Clinical efficacy and safety of arbekacin sulfate in patients with MRSA sepsis or pneumonia: a multi-institutional study

Arbekacin (ABK) is an aminoglycoside and widely used in Japan for treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). Although, ABK has concentration-dependent antibacterial activity, the peak serum concentration (C _peak) of ABK has not yet been fully investigated as an indicator of the efficacy of ABK. The present study was conducted in patients admitted to hospitals affiliated with the ABK Dose Finding Study Group, between October 2008 and June 2011, who had pneumonia or sepsis, the cause of which was identified or suspected to be MRSA. The initial target C _peak was set at 15–20 μg/mL and therapeutic drug monitoring was conducted. Then the relationship between serum concentration and efficacy/safety of ABK was prospectively examined to obtain sufficient clinical efficacy. In total, 89 patients from 11 clinical sites in Japan were enrolled and 29 of these patients were subjected to efficacy analysis. The mean initial dose and C _peak were 306.9 mg/day and 16.2 μg/mL, respectively. The efficacy rate was 95 % (19/20 patients) at 5–6 mg/kg or higher, 87.5 % (7/8) for sepsis and 90.5 % (19/21) for pneumonia, and the overall efficacy rate was 89.7 % (26/29). There was no increase in the incidence of adverse events. In conclusion, we recommend the initial dose of ABK at 5–6 mg/kg or higher and the dosage regimen should be adjusted to achieve C _peak at 10–15 μg/mL or higher in the treatment of patients with pneumonia or sepsis caused by MRSA. This strategy would surely achieve low incidence of adverse events while obtaining high clinical efficacy.     

Pharmacokinetics and pharmacodynamics of once-daily arbekacin during continuous venovenous hemodiafiltration in critically ill patients

This study examined the pharmacokinetics of arbekacin during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamics to consider arbekacin dosage adaptation in CVVHDF. Arbekacin was administered by 0.5-h infusion once daily, using a polymethyl methacrylate membrane hemofilter, to three critically ill patients undergoing CVVHDF; the flow rates were 0.8 l/h for the filtrate and 0.6 l/h for the dialysate. The drug concentrations in plasma and in the filtrate-dialysate were determined using a fluorescence polarization immunoassay and analyzed pharmacokinetically. The average sieving coefficient of arbekacin was 0.739 and the average drug clearance by CVVHDF was 1.03 l/h. A pharmacokinetic model with three compartments (1, central; 2, peripheral; 3, filtrate-dialysate side hemofilter) accurately reflected the concentration-time data for both plasma and filtrate-dialysate. The pharmacokinetic model assessed the pharmacodynamic profile of arbekacin once-daily regimens (0.5-h infusions) at filtrate-dialysate flow rates of 1.4 and 2.8 l/h, and demonstrated that only the 150-mg and 200-mg regimens achieved an effective target range for C_max (9–20 μg/ml), suggesting that empirical dosages lower than the usual 150–200 mg should be avoided in patients undergoing CVVHDF. The minimum regimens needed to achieve an effective pharmacodynamic target for the free C_max/MIC ratio (>8) were 75 mg for an MIC of 0.5 μg/ml, 200 mg for an MIC of 2 μg/ml, and 400 mg for an MIC of 4 μg/ml. These results will help us to better understand the pharmacokinetics of arbekacin during CVVHDF, while also helping in the selection of the appropriate arbekacin regimens, based on a pharmacodynamic assessment, for patients receiving this renal replacement therapy.     

A study of trends and factors associated with therapeutic drug monitoring (TDM) implementation for arbekacin treatment using a large Japanese medical claims database

IntroductionReimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus, and therapeutic drug monitoring (TDM) is recommended. This study aimed to clarify the trend in TDM implementation for ABK over time and the factors associated with TDM implementation using a claims database.MethodsData of patients aged ≥15 years who received ABK for ≥3 consecutive days between 2010 and 2019 were extracted from a large Japanese medical claims database. The proportion of reimbursements claimed for TDM, pharmacist interventions, and the setup of infectious disease teams for each year were calculated. The factors associated with TDM implementation were identified using multivariate logistic regression analysis.ResultsThe proportion of TDM implementation for ABK increased by 9.1% from 2010 to 2019, but it remained less than 40% throughout this period. The proportion of TDM implementation was higher in patients who claimed reimbursements for pharmacist interventions than in patients who did not. Logistic regression analysis showed that the stationing of pharmacists in wards and long-term ABK treatment were significantly associated with TDM implementation.ConclusionsFrom 2010 to 2019, the proportion of TDM implementation for ABK was significantly low. Moreover, the factors associated with TDM implementation were clarified. An environment wherein pharmacists can help implement TDM for patients receiving ABK would be beneficial.     

