Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus

A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open‐label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low‐dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time‐normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy‐proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3–8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients. Trial registration: NCT01025817.     

Dose-Response of Rocuronium Bromide in Children Anesthetized with Propofol: A Comparison with Succinylcholine

Background: The aim of this study was to determine the potency of rocuronium during propofol/fentanyl/N2 O anesthesia in children and to compare the time course of action of rocuronium at doses of two and three times the ED95 with that of succinylcholine.

Methods: Rocuronium (120, 160, 200, or 240 micro gram/kg) was administered to 48 children aged 2-10 yr. Neuromuscular block was assessed by monitoring the electromyographic response of the adductor digiti minimi to supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s every 10 s. Potency was determined by log-probit transformation and least-squares linear regression analysis of dose and response. In a second group of 30 children, the onset and recovery profile of rocuronium at doses of two and three times the ED95 was compared with that of succinylcholine (2 mg/kg).

Results: Values for ED50 and ED95 were 210 +/- 24 and 404 +/- 135 micro gram/kg, respectively. The time to 90% neuromuscular block after 1.2 mg/kg rocuronium (three times the ED95), 33 +/- 5 s (mean +/- SD), did not differ significantly from that after succinylcholine, at 30 +/- 7 s; however, both were significantly less than that after 0.8 mg/kg rocuronium, 46 +/- 8 s (P < 0.05). The time to 25% recovery from 1.2 micro gram/kg rocuronium, 41 +/- 13 min, was approximately 50% greater than that after 0.8 mg/kg, at 27 +/- 6 min (P < 0.001), and eight times greater than that after succinylcholine, at 5.2 +/- 1.9 min (P < 0.001).     

缩短罗库溴铵起效时间的临床研究

研究预注法和增大剂量法对罗库溴铵起效时间的影响。方法：５０例病人分为五组,每组１０例,Ⅰ组、Ⅱ组分别单次静注罗库溴铵０．６ｍｇ／ｋｇ、０．７５ｍｇ／ｋｇ。Ⅲ组、Ⅳ组为预注组,初始总剂量均为０．６ｍｇ／ｋｇ,预注量分别为０．０６ｍｇ／ｋｇ、０．１２ｍｇ／ｋｇ。预注间隔２分钟后,静注插管组,Ⅲ组０．５４ｍｇ／ｋｇ,Ⅳ组０．４８ｍｇ／ｋｇ。Ⅴ组为单次静注琥珀胆碱１．５ｍｇ／ｋｇ。观察各组肌松的起效时间、     

Laparoscopic Cholecystectomy in Cirrhotic Patients with Symptomatic Cholelithiasis: A Case-control Study

Background In this study we retrospectively evaluated a group of symptomatic cirrhotic (n = 30) and non-cirrhotic (n = 60) patients submitted to laparoscopic cholecystectomy (LC) in a public hospital in Brazil. Methods The groups were compared for surgical time, duration of hospitalization after surgery, period of permanence in the intensive care unit (ICU), use of blood derivatives, mortality rates, and transoperative and post-surgery complications. Other parameters, such as hepatic reserve capacity and presence of ascites, were also analyzed. Results Twenty-three (76.7%) of the patients of the cirrhosis group (CG) were classified as Child-Pugh A, and seven (23.3%) were Child-Pugh B. Six of them (20%) had ascites. Differences between the two groups included surgery time (p = 0.008), duration of hospitalization (p = 0.014), and post-surgery (p = 0.000) or ambulatory (p = 0.008) complications. The worst results were observed among Child B patients and in those with ascites. Blood derivatives were used in only 3.3% of the CG patients. No cases of conversion to laparotomy were observed among the two groups of patients included in this study, nor were there any deaths. Conclusions These results indicate that videolaparoscopic cholecystectomy may be safely performed in public hospitals in Brazil, with low levels of complications, no associated mortality, and no need for blood derivatives.     

