Akihito Tampo

The A3 adenosine receptor agonist CP-532,903 [N6-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel.

We examined the cardioprotective profile of the new A3 adenosine receptor (AR) agonist CP-532,903 [N6-(2,5-dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] in an in vivo mouse model of infarction and an isolated heart model of global ischemia/reperfusion injury. In radioligand binding and cAMP accumulation assays using human embryonic kidney 293 cells expressing recombinant mouse ARs, CP-532,903 was found to bind with high affinity to mouse A3ARs (Ki = 9.0 ± 2.5 nM) and with high selectivity versus mouse A1AR (100-fold) and A2AARs (1000-fold). In in vivo ischemia/reperfusion experiments, pretreating mice with 30 or 100 μg/kg CP-532,903 reduced infarct size from 59.2 ± 2.1% of the risk region in vehicle-treated mice to 42.5 ± 2.3 and 39.0 ± 2.9%, respectively. Likewise, treating isolated mouse hearts with CP-532,903 (10, 30, or 100 nM) concentration dependently improved recovery of contractile function after 20 min of global ischemia and 45 min of reperfusion, including developed pressure and maximal rate of contraction/relaxation. In both models of ischemia/reperfusion injury, CP-532,903 provided no benefit in studies using mice with genetic disruption of the A3AR gene, A3 knockout (KO) mice. In isolated heart studies, protection provided by CP-532,903 and ischemic preconditioning induced by three brief ischemia/reperfusion cycles were lost in Kir6.2 KO mice lacking expression of the pore-forming subunit of the sarcolemmal ATP-sensitive potassium (KATP) channel. Whole-cell patch-clamp recordings provided evidence that the A3AR is functionally coupled to the sarcolemmal KATP channel in murine cardiomyocytes. We conclude that CP-532,903 is a highly selective agonist of the mouse A3AR that protects against ischemia/reperfusion injury by activating sarcolemmal KATP channels.

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.

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.

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

ABSTRACT 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.

Use of a new curved forceps for McGrath MAC TM video laryngoscope to remove a foreign body causing airway obstruction

view was achieved. Tracheal intubation was performed under vision, using the image displayed on the built-in monitor of the McGrath MACTM. Some chicken meat particles were suctioned through the tracheal tube, and ventilation was performed effectively. The SpO2 rapidly returned to 99%. The patient recovered consciousness after 1 h and became rousable on vocal stimulus. The tracheal tube was removed and he recovered uneventfully within a day.

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 (&agr;-subunit), mutant KCNQ1, wild-type KCNE1 (&bgr;-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.

A successful management of difficult airway in a neonate with vallecular cyst.

Sir, Vallecular cysts are rare but cause respiratory failure in neonates and infants by obstructing the upper airway. They may also cause problems with direct laryngoscopy and tracheal intubation, and there have been several reports of difficult airway management because of a vallecular cyst in infants (1,2). We describe successful tracheal intubation with the PentaxAWS Airway Scope (AWS; HOYA, Tokyo, Japan) in a neonate with a giant vallecular cyst. The AWS is an indirect laryngoscope that has a built-in camera and LCD monitor. It is used with an attachable blade (PBlade) designed as an anatomical shape, and it has a tube channel on its side. The tube channel holds a tracheal tube and guides the tube towards the vocal cords, which are adjusted to the target symbol displayed on the monitor. Recently, a new AWS PBlade designed for neonates has become commercially available, and we have reported its potential efficacy in infant tracheal intubation (3). A 23-day-old female neonate, born at a gestational age of 39 weeks, who was 50 cm in height and weighed 3288 g, was admitted with an episode of inspiratory stridor, and a computed tomography scan revealed a 14 mm 9 15 mm cystic mass on her epiglottic vallecula. Thus, she was scheduled for emergency fenestration surgery of the vallecular cyst under general anaesthesia. To avoid the risk of airway obstruction by the movable cyst, sedatives or opioids were not given before tracheal intubation. Although an experienced paediatrician attempted tracheal intubation several times with a Miller laryngoscope, the vocal cords were not visible due to the giant cyst. Rigid scope-assisted intubation was also attempted by the paediatrician and an otolaryngologist. A part of the arytenoid region could only be visualized behind the folded epiglottis on the external monitor for a second (Fig. 1A), and a tracheal tube could not be placed into the trachea. Next, the AWS with a neonatal PBlade was used by an anaesthesiologist. The blade tip of the AWS was smoothly advanced behind the epiglottis, and the vocal cords were visualized as Cormack grade 1 on the built-in monitor. Then, the tracheal tube was advanced into the trachea, guided by the tube channel. The operation was successfully performed under general anaesthesia with sevoflurane and fentanyl administration, and the infant was intubated postoperatively for 14 hours under sedation with fentanyl and midazolam. After fiberoptic examination to exclude oedema formation and airway obstruction by the cyst wall, the patient was extubated without complications. Airway management of infant patients with vallecular cysts has been reported. For infant airway management, paraglossal straight blade laryngoscopy and fiberoptic laryngoscopy have been reported, and Kalra et al. (2) proposed that awake fiberoptic nasotracheal intubation may be the preferred choice for paediatric patients with vallecular cysts. In fiberoptic intubation, the tracheal tube passes between the vocal cords over the fiberscope in a blind manner, and this can damage laryngeal structures. Thus, devices that can provide a glottic view during tube advancement should be selected for tracheal intubation, if possible. To obtain a view of the vocal cords, the tips of both the Miller laryngoscope and the AWS are inserted behind the epiglottis. In the present case, the vallecular cyst occupied the front to middle part of the larynx and pushed the epiglottis posteriorly. The Miller laryngoscope failed to reach the back side of the epiglottis due to the cyst. On the other hand, the AWS was advanced along the posterior wall of the pharynx and larynx, and then after it reached behind the epiglottis, it was gently elevated to visualize the vocal cords. As the camera is located 20 mm away from the PBlade tip, once the tip was positioned correctly, the laryngeal structures were easily visible on the built-in monitor. With the use of a target symbol and the tube guide channel, tracheal intubation was successfully conducted with less force against the vallecular cyst. We conclude that the AWS

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.