Evaluation of once-daily dosing and target concentrations in therapeutic drug monitoring for arbekacin: A meta-analysis

IntroductionArbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug monitoring (TDM) is recommended during arbekacin treatment, little evidence for the target exposure and once-daily dosing has been reported. This study aimed to clarify the target peak/trough concentrations and the effectiveness of once-daily dosing of arbekacin against nephrotoxicity or treatment failure via meta-analysis.MethodsA literature search was performed using MEDLINE, Cochrane Library, and Ichushi-Web.ResultsNine observational cohort studies met the inclusion criteria. A peak arbekacin concentration of ≥15–16 μg/mL did not exhibit a statistically significant lower risk of treatment failure (risk ratio [RR] = 0.61, 95% confidence interval [CI] = 0.30–1.24). A trough arbekacin concentration of <2 μg/mL resulted in a significantly lower risk of nephrotoxicity (RR = 0.30, 95% CI = 0.15–0.61). Once-daily dosing significantly reduced the risk of treatment failure (RR = 0.61, 95% CI = 0.39–0.97) but not nephrotoxicity (RR = 0.54, 95% CI = 0.16–1.75).ConclusionsOnce-daily dosing can improve the therapeutic efficacy of arbekacin, and a trough arbekacin concentration of <2 μg/mL can reduce the risk of nephrotoxicity. A peak arbekacin concentration of ≥15–16 μg/mL did not exhibit the significant lower risk of treatment failure. Additional clinical trials are required to confirm these findings.     

基于评估的治疗模式对精神分裂症患者症状和功能影响的随访研究

目的 探讨基于评估的治疗模式对精神分裂症患者精神症状和社会功能的影响。方法 2017年3月至2018年3月在衡水市精神病医院进行门诊和住院治疗的符合DSM V诊断标准的精神分裂症患者120例,根据随机数字表法分为研究组和对照组各60例。研究组采用基于评估的治疗模式进行干预,即服用第二代抗精神病药物利培酮片最高剂量4~6mg/d,根据入组第2周末的阴性及阳性症状量表（positive and negative syndrome scale,PANSS）评分减分率＜20%替换为奥氮平片治疗,采用交叉换药的方式换药。对照组采用常规治疗方案,即给予利培酮片最高剂量（同研究组）,维持剂量不变至研究结束。在治疗前、治疗第2周末、第4周末、第8周末分别评估PANSS及个人和社会功能量表（personal and social performance scale,PSP）,观察患者的精神症状和社会功能,并随访半年。结果 研究组因肌注氟哌啶醇针剂或合并其他第二代抗精神病药退出共9例,不良反应退出1例,撤回知情同意1例;对照组因肌注氟哌啶醇针剂或合并口服其他第二代抗精神病药退出共7例,不良反应退出3例,撤回知情同意3例。在治疗第4周、8周末,研究组的阳性症状分、PANSS总分低于对照组（P<0.05）。而两组阴性症状分在任何时间点的差异均无统计学意义（P>0.05）;一般精神病理分仅在治疗第8周末组间差异有统计学意义（P<0.05）。在治疗第4周、8周末,研究组的PSP评分明显高于对照组（P<0.05）。随访6个月时,仍是研究组PSP评分较高（P<0.01）。结论 基于评估的治疗模式可以早期控制精神分裂症患者的精神症状,并有助于改善社会功能。     

Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases

The authors determined the safety and efficacy of recombinant high-dose interleukin-2 administration in patients with brain metastases. This retrospective review included 1,069 patients with metastatic melanoma or renal cell carcinoma who received high-dose interleukin-2 alone or in combination with other immunotherapy or chemotherapy from July 1985-July 2000. All patients were evaluated for both toxicity and response. Only the first exposure to interleukin-2 was considered. Parameters evaluated among the groups included toxicity profiles, reasons for stopping treatment, number of interleukin-2 doses per cycle, and response to therapy. Three patient groups were compared. Group I (n = 27) comprised patients with previously treated brain metastases (surgery or radiation), group 2 (n = 37) comprised patients with untreated brain metastases, and group 3 (n = 1,005) comprised patients without brain metastases. For most comparisons between patients with brain metastases and those without, no significant differences were noted in toxicity profiles or reasons for stopping interleukin-2 therapy. Patients with previously treated brain metastases received fewer interleukin-2 doses per cycle (median, 6.5) than patients with previously untreated brain metastases (median, 7.5) or patients without brain metastases (median, 7.5). Patients with previously treated brain metastases demonstrated an 18.5% overall clinical response to interleukin-2 treatment. However, patients with evaluable (previously untreated) brain metastases had an overall 5.6% response rate, which was less than the 19.8% response rate of patients without brain metastases. Two of thirty-six patients with evaluable brain metastases demonstrated objective regression of intracranial and extracranial disease after receiving interleukin-2. Carefully selected patients with brain metastases can safely receive high-dose interleukin-2, and some can experience a response to treatment at intracranial and extracranial disease sites.     

琥珀酸索利那新治疗膀胱过度活动症的疗效和安全性

目的对琥珀酸索利那新治疗膀胱过度活动症(OAB)的疗效和安全性进行评估。方法将76例确诊为OAB病程超过3个月的患者采用随机、双盲法分为2组:对照组38例,给予托特罗定2mgbid,早晚口服;实验组38例,给予琥珀酸索利那新5mgqd,早饭后口服。2组疗程均为8周。2组患者在用药前1周及用药后1周自行记录排尿日记,通过排尿日记比较2组患者服药前后1周平均24h内排尿次数和尿急次数的改善情况,同时结合患者治疗前后最大尿流率、初始尿意容量、最大膀胱压容量的变化对琥珀酸索利那新的疗效进行评价;通过用药不良反应发生率的对比分析,对其安全性进行评估。结果实验组患者的24h尿急次数和排尿次数以及初始尿意容量、最大膀胱压容量、最大尿流率较对照组有明显改善(P<0.05);实验组患者口干、视野模糊、便秘等不良反应发生率均较对照组低(P均<0.05)。结论琥珀酸索利那新治疗OAB较托特罗定有更好的效果和更高的安全性,琥珀酸索利那新将可能成为治疗OAB的首选药物。     

The role of HIV infection and drug and alcohol dependence in hospital mortality among critically ill patients

Purpose

Critical care outcomes among HIV-infected patients have improved because of advances in HIV therapy and general improvements in intensive care unit (ICU) management. There is a high co-occurrence of drug and alcohol dependence among HIV-infected patients, and the independent role of drug and alcohol dependence among patients with and without HIV infection in outcomes of critical illness is unclear.

Materials and methods

We analyzed a prospectively collected database of 7015 index ICU admissions at 2 teaching hospitals between January 1999 and January 2006. The ICU diagnoses were determined from prospective chart review and classified according to the dictionary of diagnoses developed by the Intensive Care National Audit and Research Council. We used logistic regression to determine the independent association of drug and alcohol dependence as well as HIV infection with in-hospital mortality. Covariates that were adjusted for included acute drug overdose, Acute Physiology and Chronic Health Evaluation II score, age, sex, hospital site, and socioeconomic variables.

Results

Of all patients, 4.4% (309 of 7015) were HIV infected; and of these, 56% (173 of 309) had a history of drug and alcohol dependence, whereas only 7.4% (502 of 6706) of the HIV-negative group had a history of drug and alcohol dependence. Drug and alcohol dependence was not independently associated with hospital mortality in either the model including all admissions (adjusted odds ratio [AOR] 0.80; 95% confidence interval [CI] 0.62-1.03) or the model including pneumonia and sepsis admissions only (AOR 0.92; 95% CI 0.59-1.41). Infection with HIV was independently associated with hospital mortality (AOR 2.16; 95% CI 1.60-2.93).

Conclusions

Although HIV infection is associated with increased hospital mortality, drug and alcohol dependence is not associated with an increased hospital mortality independent of HIV infection.     

