In critical care, the monitoring is essential to the daily care of ICU patients, as the optimization of patient's hemodynamic, ventilation, temperature, nutrition, and metabolism is the key to improve patients' survival. Indeed, the decisive endpoint is the supply of oxygen to tissues according to their metabolic needs in order to fuel mitochondrial respiration and, therefore, life. In this sense, both oxygenation and perfusion must be monitored in the implementation of any resuscitation strategy. The emerging concept has been the enhancement of macrocirculation through sequential optimization of heart function and then judging the adequacy of perfusion/oxygenation on specific parameters in a strategy which was aptly coined “goal directed therapy.” On the other hand, the maintenance of normal temperature is critical and should be regularly monitored. Regarding respiratory monitoring of ventilated ICU patients, it includes serial assessment of gas exchange, of respiratory system mechanics, and of patients' readiness for liberation from invasive positive pressure ventilation. Also, the monitoring of nutritional and metabolic care should allow controlling nutrients delivery, adequation between energy needs and delivery, and blood glucose. The present paper will describe the physiological basis, interpretation of, and clinical use of the major endpoints of perfusion/oxygenation adequacy and of temperature, respiratory, nutritional, and metabolic monitorings. In critical care, the optimization of patient's hemodynamic and temperature is the key to improve patient morbidity and mortality. The goal of hemodynamic monitoring is to provide data that aids in the optimization of end organ tissue oxygenation and effectively combats global tissue hypoxia, shock, and multiorgan failure. Traditional, noninvasive methods of hemodynamic monitoring pertained solely to physical examination, and invasive methods included central venous and pulmonary artery catheterization mostly. These pressure-derived preload values have been used extensively in the management of fluid resuscitation and titration. However, numerous studies of various patient populations  have challenged the notion that these indicators accurately predict volume status –7. TheseRecently, however, technologic advancements in this area have introduced new methods of noninvasive and less invasive hemodynamic monitoring. Generally, this data provides insight into the fluid status of the patient by indicating where the patient is on the Frank-Starling curve (preload) and may also provide insight into cardiac output, myocardial contractility, systemic vascular resistance, and more novel parameters related to the pulmonary vascular system. This chapter seeks to provide an overview of these new technologies and its implication in the critical care setting. Identification of patients who are on the steep part of frank starling curve and therefore are fluid responsive is a core principle of hemodynamic monitoring and aids in the determination of the extent that circulatory homeostasis can be maintained with fluids alone, versus the need for inotropes or vasopressors. Similarly the continuous assessment of cardiac output, myocardial contractility, and vascular tone is crucial to the diagnosis and management of critically ill patients, and this has long been solely provided by the PAC catheter. Recently, however there are new technologies that may provide this information in a less invasive or completely noninvasive manner.The concept of pulse contour analysis is a method of ascertaining the cardiac output from analyzing of the pulse pressure waveform. It is known that the pulse pressure is directly proportional to stroke volume and inversely related to vascular compliance. Also it is known that the pulse pressure waveform depicts the changes in stroke volume that occur with positive pressure ventilation. Specifically, during the inspiratory phase of positive pressure ventilation, intrathoracic pressure increases passively, increasing right atrial pressure and causing venous return to decrease, decreasing right ventricular output, and after two or three heart beats affecting left ventricular output. Monitoring this stroke volume variation has shown to accurately predict patients who are fluid responsive . A largeThere are several technologies that use pulse contour analysis; these include the FloTrac, PiCCO, and LiDCO plus systems. These systems differ in their modality to assess for vascular tone their requirements for invasive monitoring and need for external calibration for CO measurements. A short discussion of each of these devices is in the following.The FloTrac has a proprietary software algorithm that analyzes characteristics of the arterial pressure waveform and uses this analysis, along with patient-specific demographic information, to determine continuous CO, systemic vascular resistance, and the dynamic parameter of stroke volume variation. It carries the advantage of being able to be used for any arterial catheter in any arterial location. In addition, the device self-calibrates were based on patient demographics and waveform analysis. Differences in patient populations, study environments , FloTrac software versions, ventilatory settings, medical interventions, and reference standard(s) used , combined with the relatively small single center studies, are all central to this issue. Newer FloTrac software versions have improved the accuracy of the system's ability to determine CO. This system also uses analysis of pulse contour from an arterial line to determine stroke volume and CO. However, the main difference is that this system uses a lithium-based dye-dilution technique to calibrate its pulse contour analysis algorithm, referred to as Pulse CO. After calibration, the LiDCO plus system can generate CO measurements using pulse contour analysis; however recalibration is recommended every 8 hours. Like the LiDCO and FloTrac systems, this device provides CO through pulse contour analysis of the arterial waveform. It also requires an external calibration  for this analysis. The PiCCO monitor provides several other measurements as well including global end-diastolic volume measurements of all four heart chambers as well as extravascular lung water measurements. One of the limitations of this technology is the requirement for proximal artery catheterization with a thermistor-tipped catheter . As withThe esophageal Doppler is a flexible probe that has a Doppler transducer  at the tip that is placed in the esophagus to obtain an aortic velocity signal in the descending aorta. The technology allows one to gain insight into preload by looking at the flow time of the velocity time integral (VTI) of the aortic flow , with states of decreased preload shortening the flow time. Also it quantifies myocardial contractility by assessing the peak velocity of the aortic VTI signal . Finally, this technology derives vascular tone by analysis of the VTI waveform. A meta-analysis Dark and Singer demonstrated an 86% correlation between cardiac output as determined by esophageal Doppler and PAC . ClinicaUsing low voltage, electrical impedance (or resistance) across the chest is measured. The higher the fluid content, the lower the impedance since fluid conducts electricity. As the volume of blood in the thorax changes during the heart cycles through systole and diastole, these variations can be measured electrically . Many ofRecent advances in point of care ultrasound devices have tremendously increased the utility of echocardiography in the critical care