美维库铵持续静滴与单次静注肌松效应及恢复过程的临床药效学观察

目的 :观察美维库铵持续静滴和单次静注肌松效应及术后恢复的临床药效学指标。方法 :6 0例ASA分级Ⅰ～Ⅱ级复合全麻患者随机分为四组 ,每组 15例。美维库铵 0 2 5mg/kg给药后行气管插管 ,Ⅰ、Ⅱ组以微量泵持续静滴美维库铵 ,Ⅲ、Ⅳ组单次静注美维库铵维持肌松。术后Ⅰ、Ⅲ组患者待肌松自主恢复 ,Ⅱ、Ⅳ组静注新斯的明5 0 μg/kg、阿托品 10 μg/kg拮抗。结果 :实验提示 0 2 5mg/kg的美维库铵剂量可于 2 4± 0 6分钟内产生满意的插管条件 ,优秀率 95 %以上。Ⅰ、Ⅱ、Ⅲ、Ⅳ组平均用药量分别为 4 7± 1 2、5 0± 1 9、5 2± 2 2和 4 9± 1 8μg·kg-1·min-1,持续静滴组与单次静注组用药量无显著性差异 (P >0 0 5 )。Ⅰ、Ⅲ组恢复指数分别为 8 1± 2 3分钟和 8 7± 2 2分钟 (P >0 0 5 )。Ⅱ、Ⅳ组的恢复指数亦无明显差异 ,但比自然恢复组约缩短 2分钟左右。结论 :美维库铵持续静滴与单次静注用药量无明显差异 ,持续静滴可获得较好的肌松效果。术后使用新斯的明拮抗虽可加快肌缩力的恢复 ,但因其短效作用 ,故术后无需常规拮抗。     

哌布可罗宁潘可罗宁临床药效的比较研究

应用剂量递增法检测哌布可罗宁，潘呆罗宁的ＥＤ９５值，并观测不同等效剂量ｐｉｐ，ｐａｎ神经－肌阻滞效应及气管插管时肌松条件。结果表明：ｐｉｐ的ＥＤ９５小于ｐａｎ，肌松效能略强于后者，但等效剂量两药的起铲时间，气管插管时的肌松条件，恢复相似于；１．５及２倍ＥＤ９５剂量的ｐｉｐ，ｐａｎ均可获得较满意的气管插管条件，２ＥＤ９５剂量可缩短起效时间及提前进行气管插管，但２ＥＤ９５ｐｉｐ明显延长肌松作用时间及增     

肝硬变门静脉高压症患者肝体积测量研究及其临床意义

目的探讨用个人电脑及自行开发的软件对肝脏CT断层图像进行三维重建和测量及其在肝硬变门静脉高压症患者中的临床意义.方法术前对46例行原位肝移植的肝硬变门静脉高压症患者和30例正常对照者的肝脏CT断层图像进行三维重建和测量,术后与肝硬变门静脉高压症患者切除的受体实测肝体积进行对比分析.结果46例肝硬变门静脉高压症患者用本方法测得平均肝脏体积为(983.33±206.11)cm3,同组实测平均肝脏体积为(904.93±209.56)cm3,二者之间呈高度正相关(r=0.969,P＜0.01),本方法测定值的平均误差为8.66%.正常对照组用本方法测得平均肝脏体积为(1 287.00±96.18)cm3,与其身高、体重和体表面积之间均存在着正相关关系(r值分别为0.845、0.833和0.932,P＜0.01).肝硬变门静脉高压症患者肝脏体积与Child-Pugh分级有关,C级患者肝脏体积明显小于B级者;也与血浆白蛋白水平呈显著正相关(r=0.496,P＜0.01),与总胆红素水平(r=-0.493,P＜0.01)及凝血酶原时间(r=-0.517,P＜0.01)呈显著负相关,与ALT值(r=0.206,P＞0.05)、门静脉压力(r=-0.093,P=0.539)及门体自然分流指数(r=0.044,P=0.769)无明显相关关系.结论运用该方法对肝脏CT断层图像进行三维重建和测量准确性较高.肝脏体积大小与肝功能有密切关系,肝脏体积可较敏感地反映肝脏储备功能状况.     

A Clinical Study of Protein Sparing Modified Fast (PSMF) Administered Preoperatively to Morbidly Obese Patients: comparison of PSMF with natural food products to originally prepared PSMF

Morbidly obese patients are generally in a malnutritional state with an extremely high operative risk. In order to reduce the operative risk, surgeons should make every effort before the operation. A protein sparing modified fast (PSMF) may exhibit its high effectiveness when taken at least for 2 weeks preoperatively. In this study, PSMF prescribed with natural food products was compared with prepared PSMF having an ideal composition from the clinical standpoint. Though it is natural for patients to favor the former, the latter proved to have a superior effect in clinical practice. By performing a PSMF for 2 weeks preoperatively, however, even the PSMF with natural food products seemed to fulfill its purpose sufficiently.     