Comparative efficacy and safety of gemtuzumab ozogamicin monotherapy and high-dose cytarabine combination therapy in patients with acute myeloid leukemia in first relapse

Gemtuzumab ozogamicin was recently approved in the United States for the treatment of older patients with CD33-positive acute myeloid leukemia (AML) in first relapse. However, the lack of randomized clinical trials makes it so difficult to determine which patients are best suited for this compared with other treatment regimens. Results for 128 patients given gemtuzumab ozogamicin in phase II trials were compared with those for 128 patients given high-dose cytarabine (HDAC) combination therapy in different trials Multivariate logistic regression was used to analyze age, duration of first complete remission (CR1), and cytogenetics for potential differences between the groups. rare of overall remission )combined complete remission [CR] plus CR with incomplete platelet recovery [CRp]) following treatment with gemtuzumab ozogamicin or HDAC therapy were 38% and 41%, respectively. Gemtuzumab ozogamicin treatment was associated with a higher overall remission rate compared with HDAC treatment if CR1 duration was 3-10.5 months. In contrast, HDAC treatment was associated with a higher overall remission rate than gemtuzumab ozogamicin treatment if CR1 duration was >19 months. If CR1 duration was between 10.5 and 19 months, the differences in treatment responses were not statistically significant. Thee results reflect the much stronger treatment than with gemtuzumab ozogamicin treatment. Early death (occurring within the first 6 weeks of therapy) was less likely in patients <45 years of age after ADAC and was less likely in patients >75 years of age after gemtuzumab ozogamicin treatment. These data support the recommended use of gemtuzumab ozogamicin as monotherapy in older patients with AML in first relapse, but caution against this use in patients, particularly younger ones, with a long duration of CR1.     

Safety and efficacy of high-dose treatment with imipenem-cilastatin in seriously ill patients.

Imipenem-cilastatin was given in doses of 1 g intravenously every 6 h to 31 patients. Twenty-five patients, with 27 infections, were clinically evaluable and received 20 to 210 g of imipenem for a duration of 5 to 56 days (average 16.3 days). Infections included seven cases of osteomyelitis, seven of bacteremia, five of cellulitis, two of pneumonia, three of pelvic cellulitis, two of intraabdominal abscess, and one each of empyema, mediastinitis, and endometritis. Fifty-five percent of the infections were caused by gram-negative bacilli, 33% were due to gram-positive organisms, and 10% were caused by anaerobes. Twenty-two patients (81%) were cured, three improved, one relapsed, and one became superinfected with a resistant organism. In 5 of 11 cases with Pseudomonas aeruginosa, the imipenem MIC for organisms isolated by the end of treatment was higher than it was initially, raising concern that imipenem should not be used alone to treat Pseudomonas aeruginosa infections. Twenty-one patients had no adverse reaction; of the remaining 10 patients, 4 had nausea, 1 had urticaria, and 6 had mild abnormalities in hepatic function; three episodes of diarrhea included two with Clostridium difficile toxin in stool and one with pseudomembranous colitis, as determined by sigmoidoscopy. Levels of creatinine, hemoglobin, leukocytes, platelets, prothrombin, and urine components were unchanged. Imipenem-cilastatin is a clinically effective antibiotic with freedom from nephrotoxicity and hematological abnormalities in the large doses used in this study.     

Efficacy and safety of once-daily combination therapy with didanosine, lamivudine and nevirapine in antiretroviral-naive HIV-infected patients

BACKGROUND: Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection. METHODS: This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis. RESULTS: Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10log10 copies/ml, and mean CD4 cell count was 262 cells/microl. At month 12, 67% (95% CI: 56-78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/microl. The treatment was more effective in patients with baseline CD4 counts >100 cells/microl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol. CONCLUSION: A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline.     

冠心病患者发生重症感染的处理

冠心病的发病率呈逐年增长的趋势。经皮支架植入术和冠脉搭桥术成为治疗冠心病的主要方法。然而,相关的手术也带来了一系列的并发症,对患者及社会均造成了极大的负担。本文主要就冠心病术后感染的特点、临床表现以及对于冠心病患者发生重症感染后的处理措施作一综述。     

