Sheldon Magder

Reactive oxygen species: toxic molecules or spark of life?

Increases in reactive oxygen species (ROS) and tissue evidence of oxidative injury are common in patients with inflammatory processes or tissue injury. This has led to many clinical attempts to scavenge ROS and reduce oxidative injury. However, we live in an oxygen rich environment and ROS and their chemical reactions are part of the basic chemical processes of normal metabolism. Accordingly, organisms have evolved sophisticated mechanisms to control these reactive molecules. Recently, it has become increasingly evident that ROS also play a role in the regulation of many intracellular signaling pathways that are important for normal cell growth and inflammatory responses that are essential for host defense. Thus, simply trying to scavenge ROS is likely not possible and potentially harmful. The normal level of ROS will also likely vary in different tissues and even in different parts of cells. In this paper, the terminology and basic chemistry of reactive species are reviewed. Examples and mechanisms of tissue injury by ROS as well as their positive role as signaling molecules are discussed. Hopefully, a better understanding of the nature of ROS will lead to better planned therapeutic attempts to manipulate the concentrations of these important molecules. We need to regulate ROS, not eradicate them.

The Clinical Role of Central Venous Pressure Measurements

Central venous pressure (CVP) is commonly measured, but its clinical use is still not clear. We argue that the interpretation of the CVP needs to be considered in conjunction with an assessment of cardiac output. The objective of this study was to define an elevated CVP as one in which there is a low probability for cardiac output to increase with a volume infusion through a Starling mechanism by relating the initial CVP (measured relative to a reference point 5 cm below the sternal angle) to the response in cardiac output with volume infusion. The authors studied consecutive patients who had pulmonary artery catheters in place and who had a volume challenge as part of routine management as ordered by the treating physician. To ensure an adequate test of the Starling mechanism, data were included only if the volume infusion increased CVP by≥2 mm Hg. Responders were defined a priori as those with an increase in cardiac index ≥300 and nonresponders as <300 mL/min/m2. Patients failed to respond to volume infusion at all CVP values, and even 25% of those with CVP <5 mm Hg were nonresponders. However, when CVP was >10 mm Hg, physicians prescribed less fluid challenges, and when they did, a positive response was much less likely. Change in blood pressure or changes in urine output with volume infusion correlated poorly with change in cardiac index. A CVP of>10 mm Hg should be considered high, and the probability of an increase in cardiac output with volume infusion is low. This value is a reasonable upper limit for algorithms for empiric fluid challenges.

Treatment with 17-β-estradiol reduces superoxide production in aorta of ovariectomized rats

OBJECTIVEnOxidant stress contributes to vascular injury and atherosclerosis. We hypothesized that estrogen treatment of ovariectomized rats decreases O(2)(-) by decreasing the activity of NAD(P)H oxidase and this reduction in O(2)(-) could have a vasculoprotective effect.nnnMETHODS AND RESULTSnOvariectomized rats were treated with 17-beta-estradiol E2 (0.25mg) or oil placebo for 21 days. Aorta were removed for contractility studies and O(2)(-) production was measured by lucigenin enhanced chemiluminescence (230 and 5microM). E2 treatment decreased basal O(2)(-) production but did not alter NADH or NADPH stimulated O(2)(-) production. Total p47phox and p47phox in membrane fractions of cardiac tissue were decreased, which suggests less activation of NAD(P)H oxidase in E2 treated rats. E2 did not change expression of other components of NAD(P)H oxidase in heart, lung, spleen and diaphragm. Expression of eNOS was also lower in E2 treated rats. E2 did not affect the contractile response to phenylepherine, dilation with acetylcholine, dilation with superoxide dismutase or constriction with l-NAME. This argues against changes in bioavailable NO.nnnCONCLUSIONSnE2 decreases activation of p47phox and O(2)(-) production by NAD(P)H oxidase. This did not affect contractile properties of the vessel, but could still potentially alter cell signaling from oxidant increasing stresses.

