EBM,HTA, and CER: Clearing the Confusion

Context: The terms evidence-based medicine (EBM), health technology assessment (HTA), comparative effectiveness research (CER), and other related terms lack clarity and so could lead to miscommunication, confusion, and poor decision making. The objective of this article is to clarify their definitions and the relationships among key terms and concepts.Methods: This article used the relevant methods and policy literature as well as the websites of organizations engaged in evidence-based activities to develop a framework to explain the relationships among the terms EBM, HTA, and CER.Findings: This article proposes an organizing framework and presents a graphic demonstrating the differences and relationships among these terms and concepts.Conclusions: More specific terminology and concepts are necessary for an informed and clear public policy debate. They are even more important to inform decision making at all levels and to engender more accountability by the organizations and individuals responsible for these decisions.     

Dopamine increases renal oxygenation: a clinical study in post‐cardiac surgery patients

Background: Imbalance of the renal medullary oxygen supply/demand relationship can cause ischaemic acute renal failure (ARF). The use of dopamine for prevention/treatment of ischaemic ARF has been questioned. It has been suggested that dopamine may increase renal oxygen consumption (RVO₂) due to increased solute delivery to tubular cells, which may jeopardise renal oxygenation. Information on the effects of dopamine on renal perfusion, filtration and oxygenation in man is, however, lacking. We evaluated the effects of dopamine on renal blood flow (RBF), glomerular filtration rate (GFR), RVO₂ and renal O₂ demand/supply relationship, i.e. renal oxygen extraction (RO₂Ex). Methods: Twelve uncomplicated, mechanically ventilated and sedated post‐cardiac surgery patients with pre‐operatively normal renal function were studied. Dopamine was sequentially infused at 2 and 4 ug/kg/min. Systemic haemodynamics were evaluated by a pulmonary artery catheter. Absolute RBF was measured using two independent techniques: by the renal vein thermodilution technique and by infusion clearance of paraaminohippuric acid (PAH), with a correction for renal extraction of PAH. The filtration fraction (FF) was measured by the renal extraction of ⁵¹Cr‐EDTA. Results: Neither GFR, tubular sodium reabsorption nor RVO₂ was affected by dopamine, which increased RBF (45–55%) with both methods, decreased renal vascular resistance (30–35%), FF (21–26%) and RO₂Ex (28–34%). The RBF/CI ratio increased with dopamine. Dopamine decreased renal PAH extraction, suggestive of a flow distribution to the medulla. Conclusions: In post‐cardiac surgery patients, dopamine increases the renal oxygenation by a pronounced renal pre‐and post‐glomerular vasodilation with no increases in GFR, tubular sodium reabsorption or renal oxygen consumption.     

ON THE DIAGNOSIS OF SYMPTOMATIC NEONATAL HYPOGLYCEMIA

Eighteen newborn infants, 11 males and 7 females, with hypoglycemia, i.e. with blood glucose concentration of less than 20 mg per 100 ml were studied. Twelve infants were diagnosed as cases of symptomatic and 6 as cases of asymptomatic hypoglycemia. All infants with asymptomatic hypoglycemia were small for gestational age, whereas the symptomatic group was heterogenous from a clinical point of view. The disappearance rate of intravenously administered glucose (k_G-value) was studied before any treatment was started. The k_G-values were high in all infants with symptomatic hypoglycemia, in 10 exceeding +2 s.D. for normal infants of the same age. The symptomatic infants were treated with hydrocortisone or human growth hormone in addition to continuous glucose infusion. After the institution of therapy there was a rapid normalization of the k_G-values. The 6 infants with asymptomatic hypoglycemia had normal k_G;-values. They were only given a high caloric supply by means of breast milk. In two infants with symptomatic hypoglycemia repeated simultaneous determinations of k_G-values and the plasma concentration of free fatty acids revealed no relationship. At follow-up examinations at ages from 5 months to 2 years, 2 out of the 12 infants in the symptomatic group were found to have severe cerebral damage. All infants with asymptomatic hypoglycemia were completely normal. The findings seem to have some clinical applications. Determination of the disappearance rate of intravenously administered glucose, primarily given as a diagnostic test, may differentiate between symptomatic and asymptomatic hypoglycemia. If in a doubtful case the k_G-value is normal, the likely diagnosis is asymptomatic hypoglycemia. In cases of symptomatic neonatal hypoglycemia repeated determinations of the k_G-value may provide a sensitive guide as to the effect of treatment.     

EVALUATION OF THREE SPIROMETERS ON HEALTHY CHILDREN

ABSTRACT. Two electronic spirometers (Dräger Spirotron and Monaghan M403) and one wedge bellows spirometer (Vitalograph) were compared with a Bernstein spirometer. Healthy children, 30 girls and 31 boys, were investigated. The regression lines of VC and FEV_1.0 in relation to the body height to the third power are very close and the S.D. values around the lines are very similar. The correlation coefficients of the regression lines are high for all the spirometers. An analysis of the paired differences showed slight differences of the mean values. The S.D. of paired differences was for VC 4.6–6.6% and for FEV_1.0 4.8-6.2%. The PEFR values obtained by the two electronic spirometers deviated substantially and highly significantly from the values obtained by the Wright peak flow meter.     