setting. The benefit of echocardiography lies in the fact that it allows the clinician to directly visualize the cardiac anatomy as well assess flow dynamics and thus rapidly assess structural abnormalities, contractility, and intravascular volume. While historically echocardiography has required extensive specialty training, recent literature supports the ability to train noncardiologist to perform and interpret a limited transthoracic echocardiography exam , 30. RecIn summary, no device stands out as being better than another and although not perfectly accurate, all the devices are able to detect alterations in cardiac output. Therefore, the true benefit lies with correct application of these devices by understanding the technology as well as the limitations for each device.Shock is defined as “inadequate tissue oxygen for aerobic cellular respiration.” Therein lie the issues of shock management: the relationship between oxygen delivery and perfusion, the issues of mitochondrial dysfunction and lactate, and the issue of inadequate delivery to demand. Shock results from varying macrocirculatory and microcirculatory failure leading to hypoperfusion. Additionally, mitochondrial dysfunction may result in cellular oxygen misuse. Furthermore, stress and physiological compensation increase oxygen demand in situations of poor delivery. This oxygen delivery and demand inadequacy compound organ failure and can ultimately result in death despite optimal management. 2), and central or mixed venous oxygen saturation (ScvO2 or SvO2). Shock management has included “restoring” or “maximizing” oxygen delivery and tissue oxygenation, albeit with varying results. A meta-analysis  showed t2, to assess oxygen delivery adequacy. A >5% drop in ScvO2 led to Hb level assessment/transfusion, CO assessment/inotropes, or intubation, ventilation, and sedation to decrease O2 demand. Interestingly, EGDT led to increased fluid loading, blood transfusion, and inotropes. Regardless of controversies [Rather than a “holy grail” endpoint, the past decade has been marked by the early goal directed therapy (EGDT) approach of Rivers . EGDT isoversies , EGDT haoversies –36. 2 to assess adequate tissue perfusion/oxygenation [2 can coexist with hypoperfusion [2 >70%, judging tissue perfusion may require other parameters such as lactate clearance or venoarterial PCO2 gradient and/or the visualization of microcirculation.However, impaired oxygen extraction in sepsis and altered flow impede the use of ScvOgenation , and higerfusion . TherefoAn important subject characterizing critically ill patients is that capillary circulation cannot be predicted by macrohemodynamic parameters. As depicted in situations like septic shock , 40 or h2 of the stomach wall. It is assumed that the increased gastric mucosal CO2 leading to gastric mucosal acidosis is a result of anaerobic metabolism consequent to splanchnic hypoperfusion. Previous studies indicate that gastric tonometry is a highly sensitive predictor of outcome in patients undergoing cardiac surgery [2 will be elevated when local perfusion is compromised secondary to resulting anaerobic cellular metabolism from reduced oxygen delivery. In addition, the concept has yielded a very poor specificity secondary to multiple confounders such as inappropriate measurement of stomach content PCO2, temperature  buffering of gastric acid by duodenal/esophageal reflux, difference in arterial supply, and enteral feeding. It is a known phenomenon that early on in hemodynamic stressed states there is a flow distribution away from the gastrointestinal tract, resulting in an increase in the PCO surgery , admitte surgery , in seps surgery , or with surgery . However2 monitoring.Recently sublingual capnometry has been introduced as a method of resolving many of these difficulties associated with gastric tonometry. Sublingual capnometry is a technically simple, noninvasive, inexpensive technology that has been shown to provide insight into the adequacy of tissue perfusion during both hemorrhagic and septic shock , 49, 50.2) when coupled with a functional hemodynamic monitoring test, such as the vascular occlusion test (VOT). Noninvasive measurement of StO2 using near infrared spectroscopy (NIRs) has been shown as a valid method to assess the microcirculation status, especially in septic and trauma patients [2 to identify tissue hypoperfusion [The assessment of end organ oxygenation may be of value when caring for the critically ill patient. Previous studies have shown that impaired tissue oxygenation events are not easily detected by usual monitoring of heart rate, urine output, central venous pressure (CVP), cardiac output (CO), and blood pressure (BP) , 52 secopatients . The adderfusion .2) and serum lactate levels are markers of global oxygen supply and demand and may be a poor reflection of splanchnic regional oxygen delivery and regional tissue viability [2, lactate, HR, UOP, BP, CVP) are affected. Preliminary data with an esophageal probe T-STAT 303  utilizing visible light spectroscopy (VLS) has shown positive results with its ability to detect ischemia to the splanchnic bed [Similarly, the ability to continuously assess oxygen delivery to organs supplied by the splanchnic circulation may be of critical importance since blood flow abnormalities to this region are associated with a range of morbidities, perhaps most notably multiple organ failure that can lead to death . Markersiability , 55–57. hnic bed , 59.2 and Hb conditions, SvO2 should be >70%. During effort, oxygen uptake increases with transport. The oxygen transport (TO2) and uptake (VO2) relationship is defined by the extraction ratio of oxygen (ERO2):2 is 100%:2 values of 70–75% correspond to normal ERO2 of 25–30% delivered oxygen. Oxygen extraction depends on activity, tissue, and mitochondrial function. During effort, increased oxygen demand leads to increased extraction and decreased SvO2. While SvO2 normally drops to 60% through ERO2 increase to 40%, SvO2 may drop to 40% with ERO2 reaching up to a maximum of 60%. If this ERO2MAX is reached, any further demand leads to anaerobic lactate production. This maximal “critical ERO2” corresponds to a “critical SvO2” of 40% below which inadequate transport-to-demand, and therefore shock, is inevitable [In normal SaO2 is the net result of pathophysiological processes and therapeutic compensations of VO2 and TO2  must be considered and managed. Conversely, before ascribing a decrease in SvO2 to decreased TO2 and increasing it, causes of increased VO2  should be considered and managed. Of note, ScvO2 is more easily obtainable from a central line placed the in superior vena cava (rather than a right cardiac catheter for SvO2) and correlates well with SvO2 [2 in shock, once increased VO2 has been managed, reflects increased ERO2 compensating for decreased TO2, which must be explored. These are the principles underlying EGDT [SvO and TO2 . Before ith SvO2 . Thus, ding EGDT .2 may reflect two situations: either an increase in TO2 relative to VO2, in a successfully optimized, stabilized, or recovering patient, or a decrease in VO2 relative to TO2, due to mitochondrial dysfunction [Increased ScvOfunction .2 is a marker of inadequate global oxygenation which can only be interpreted by taking into account factors related to VO2 increase on one hand and TO2 decrease on the other and (2) “normal” ScvO2 is not a reliable marker of adequate oxygen transport-to-demand when oxygen uptake may be impaired.These issues highlight that (1) decreased ScvO2 relative to VO2 resulting in decreased ScvO2. However, while