Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study

Purpose

The role of dobutamine during septic shock resuscitation is still controversial since most clinical studies have been uncontrolled and no physiological study has unequivocally demonstrated a beneficial effect on tissue perfusion. Our objective was to determine the potential benefits of dobutamine on hemodynamic, metabolic, peripheral, hepatosplanchnic and microcirculatory perfusion parameters during early septic shock resuscitation.

Methods

We designed a randomized, controlled, double-blind, crossover study comparing the effects of 2.5-h infusion of dobutamine (5 mcg/kg/min fixed-dose) or placebo in 20 septic shock patients with cardiac index ≥2.5 l/min/m² and hyperlactatemia. Primary outcome was sublingual perfused microvascular density.

Results

Despite an increasing cardiac index, heart rate and left ventricular ejection fraction, dobutamine had no effect on sublingual perfused vessel density [9.0 (7.9–10.1) vs. 9.1 n/mm (7.9–9.9); p = 0.24] or microvascular flow index [2.1 (1.8–2.5) vs. 2.1 (1.9–2.5); p = 0.73] compared to placebo. No differences between dobutamine and placebo were found for the lactate levels, mixed venous-arterial pCO₂ gradient, thenar muscle oxygen saturation, capillary refill time or gastric-to-arterial pCO₂ gradient. The indocyanine green plasma disappearance rate [14.4 (9.5–25.6) vs. 18.8 %/min (11.7–24.6); p = 0.03] and the recovery slope of thenar muscle oxygen saturation after a vascular occlusion test [2.1 (1.1–3.1) vs. 2.5 %/s (1.2–3.4); p = 0.01] were worse with dobutamine compared to placebo.

Conclusions

Dobutamine failed to improve sublingual microcirculatory, metabolic, hepatosplanchnic or peripheral perfusion parameters despite inducing a significant increase in systemic hemodynamic variables in septic shock patients without low cardiac output but with persistent hypoperfusion.     

南京地区33家医院2009-2011年大环内酯类抗菌药物利用分析

目的:评价南京地区医院大环内酯类抗菌药物的利用情况。方法:采用回顾性方法,对南京地区33家医院2009-2011年大环内酯类抗菌药物的销售金额、用药频度(DDDs)等进行统计、分析。结果:该地区医院大环内酯类抗菌药物的销售金额及总DDDs各年度均有所降低,年均降幅分别为9.77%和8.23%。品种方面,2010-2011年较2009年增加了2种,即螺旋霉素和地红霉素。第2代大环内酯类的用量远大于第1代,占整个大环内酯类的94.97%。各年度销售金额及DDDs排序列前3位的药物为阿奇霉素、克拉霉素、罗红霉素;销售金额排序列前3位的生产厂家为江苏扬子江药业、江苏恒瑞医药集团、辽宁沈阳第一制药厂;销售金额排序列前5位的产品为罗红霉素细粒剂(仁苏)、克拉霉素缓释片(诺邦)、克拉霉素分散片(锋锐)、阿奇霉素胶囊(希舒美)、注射用乳糖酸阿奇霉素(其仙)。结论:该地区医院大环内酯类抗菌药物的应用呈下降趋势,应用排序列前3位的是阿奇霉素、克拉霉素、罗红霉素,均为第2代大环内酯类。     

睫状神经营养因子对大鼠视神经不全损伤后轴浆运输的影响

目的探讨睫状神经营养因子(CNTF)对大鼠视神经(optic nerve, ON)中度不全损伤后轴浆运输的影响.方法成年雌性Wistar大鼠50只,用无创血管夹于球后1.5 mm钳夹ON 10 s,造成ON中度损伤,于伤后即刻、伤后1、2、4和8周CNTF治疗组玻璃体腔内注射人重组睫状神经营养因子(rhCNTF)2 μg,对照组注射等量双蒸水.分别在不同的时间(1、2、4、8和12周)应用辣根过氧化物酶(horseradish peroxidase, HRP)观察ON不全损伤后顺行轴浆运输的变化.结果伤后1～2周在损伤点后HRP顺染纤维度骤然下降,于上丘均未见HRP显色;伤后4周ON及上丘顺染密度逐渐增强至8周达高峰,对照组ON损伤远端顺染纤维度恢复至正常的12.87%,而治疗组至31.86%.两组间于ON损伤远端和上丘HRP顺染密度均有非常显著性差异(P<0.01).结论 CNTF可改善ON不全损伤后轴浆运输状况,促进ON结构的恢复.     

