A framework for considering the risk‐benefit trade‐off in designing noninferiority trials using composite outcome approaches

When a new treatment regimen is expected to have comparable or slightly worse efficacy to that of the control regimen but has benefits in other domains such as safety and tolerability, a noninferiority (NI) trial may be appropriate but is fraught with difficulty in justifying an acceptable NI margin that is based on both clinical and statistical input. To overcome this, we propose to utilize composite risk‐benefit outcomes that combine elements from domains of importance (eg, efficacy, safety, and tolerability). The composite outcome itself may be analyzed using a superiority framework, or it can be used as a tool at the design stage of a NI trial for selecting an NI margin for efficacy that balances changes in risks and benefits. In the latter case, the choice of NI margin may be based on a novel quantity called the maximum allowable decrease in efficacy (MADE), defined as the marginal difference in efficacy between arms that would yield a null treatment effect for the composite outcome given an assumed distribution for the composite outcome. We observe that MADE: (1) is larger when the safety improvement for the experimental arm is larger, (2) depends on the association between the efficacy and safety outcomes, and (3) depends on the control arm efficacy rate. We use a numerical example for power comparisons between a superiority test for the composite outcome vs a noninferiority test for efficacy using the MADE as the NI margin, and apply the methods to a TB treatment trial.     

Growth hormone responses to treadmill sprinting in sprint- and endurance-trained athletes

The purpose of the present study was to examine the growth hormone (GH) response to treadmill sprinting in male (M) and female (F) sprint- and endurance-trained atheletes. A group of 11 sprint-trained (ST; 6M, 5F) and 12 endurance-trained (ET; 6M, 6F) athletes performed a maximal 30-s sprint on a nonmotorized treadmill. Peak power and mean power expressed in watts or in watts per kilogram body mass were higher in ST than in ET (P < 0.01) and in the men compared to the women (P < 0.01). Serum GH was greater in ST than in ET athletes, but was not statistically significantly different between the men and the women [mean peak GH: ST 72.4 (SEM 12.5) compared to ET 26.3 (SEM 4.9) mU · I^–1, P < 0.01; men 59.8 (SEM 13.3) compared to the women 35.8 (SEM 7.4) mU · l^–1, n.s.]. Plasma ammonia and blood lactate concentrations were higher and blood pH lower during 1 h of recovery after the sprint in ST compared to ET (all P < 0.01). Multiple log linear regression showed that 82% of the variation in the serum peak GH response was explained by the peak power output and peak blood lactate response to the sprint. As serum GH was still approximately ten times the basal value in ST athletes after 1 h of recovery, it is suggested that the exercise-induced increase in GH could have important physiological effects in this group of athletes, including increased protein synthesis and sparing of protein degradation leading to maintained or increased muscle mass.This work was completed at Department of Physical Education, Sports Science and Recreation Management, Loughborough University     

不同浓度乙醇灌流液对蟾蜍离体心脏活动影响的比较分析

用不同浓度乙醇灌流液灌流蟾蜍离体心脏,观察其对离体心脏心率、心肌收缩力和心输出量的变化。结果显示：心率减慢,但在１０ ｍ ｍｏｌ／Ｌ 稍有加快（ Ｐ ＞ ０ ．０５） ,浓度在２０ ｍ ｍ ｏｌ／Ｌ 以上时减慢才明显（ Ｐ ＜ ０ ．０５） ;心肌收缩幅度下降,其表现浓度越大下降越明显（ Ｐ ＜ ０ ．０５ ～０ ．０１） ;心输出量在１０ ｍ ｍｏｌ／Ｌ、１５ ｍ ｍｏｌ／Ｌ 时略有增加,超过３０ ｍ ｍｏｌ／Ｌ 以后心输出量下降,但不明显（ Ｐ ＞ ０ ．０５） 。表明乙醇过量有减慢心率和抑制心肌收缩力的作用,而对输出量影响不大。     