脓毒血症AKI患者采用CRRT治疗的临床疗效

目的分析脓毒血症急性肾损伤(AKI)患者行连续性肾脏替代治疗(CRRT)的临床疗效。方法选取2012年1月至2014年7月因脓毒血症AKI住院治疗的患者共92例,随机分为实验组和对照组。实验组予以CRRT治疗,对照组予以常规药物治疗。对比两组患者治疗前及治疗3 d后的生命体征、血清学指标、7 d及28 d病死率。结果两组患者治疗3 d后的收缩压(SBP)、舒张压(DBP)、平均动脉压(MAP)、尿量和氧饱和度(Sp O2)均显著高于治疗前(P0.05);实验组治疗3 d后的SBP、DBP、MAP、尿量和Sp O2均显著高于对照组(P0.05)。两组患者治疗3 d后的高敏C-反应蛋白(hs CRP)、降钙素原(PCT)、血肌酐(SCr)、血尿素氮(BUN)和中性粒细胞百分比(N%)均显著低于治疗前(P0.05);实验组治疗3 d后的hs CRP、PCT、SCr、BUN和N%均显著低于对照组(P0.05)。两组患者7 d病死率无显著差异(P0.05);实验组28 d病死率显著低于对照组(P0.05)。结论对于脓毒血症AKI患者早期行CRRT治疗,可有效消除炎症介质,改善肾功能,提高患者存活率。     

含大剂量阿糖胞苷方案强化治疗伴t(8;21)和正常核型急性髓系白血病M2患者疗效比较

目的 比较伴t(8;21)和正常核型的急性髓系白血病(AML)M2患者在诱导缓解后,应用含大剂量阿糖胞苷(HD-Ara-C)方案进行强化巩固治疗的疗效.方法 伴t(8;21)(q22;q22)AML-M2患者21例,正常核型AML-M2患者23例,在诱导缓解后,给予4个疗程HD-Ara-C方案强化治疗:Ara-C 3.0 g/m2,每12 h 1次,静脉滴注持续3 h,第1～3天,同时交替联合使用其他药物(米托蒽醌7mg·m-2·d-1第1～3天或阿克拉霉素30 mg·m-2·d-1第1～3天或依托泊甙70 mg·m-2·d-1第1～3天等).结果 伴t(8;21)患者组复发率29%,3年总体生存(OS)率76%,3年无病生存(DFS)率71%;正常核型组复发率57%,3年OS率65%,3年DFS率43%.两组患者复发率及3年DFS率差异有统计学意义(P《0.05),3年OS率差异无统计学意义(P＞0.05).结论 伴t(8;21)AML-M2患者诱导缓解后,应用4个疗程含HD-Ara-C方案进行强化巩固治疗,复发率低,可以提高DFS率.     

The efficacy,safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly

Biapenem has been widely used to treat bacterial pneumonia; however, there is little information concerning its efficacy and safety in elderly patients. Based on pharmacokinetic–pharmacodynamic theory, administration of biapenem thrice rather than twice daily would be expected to be more effective because of longer time above the minimum inhibitory concentration. In this study, we aimed to evaluate the efficacy, safety, and pharmacokinetics of biapenem (300 mg) administered thrice daily in pneumonic patients aged 65 years or older. Biapenem was effective in 22 of 25 patients, as assessed by the improvement in clinical symptoms and/or the eradication of the causative organisms, and caused no serious adverse events. The pharmacokinetic profile was established based on simulations using a modeling program. Among 17 patients whose causative organisms were detected, time above the minimum inhibitory concentration was estimated to be 100% in 16 patients, all of whom showed clinical improvement. The results of this study confirmed the efficacy and safety of 300 mg of biapenem administered thrice daily for the treatment of pneumonia in elderly patients.     

ICU重症脓毒症患者的镇痛镇静治疗

镇痛镇静治疗是ICU中的基本治疗,其目的不仅在于减轻患者的痛苦、保证治疗的安全,更在于通过对于神经内分泌功能的调节而干预机体的炎性应激反应,使得器官功能相互适应与匹配,达到调整细胞物质代谢、保护器官功能、拯救生命的目的。但是镇痛镇静,特别是镇静治疗药物仍然是双刃剑,其对于机体神经内分泌功能的调节必须时刻保持在"适度"的水平,一旦"过度"或"不足",均可能对器官功能造成伤害;因此镇痛镇静治疗必须以对于重要生命体征的监测作为基础:无监测,勿镇静。     

The safety of high-dose insulin euglycaemia therapy in toxin-induced cardiac toxicity

Context: High-dose insulin euglycaemia (HIE) is recommended in the management of toxin-induced cardiac toxicity, with increasing insulin doses now being used. We aimed to investigate the safety of HIE in toxin-induced cardiac toxicity.