Heart, kidney, and intestine have different tolerances for anemia

Organ systems do not respond uniformly to changes in systemic oxygen delivery because of global and local redistributive mechanisms. We hypothesized that progressive hemodilution would evoke a different response in the microvascular oxygenation of the heart compared with kidney and gut. To evaluate this hypothesis, we studied the effect of stepwise isovolemic hemodilution on systemic hemodynamic and oxygenation parameters as well as the relation between systemic hematocrit (Ht) and microvascular PO(2) (microPO(2)) in heart, kidney, and intestines in an anesthetized and mechanically ventilated rat model. Baseline conditions were similar in the hemodilution group and in the control group. In the hemodilution group, Ht was diminished from 46.6 +/- 3.8% to 7.0 +/- 1.8% [mean +/- standard deviation (SD)]. This group had no effect on measured hemodynamics; only when Ht fell below 10% did blood pressure start to decrease. The microPO(2) values in heart, kidney, and intestines did not respond uniformly. Renal microPO(2) (56 +/- 10 mm Hg at baseline) started to decrease at a Ht of 38.5 +/- 8.6%, whereas intestinal microPO(2) (59 +/- 6 mm Hg at baseline) did not start to decrease until Ht reached 17.4 +/- 7.1%. Finally, cardiac microPO(2) (40 +/- 6 mm Hg at baseline) decreased only in the ultimate stage of the experiment at Ht of 8.7 +/- 3.5%. Based on these observations, we conclude that the regulation of microvascular oxygenation during progressive anemia is specific for each organ system. The relation between these observations and organ function and damage needs to be determined.     

Duarte (DG) galactosemia: a pilot study of biochemical and neurodevelopmental assessment in children detected by newborn screening

Newborn screening for galactosemia has shown a high prevalence of partial galactose uridyl transferase deficiencies such as Duarte (DG) galactosemia.Study objective: To determine whether (a) there is any clinical impact of DG galactosemia on development (b) there is a relationship between outcome and biochemical parameters in patients who receive no treatment.Study population: Twenty-eight children with DG galactosemia. Group-I—17 children had a lactose restricted diet in the first year of life. Group-II—11 children had a regular diet since birth.Methods: Developmental, physical, and ophthalmologic assessments were completed on both DG groups. RBC gal-1-p and urine galactitol were monitored during the follow-up visits in every child with DG galactosemia. Gal-1-p, urine galactitol, liver function tests, and FSH were tested at the time of study visit.Results: The groups had statistically significant differences on RBC gal-1-p and urine galactitol at the 2 week, 1 month, 6 month, and 1 year time points. There was no statistical difference of gal-1-p or urine galactitol in group-I and -II at the time of study. The groups had statistically significant differences on adaptive scores, but not on language or IQ. None of the DG subjects had abnormal liver function at the time of diagnosis or the study visit. The FSH levels were normal. There were no statistically significant relationships between the first year metabolic values and developmental outcomes.Conclusions: The data presented here indicate that clinical and developmental outcomes in DG galactosemics are good regardless of any diet changes.     

加味四逆散抗慢性心理应激损伤的机理研究--对下丘脑促肾上腺皮质激素释放激素及环核苷酸系统的影响

[目的]观察加味四逆散(JSS)对慢性心理应激大鼠下丘脑促肾上腺皮质激素释放激素(CRH)及环核苷酸系统的影响.[方法]Wistar大鼠随机分为3组,即正常组、模型组和加味四逆散(JSS)组;除正常组外,其他组大鼠均采用束缚法复制慢性心理应激反应模型,JSS组于造模前1 h按3.38g/kg剂量灌胃给药,连续14 d;采用逆转录聚合酶链反应(RT-PCR)法检测下丘脑CRH信使核糖核酸(CRH mRNA)的表达,放射免疫法检测下丘脑环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)含量.[结果]慢性心理应激大鼠下丘脑CRH mRNA表达显著增高(P＜0.05),JSS可降低下丘脑CRH mRNA的表达(P＜0.05);慢性心理应激可使大鼠下丘脑cAMP、cGMP均显著升高(P＜0.01),JSS可显著降低下丘脑cAMP含量(P＜0.05),但对cGMP无显著影响.[结论]JSS可通过影响下丘脑CRH和环核苷酸系统参与对慢性心理应激反应的调控,CRH和cAMP可能是JSS抗慢性心理应激损伤的作用环节或靶点.     