Monitoring during paediatric cardiac anaesthesia

Monitoring of paediatric anaesthesia has become increasingly more complex in recent years and this is particulary true of cardiac anaesthesia. The purpose of this review is to give a comprehensive update of published material related to both routine and specialized cardiac monitoring. Routine monitoring can be particularly affected by the alterations of cardiac rhythm, blood flow, cardiac output and oxygenation which result from the congenital heart abnormalities themselves, the type of surgery undertaken and the effects of cardiopulmonary bypass. The use of specialized monitoring is becoming more widespread, particularly in the areas of cerebral function, mixed venous oxygenation, cardiac output measurement and coagulation. In the last five years, with the development of smaller probes, a great deal has been published on transoesophageal echocardiography. The use of the current monitors of cerebral function still remains controversial despite the need for a monitor of adequate brain perfusion, reflecting the need for a great deal of further research in this area. This review will concentrate on particular areas which have seen the most profound changes and on monitoring that may form the standards of tomorrow. Finally, amongst all the technology, it should not be forgotten that the most important clinical monitor is the bedside clinical monitoring of the physicians themselves. Depuis quelques années, le monitorage de l’anesthésie pédiatrique devient déplus en plus complexe et tout particulièrement en anesthésie cardiaque. L’objectif de ce travail consiste à passer en revue la littérature actuelle qui traite du monitorage usuel et spécialisé. Le monitorage usuel peut être influencé par les modifications de la fréquence cardiaque, du courant sanguin, du débit cardiaque et de l’oxygénation provoqués par les anomalies cardiaques congénitales, du type de chirurgie et des retentissements de la circulation extracorporelle. L’utilisation du monitorage spécialisé est de plus en plus répandu et concerne particulièrement la circulation cérébrale, l’oxygénation du sang veineux mêlé, la mesure du débit cardiaque et la coagulation. Au cours des cinq dernières années, le développement de sondes plus petites a généré de nombreuses publications sur l’échocardiographie transoesophagienne. L’utilisation des moniteurs actuels de la fonction cérébrale demeure sujet à controverse bien qu ’un moniteur de perfusion cérébrale adéquat demeure toujours aussi essentiel, confirmant ainsi le besoin de recherches supplémentaires sur ce sujet. Ce survol se portera spécialement sur les champs d’activités qui ont connu les changements les plus profonds et sur le monitorage qui établira les standards du futur. Finalement, au milieu de cette technologie, il ne faut jamais oublier que le moniteur clinique le plus important se trouve au chevet du malade en la personne du médecin.     

Cardiac output measurement by the thermodilution method: An in vitro test of accuracy of three commercially available automatic cardiac output computers

Objective To describe the accuracy and the reproducibility of the thermodilution flow measurements obtained using 3 commercially available cardiac output computers commonly used in intensive care units.Design An experimental in vitro study. Twelve different values of control flow (Qctr) were measured (Qmsr) using 3 different cardiac output computers (Abbott Critical Care System, Oximetrix 3 SvO₂/CO Computer, Baxter Oximeter/Cardiac Output Computer SAT-1^TM; American Edwards Laboratories, 9520 A Cardiac Output Computer). Standard equipment and techniques were employed, taking account of the specific weight and heat of warm water relative to blood. In addition, separate sets of measurements were performed in order to investigate the effect on Qmsr of some variables which may influence the indicator loss (time for injection, depth of immersion of the catheter, temperature of the injected fluid).Setting Our laboratory, inside the intensive care unit.Measurements and results The analysis of the linear regression of Qmsr versus Qctr (r values between 0.992 and 0.984; residual standard deviation values comprised between 0.24 and 0.49 l/min; intercepts and slopes not significantly different from identity line), the values of the percentage errors (PE=[Qctr–Qmsr]·100/Qctr; PE mean values 7.9, 5.0 and 13.1), and those of the coefficients of variability (CV=standard deviation mean value, %; CV mean values 5.4, 5.8 and 4.6), show a good level of accuracy and reproducibility of the measurements. Our data confirm previously reported results. Furthermore, the cumulative effect of variables capable of influencing the indicator loss, even if corrected according to the calculation constant the manufacturers provide, was found to result in statistically significant changes of Qmsr.Conclusion The accuracy and reproducibility of the automatic cardiac computers tested is sufficient for practical clinical purpose. It may also depend on the modality of injection of the cooling bolus, which may significantly influence the effective indicator losses.     

甲型肝炎疫苗免疫前后发病情况分析

为比较沙县在甲型肝炎（甲肝）疫苗免疫前后甲肝的发病情况,对本站疫情定收集的1990～1997年报告的882例甲肝病例进行了分析。结果表明,疫苗免疫前甲肝发病率在63.36／10万～99.90／10万,免疫后为16.20／10万～21.87／10万,免疫前后平均发病率之比为422：1。按＜15岁、15～44岁和≥45岁分组,发病率下降最明显的是＜15岁,其次是15～44岁和≥45岁,依次下降了91.9％、70.1％和37.1％．工人、农民、学生（大、小、小学生）不同职业人群,以学生下降最明显,农民下降不明显,存在差别的原因可能是甲肝疫苗接种率的高低。甲肝疫苗接种的成本效益为1：953．     

Nitric oxide inhalation as a chemical assist for circulation in patients after cardiovascular surgery