In reply: advantage of Parker Flex-tip Tube® in endotracheal intubation using AirwayScope® videolaryngoscope

To the Editor: Difficult tube insertion due to impingement of the straight reinforced tube in combination with the PentaxAWS (AWS) has been well recognized [1], as the Intlock blade is designed for a curved, not for the straight, tube. Dr. Kinoshita introduced their work that the insertion of the straight reinforced tube can be facilitated when the AWS blade tip is inserted into the vallecula (Macintoshtype approach) [2]. Although we did reported the successful intubation with the AWS by the Macintosh approach after the blade tip failed to lift the epiglottis [3], we are not aiming to introduce the solution after failed tube insertion in our human study, as the title shows [4]. We simply proposed that the AWS can be used with either the blade inserted into the vallecula or inserted posterior to the epiglottis for laryngeal exposure with the Parker tube. Generally, when the AWS blade tip was inserted posterior to the epiglottis, standard curved-tube insertion was easily performed by maneuvering the blade tip direction to adjust the target symbol on the vocal cords seen in the monitor. Therefore, we think the incidence of difficult tube advancement for the curved tube is very low. The impossibility of lifting the epiglottis by the blade tip is also rare in the Japanese population, and our single case [3] was only one of 2,000 cases in our hospital. Recently, Cavus proposed ‘‘the straight-blade technique’’ for the curved videolaryngoscope and that direct elevation of the epiglottis (Miller-type approach) can improve the view and increase the chance of successful intubation [5]. Our report proposed the AWS can be used not only with the Miller-type approach but also with the Macintosh-type approach for laryngeal exposure during intubation when combined with the Parker tube. We also reported that both Miller and Macintosh approaches can be effectively used for nasotracheal intubation with the AWS [6]. These ‘‘tips’’ can enhance the usefulness of the AWS in the clinical setting.

Nasotracheal intubation by combined use of a Bullard™ laryngoscope and a cuff inflation technique in a patient with a severely restricted mouth opening

To the Editor, The Bullard laryngoscope (Circon ACMI, Stamford, CT, USA) is an anatomically shaped rigid fibreoptic laryngoscope that has been used for more than two decades. One of its unique characteristics is a very thin blade that requires only a 6-mm mouth opening for insertion. We report a case in which nasotracheal intubation was performed by combined use of a Bullard laryngoscope and a cuff inflation technique in a patient with a severely restricted mouth opening. The patient provided written informed consent for publication of this case. A 66-yr-old male patient, 157 cm tall and weighing 45.5 kg, was scheduled for keratoplasty. The size of his mouth opening was only about 9.5 mm because of previous radiation therapy for maxillary sinus cancer; thus, nasotracheal intubation was planned for airway management. The Bullard laryngoscope was selected for this procedure instead of a fibrescope because with the fibrescope, the tracheal tube is advanced in a blind manner and this may cause airway trauma; arytenoid cartilage dislocation or vocal cord trauma. General anesthesia was induced with fentanyl 150 lg and propofol 30 mg. Bag and mask ventilation was performed successfully, and then rocuronium 40 mg and remifentanil 0.3 lg kg min were administered. Even after neuromuscular blockade, no additional mouth opening was obtained. A 7.5-mm internal diameter tracheal tube was inserted nasally, and the Bullard laryngoscope was inserted orally to lift the epiglottis directly. A laryngeal view was easily obtained through the eyepiece of the Bullard laryngoscope, and then the tracheal tube was advanced carefully into the field of view. Before the laryngeal inlet was reached, the tracheal tube cuff was inflated to lift the tube tip and direct it towards the vocal cords. The cuff was then deflated to pass through the vocal cords. The tracheal tube was successfully inserted into the trachea, and general anesthesia was maintained throughout the operation without any complications. Also, no complications were encountered during postanesthesia rounds. In the past several years, anatomically shaped indirect laryngoscopes with a tracheal tube guide channel, such as the Pentax Airway Scope (HOYA, Tokyo, Japan) and the Airtraq (Prodol Meditec SA, Vizcaya, Spain), have become very popular and have been reported to be useful in airway management. Although several studies have shown that the Airway Scope and Airtraq are more useful than the Bullard laryngoscope for orotracheal intubation and even for nasotracheal intubation, these laryngoscopes have a bulky blade configuration because the tube channel is thicker than the tube diameter (Figure). Even the version of the Airtraq designed for nasotracheal intubation, which is devoid of a tube guide channel, requires an 18-mm mouth opening for insertion; therefore, in our case, the thinner blade of the Bullard laryngoscope was adequate to obtain a laryngeal view. The alternative approaches we could have considered in our case include a fibreoptic bronchoscopic intubation or a lightwandguided technique through the nostril. However, both techniques involve tracheal tube advancement in a blind manner, which may cause trauma, particularly to the arytenoid cartilage or vocal cords. A Bullard laryngoscope-assisted nasotracheal intubation can be a useful approach in patients with a severely restricted mouth opening because it provides a good laryngeal view and continuous observation of tube insertion throughout the procedure. A. Tampo, MD, PhD (&) A. Suzuki, MD, PhD M. Matsumoto, MD H. Iwasaki, MD, PhD Asahikawa Medical University, Asahikawa, Hokkaido, Japan e-mail: atampo1031@gmail.com