Estrogen decreases TNF-α and oxidized LDL induced apoptosis in endothelial cells

Abstract Apoptosis induced by oxidized low-density lipoproteins (oxLDL) and tumor necrosis factor-α (TNF-α) is believed to contribute to atherosclerosis and vascular dysfunction. Estrogen treatment reduces apoptosis due to TNF-α and we hypothesized that it would also reduce apoptosis due to oxLDL. We also explored the anti-apoptotic mechanisms. We used early passage human umbilical vein endothelial cells (HUVEC) grown in steroid-depleted, red phenol-free medium. Cells were synchronized by starvation for 6xa0h and then treated with oxLDL (75xa0μg/ml) or TNF-α (20xa0ng/ml) in the presence of 17-β-estradiol (E2) (20xa0nM). Apoptosis was analyzed by flow cytometry and caspase-3 cleavage. We also assessed expression of Bcl-2 and Bcl-xL and phosphorylation of BAD. At 6xa0h TNF-α induced apoptosis but oxLDL did not; E2 did not affect this TNF-α induced apoptosis and there was no change in Bcl-2 or Bcl-xL expression. At 24xa0h both TNF-α and oxLDL increased apoptosis and E2 reduced the increase. E2 also increased expression of the anti-apoptotic Bcl-2 and Bcl-xL and increased phosphorylation of proapoptotic BAD which reduces its proapoptotic activity at 1xa0h. However at 24xa0h there was also an increase in total BAD so that the proportion of phosphorylation of BAD decreased. oxLDL induced apoptosis occurs later than that of TNF-α. E2 decreased this late phase apoptosis and this likely requires the production of anti-apoptotic proteins.

Bench-to-bedside review: An approach to hemodynamic monitoring - Guyton at the bedside

Hemodynamic monitoring is used to identify deviations from hemodynamic goals and to assess responses to therapy. To accomplish these goals one must understand how the circulation is regulated. In this review I begin with an historical review of the work of Arthur Guyton and his conceptual understanding of the circulation and then present an approach by which Guytons concepts can be applied at the bedside. Guyton argued that cardiac output and central venous pressure are determined by the interaction of two functions: cardiac function, which is determined by cardiac performance; and a return function, which is determined by the return of blood to the heart. This means that changes in cardiac output are dependent upon changes of one of these two functions or of both. I start with an approach based on the approximation that blood pressure is determined by the product of cardiac output and systemic vascular resistance and that cardiac output is determined by cardiac function and venous return. A fall in blood pressure with no change in or a rise in cardiac output indicates that a decrease in vascular resistance is the dominant factor. If the fall in blood pressure is due to a fall in cardiac output then the role of a change in the return function and cardiac function can be separated by the patterns of changes in central venous pressure and cardiac output. Measurement of cardiac output is a central component to this approach but until recently it was not easy to obtain and was estimated from surrogates. However, there are now a number of non-invasive devices that can give measures of cardiac output and permit the use of physiological principles to more rapidly appreciate the primary pathophysiology behind hemodynamic abnormalities and to provide directed therapy.

Volume and its relationship to cardiac output and venous return

Volume infusions are one of the commonest clinical interventions in critically ill patients yet the relationship of volume to cardiac output is not well understood. Blood volume has a stressed and unstressed component but only the stressed component determines flow. It is usually about 30 % of total volume. Stressed volume is relatively constant under steady state conditions. It creates an elastic recoil pressure that is an important factor in the generation of blood flow. The heart creates circulatory flow by lowering the right atrial pressure and allowing the recoil pressure in veins and venules to drain blood back to the heart. The heart then puts the volume back into the systemic circulation so that stroke return equals stroke volume. The heart cannot pump out more volume than comes back. Changes in cardiac output without changes in stressed volume occur because of changes in arterial and venous resistances which redistribute blood volume and change pressure gradients throughout the vasculature. Stressed volume also can be increased by decreasing vascular capacitance, which means recruiting unstressed volume into stressed volume. This is the equivalent of an auto-transfusion. It is worth noting that during exercise in normal young males, cardiac output can increase five-fold with only small changes in stressed blood volume. The mechanical characteristics of the cardiac chambers and the circulation thus ultimately determine the relationship between volume and cardiac output and are the subject of this review.

Balanced versus unbalanced salt solutions: What difference does it make?

BACKGROUNDnThe infusion of crystalloid solutions is a fundamental part of the management of critically ill patients. These solutions are used to maintain the balance of water and essential electrolytes and replace losses when patients have limited gastrointestinal intake. They also act as carriers for intravenous infusion of medication and red cells. The most commonly used solution, 0.9% saline, has equal concentrations of Na(+) and Cl(-) even though the plasma concentration of Na(+) normally is 40xa0meq/L higher than that of Cl(-). The use of this fluid thus can produce a hyperchloremic acidosis in a dose-dependent manner, but it is not known whether this has clinical significance.nnnAPPROACHnThe first part of this article deals with the significance of Na(+) and Cl(-) in normal physiology. This begins with examination of their roles in the regulation of osmolality, acid-base balance, and generation of electrochemical gradients and why the concentration of Cl(-) normally is considerably lower than that of Na(+). The next part deals with how their concentrations are regulated by the gastrointestinal tract and kidney. Based on the physiology, it would seem that solutions in which the concentration of Na(+) is balanced by a substance other than Cl(-) would be advantageous. The final part examines the evidence to support that point.nnnCONCLUSIONSnThere are strong observational data that support the notion that avoiding an elevated Cl(-) concentration or using fluids that reduce the rise in Cl(-) reduces renal dysfunction, infections, and possibly even mortality. However, observational studies only can indicate an association and cannot indicate causality. Unfortunately, randomized trials to date are far too limited to address this crucial issue. What is clear is that appropriate randomized trials will require very large populations. It also is not known whether the important variable is the concentration of Cl(-), the difference in concentrations of Na(+) and Cl(-), or the total body mass of Cl(-).