The objective of this study was to investigate whether nitric oxide (NO) inhalation might be an alternative strategy as a chemical assist for the circulation in patients showing a deterioration in oxygen delivery. Twelve adult patients whose oxygen delivery indices (DO2I) were less than 400 ml/min/m2 after cardiovascular surgery were included in this study. NO was administered via a premixing system or a side stream system at doses between 1 and 10 (5.1+/-2.4) ppm. Data obtained before and during a 120 min NO inhalation were compared using the paired Student's t-test. The increase in PaO2/FiO2 resulting from NO inhalation was significant (from 162 to 251 mm Hg). DO2I increased significantly from 326 to 417 ml/min/m2 concomitantly with significant increases in both arterial oxygen content (CaO2) and cardiac index (CI) (from 14.1 to 15.4 vol% and from 2.31 to 2.71 L/min/m2 , respectively). The increase in SvO2 during NO inhalation was significant (from 55.2 to 62.6%). Among the other hemodynamic parameters, both total pulmonary resistance and systolic pulmonary arterial pressure (SPAP) showed significant decreases during NO inhalation, but right atrial pressure did not change significantly. There was a close relationship between the baseline SPAP level (bSPAP) and the decrease in SPAP during NO inhalation (dSPAP) (r = -0.88). However, negative correlations were observed between bSPAP and percentage increase in CI (%CI) (r = -0.61) and between bSPAP and percentage increase in DO2I (%DO2I) (r = -0.48). Moreover, positive relationships were observed between dSPAP and %CI (r = 0.62) and between dSPAP and %DO2I (r = 0.45). Hemoglobin (Hb) increased significantly from 11.0 to 11.4 g/dl. There were no significant changes in Fio2, pH, PacO2, or base excess (BE) during NO inhalation. The level of methemoglobin measured during the study period remained within the normal range (0.86+/-0.23%). In conclusion, NO inhalation could be an efficient and alternative assist for the circulation in patients whose oxygen delivery deteriorates after cardiovascular surgery.     

儿童接种肾综合征出血热Ⅰ型灭活疫苗的成本效益和效果分析

采用建德市肾综合征出血热Ⅰ型灭活疫苗效果考核现场资料,计算５～９岁和１０～１４岁各年龄组的效益费用比（ＢＣＲ）和效果费用比（ＣＥＲ）。结果各年龄组ＢＣＲ和ＣＥＲ均小于１或大于０;５～９岁年龄组儿童接种疫苗后的ＣＥＲ和预防一个病人的费用是１０～１４岁年龄组的一倍左右。结论：可在高发区１０～１４岁儿童中开展ＨＦＲＳ疫苗预防接种。     

Measurement of cardiac output-transtracheal Doppler versus thermodilution

The ABCOM 1 transtracheal Doppler (TTD) has been developed as a non-invasive cardiac output monitor. With this device, cardiac output is continuously calculated from ascending aortic blood flow velocity and aortic diameter obtained via an ultrasound transducer incorporated into the tip of an endotracheal tube. We evaluated the clinical use of the ABCOM 1 monitor and compared cardiac outputs obtained using the TTD system with simultaneous thermodilution (TD) measurements. We found the operation of the ABCOM 1 monitor to be difficult and time-consuming. In our operating rooms, acceptable Doppler signal quality was difficult to obtain. There was no correlation between 36 simultaneously obtained TTD and TD cardiac output measurements. The average difference between measurement techniques and the limits of agreement were unacceptably large (mean difference = 3.04 L.min-1, mean +/- 2 SD = -6.04 to 12.48 L.min-1). Separately analyzing only those measurements during which Doppler signal quality was adequate did not improve agreement between TTD and TD measurements. On the basis of these findings, TTD cannot be recommended as a clinical cardiac output measurement technique.     

Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel tube” model using lidocaine in the perfused rat liverin situ preparation

Theoretical analysis of two models of hepatic drug clearance revealed that one powerful discriminator between them is the effect of changes of hepatic blood flow on either the emergent drug concentration or the availability of a highly extracted compound when operating under linear conditions. Lidocaine (extraction ratio 0.997) was employed in the discriminatory studies. The behavior of this drug under linear conditions (input lidocaine concentrations < 5 mg/ liter) to changes in hepatic blood flow rate (10–16 ml/min per liver) was examined in the perfused rat liver in situpreparation. The steady-state output lidocaine concentration in the blood leaving the liver was predicted better by a well-stirred model than by a parallel tube model. As anticipated, the clearance of a poorly extracted compound, antipyrine (extraction ratio 0.08),was unaltered by changes in hepatic blood flow. These experimental findings, and the data from the literature, point to the acceptance of the well-stirred model, which describes the liver as a well-stirred compartment with the drug in the hepatic venous blood being in equilibrium with that in the liver.Supported in part by National Institutes of Health Grant GM 16496 and the Patent Fund, Graduate Division, University of California, San Francisco.Abstracted in part from a dissertation submitted by K. Sandy Pang to the Graduate Division, University of California, San Francisco, California, in partial fulfillment of the Doctor of Philosophy degree requirements.