Response to a Vaccination Schedule With 4 Doses of 40 μg Against Hepatitis B Virus in Cirrhotic Patients Evaluated for Liver Transplantation

We conducted a retrospective study to evaluate the response to recombinant hepatitis B vaccine after 4 intramuscular doses (40 μg) administered at 0, 1, 2, and 6 months in 157 cirrhotic patients who were liver transplant candidates. Seventeen nonresponders were revaccinated with the same schedule. We studied the association between the following variables and the vaccine response: age, gender, etiology of cirrhosis, diabetes, severity of liver disease (Child-Pugh class and Model for End-Stage Liver Disease [MELD] score), and the number of administered doses. The response rates were: 1 dose, 40% (2/5); 2 doses, 0% (0/7); 3 doses, 32.7% (16/49); and 4 doses, 31.3% (30/96) of patients. The median hepatitis B surface antibody (anti-HBs) titer was 45 mU/mL (range, 11-620 mU/mL). The response rate to revaccination was 41.2% (median anti-HBs titer, 88 mU/mL; range, 18-190 mU/mL). Diabetics showed a lower response rate than nondiabetic patients (17.2% vs 35.3%; P = .046). No association was observed between the response rate to vaccine and the other variables. In conclusion, the response rate to hepatitis B vaccine reached a little more than 30% in cirrhotic patients who received 3 or 4 doses. No higher response rate was observed among patients who received 4 doses. Diabetes was associated with a lower response rate. Anti-HBs seroconversion rates were not associated with the other variables. Revaccination may significantly increase the response rate to hepatitis B vaccine in cirrhotic patients, and may be considered in nonresponders after the third dose. Early vaccination against HBV should be considered in such patients.     

Cytoreductive Surgery and Intraoperative Hyperthermic Intraperitoneal Chemotherapy with Paclitaxel: A Clinical and Pharmacokinetic Study

Background Intraperitoneal chemotherapy has been recommended as a treatment option for ovarian cancer with peritoneal dissemination. Although its treatment duration is significantly shorter, intraoperative hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) has several advantages over simple intraperitoneal instillation chemotherapy. While platinum compounds have usually been used, only a few have administered paclitaxel during HIPEC. Its large molecular weight suggests a much more favorable pharmacokinetic profile than that of platinum compounds. The pharmacokinetics of paclitaxel during and after HIPEC have not been studied before. Methods Thirteen women, mainly with ovarian cancer, underwent cytoreductive surgery and HIPEC with 175 mg/m² paclitaxel for 2 h. Morbidity was noted. Peritoneal fluid samples and blood samples were harvested during and until 5 days after HIPEC for pharmacokinetic study in ten patients. Results No treatment-related mortality was noted. Overall morbidity was 38% (two wound infections, one deep venous thrombosis, two grade 1 thrombopenia, one grade 2 neutropenia, and one grade 3 pancytopenia). Mean maximal intraperitoneal paclitaxel concentration was 101 mg/L, which was an average of 1178 times higher than the peak plasma levels. The peritoneal fluid versus plasma AUC ratio was 1462 for the 2-h HIPEC duration and 366 for the total 5-day study period. Cytotoxic drug concentrations were detected in peritoneal fluid for a mean period of 2.7 days, despite drainage of the drug solution after 2 h of treatment. Conclusions HIPEC with paclitaxel following cytoreductive surgery is feasible, relatively safe, and associated with a highly favorable pharmacokinetic profile, despite its short treatment duration. Larger studies with a more homogenous patient cohort and adequate follow-up should be performed to demonstrate its efficacy.     

Long-term Outcome of Patients with Acute Cholecystitis Receiving Antibiotic Treatment: A Retrospective Cohort Study

Background

Few studies have followed patients who received antibiotic treatment for acute cholecystitis (AC). The present retrospective study investigated recurrence rates of AC and analyzed factors associated with recurrence after antibiotic treatment in adult AC patients.

Methods

We analyzed patients treated with antibiotics for AC between October 1, 2004, and November 30, 2010. A Cox proportional hazards model was used to identify factors associated with early recurrence. Generalized additive models were applied to detect the nonlinear effects of continuous covariates.