ScvO2-guided therapy reduced mortality in septic shock, 30% mortality remained, due to multiorgan failure with hypoperfusion [2 to explore locoregional or microcirculatory perfusion. Indeed, perfusion heterogeneity, such as in septic shock [2. Oxygenation cannot be dissociated from perfusion. Indeed, when global perfusion is decreased due to decreased CO, all circulations have low flow and decreased TOerfusion . The mosic shock , will leic shock . However2 despite overt or occult hypoperfusion.This also occurs locally with some circulations hypoperfused while contributing little desaturated blood to venous return, and others maintained through macrocirculatory optimization contributing much overly saturated venous blood, again resulting in a net normal ScvO2 cannot see local/microcirculatory hypoperfusion, and normal ScvO2 should not be considered the ultimate endpoint [Therefore, ScvOendpoint .Glycolysis produces pyruvate, which either enters aerobic mitochondrial respiration requiring oxygen or, in tissue hypoxia, is transformed into lactate metabolized by the liver, kidneys, and skeletal muscle. In low flow, increased lactate is related to tissue hypoxia by hypoperfusion , 67. In 2 [2.De Backer et al. studying local sublingual capillary perfusion in patients with septic shock showed that lactate clearance was correlated to capillary reperfusion following dobutamine independently of cardiac index, arterial pressure, systemic vascular resistance, or VO2 . Lactate2 , 72, car2 , 74, sep2 , 76, and2 . Therefo2 goal was inferior to reaching only the lactate clearance goal [2 and lactate clearance must be used hierarchically. Interestingly, Rivers participated in a noncomparative study prior to EGDT in which both ScvO2 and lactate clearance were used as subsequent endpoints and allowed a low mortality rate of 14% [Simultaneous ScvO2 and lactate clearance were also measured in a study of 203 patients with septic shock in which reaching only the ScvOnce goal . This sue of 14% .2 or lactate clearance performed similarly and concluded that lactate clearance could be used instead of ScvO2 [In the largest RCT comparing two EGDTs in septic shock, Jones et al. showed that ScvOof ScvO2 .2, but if it should be an additional endpoint. Strikingly, while Jones et al. did not find any difference when replacing ScvO2 by lactate clearance, Nguyen et al., in a study of sepsis bundles, showed that by adding lactate clearance to ScvO2, mortality decreased even further from 24.5% to 17.9% [However the real question is not whether lactate clearance should replace ScvOto 17.9% .2 is a byproduct of oxidative metabolism. Tissue production of CO2 (VCO2) is related to oxygen uptake:R is the respiratory quotient which ranges from 0.7, for pure fat, to 1.0, for pure carbohydrate, as is usually the case in patients with shock; therefore,2 is the venoarterial PCO2 gradient and k the coefficient between CO2 concentrations and partial pressures.COThe previously mentioned Equation (a) can be transformed:2 gradient is proportional to VCO2, itself inversely proportional to the CO2 clearance from tissues (washout). Given its diffusible nature CO2 washout depends mainly on cardiac output (CO) and tissue perfusion. The determinants of P(v-a)CO2 are therefore VCO2, CO, and tissue perfusion  mal flow , leading >6 mmHg . 2 clearance in patients with chronic heart failure and low cardiac output in whom P(v-a)CO2 >6 mmHg decreased to normal following dobutamine [2 increased in conditions of perfusion dependency [2 differences correlated to hypoperfusion [Teboul et al. demonstrated the role of cardiac output in CObutamine . Vallet pendency . This haerfusion .2 and cardiac output is curvilinear, with asymptotic VCO2 isopleths CO2 remains normal when cardiac output is normal or increased. These are major issues for interpretation: (1) decreased cardiac output will increase P(v-a)CO2 >6 mmHg independently of underlying hypoperfusion COsopleths : increas2) seeking to discriminate patients with or without hypoperfusion defined as blood lactate >2 mmol/L. Neither SvO2 nor mixed venous PvCO2 was discriminant. However, increased P(v-a)CO2 was correlated to increased blood lactate levels with an optimal cutoff at 6 mmHg [Mekontso-Dessap et al. studied 89 critically ill patients with normal cardiac index  using in vivo sublingual microcirculation imaging and sublingual tonometric assessment of PCO2, in which sublingual PCO2-PaCO2 difference was correlated to hypoperfusion and decreased with reperfusion following low-dose dobutamine [2 >70% [2 >6 mmHg had slower and lower lactate clearance and increasing organ failure than patients with normal P(v-a)CO2.This was also shown, by Creteur et al., in patients with resuscitated septic shock and normal cardiac index CO2 were correlated to postoperative complications [2 (>70%) were detected by increased P(v-a)CO2. This prognostic value of P(v-a)COications . Interes2 in resuscitated septic shock or high-risk surgical states may (1) reflect inadequate cardiac output, and, (2) in patients with normal/increased cardiac output, increased P(cv-a)CO2 may reflect underlying occult hypoperfusion; (3) targeting P(cv-a)CO2 <6 mmHg might be of benefit although it remains unclear how best to achieve this [It appears that increased P(cv-a)COeve this .2, adequacy of cardiac output to perfusion such as P(cv-a)CO2, global perfusion such as lactate clearance and local perfusion indices. All the clinical tools already exist; however, while some can be monitored continuously such as ScvO2, others such as P(cv-a)CO2 and blood lactate require repeated sampling and blood gas analysis. What remains in order to encourage development of tools for continuous perfusion monitoring through these parameters is to design and carry out studies implementing comprehensive, stepwise, multiple-endpoint, EGDT-like approaches.The future of perfusion monitoring may be comprehensive EGDT-like approaches integrating endpoints of global oxygenation such as ScvOMaintenance of normal body temperature is critical in the intensive care setting and should be regularly monitored. While assessment of core temperature is ideal, there are other sites that can be used in critically ill patients, and understanding the limitations of any device and the site monitored is essential for clinical decision making.Indeed, numerous trials have shown that even mild hypothermia causes numerous adverse outcomes  includinCore temperature relates to the compartment that is composed of highly perfused tissues whose temperature is uniform. This fact makes that accurate measurement of this temperature has been shown in the pulmonary artery, distal esophagus, tympanic membrane, or nasopharynx , 98. HowSince these sites are always available or convenient, a variety of “near-core” sites are also used clinically. These include the mouth, axilla, bladder, rectum, and skin surface, all of which have their own limitations. Oral temperature can be inaccurate secondary to recent PO intake and airflow. Axillary temperature may be accurate with correct positioning (over the axillary artery with the patients arm kept by their side) . HoweverMonitoring of the respiratory system is integral to the daily ICU care of all ventilated patients. Such monitoring in its broader sense includes serial assessment of gas exchange, of respiratory system mechanics, and of patients' readiness for liberation from invasive positive pressure ventilation. Tracking respiratory system changes over time may help minimize ventilator-associated complications, optimize patient-ventilator synchrony, and provide