The effectiveness and safety of landiolol hydrochloride, an ultra-short-acting ß1-blocker, in postoperative patients with supraventricular tachyarrhythmias: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Persistent postoperative supraventricular tachyarrhythmias (SVTs) increase cardiac burden and aggravate cardiac hemodynamics. Therefore, for patients in unstable conditions after surgery, prompt and sustained control of heart rate is essential. The importance of ß-adrenoceptor antagonists (ß-blockers) in controlling such postoperative atrial fibrillation or atrial flutter has been established, and the usefulness of ultra-short-acting ß1-blockers with high ß1 selectivity has been suggested based on their safety and efficacy under such circumstances. OBJECTIVES: Our objectives were to evaluate the effectiveness and safety of landiolol hydrochloride, an ultra-short-acting ß1-selective blocker, in the treatment of postoperative SVT in patients with a high risk of myocardial ischemia, or in patients after highly invasive surgery, in a multicenter, randomized, double-blind, placebo-controlled, group-comparative study. METHODS: A total of 165 patients were randomly allocated to three groups and received LM or MH doses of landiolol hydrochloride or placebo. LM group: dose L (1-min loading dose at a rate of 0.03 mg/kg/min, followed by a 10-min infusion at 0.01 mg/kg/min) followed by dose M (1-min loading at a rate of 0.06 mg/kg/min, followed by a 10-min infusion at 0.02 mg/kg/min); MH group: dose M followed by dose H (1-min loading dose at a rate of 0.125 mg/kg/min, followed by a 10-min infusion at 0.04 mg/kg/min); placebo (PP) group: dose P (1-min loading dose at a rate of 0 mg/kg/min, followed by a 10-min infusion at 0 mg/kg/min) followed by another round of dose P. If the targeted heart-rate reduction was not obtained at the end of the first 10-min infusion, the higher dose was started. The primary endpoint was the percentage of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min). The safety endpoint was the incidence of adverse events in each of the three groups. RESULTS: The percentages of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min) were 0.0, 60.4, and 42.0 % in the PP, LM, and MH groups, respectively. There were significant differences in the LM and MH groups relative to the PP group, but there was no significant difference between the LM and MH groups. No significant difference was observed in the incidence of adverse events among the three groups: 29.6 % in the PP group, 45.5 % in the LM group, and 43.1 % in the MH group. CONCLUSION: Landiolol hydrochloride is effective and safe for patients with postoperative SVT.

Dose-dependent effect of landiolol, a new ultra-short-acting ß(1)-blocker, on supraventricular tachyarrhythmias in postoperative patients.

BACKGROUND: ß-Adrenoceptor antagonists (ß-blockers) have been reported to be effective for regulation of heart rate (HR) and restoring sinus rhythm in postoperative atrial fibrillation and atrial flutter, as well as in the prevention of those arrhythmias after open-heart surgery. OBJECTIVES: The objectives of this study were to evaluate the dose-dependent effects of landiolol, an ultra-short-acting ß1-blocker, as well as the effectiveness and safety of the drug in suppressing supraventricular tachyarrhythmias (SVT) in postoperative patients. METHODS: Landiolol was administered as a four-dose titration regimen (LL, L, M, and H doses) to postoperative patients who developed SVT. The titration sequence began with a 1-min loading infusion at a rate of 0.015 mg/kg/min, followed by a 10-min continuous infusion at 0.005 mg/kg/min (the LL dose). Infusions at progressively higher doses followed in sequence until 20 % reduction in HR was achieved. The L dose was a 1-min loading infusion at 0.03 mg/kg/min, followed by a 10-min continuous infusion at 0.01 mg/kg/min. The M dose was a 1-min loading infusion at 0.06 mg/kg/min, followed by a 10-min continuous infusion at 0.02 mg/kg/min. The H dose was a 1-min loading infusion at 0.125 mg/kg/min, followed by a 10-min continuous infusion at 0.04 mg/kg/min. The patient was then observed for 30 min to determine the cardiovascular responses to withdrawal of the medication. After completion of this follow-up period, additional maintenance infusion for up to 6 h was permitted if considered necessary by the investigator. RESULTS: A total of 108 patients were enrolled in this study. The cumulative improvement rates (percentage of patients obtaining ≥20 % reduction in HR) were 11.4, 32.4, 63.1, and 87.3 % at the LL, L, M, and H doses, respectively, demonstrating the dose-dependent effectiveness of landiolol. Additional infusion for up to 6 h was conducted in 16 patients. HR was maintained between 95.5 and 116.8 beats/min during the maintenance period (mean 259.8 min). Landiolol was generally well tolerated, although one patient with sick sinus syndrome developed an approximately 5-s cardiac arrest. CONCLUSIONS: The overall results, including those pertaining to patient safety, demonstrate that landiolol is effective and useful for the treatment of postoperative SVT.

Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) severe respiratory failure in Japan.

PURPOSE: To evaluate procedures and outcomes of extracorporeal membrane oxygenation (ECMO) therapy applied to 2009 influenza A(H1N1) severe respiratory failure patients in Japan. METHODS: This observational study used database information about adults who received ECMO therapy for H1N1-related severe respiratory failure from April 1, 2010 to March 31, 2011. RESULTS: Fourteen patients from 12 facilities were enrolled. Anti-influenza drugs were used in all cases. Before the start of ECMO, the lowest PaO(2)/FiO(2) was median (interquartile) of 50 (40-55) mmHg, the highest peak inspiratory pressure was 30 (29-35) cmH(2)O, and mechanical ventilation had been applied for at least 7 days in 5 patients. None of the facilities had extensive experience with ECMO for respiratory failure (6 facilities, no previous experience; 5 facilities, one or two cases annually). The blood drainage cannula was smaller than 20 Fr. in 10 patients (71.4 %). The duration of ECMO was 8.5 (4.0-10.8) days. The duration of each circuit was only 4.0 (3.2-5.3) days, and the ECMO circuit had to be renewed 19 times (10 cases). Thirteen patients (92.9 %) developed adverse events associated with ECMO, such as oxygenator failure, massive bleeding, and disseminated intravascular coagulation. The survival rate was 35.7 % (5 patients). CONCLUSION: ECMO therapy for H1N1-related severe respiratory failure in Japan has very poor outcomes, and most patients developed adverse events. However, this result does not refute the effectiveness of ECMO. One possible cause of these poor outcomes is the lack of satisfactory equipment, therapeutic guidelines, and systems for patient transfer to central facilities.

Reevaluation of the efficacy and safety of the neutrophil elastase inhibitor, Sivelestat, for the treatment of acute lung injury associated with systemic inflammatory response syndrome; a phase IV study.

INTRODUCTION: Sivelestat, a neutrophil elastase inhibitor, has been approved in Japan for the treatment of patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome (SIRS). The Pharmaceuticals and Medical Devices Agency (PMDA) has ordered to conduct a postmarket clinical study in order to reevaluate the efficacy and safety of Sivelestat in actual clinical settings in Japan. METHODS: According to the PMDA's order, we evaluated the efficacy and safety of Sivelestat in Japanese patients with ALI associated with SIRS using ventilator-free days (VFD) as the primary endpoint. The surrogate endpoints are ventilator-weaning rate, ICU discharge rate, and 180-day survival rate. Study design was an open-label, non-randomized, multi-center clinical trial. Sivelestat was intravenously administered at 0.2 mg/kg/h continuously for a maximum of 14 days. Sivelestat group and control group were compared by adjusting the outcome values using an inverse probability of treatment weighted method based on the propensity scores. RESULTS: Four hundred and four Sivelestat group patients and 177 control group patients were enrolled. The adjusted mean number of VFD was 15.7 and 12.1 in the Sivelestat group and control group, respectively (P = 0.0022). Both the adjusted ventilator-weaning rate and ICU discharge rate were significantly higher in the Sivelestat group than in the control group (P = 0.0028 and P = 0.019, respectively). The adjusted 180-day survival rate was significantly higher in the Sivelestat group than in the control group (71.8 percent vs. 56.3 percent). CONCLUSIONS: Sivelestat contributed to early weaning from the mechanical ventilation, while showing no negative effect on the long-term outcomes of ALI associated with SIRS. The results of this study suggest the clinical usefulness of Sivelestat in this patient population.

[Actigraphic assessment of the effects of hypnotics on the night before surgery in relation with the severity of surgery].

BACKGROUND: Hypnotics have been used to provide adequate sleep on the night before surgery, but these effects have rarely been investigated. We investigated whether the preoperative hypnotic effects are related with the severity of surgery with quantitative evaluation using actigraph. METHODS: Sleep time on the night before surgery was evaluated after the administration of brotizolam 0.25 mg in 40 patients awaiting surgery; 20 patients for cardiovascular surgeries (Group I) and 20 patients for general surgeries (Group II). Sleep and awake state were identified by wrist activity measured with a motion-logger actigraph. Sleep time was assessed in total period from 22:00 to 6:00 and its 4 subdivided 2-hour periods (22:00-24:00, 24:00-2:00, 2:00-4:00, 4:00-6:00). RESULTS: The total sleep time in Group II (448 +/- 22 min) was significantly longer than that in Group I (409 +/- 44 min). Group I showed a significant reduction in sleep time in the period of 4:00-6:00 compared with other periods, whereas Group II did not show any difference among 4 periods. Group I showed significant shorter sleep time in the period of 4:00-6:00 compared with Group II. CONCLUSIONS: An actigraphic assessment of sleep time has demonstrated the possible influence of the severity of surgery on the sleep time on the night before surgery.