Local cerebral blood flow in the brain during bicuculline-induced seizures and the modulating influence of inhibition of prostaglandin synthesis

The purpose of this study was to measure changes in local cerebral blood flow (1-CBF) during generalized seizures, and to study whether or not formation of prostaglandins or related substances contributes to the increased flow rates. Seizures were induced in ventilated rats maintained on 70% N₂O and 30% O₂ by the i. v. injection of the GABA receptor blocker bicuculline (1.2 mg-kg^-1). Formation of prostaglandins was inhibited by the administration of the fatty acid cyclo-oxygenase inhibitor indomethacin (10 mg · kg^-1)-Local CBF in 21 defined brain structures was measured autoradiographically with ^HC-iodoantipyrine as the diffusible tracer. After 20 min of continuous seizure activity 1-CBF increased 1.5-5-fold, the smallest increases (<200% of control) being observed in frontal and auditory cortex and in the caudoputamen, and the largest (>400% of control) in substantia nigra, thalamus, visual cortex, lateral geniculate and hypothalamus. In general, the largest increases in 1-CBF occurred in sensory and limbic systems (and hypothalamus) while motor systems showed a pronounced variability. In the majority of structures examined indomethacin failed to modify the CBF response during seizures. Although this result suggests that seizures, in contrast to hypercapnia, lead to an increased CBF by other mechanisms than those related to prostaglandin formation, some structures (nucleus ruber, cerebellum, and superior colliculus) showed a clearly reduced 1-CBF in indomethacin-treated animals.     

Structural and mechanical alterations in hypertrophic venous smooth muscle

Portal hypertension was induced in rats by partial ligation of the hepatic branches of the portal vein. After 5 days the transluminal pressure of the portal vein was measured, and the vessel was fixed in situ for electron-microscopy, or dissected out and mounted in an apparatus recording force and shortening. Portal veins from sham-operated animals were used as controls. Portal venous pressure had increased about twofold after the partial ligation and the cross-sectional area of the longitudinal muscle layer about twofold. Number of muscle cells per mm² cross-sectional area decreased to half of the control value, whereas extracellular space in the muscle layer and the dry weight of the preparations were unaltered. Number of cells was unchanged suggesting that no hyperplasia had occurred. Length-passive force relations were shifted towards higher force values in the hypertrophic vessels, whereas passive stress-strain characteristics were similar. The structures that carry passive tension have thus increased in proportion to the vessel as a whole. Length-active tension curves obtained by stimulation with AC current or high K+ solutions indicated that the hypertrophic vessels could not, in relation to optimal length for active force, shorten to the same extent as control vessels. Maximum active tension per vessel was unaltered whereas force per unit muscle area and force per cell had decreased. As the preparations were supramaximally stimulated and had optimal extracellular Ca²⁺ concentrations we suggest that the amount of functional contractile proteins has not increased in proportion to the increase in size of the muscle cells.     

Renal proximal tubular acidification. Role of brush-border and cytoplasmic carbonic anhydrase

Carbonic anhydrase is found in the cytoplasm and brush border membranes of renal proximal tubular cells. Both the soluble and the membrane-bound enzyme have been assigned roles for the secretion of hydrogen ions into the tubular fluid and hence also for the reabsorption of bicarbonate. Attempts were made to differentiate between the roles of these enzymes for the rate of proximal tubular acidification. Proximal tubules of rats were instilled and perfused with bicarbonate solutions containing carbonic anhydrase inhibitors, especially designed to be impermeable to cell membranes. The acidification rate was measured with an antimony micro-electrode system–the only instantly responding micro-pH electrode. The membrane impermeable inhibitors had no effect on this rate in contrast to acetazolamide, which markedly inhibited the acidification rate when administered in-traluminally. It is therefore concluded that the cytoplasmic carbonic anhydrase is the important enzyme for the proximal tubular acidification rate, and hence the rate of bicarbonate reabsorption. The function of the brush border enzyme remains an outstanding problem.     

Relation between cell length and force production in urinary bladder smooth muscle

Guinea-pig and rabbit urinary bladders were fixed in glutaraldehyde at different volumes. Strips were dissected out, embedded and cut for phase contrast and electron microscopy. Muscle wall thickness decreased with increased bladder volume as did the radial number of muscle cells. Cell length, measured by a morphometric method increased linearly with bladder radius, indicating that no slippage between the muscle cells occurred. Number of cells per mm² cross sectional area increased linearly with bladder radius. Volume-active force relations were obtained by pelvic nerve stimulations of guinea pig bladders filled to different volumes. Maximum pressure was obtained at 0.15 ml bladder volume, and maximum wall tension at a volume of 2.5 ml which corresponds to a cell length of 400 μm and a cell packing density of about 107000×mm^-2. Estimation of the length-active tension curve for the average muscle cell in the guinea-pig bladder indicated a maximum active force of 5.5 μN/cell. Maximum active force per cm² muscle bundle was calculated to be about 59 N. No compensation for extracellular space and nonmuscular tissue within the muscle bundle was made.     

Effects of carbachol on isoprenaline evoked amylase release from the rabbit parotid gland in vitro

Amylase secretion from dispersed lobules of the parotid gland of the rabbit was studied in response to isoprenaline (10^-8–10^-8M) and to carbachol (10^-8–10^-5M). The effects of each agent were investigated alone and in combination at certain concentrations. Isoprenaline produced a dose-related amylase secretion with an average maximum of 688 units/100 mg, at 10^- 5M. The amylase secretion produced by submaximal concentrations of isoprenaline could be further increased by carbachol, already in low concentrations (10^-8–10^-7M), that were subthreshold for amylase secretion. This potentiating effect was seen not only as a larger secretion but also as a greater depletion of amylase from the tissue. In contrast to what is known from experiments in vivo, carbachol in a high concentration (10^-5M), by activating muscarinic receptors only, released amylase to the same extent as that released by isoprenaline. This concentration of carbachol regularly decreased the amylase secretion evoked by isoprenaline, and may be regarded as unphysiologically high. The increase in isoprenaline evoked amylase secretion, brought about by carbachol in lower concentrations, may be due to an improved transport of amylase, because of secretion of fluid, but could also be caused by augmentation of the β-adrenoceptor mediated effects.