important clues regarding possible causes for alarm sounding and/or changes in patients' conditions. A prerequisite for such an approach is a good understanding of the physiology behind the variables being monitored. Despite the importance of respiratory monitoring in ventilated ICU patients, this is not always performed as often or interpreted accurately particularly by some residents and younger colleagues. This is probably due to the general prejudice that some measurements are cumbersome to obtain and/or to interpret in part due to increased role of protocols and to the decreased understanding of physiology specifically at the bedside. Other measurements are taken for granted , and the limitations of the methods are not always taken into consideration. In this paper, our goal is to give a brief overview of key basic readily available parameters and the principles underlying their alterations. These parameters related to respiratory mechanics and gas exchange should be obtained at initiation of mechanical ventilation and at regular interval thereafter particularly in patients who are difficult to ventilate and oxygenate and require heavy sedation and paralysis. These patients have a higher risk of complications, and adequate monitoring becomes even more critical. While certain measures require an active patient , most bedside measures and estimations of the respiratory system (RS) mechanics require a passive patient. Modern ventilators display real time pressure, volume, and flow time curves. Reviewing these curves daily is essential to assess whether the ventilator settings are safe and adapted to the patients' conditions. Partitioning the contribution of the lung from that of the chest wall to the RS mechanics would require measuring pleural pressures and placement of an esophageal probe. Although this measure is not done routinely, understanding and considering chest wall contribution to mechanics are still required. Let us now review key selected measures that should be routinely obtained at the time of initiation of ventilation and thereafter in the passively ventilated patient.P) needed to deliver a tidal volume can be calculated as follows:VT = tidal volume, CRS and RRS = overall compliance and resistance of the respiratory system (RS), respectively, Ti = inspiratory time and VT/Ti = inspiratory flow and PEEP = positive end expiratory pressure. The relationship between pressure, flow, volume, and the mechanics of the respiratory system is best approached using the simplified equation of motion  which stPao) is equal to pressure generated by the ventilator (Pv). If the respiratory muscles are actively contributing to inspiration, then Pao = Pv – Pmus (negative intrathoracic pressures generated by the inspiratory muscles). The equation of motion remains valid when mechanical ventilation is delivered by using primarily a volume or a pressure-controlled mode. In the former mode, volume is the set (independent) variable, and pressure becomes the dependent variable whereas in the latter mode pressure is the set and volume is the dependent variable. The equation of motion clearly stresses that the pressure needed to deliver a given VT is the sum of three distinct pressures that have to be offset: (1) elastic pressure (VT/CRS), (2) resistive pressure (RRS × VT/Ti), and (3) the pressure already present in system at the end of expiration .In a passively ventilated patient, the pressure measured at the airway opening (CRS is determined by the compliance of both the lung (CL) and the chest wall (Cw). It is measured by applying an inspiratory pause long enough (1.5–2 sec) to allow the Pao to reach zero flow condition to ensure that Pao = plateau pressure (Pplat) = alveolar pressure . When flow = VT/Ti = 0, then rearranging the equation of motion allows to calculate CRS = δVRS/δPRS = VT/. Note that CRS bears a complex relationship to the lung and chest wall compliance since chest wall and lung are in parallel: 1/CRS = 1/CL + 1/Cw and CRS = (CL × Cw)/(CL + Cw) [L + Cw) . CRS, VT should ideally be corrected for the compressed gas in the circuit. This correction is rarely done clinically and probably not needed to simply track CRS unless one operates at very high airway pressures, the circuit tubing is quite distensible, or one changes the type of tubing between measures. It is important, however, to use total PEEP and not simply the external PEEP for this calculation and to keep in mind that the distending pressures for the lung are in reality the transpulmonary pressures (Ptp = Pplat − Ppl) not simply Pplat. The importance of thinking in terms of transpulmonary pressure lies in the fact that the latter is instrumental in causing lung overdistension and injury when excessive. Since pleural pressure is not routinely measured, interpreting airway pressure requires to consider the contribution of the chest wall and inspiratory muscle to the pleural pressure to estimate the transpulmonary pressure associated with a given airway pressure. For instance, a 35 cm H2O Pplat in patients with morbid obesity or high intra-abdominal pressure (low Cw) that elevates Ppl (e.g. 10 cm H2O) is associated with a lower Ptp (25 cm H2O) than the same Pplat in a patient with normal chest wall compliance actively inspiring with a Ppl of −5 cm H2O (Ptp = 40 cm H2O).To calculate CRS with an alteration in the intrinsic elasticity of the lung. As demonstrated by Gattinoni et al. [CL) of the aerated lung in patients with ARDS remains normal . The overall low measured CRS is thus mainly the result of a reduction in the effective lung volume in this population. In other words, CRS tracks the volume of aerated lung available for ventilation or the size of the “baby” lung. The drop in the static CRS observed following the accidental migration of the endotracheal tube in the right main bronchus best illustrates this. In addition, since CRS is the slope of the pressure-volume curve of the RS which tends to become nonlinear and to flatten at low and high lung volume (upper and lower inflection points describing larger pressure change for a given volume change), CRS tends to be the highest around FRC and to decrease at high lung volume if the system becomes overdistended or at low lung volume with the loss of aerated unit (derecruitment). Changes in CRS may thus reflect change in the position of tidal ventilation relative to inflection points on the pressure volume curve and/or shift of curve. In conclusion, CRS therefore is helpful to size the tidal volume relative to the size of the baby lung and to track if recruitment, derecruitment, or overdistension may occur over time. The stress index proposed to monitor ARDS patients ventilated with constant flow using the shape of the pressure time curve applies the same principle to detect tidal recruitment and overdistension [It is important not to equate a change in static i et al. , the elastension .CRS can provide useful information to set tidal volume relative to the size of the lung. Tracking its change over time is helpful to alert the possibility that derecruitment, overdistension (decreasing CRS), or recruitment (increased CRS) is taking place. Everything else being equal, this can be done as often as needed by monitoring Pplat as long as the patient remains passive and the ventilator settings are the same. Pplat is an important variable that reflects alveolar pressure and is often used at the bedside to estimate the risk of ventilator-associated lung injury. Pplat has been found to be associated with outcome in ARDS [Pplat therefore warrants a thorough assessment of the patients