Differences in neuropeptide Y-induced secretion of endothelin-1 in left and right human endocardial endothelial cells.

The aim of the study was to test the hypothesis that neuropeptide Y (NPY) may induce endothelin-1 (ET-1) secretion in left (hLEECs) and right (hREECs) human endocardial endothelial cells. Furthermore, the type of NPY receptor implicated could be different in NPY-induced secretion in hLEECs and hREECs. Using immunofluorescence coupled to real 3D confocal microscopy and ELISA, our results showed that stimulation of secretion by NPY induced the release of ET-1 from both right and left human ventricular endocardial endothelial cells (hEECs) in a time-dependent manner. Furthermore, the secretory capacity of hREECs was higher than that of hLEECs. In addition, our results showed that the effect of NPY on ET-1 secretion in hLEECs was only due to activation of Y(5) receptors. However, the effect of NPY on ET-1 secretion in hREECs was due to mainly Y(2) and partially Y(5) receptors activation. In conclusion, our results suggest that differences in excitation-secretion coupling exist between hREECS and hLEECs which may contribute to the functional differences between right and left ventricular muscle. Furthermore, high NPY level contributes to ET-1 release by hEECs and Y(2) and Y(5) receptors antagonists may be used for regulation of ET-1 secretion in the heart.

Bench-to-bedside review: Ventilatory abnormalities in sepsis

In septic patients increased central drive and increased metabolic demands combine to increase energy demands on the ventilatory muscles. This occurs at a time when energy supplies are limited and energy production hindered, and it leads to an energy supply-demand imbalance and often ventilatory failure. Problems related to contractile function of the ventilatory muscles also contribute, especially when the clinical course is prolonged. The increased ventilatory activity increases interactions between the ventilatory and cardiovascular systems, and when ventilatory muscles fail and mechanical ventilatory support is required a new set of problems emerges. In this review I discuss factors related to ventilatory muscle failure, giving emphasis to mechanical and supply demand aspects. I also review the implications of changes in ventilatory patterns for heart-lung interactions.

A comparison of prognostic significance of strong ion gap (SIG) with other acid-base markers in the critically ill: a cohort study

BackgroundThis cohort study compared the prognostic significance of strong ion gap (SIG) with other acid-base markers in the critically ill.MethodsThe relationships between SIG, lactate, anion gap (AG), anion gap albumin-corrected (AG-corrected), base excess or strong ion difference-effective (SIDe), all obtained within the first hour of intensive care unit (ICU) admission, and the hospital mortality of 6878 patients were analysed. The prognostic significance of each acid-base marker, both alone and in combination with the Admission Mortality Prediction Model (MPM0 III) predicted mortality, were assessed by the area under the receiver operating characteristic curve (AUROC).ResultsOf the 6878 patients included in the study, 924 patients (13.4xa0%) died after ICU admission. Except for plasma chloride concentrations, all acid-base markers were significantly different between the survivors and non-survivors. SIG (with lactate: AUROC 0.631, confidence interval [CI] 0.611–0.652; without lactate: AUROC 0.521, 95xa0% CI 0.500–0.542) only had a modest ability to predict hospital mortality, and this was no better than using lactate concentration alone (AUROC 0.701, 95xa0% 0.682–0.721). Adding AG-corrected or SIG to a combination of lactate and MPM0 III predicted risks also did not substantially improve the latter’s ability to differentiate between survivors and non-survivors. Arterial lactate concentrations explained about 11xa0% of the variability in the observed mortality, and it was more important than SIG (0.6xa0%) and SIDe (0.9xa0%) in predicting hospital mortality after adjusting for MPM0 III predicted risks. Lactate remained as the strongest predictor for mortality in a sensitivity multivariate analysis, allowing for non-linearity of all acid-base markers.ConclusionsThe prognostic significance of SIG was modest and inferior to arterial lactate concentration for the critically ill. Lactate concentration should always be considered regardless whether physiological, base excess or physical-chemical approach is used to interpret acid-base disturbances in critically ill patients.