Neuropeptide co-release with GABA may explain functional non-monotonic uncertainty responses in dopamine neurons

Co-release of the inhibitory neurotransmitter GABA and the neuropeptide substance-P (SP) from single axons is a conspicuous feature of the basal ganglia, yet its computational role, if any, has not been resolved. In a new learning model, co-release of GABA and SP from axons of striatal projection neurons emerges as a highly efficient way to compute the uncertainty responses that are exhibited by dopamine (DA) neurons when animals adapt to probabilistic contingencies between rewards and the stimuli that predict their delivery. Such uncertainty-related dopamine release appears to be an adaptive phenotype, because it promotes behavioral switching at opportune times. Understanding the computational linkages between SP and DA in the basal ganglia is important, because Huntington’s disease is characterized by massive SP depletion, whereas Parkinson’s disease is characterized by massive DA depletion.     

Can the apparent adaptation of dopamine neurons’ mismatch sensitivities be reconciled with their computation of reward prediction errors?

According to modern reinforcement learning theories, midbrain dopamine (DA) neurons are part of an adaptive system within which learned expectations filter reward-related signals to enable computation of reward prediction errors (RPEs). Recent electrophysiological data on DA neuron responses to probabilistic reward schedules inspired the idea that DA neurons might be adapting their mismatch sensitivities to reflect variances of expected rewards. Taken literally as a mathematical hypothesis, this idea contradicts reinforcement learning theory, and most computational models of basal ganglia learning. Here, we report a qualitative mathematical derivation of the implications of a generic class of circuit models for learning to compute RPEs. This analysis and concordant circuit simulations, both of which predict DA neuron responses on probabilistic schedules, support a reinterpretation of the electrophysiological data that is fully compatible with the examined class of RPE models. This reinterpretation implies a novel and readily testable prediction.     

Pharmacokinetics, biodistribution, efficacy and safety of N-octyl-O-sulfate chitosan micelles loaded with paclitaxel

Paclitaxel (Taxol), PTX) is a promising anti-cancer drug and has been successfully used to treat a wide variety of cancers. Unfortunately, serious clinical side effects are associated with it, which are caused by PTX itself and non-aqueous vehicle containing Cremophor EL. Development of new formulation of PTX with better efficacy and fewer side effects is extremely urgent. In the present study, a N-octyl-O-sulfate chitosan (NOSC) micelle was developed and used as the delivery system for PTX. The pharmacokinetics, biodistribution, efficacy and safety of PTX-loaded NOSC micelles (PTX-M) were evaluated. The results showed that NOSC micelles had high drug loading capacity (69.9%) and entrapment efficiency (97.26%). The plasma AUC of PTX-M was 3.6-fold lower than that of Taxol; but the V(d) and CL of PTX-M were increased by 5.7 and 3.5-fold, respectively. Biodistribution study indicated that most of the PTX were distributed in liver, kidney, spleen, and lung and the longest retention effect was observed in the lung. Drug safety assessment studies including acute toxicity, hemolysis test, intravenous stimulation and injection anaphylaxis revealed that the PTX-M was safe for intravenous injection. Furthermore, the comparable antitumor efficacy of PTX-M and Taxol was observed at the same dose of 10 mg/kg in in vivo antitumor mice models inoculated with sarcoma180, enrich solid carcinoma (EC), hepatoma solidity (Heps), Lewis lung cancer cells and A-549 human lung cancer cells. These results clearly showed that PTX-M had the similar antitumor efficacy as Taxol, but significantly reduced the toxicity and improved the bioavailability of PTX.