using the principles outlined previously, and one has to incorporate in this process consideration for the pleural pressure. For a practical standpoint, measuring  in ARDS , 111. AnQ) and Pressure Drop (ÄP) across the airways are used to calculate the resistance RRS = Q/ÄP. Since flow occurs during inspiration and expiration, resistance can be defined as RRSI and RRSE. Flow (Ppeak) to Pplat, and Ppeak − Pplat tracks the resistive pressure that must be overcome to deliver VT at a given flow. If flow during inspiration is known, RRSI can be easily calculated. More pragmatically, it is important at initiation of ventilation to measure Ppeak and Pplat and to make note of the pressure difference between those two pressures to assess whether the patient may have abnormal airway resistance (large Ppeak to Pplat difference), keeping in mind that an inappropriately high set flow rate or a small endotracheal tube may both increase this pressure difference. The initially recorded Ppeak and Pplat difference will then allow one to monitor for any change in CRS and RRSI and to establish when facing a Ppeak pressure alarm (during volume controlled ventilation), if a Ppeak change is due to a compliance or resistance alteration. For instance, a sudden increase in peak pressures associated with a larger Ppeak to Pplat difference is most consistent with an increase in resistance secondary to the native airway problem  or partial obstruction of the artificial airways  In contrast, an unchanged Ppeak to Pplat difference strongly supports a change in static CRS  as the cause of the Ppeak pressure alarm.By applying an inspiratory pause as indicated previously, airway pressure drops from its peak value (RRSE). A first important step is thus to identify the site responsible for any abnormal airway resistance. RRSE is a parameter that is neither easy nor necessary to measure routinely. What is always needed, however, is to recognize the presence of an abnormally high resistance, to identify and treat its cause, and to monitor and minimize its consequences. Consequence could be dynamic hyperinflation and auto-PEEP, which increases the work of breathing and the risk of barotraumas and/or hypotension [Expiratory flow and airway resistance vary with lung volume and flow decays exponentially in normal circumstances. The endotracheal tube, exhalation valve, heat moisture exchangers—when present—as well as the native airways all contribute to the expiratory resistance . Most modern ventilators have the capacity to measure auto-PEEP semiautomatically. Auto-PEEP may develop for a variety of reasons . As discussed previously, dynamic hyperinflation is important to monitor and recognize. Measuring auto-PEEP and Auto-PEEP does not necessarily mean that dynamic hyperinflation is present. It is thus not synonymous with dynamic hyperinflation. If a patient is actively expiring, the calculated auto-PEEP may merely reflect active expiration and not necessarily the degree of hyperinflation, if any. This can be detected by observing the patient and by placing a hand on the patient's abdomen to feel for contraction of the abdominal muscle during expiration and the measurement. Pplat, and the tidal volume is delivered on top of the trapped gas. It is therefore important to monitor both auto-PEEP and Pplat in patients with obstructive physiology and to adjust the ventilator to minimize dynamic hyperinflation and address its cause. This often requires decreasing minute ventilation and accepting some degree of respiratory acidosis (permissive hypercapnia). Sometimes increasing the external PEEP helps reduce airway collapse during expiration and reduce the work needed to trigger the ventilation. When PEEP is used in this setting, it is typically set at a level below the measured total PEEP but one subsequently measures the resulting changes in Pplat and trapped volume, as the effects of external PEEP on Pplat are difficult to predict [In addition, even in a passive patient, auto-PEEP may underestimate the degree of hyperinflation. Auto-PEEP is a measure of the average positive pressure present in the system at the end of expiration. Some lung regions with high auto-PEEP may not contribute to the average auto-PEEP measured due to airway closure (hidden PEEP) . This pr predict . The adequacy of tissue oxygen delivery and utilization cannot be measured directly, and the oxygenation status of vital organ is typically inferred and monitored by using data from different sources. Arterial Oximetry. Oximetry is a widely used monitoring technique in ICU. Despite its accepted utility, it is not a substitute for arterial blood gas monitoring as it provides no information about the ventilatory status and has several other limitations. Probe placement is important as both high and low values could be seen with partial alignment of the probe electrodes [ectrodes , presencectrodes , excessiectrodes , 118, anectrodes , 120. Erroneous readings may also be caused by hypotension  and hypoEfficacy of Oxygen Exchange. Oximetry is not a sensitive guide to gas exchange in patients with high baseline PaO2 because of the shape of the oxygen dissociation curve. On the upper horizontal portion of the curve large changes in PaO2 may occur with little change in pulse oximetry (SpO2) [2 is in the mid sixty range. It is thus wise to adjust the inspired O2 to keep the hemoglobin saturation below 100 percent. Numbers of indices have been used to assess the efficiency of oxygen exchange including venous admixture and shunt fraction. The calculation of these indices involves mixed venous blood sampling with a PA catheter, which are not commonly used anymore in most centers. These indices are thus more helpful for research than for daily care. Alveolar-arterial oxygen tension difference has been used in the past but it is limited, and it changes unpredictably with FiO2 changes in critically ill patients with combination of etiologies of hypoxia. y (SpO2)  till the2 include (1) hypoventilation, (2) impaired diffusion, (3) ventilation/perfusion mismatching, and (4) shunting. Significant shunting as opposed to ventilation/perfusion mismatching is likely present if 60% or greater FiO2 is required to keep the arterial O2 saturation above 90%. Since PaO2 is loosely related to gas exchange efficiency unless the FiO2 is also taken into consideration, the PaO2 : FiO2 ratio is thus generally used to quantify the degree of pulmonary gas exchange dysfunction and lung injury. Indeed, this ratio is integral to the definition of ALI and ARDS [2 : FiO2 ratio in the 500–300 range is consistent with normal-to-mild impaired oxygen exchange; values less than 300 indicates moderately impaired gas exchange as seen in ALI, and values of less than 200 are supportive of significant shunt physiology as encountered in ARDS. The ratio can also be used to assess the response to therapeutic interventions [Conditions encountered in the ICU associated with a low PaOand ARDS . PaO2 : ventions , 133.2 : FIO2 ratio exhibited stability at FiO2 values of ≥0.5 and PaO2 values of ≤100 torr (≤13.3 kPa), others have found the PaO2 : FiO2 ratio to have poor association with pulmonary shunt [2 : FiO2 occurred when the FiO2 is changed [2 saturation on the high side (e.g close to 99%) as opposed to the low side  may cause certain patients to have to be reclassified from ARDS to ALI. Another important limitation of the PaO2 : FiO2 ratio to assess the gas exchange function is that it is also affected by the ventilatory strategy such as the size of the tidal volume used [2 : FiO2 ratio has not been shown to correlate