However, quintile-stratified propensity score analysis (n = 1,784, odds ratio: 0.823 [0.646-1.050], P = 0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649-1.125], P = 0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (P = 0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

Characteristics, treatments, and outcomes of severe sepsis of 3195 ICU-treated adult patients throughout Japan during 2011-2013.

Severe sepsis is a major concern in the intensive care unit (ICU), although there is very little epidemiological information regarding severe sepsis in Japan. This study evaluated 3195 patients with severe sepsis in 42 ICUs throughout Japan. The patients with severe sepsis had a mean age of 70 ± 15 years and a mean Acute Physiology and Chronic Health Evaluation II score of 23 ± 9. The estimated survival rates at 28 and 90 days after ICU admission were 73.6 and 56.3 %, respectively.

Computed tomography findings of complications resulting from cardiopulmonary resuscitation.

INTRODUCTION: This retrospective study was conducted to evaluate injuries related to cardiopulmonary resuscitation (CPR) and their associated factors using postmortem computed tomography (PMCT) and whole body CT after successful resuscitation. METHODS: The inclusion criteria were adult, non-traumatic, out-of-hospital cardiac arrest patients who were transported to our emergency room between April 1, 2008 and March 31, 2013. Following CPR, PMCT was performed in patients who died without return of spontaneous circulation (ROSC). Similarly, CT scans were performed in patients who were successfully resuscitated within 72h after ROSC. The injuries associated with CPR were analysed retrospectively on CT images. RESULTS: During the study period, 309 patients who suffered out-of hospital cardiac arrest were transported to our emergency room and received CPR; 223 were enrolled in the study. The CT images showed that 156 patients (70.0%) had rib fractures, and 18 patients (8.1%) had sternal fractures. Rib fractures were associated with older age (78.0 years vs. 66.0 years, p<0.01), longer duration of CPR (41min vs. 33min, p<0.01), and lower rate of ROSC (26.3% vs. 55.3%, p<0.01). All sternal fractures occurred with rib fractures and were associated with a greater number of rib fractures, higher age, and a lower rate of ROSC than rib fractures only cases. Bilateral pneumothorax was observed in two patients with rib fractures. CONCLUSIONS: PMCT is useful for evaluating complications related to chest compression. Further investigations with PMCT are needed to reduce complications and improve the quality of CPR.

Enhanced effects of isoflurane on the long QT syndrome 1-associated A341V mutant.

BACKGROUND: The impact of volatile anesthetics on patients with inherited long QT syndrome (LQTS) is not well understood. This is further complicated by the different genotypes underlying LQTS. No studies have reported on the direct effects of volatile anesthetics on specific LQTS-associated mutations. We investigated the effects of isoflurane on a common LQTS type 1 mutation, A341V, with an unusually severe phenotype. METHODS: Whole cell potassium currents (IKs) were recorded from HEK293 and HL-1 cells transiently expressing/coexpressing wild-type KCNQ1 (α-subunit), mutant KCNQ1, wild-type KCNE1 (ß-subunit), and fusion KCNQ1 + KCNE1. Current was monitored in the absence and presence of clinically relevant concentration of isoflurane (0.54 ± 0.05 mM, 1.14 vol %). Computer simulations determined the resulting impact on the cardiac action potential. RESULTS: Isoflurane had significantly greater inhibitory effect on A341V + KCNE1 (62.2 ± 3.4%, n = 8) than on wild-type KCNQ1 + KCNE1 (40.7 ± 4.5%; n = 9) in transfected HEK293 cells. Under heterozygous conditions, isoflurane inhibited A341V + KCNQ1 + KCNE1 by 65.2 ± 3.0% (n = 13) and wild-type KCNQ1 + KCNE1 (2:1 ratio) by 32.0 ± 4.5% (n = 11). A341V exerted a dominant negative effect on IKs. Similar differential effects of isoflurane were also observed in experiments using the cardiac HL-1 cells. Mutations of the neighboring F340 residue significantly attenuated the effects of isoflurane, and fusion proteins revealed the modulatory effect of KCNE1. Action potential simulations revealed a stimulation frequency-dependent effect of A341V. CONCLUSIONS: The LQTS-associated A341V mutation rendered the IKs channel more sensitive to the inhibitory effects of isoflurane compared to wild-type IKs in transfected cell lines; F340 is a key residue for anesthetic action.