Results

The study included 226 patients (mean age: 62.2 years; 144 men [63.7 %]). The average duration of parenteral antibiotics was 8.0 days. Second-generation cephalosporins were administered to 199 patients (88.1 %). The Kaplan–Meier plot indicated that recurrences were more frequent within 100 days of AC; these were defined as early recurrences. The recurrence rate was 13.7 % (31/226) at a median follow-up of 308.5 days (early recurrences: 19/226 [8.4 %]). The duration of parenteral antibiotic use significantly correlated with early recurrence (hazard ratio: 0.83; 95 % confidence interval, 0.73–0.95; p = 0.005). Generalized additive models revealed that patients using parenteral antibiotics longer than 8 days were less likely to suffer from early recurrence.

Conclusions

The rate of recurrence of AC in patients who received antibiotics alone was low. The recurrence rate was higher within 100 days of AC. Because of the inherent limitations of a retrospective study, further research is needed to identify factors associated with early recurrence.     

罗库溴铵 维库溴铵及美维松肌松效应的临床比较

目的比较罗库溴铵、维库溴铵及美维松的 肌松效应。方法45例ASAⅠ～Ⅱ级 全麻手术病人随机分为三组,各组分别于气管插管后注入相当于2倍ED     

Geographic Regional Differences in Rocuronium Bromide Dose-Response Relation and Time Course of Action: An Overlooked Factor in Determining Recommended Dosage

Background: Geographic location is not acknowledged as a stratifying factor that can directly affect drug potency, because drugs are still licensed with the same recommended dose for different geographic regions. The aim of the current study was to compare the potency and duration of action of rocuronium bromide in 54 patients in three countries with different life habits, diet, and ambient conditions, namely white Austrians, white North Americans, and Han Chinese in China.

Methods: Neuromuscular block of six consecutive 50-[mu]g/kg rocuronium incremental doses followed by 300 [mu]g/kg was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, Holland). Dose-response curves were created using log-dose-probit transformation. The authors compared rocuronium bromide ED50, ED90, and ED95 (effective doses required for 50%, 90%, and 95% first twitch depression, respectively) as well as Dur25 and Dur0.8 (times from last incremental dose administration until 25% first twitch and 0.8 train-of-four ratio recovery, respectively) in patients of the three countries.

Results: Rocuronium ED50, ED90, and ED95 were significantly higher in Austrian patients (258 +/- 68, 530 +/- 159, and 598 +/- 189 [mu]g/kg) and Chinese patients (201 +/- 59, 413 +/- 107, and 475 +/- 155 [mu]g/kg) compared with American patients (148 +/- 48, 316 +/- 116, and 362 +/- 149 [mu]g/kg, respectively). Dur25 and Dur0.8 were significantly shorter in Austrian patients (22.3 +/- 5.5 and 36.9 +/- 12.8 min) and Chinese patients (30.4 +/- 7.5 and 45.7 +/- 15.9 min) compared with American patients (36.7 +/- 8.5 and 56.2 +/- 16.7 min, respectively).     

Lack of Benefit of Early Protocol Biopsies in Renal Transplant Patients Receiving TAC and MMF: A Randomized Study

We conducted a randomized, multicenter study to determine whether treatment of subclinical rejection with increased corticosteroids resulted in beneficial outcomes in renal transplant patients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and prednisone. One hundred and twenty-one patients were randomized to biopsies at 0,1,2,3 and 6 months (Biopsy arm), and 119 to biopsies at 0 and 6 months only (Control arm). The primary endpoint of the study was the prevalence of the sum of the interstitial and tubular scores (ci + ct)> 2 (Banff) at 6 months. Secondary endpoints included clinical and subclinical rejection and renal function. At 6 months, 34.8% of the Biopsy and 20.5% of the Control arm patients had a ci + ct score >or= 2 (p = 0.07). Between months 0 and 6, clinical rejection episodes were 12 in 10 Biopsy arm patients and 8 in 8 Control arm patients (p = 0.44). Overall prevalence of subclinical rejection in the Biopsy arm was 4.6%. Creatinine clearance at 6 months was 72.9 +/- 21.7 in the Biopsy and 68.90 mL/min +/- 18.35 mL/min in the Control arm patients (p = 0.18). In conclusion, we found no benefit to the procurement of early protocol biopsies in renal transplant patients receiving TAC, MMF and prednisone, at least in the short term. This is likely due to their low prevalence of subclinical rejection.     