[A case of continuous infusion of milrinone during continuous venovenous hemofiltration causing high plasma concentration of milrinone].

A 79-year-old woman was undergoing chronic hemodyalysis. She received a continuous infusion of milrinone of 0.25 microg x kg(-1) x min(-1) for 77 hours, 0.2 microg x kg(-1) x min(-1) for 39 hours and 0.1 microg x kg(-1) x min(-1) for one hour due to heart failure after mitral valve repair. While receiving continuous infusion of milrinone, she was undergoing continuous venovenous hemofiltration. After infusion of milrinone for three days no arrhythmia was seen except atrial fibliration, but blood pressure remained low. After stopping infusion of milrinone, the plasma concentration of milrinone was 792.7 ng x ml(-1) (therapeutic plasma concentration: 100-200 ng x ml(-1)). Now few data are available regarding the pharmacokinetic of milrinone in patients with severe renal failure and during CVVH. Therefore we should design a dose modification for intravenous milrinone in renal failure patients.

Relationship between neutrophil elastase and acute lung injury in humans.

We conducted clinical trials in patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome using a selective neutrophil elastase inhibitor, sivelestat sodium hydrate (Sivelestat), to investigate the involvement of neutrophil elastase in ALI. In the phase III double-blind study (Study 1) in 230 patients, the efficacy of Sivelestat was evaluated with the pulmonary function improvement (PFI) rating as the primary endpoint, and the weaning rate from mechanical ventilator, the discharge rate from intensive care unit (ICU), and the survival rate as secondary endpoints. Afterwards, an unblinded study (Study 2) in 20 patients was conducted using procedures for weaning from mechanical ventilation to reevaluate its efficacy with ventilator-free days (VFD) value, the primary endpoint, and to compare with that of Study 1 subgroup, which met the selection criteria used in Study 2. Sivelestat increased PFI rating, reduced duration of mechanical ventilation, and shortened stay in ICU in Study 1, although there was no significant efficacy on the survival rate. VFD value in Study 2 was comparable to that in the optimal-dose group of Study 1 subgroup, and increase in VFD value correlated with PFI rating and increase in ICU free days. It was concluded that neutrophil elastase may be involved in the pathogenesis of ALI in humans.

Does the tube-compensation function of two modern mechanical ventilators provide effective work of breathing relief?

OBJECTIVE: An endotracheal tube (ETT) imposes work of breathing on mechanically ventilated patients. Using a bellows-in-a-box model lung, we compared the tube compensation (TC) performances of the Nellcor Puritan-Bennett 840 ventilator and of the Dräger Evita 4 ventilator. MEASUREMENTS AND RESULTS: Each ventilator was connected to the model lung. The respiratory rate of the model lung was set at 10 breaths/min with 1 s inspiratory time. Inspiratory flows were 30 or 60 l/min. A full-length 8 mm bore ETT was inserted between the ventilator circuit and the model lung. The TC was set at 0%, 10%, 50%, and 100% for both ventilators. Pressure was monitored at the airway, the trachea, and the pleura, and the data were recorded on a computer for later analysis of the delay time, of the inspiratory trigger pressure, and of the pressure-time product (PTP). The delay time was calculated as the time between the start of inspiration and minimum airway pressure, and the inspiratory trigger pressure was defined as the most negative pressure level. The same measurements were performed under pressure support ventilation of 4 and 8 cmH2O. The PTP increased according to the magnitude of inspiratory flow. Even with 100% TC, neither ventilator could completely compensate for the PTP imposed by the ETT. At 0% TC the PTP tended to be less with the Nellcor Puritan-Bennett 840 ventilator, while at 100% TC the PTP tended to be less with the Dräger Evita 4 ventilator. A small amount of pressure support can be equally effective to reduce the inspiratory effort compared with the TC. CONCLUSION: Although both ventilators provided effective TC, even when set to 100% TC they could not entirely compensate for a ventilator and ETT-imposed work of breathing. The effect of TC is less than that of pressure support ventilation. Physicians should be aware of this when using TC in weaning trials.

Validity of gastric intramucosal pH (pHi) for circulatory evaluation in pediatric patients.