[Role of ultrasound in airway management].

Recent advancement in ultrasound technology allows us to visualize detailed structures around the airway. One of the important roles of the airway ultrasound is to identify cricothyroid membrane where the emergent invasive access should be performed. Now we can assess the risk of difficult cricothyroidotomy before anesthesia of which the new ASA difficult airway guideline suggests. Airway ultrasound can also be used to confirm correct position of the tracheal tube and laryngeal mask, difficult laryngoscopy prediction in obese patients, assessing vocal cord function, prediction of the post extubation stridor, and so on. We also introduce perioperative evaluation of the airway via sonography (PEAS) protocol in this review.

Parker Flex-Tip Tube® provides higher intubation success with the Pentax-AWS Airwayscope® despite the AWS tip being inserted into the vallecula.

The Parker Flex-Tip(®) tube, in combination with the Pentax-Airwayscope(®) (AWS), is anecdotally reported to facilitate intubation when the AWS tip fails to be inserted behind the epiglottis. We examined whether the Parker tube facilitates intubation when the AWS tip is inserted into the vallecula. Forty patients were randomly assigned into either the standard or Parker tube group. Following general anesthesia induction, AWS intubation was attempted with the blade tip inserted into the vallecula. After obtaining an optimal laryngeal view, the tube was advanced toward the glottis. The laryngoscopist allowed additional adjustment of the blade tip direction when the first tube insertion failed because of involvement or folding of the epiglottis resulting from advancement of the tube. The primary outcome was defined as the success rate for intubation and secondary outcome as the time needed for tube placement. The Parker tube provided both a higher intubation success rate (17/20 vs. 4/20, P < 0.01), and a faster intubation time (17 ± 5 s vs. 25 ± 4 s, P < 0.01), than the standard tube. We conclude the use of the Parker tube in combination with the AWS is an optional technique allowing the laryngoscopist to obtain more reliable intubation success despite insertion of the AWS tip into the vallecula.

Protective actions of epoxyeicosatrienoic acid: dual targeting of cardiovascular PI3K and KATP channels.

Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (KATP) channels (sarcolemmal and mitochondrial), calcium-activated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K). We tested if EETs protect human atrial tissue ex vivo from hypoxia/reoxygenation (H/R) injury, and compared our results with myocardium from two rodent species, rats and mice. EETs reduced myocardial caspase 3 activity in all three species and protected against loss of mitochondrial membrane potential in primary cultures of neonatal rat ventricular myocytes submitted to H/R. In addition, EETs protected mouse pulmonary arteries ex vivo exposed to H/R. Myocardium and pulmonary arteries from genetically engineered mice having elevated plasma levels of EETs (Ephx2-/-) exhibited protection from H/R-induced injury over that of wild type controls, suggesting that endogenously produced EETs may have pro-survival effects. Electrophysiological studies in myocytes demonstrated that EETs can stimulate KATP currents even when PI3K is inhibited. Similarly, activation of PI3K/Akt occurred in the presence of the KATP channel blocker glibenclamide. Based upon loss of protection with EETs in the presence of either wortmannin (a PI3K inhibitor) or glibenclamide, simultaneous activation of at least 2 pathways, PI3K and KATP channels respectively, appears to be required for protection. In conclusion, we demonstrate that exogenous and endogenous EETs have powerful pro-survival effects in cardiovascular tissues including diseased human myocardium, mediated by activation of not only one but at least two pathways, PI3K and KATP channels.