Methods: This was a retrospective review of cases from two clinical toxicology units. Demographics, toxin(s) ingested, clinical effects, investigations (serum glucose, electrolytes), treatments (insulin, glucose, electrolyte replacement), length of stay (LOS) and outcomes were extracted from the patients’ medical records. Associations between insulin and glucose/electrolyte homeostasis were explored by comparing insulin administration and glucose or electrolyte concentrations and replacement.

Results: There were 22 patients (12 females), median age 57 years (15–88 years) treated with HIE. There were 12 beta-blocker, six calcium channel blocker and three combined beta-blocker and calcium channel blocker ingestions. A total of 19 patients had a systolic blood pressure?<80mmHg and 18 patients required inotropes in addition to HIE. There were three deaths. Despite glucose and electrolyte replacement, 16 patients (73%) developed hypoglycaemia (Reference range [RR]?There was no apparent association between insulin dosing and severity of hypoglycaemia or hypokalaemia, or in glucose or potassium replacement. Median insulin loading dose was 80U (range 50–125?U) and the median maximum insulin infusion rate was 150?U/h (range 38–1500?U/h). Median glucose infusions rates were 37.5g/h (range 4–75g/h). There was no apparent association between insulin and glucose administration. Glucose was administered for a median of 18h after ceasing insulin. The duration of glucose administration after ceasing insulin increased with the rate and total insulin administered during HIE.

Discussion: Despite the benefits of HIE in toxin-induced cardiac toxicity, it caused significant disruption to glucose and electrolyte homeostasis, although there were no apparent complications from this. There was no association by comparing the amount of insulin administered on adverse effects or glucose administered, suggesting higher doses of insulin are associated with no more adverse effects.     

Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock

Objective  To determine the efficacy and safety of extended drotrecogin alfa (activated) (DAA) therapy. Design  Multicentre, randomised, double-blind, placebo-controlled study. Setting  Sixty-four intensive care units in nine countries. Patients  Adults with severe sepsis and vasopressor-dependent hypotension after a 96-h infusion of standard DAA. Interventions  A total of 193 patients received an intravenous infusion of extended DAA 24 μg/kg/h or sodium chloride placebo for a maximum of 72 h. Measurements and results  At extended therapy initiation (baseline), DAA-group patients had lower protein C levels (P = 0.23) and higher vasopressor requirements, particularly for the primary vasopressor used, norepinephrine (P = 0.03), compared with placebo-group patients. DAA treatment did not result in a difference in the primary outcome of time to resolution of vasopressor-dependent hypotension versus placebo (P = 0.419). However, few patients reached resolution (DAA 34%, placebo 40%) as most continued to require vasopressor support after 72 additional hours of treatment. Treatment did not reduce 28-day all-cause mortality and in-hospital mortality or improve organ function compared with placebo, although there was a lower percentage change in D-dimers (P < 0.001) and increases in protein C levels were numerically greater on extended infusion. There was no difference in serious adverse events including bleeding events. Conclusions  Extended DAA treatment did not result in more rapid resolution of vasopressor-dependent hypotension, despite demonstrating anticipated biological effects on D-dimer and protein C levels. A reduced planned sample size combined with baseline imbalances in protein C levels and vasopressor requirements may have limited the ability to demonstrate a clinical benefit. An erratum to this article can be found at     

Combination therapy with methylprednisolone (mPSL) and high-dose immunoglobulin (IVIg)

An open study in the Netherlands have investigated the efficacy of combination therapy with methylprednisolone(mPSL) and high-dose immunoglobulin (IVIg) for Guillain-Barré syndrome (GBS) patients. The study suggested that the combination therapy is more effective than treatment with IVIg alone. Following the study, randomized trial of the combination therapy for the GBS patients was performed by the Dutch GBS study group in 2004. The randomized trial revealed that it was associated with a slightly, but not significantly, higher percentage of patients who recovered by more than grade 1 in the disability score. In addition, the long-term outcome (52 weeks) of the combination did not significantly differ from that of non-combination therapy; however, the median time to independent ambulation tended to be shorter in patients undergoing the combination therapy. We have summarized the recent advances in our understanding of the therapy for the patients with GBS. GBS consists of at least two subtypes of acute peripheral neuropathy, such as acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP). It has been reported that the subtype of AMAN is morecommon in Japan, as compared with the Western countries. Further studies are needed to clarify the effectiveness of the combination therapy, because of the difference of the subtype between Japan and the Western countries.