with the mortality in ARDS/ALI [2 : FiO2 ratio is easy to obtain at the bedside to track cardiorespiratory changes. It is important to keep in mind the above limitations, its lack of correlation with outcome, and that the overall goal of mechanical ventilation is to achieve acceptable gas exchange with minimal stress and not to achieve the highest PaO2 : FiO2 ratio as such strategy has the potential to be counterproductive. Although in one study  PaO2 : Fry shunt  and that changed . Such vaume used , the PEEume used , and theARDS/ALI . Despite2 depends on CO2 production relative to its elimination by the lungs. In sedated and passively ventilated patients who have a fixed imposed minute ventilation, PCO2 may rise due to increased metabolic rates such as seen, for instance, with fever, a high carbohydrate load, and/or overfeeding. Blood PCO2 level is also governed by acid-base fluctuations and perfusion adequacy. Finally, PCO2 may rise if alveolar ventilation decreases as dead space increases. We shall now briefly discuss monitoring of PCO2 and dead space. Arterial PCOAssessment of PaCO2. Traditionally in the ICU, gas exchange is assessed on the arterial side by measurement of PaO2, PaCO2, and pH. There has been a long-standing interest in alternate methods for measurement of PaCO2. 2 can be continuously monitored using miniaturized electrochemical or optical sensors. End-tidal CO2 (etCO2) and transcutaneous PCO2 (tcPCO2) are commonly used in operative rooms and sleep centers. tcPCO2 measurement uses a sensor to detect CO2 that is diffusing out through the body tissues and skin and could be a helpful alternative to blood gas measurement. The tcPCO2 measured by this technique measures tissue CO2 that is slightly higher than the arterial value requiring corrective algorithms. tcPCO2 can be used to estimate and to trend PaCO2 in different settings such as adult critical care [tcPCO2 measurement is limited during severe vasoconstriction or presence of skin edema. Other limitations include the need for periodically changing the membrane and calibrating the sensor when using electrochemical measurement technique. PaCOcal care , 140, mecal care , 142, ancal care , 143. Ho2, PaO2, pH in peripheral and central venous blood instead of arterial blood. In the studies venous PCO2 and pH were a reasonable surrogate of arterial PCO2 and pH. In normal conditions venous PCO2 is 3-4 mmHg higher than the arterial blood that leads to an increase in bicarbonate levels (1–1.5 mmol per liter) and a simultaneous decrease in a pH by 0.03–0.05 pH units. However, in the presence of shock or cardiac arrest the arterial-to-venous PCO2 and pH difference increases. Such an increase in difference may be an important clue that tissue hypoperfusion is present, and the case has been made that in cardiac arrest patient venous blood gas may better reflect tissue acid-base status and oxygenation than arterial blood gas [Recent publications , 145 havlood gas . Dead Space Ventilation and PCO2  in ICU. The physiologic dead space (VD) refers to the portion of tidal breath, which fails to participate in effective CO2 exchange and is made of the sum of the “anatomic” and the “alveolar” dead space. The dead space fraction can be estimated by simultaneous measurement of arterial PCO2 and partial pressure of exhaled gas CO2:VD include low cardiac output states, pulmonary embolism, pulmonary vasoconstriction, and mechanical ventilation with excessive tidal volume or PEEP particularly when blood volume is low [ holding , 148 and holding , 150. Ote is low . VD/VT to rise to values that exceed 0.65  [VE requirements and CO2 retention seen in lung injury and hypoxic respiratory failure. Overdistention leading to increased dead space should be suspected when under controlled constant inspiratory flow ventilation, examination of the pressure time curve demonstrates concavity or an upward inflection. It should be considered in the differential when associated with an elevated Pplat. In these situations, reducing the tidal volume or PEEP could help reduce VD/VT. In critically ill patients, it is not exceptional for the al 0.35) , 153. De2 : FiO2 (oxygenation), has been shown to be associated with alteration of the lung structure [In patients with ARDS, increased dead space, rather than a decrease in PaOtructure  and incrtructure –156. It per se may have a lung protective effect in experimental ventilator-induced lung injury model [In ARDS, hypercapnia could result from lung protective ventilation (permissive hypercapnia), due to increased dead space due to damaged lung or a combination of both. It is important to differentiate respiratory acidosis due to increased dead space associated with an elevated minute ventilation and mortality from the one that results from a lung protective strategy (permissive hypercapnia) associated with lower mortality  and deliry model  and in pry model , respirary model , 161. In2 and/or PaCO2 to normal levels, the underlying alteration in the respiratory physiology and mechanics needs to be understood and its cause addressed whenever possible. It is also essential to weigh the risk benefits specifically in regard to mechanical stress on the lungs before attempting to correct abnormal blood gas values. Monitoring in the ICU should aim to keep the patients within a safety zone and does not imply we need to act on all abnormal values. First do no harm.In summary, monitoring of oxygenation and ventilation is important but before attempting to adjust the ventilator to correct the PaOThe monitoring of nutritional and metabolic care in the ICU has three main goals: first, the control of macronutrients  and micronutrients (vitamins and trace-elements) delivery, second, the assessment of the adequation between energy needs and delivery, and, finally, the glycaemic control. This issue is of high relevance, since a plenty of evidence indicates that an insufficient coverage of protein and energy needs and an impaired glycaemic control are both related to a worse clinical outcome in the ICU. Several studies have demonstrated that computer-assisted systems allow an accurate monitoring of nutrition and metabolic parameters and contribute to optimize protein-energy delivery and glycaemic control. Therefore, a daily computerized monitoring of nutrition support could contribute to improve the adherence to guidelines and the clinical outcome of ICU patients .In the ICU, the first line recommended nutrition support is the early enteral nutrition (EN) , 163, siCurrent guidelines recommend the use of indirect calorimetry to measure energy needs , 163. InIn the past 20 years, it was extensively demonstrated that PN could induce metabolic disorders, such as hyperglycaemia, hypertriglyceridemia, liver steatosis, endocrine dysfunction, impairment of immunity, infections, and increased mortality . PN-relaComputerized systems have to be used for the constitution of insulin algorithms that have been shown to improve the glycaemic control in comparison with manual protocols . In addiIn summary, the monitoring of the nutritional and metabolical care is part of the management of the ICU patient. The use of a computer-based monitoring system of nutrients delivery and glycaemic control contributes to reinforce the adherence of clinical practice to guidelines. In addition, computer-based monitoring systems, by preventing protein-energy deficit and overfeeding and optimizing glycaemic control, should contribute to improve the clinical outcome of ICU patients. The medicoeconomic impact of computer-based monitoring systems remains to be evaluated.