Repeated Clinical and Laboratory Examinations in Patients with an Equivocal Diagnosis of Appendicitis

In-hospital observation with repeated clinical examinations is commonly used in patients with an equivocal diagnosis of appendicitis. It is not known if repeated measurements of temperature and laboratory examinations have any diagnostic importance in this situation. The importance of repeated measurements of the body temperature, white blood cell (WBC) and differential cell counts, C-reactive protein concentration (CRP) and of the surgeon's repeated assessments was prospectively analyzed in 420 patients with an equivocal diagnosis of appendicitis at admission who were reexamined after a median of 6 hours of observation. The final diagnosis was appendicitis in 137 patients. After observation the inflammatory response was increasing among patients with appendicitis and decreasing among patients without appendicitis. The variables discriminating power for appendicitis consequently increased, from an area under the receiver operating characteristic (ROC) curve of 0.56 to 0.77 at admission, to 0.75 to 0.85 after observation. The ROC area of the surgeons' clinical assessment increased from 0.69 to 0.89. The WBC and differential cell counts were the best discriminators at the repeat examination. The change in the variables between the observations had weak discriminating power and had no additional importance in addition to the actual level at the repeat examination. To conclude, the diagnostic information of the temperature and laboratory examinations increased after observation. Repeated controls of the body temperature and laboratory examinations are therefore useful in the management of patients with equivocal signs of appendicitis, but the result of the examinations must be integrated with the clinical assessment.     

Recovery from Sevoflurane Anesthesia: A Comparison to Isoflurane and Propofol Anesthesia

Backgroud: Sevoflurane has a lower blood:gas partition coefficient than isoflurane, which may cause a more rapid recovery from anesthesia; it also might cause faster emergence times than for propofol-based anesthesia. We evaluated a database that included recovery endpoints from controlled, randomized, prospective studies sponsored by Abbott Laboratories that compared sevoflurane to isoflurane or propofol when extubation was planned immediately after completion of elective surgery in adult patients.

Methods: Sevoflurane was compared to isoflurane in eight studies (N = 2,008) and to propofol in three studies (N = 436). Analysis of variance was applied using least squares method mean values to calculate the pooled mean difference in recovery endpoints between primary anesthetics. The effects of patient age and case duration also were determined.

Results: Sevoflurane resulted in statistically significant shorter times to emergence (-3.3 min), response to command (-3.1 min), orientation (-4.0 min) and first analgesic (-8.9 min) but not time to eligibility for discharge (-1.7 min) compared to isoflurane (mean difference). Times to recovery endpoints increased with increasing case duration with isoflurane but not with sevoflurane (patients receiving isoflurane took 4-5 min more to emerge and respond to commands and 8.6 min more to achieve orientation during cases longer than 3 hr in duration than those receiving sevoflurane). Patients older than 65 yr had longer times to orientation, but within any age group, orientation was always faster after sevoflurane. There were no differences in recovery times between sevoflurane and propofol.     

Progression of Alphafetoprotein Before Liver Transplantation for Hepatocellular Carcinoma in Cirrhotic Patients: A Critical Factor

Liver transplantation (LT) for cirrhotic/Hepatocellular carcinoma (HCC) is associated with reduced survival in patients with poor histological features. Preoperative levels of alphafetoprotein (AFP) could predict negative biological features. AFP progression could be more relevant than static AFP levels in predicting LT outcomes. A total of 252 cirrhotic/HCC patients transplanted between 1985 and 2005 were reviewed. One hundred fifty‐three patients were analyzed, 99 excluded (for nonsecreting tumors and/or salvage transplantation). Using receiver operating characteristics analysis for recurrence after LT, ‘progression’ of AFP was defined by >15 μg/L per month before LT. A total of 127 (83%) were transplanted under and 26(16%) over this threshold. After 45 months of follow‐up (median), 5‐year overall survival (OS) and recurrence free‐survival (RFS) were 72% and 69%, respectively. Five‐year survival in the progression group was lower than the nonprogression group (OS 54% vs. 77%; RFS 47% vs. 74%). Multivariate analysis showed progression of AFP >15 μg/L per month and preoperative nodules >3 were associated with decreased OS. Progression group and age >60 years were associated with decreased RFS. Male gender, progression of AFP and size of tumor >30 mm were associated with satellite nodules and/or vascular invasion. In conclusion, increasing AFP >15 μg/L/month while waiting for LT is the most relevant preoperative prognostic factor for low OS/DFS. AFP progression could be a pathological preoperative marker of tumor aggressiveness.