OBJECTIVE: To determine if the measurement of gastric intramucosal pH (pHi) is useful for evaluation of circulatory status of critically ill pediatric patients. DESIGN: Prospective clinical study. SETTING: General intensive care unit in a university hospital. PATIENTS: Seven pediatric patients (mean age: 2 y.o.); six post-cardiac surgery, one receiving barbiturate therapy. INTERVENTIONS: Tonometric catheters were placed via nasogastric approach. pHi was measured after confirmation of the catheter position by X-ray. MEASUREMENTS AND MAIN RESULTS: Saturation of venous blood oxygen (SvO2), arterial keton body ratio (AKBR), serum lactate level and pHi were evaluated simultaneously. No patients survived with pHi below 7.22; pHi above 7.11 significantly correlated with SvO2 values (r = 0.814, p < 0.001); pHi below 7.11 did not show any significant correlation with SvO2. Whereas SvO2 values of under 40% were distributed in the pHi range from 7.11 to 7.19, pHi below 7.11 occurred when SvO2 values were more than 40%. AKBR and serum lactate level did not correlate with pHi. CONCLUSION: pHi can be a useful parameter for evaluating the circulatory status of critically ill pediatric patients; it allows reliable evaluation of splanchnic and peripheral perfusion.

[Postoperative management in single-lung transplantation for lymphangioleiomyomatosis].

A 35-yr-old woman presented with dyspnea has been diagnosed as having lymphangioleiomyomatosis (LAM). Despite treatment with estrogen, her pulmonary function deteriorated progressively. In January 2001, a left single-lung transplantation was performed on her from a cadaveric donor. On admission to the ICU after the transplantation, arterial blood gas analysis showed a severe respiratory acidosis. A double-lumen endotracheal tube (ETT) was replaced by a single-lumen ETT for a better suctioning of secretion. Gas exchange improved after the replacement of ETT and suctioning of secretion by bronchoscopy. Five hours after the admission to the ICU, the breath sound decreased over the right thorax. The chest X-ray showed right pneumothorax, and a chest tube was inserted. The patient was weaned from mechanical ventilation gradually and extubated on the 6th ICU day. The patient was discharged from ICU to the general ward on the 9th ICU day without pneumonia and other complications. The development of pneumothorax in the recipient lung should be kept in mind during the perioperative period of lung transplantation for LAM.

A cross-cultural comparison of critical care delivery: Japan and the United States.

OBJECTIVE: To compare the utilization and outcomes of critical care services in a cohort of hospitals in the United States and Japan. DESIGN: Prospective data collection on 5,107 patients and detailed organizational characteristics from each of the participating Japanese study hospitals between 1993 and 1995, with comparisons made to prospectively collected data on the 17,440 patients included in the US APACHE (acute physiology and chronic health evaluation) III database. SETTING: Twenty-two Japanese and 40 US hospitals. PATIENTS: Consecutive, unselected patients from medical, surgical, and mixed medical/surgical ICUs. MEASUREMENTS: Severity of illness, predicted risk of in-hospital death, and ICU and hospital length of stay (LOS) were assessed using APACHE III. Japanese ICU directors completed a detailed survey describing their units. MAIN RESULTS: US and Japanese ICUs have a similar array of modalities available for care. Only 1.0% (range, 0.56 to 2.7%) of beds in Japanese hospitals were designated as ICUs. The organization of the Japanese and US ICUs varied by hospital, but Japanese ICUs were more likely to be organized to care for heterogeneous diagnostic populations. Sample case-mix differences reflect different disease prevalence. ICU utilization for women is significantly lower (35.5% vs 44.8% of patients) and there were relatively fewer patients > or = 85 years old in the Japanese ICU cohort (1.2% vs 4.6%), despite a higher per capita rate of individuals > or = 85 years old in Japan. The utilization of ICUs for patients at low risk of death significantly less in Japan (10.2%) than in the United States (12.9%). The APACHE III score stratified patient risk. Overall mortality was similar in both national samples after accounting for differences in hospital LOS, utilizing a model that was highly discriminating (receiver operating characteristic, 0.87) when applied to the Japanese sample. The application of a US-based mortality model to a Japanese sample overestimated mortality across all but the highest (> 90%) deciles of risk. Significant variation in expected performance was noted between hospitals. Risk-adjusted ICU LOS was not significantly longer in Japan; however, total hospital stay was nearly twice that found in the US hospitals, reflecting differences in hospital utilization philosophies. CONCLUSIONS: Similar high-technology critical care is available in both countries. Variations in ICU utilization reflect differences in case-mix and bed availability. Japanese ICU utilization by gender reflects differences in disease prevalence, whereas differences in utilization by age may reflect differences in cultural norms regarding the limits of care. Such differences provide context from which to assess the delivery of care across international borders. Miscalibration of predictive models applied to international data samples highlight the impact that differences in resource use and local practice cultures have on outcomes. Models may require modification in order to account for these differences. Nevertheless, with large databases, it is possible to assess critical care delivery systems between countries accounting for differences in case-mix, severity of illness, and cultural normative standards facilitating the design and management such systems.