Traumatic brain injury (TBI) is a major cause of permanent disability and death in young patients. Controversy exists regarding the optimal cerebral perfusion pressure (CPP) required in TBI management. A tool for monitoring autoregulation and determining an optimal CPP is the pressure reactivity index (PRx), defined as a moving correlation coefficient between the mean arterial blood pressure (MAP) and intracranial pressure (ICP) at a frequency of at least 60 Hz. This requirement of high frequency has constrained its use to a few academic centers. An association was shown between outcome and continuous optimal CPP based on 4 hours of PRx . We presA total of 182 patients from the Brain-IT [On the Brain-IT database, LAx resulted in an optimal CPP for 90% of the first 48 hours. Table The differences in optimal CPPs derived from PRx and LAx were not clinically significant. LAx allowed for recommendations to be computed for longer periods. Significantly better outcome Table  was obse


According to the National Heart, Lung, and Blood Institute of the National Institute of Health, hypotension refers to an abnormally low blood pressure (BP). In childhood, hypotension can be determined according to two different definitions: BP below the 5th percentile or below two standard deviations (SDs) of the mean for age and gender . A graphThe objective of this study was to update the graphic representation of pediatric hypotension.We used a computerized calculation method to develop high-resolution graphics containing 5,841 points each, to depict the main percentiles associated with low BP for boys from 1 to 17 years old in the 50th percentile of height. Each point represents the calculation of the polynomial equation that includes the statistical processing of the last Report on Blood Pressure . We alsoFive monotonic curves of diastolic BP for boys representing the 50th, 25th, 10th, 5th, and 2.275th (-2SD) percentiles were built (Figure The correction of diastolic BP for height is of little significance, and this updated graphic can be used to diagnose low diastolic BP for boys. Clinical studies are necessary to determine the SBP percentile that better represents clinically significant hypotension.


Homoarginine, a precursor of nitric oxide, is an inverse predictor of death in dialysis patients and in subjects with cardiovascular disease and normal kidney function but its relationship with clinical outcomes in chronic kidney disease (CKD) patients not yet on dialysis is unknown.2) referred to a tertiary care centre and measured laboratory data on kidney function and cardiovascular risk factors. We modeled progression to dialysis or death as a function of homoarginine, using Cox’s regression, accounting for clinical characteristics, baseline levels of kidney function, and markers of inflammation.We enrolled 168 consecutive predialysis CKD patients  56 patients started dialysis and 103 died and homoarginine was a strong inverse predictor of the incidence rate of both outcomes (P = 0.002 and P = 0.017).Homoarginine declines with advancing renal disease and is inversely related to progression to dialysis and mortality. The nature of the link between homoarginine and clinical outcomes is amenable to testing in clinical trials. This finding indicates that in the normal eGFR range a gradual decrease in circulating homoarginine may occur at progressively lower eGFR levels Reduced nitric oxide (NO) bioavailability is a major risk factor for cardiovascular disease and progression to kidney failure in patients with chronic kidney disease (CKD) In this study we investigated the relationship between circulating homoarginine with traditional and non-traditional cardiovascular risk factors in an incident cohort of CKD patients and tested the relationship between this aminoacid and all-cause and cardiovascular death, and renal outcomes.This cohort study was designed to investigate the impact of non-traditional cardiovascular risk factors on renal function decline and patient outcomes in CKD. The study protocol was submitted to the Ethical Committee of our institution, resulted to be in conformity with the ethical guidelines and was specifically approved by the Ethical Committee of Azienda Ospedaliera “Istituti Ospitalieri” di Cremona . Written informed consent was obtained from each participant.All consecutive subjects 18 year-old or older, with stage 1 to 5 CKD, referred to the outpatient clinic of the Renal Unit of Cremona Hospital from January 2002 until April 2003 were enrolled in the study. Data on baseline characteristics, renal disease causes, previous or actual smoking habit, documented diagnosis of diabetes, cerebro-vascular disease, peripheral artery disease, coronary artery disease, heart failure, neoplasm, and history of hypertension were collected at the first referral and defined based on the diagnosis-related group classification and International Classification of Diseases, Ninth Revision. Patients were subsequently followed regularly with frequency dependent on the levels of kidney function within a structured multi-disciplinary CKD clinic All patients were carefully instructed for 24 hours urine collection and additional urine spot for proteinuria assessment. Blood sampling was performed after 20 to 30 min of quiet resting in a semi-recumbent position. A fasting blood sample for serum cholesterol, creatinine, albumin, fibrinogen, C-reactive protein, total homocysteine, calcium, phosphate, total PTH, 25-hydroxy Vit. D, 1,25-hydroxy Vit. D and hemoglobin was obtained from all patients at baseline. Plasma was stored at −80°C until analysis. Glomerular filtration rate (GFR) was estimated using the MDRD formula (eGFR). Plasma total homocysteine  and serum C-reactive protein  were measured by using commercially available kits.Plasma concentrations of asymmetric L-dimetylarginine (ADMA), L-homoarginine and L-arginine were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS) using minor modifications of a method that we previously validated for asymmetric L-dimethylarginine and L-arginine After the initial assessments, laboratory and clinical data including cardiovascular events and death, and the need for dialysis due to end-stage renal disease were accurately recorded. To avoid loss to follow-up, patients were contacted by phone in case they missed any appointment and at the study end date  if they were not known to be already on dialysis or dead. Each death was reviewed and assigned an underlying cause by 3 physicians, on the basis of all available medical information. In cases of out-of hospital deaths, family members were interviewed by telephone to ascertain the circumstances surrounding the death Data are expressed as mean ± standard deviation (SD), median and range or as percent frequency, as appropriate. Variables deviating from the normal distribution were log-transformed in regression analyses.Plasma homoarginine was modelled as a function of traditional and non-traditional risk factors including clinical data and laboratory measures described above (excluding eGFR) on the basis of their univariate association or clinical plausibility. Since homoarginine was log-transformed for this analysis, the exponential of the corresponding regression coefficients [calculated by elevating the Neper number (2.7183) to the coefficients] are interpreted as percent change in the dependent variable per unit change in the predictor. The independent relationship of homoarginine on eGFR was subsequently tested using linear regression with GFR as response variable.The Cox’s procedure was used to model time to dialysis start and death as a function of homoarginine levels. We fitted model for correlated failure events of different types , because more than one event could occur for the same subject 2. The prevalence of diabetes was 26%.On crude Figure 1There was a log-linear relationship between eGFR and homoarginine values, which was unaffected by gender, but shifted toward lower average values of GFR in diabetic patients. 2 (0.20 per person-years [95% CI 0.08 to 0.14]) than in patients referred with eGFR ≥30 ml/min/1.73 m2 . The cause of death was undetermined in 20% of the patients and related to cardiovascular disease in 70% of the patients. There was an inverse linear relationship between homoarginine levels and the risk of progression to dialysis and mortality (the lower homoarginine the higher the risk for adverse outcomes), which was stronger for values below the median . During the study, 56 patients started dialysis and 103 died . Mortality rate was on average 0.15 events per person-years (95% CI from 0.12 to 0.18), significantly higher in patients referred with eGFR <30 ml/min/1.73 median andTable 4In pre-dialysis CKD patients, plasma homoarginine concentration is associated with the severity of renal dysfunction as well as with biomarkers of protein energy wasting and inflammation . Furthermore, homoarginine predicts the risk of progression to dialysis and death in CKD.The kidney is the major site of homoarginine synthesis and disposal, and genetic control of the key enzyme for the biosynthesis of this aminoacid, alanine-glycine aminotransferase. Therefore studying the link between homoarginine and clinical outcomes in CKD is a relevant undertaking to explore the potential implication of this aminoacid in human disease. Extending observations by März in patients with heart failure and substantially normal eGFR CKD is a typical age-related chronic disease, and our incident CKD cohort had an average age of 71 years. We found that homoarginine is inversely associated with all cause death independent of classical risk factors, risk factors peculiar to CKD and of key players in NO metabolism in this population, namely L-Arginine and of the main endogenous inhibitor of NO synthase, asymmetric dimethylarginine. Homoarginine is a less important substrate for NO synthase than L-arginine. Although consistent with findings from studies in cardiac patients with normal kidney function Our study has limitations. First, our cohort was relatively small and composed by individuals of Caucasian descent and therefore our observations need to be replicated in other cohorts and in other ethnicities. Second, the observational design of our study does not allow us to draw conclusions about the nature  of our findings which need to be confirmed in in mechanistic and interventional studies.In summary, we found that levels of homoarginine are lower in people with reduced kidney function not yet on dialysis and directly related to glomerular filtration rate. Greater levels of homoarginine independently predict longer survival in chronic kidney disease and a reduced risk of progression to dialysis. These observations form the basis for designing clinical trials based on homoarginine supplementation in patients with CKD.


Hypertension is a risk factor for cardiovascular disease, and the prevalence of hypertension tends to increase with age. Current treatments for hypertension have side effects and poor adherence. Qigong has been studied as an alternative therapy for hypertension; however, the types of qigong used in those studies were diverse, and there have not been many well-designed randomized controlled trials. Our objective is to evaluate the effects of qigong on blood pressure, health status and hormone levels for pre- or mild hypertension.Forty subjects with pre- or mild hypertension were randomized to either the qigong exercise group or the non-treated group. Participants in the qigong group conducted qigong exercises 5 times per week for 8 weeks, and participants in the non-treated group maintained their current lifestyle, including diet and exercise. The use of antihypertensive medication was not permitted. The primary endpoint was a change in patient blood pressure. Secondary endpoints were patient health status (as measured by the MYMOP2 questionnaires) and changes in hormone levels.Of the 40 participants that were randomized, 35 completed the study. Systolic and diastolic blood pressures were significantly decreased after qigong treatment compare to baseline only in the qigong group . In the non-treated group, there was no significant difference in blood pressure. Change of blood pressure between the qigong and the non-treated group was significant (p<.01 in SBP and DBP). The score of MYMOP2 showed a more significant decrease in the qigong group than the non-treated group (p=.035). Any differences in the hormones renin, angiotensin, cortisol, or norepinephrine were not significant between the two groups.Qigong appears safe and has a positive effect on blood pressure and health status in pre and mild hypertension patients. Further long-term studies with a larger number of subjects are warranted.


Central aortic systolic pressure (CASP) strongly predicts cardiovascular outcomes. We undertook to measure ambulatory CASP in 74 prevalent dialysis patients using the BPro  device. We also determined whether coronary or abdominal aortic calcification was associated with changes in CASP and whether interdialytic CASP predicted ambulatory measurement.All patients underwent computed tomography for coronary calcium score, lateral abdominal radiography for aortic calcium score, echocardiography for left ventricular mass index and ambulatory blood pressure measurement using BPro calibrated to brachial blood pressure. HealthStats was able to convert standard BPro SOFT® data into ambulatory CASP.p = 0.6) or aortic  calcification. Furthermore, when expressed as a percentage of brachial systolic blood pressure to control for peripheral blood pressure, any difference in CASP was abolished: CASP: brachial systolic blood pressure ratio = 0.9 across all categories regardless of the presence of coronary or aortic calcification . Supporting this finding, left ventricular mass index was also not different in those with or without vascular calcification . Inter-dialytic office blood pressure and CASP correlated excellently with ambulatory measurements (r = 0.9 for both).Ambulatory CASP was not different in those without and with coronary (137.6 vs 141.8 mmHg, respectively, Vascular calcification was not associated with changes in ambulatory central aortic systolic pressure in this cohort of prevalent dialysis patients. Inter-dialytic blood pressure and CASP correlated very well with ambulatory measurement. Vascular calcification (VC) is a novel vascular risk factor strongly associated with mortality in dialysis patients.6Not surprisingly therefore, central blood pressure parameters have been shown to predict hard cardiovascular endpoints  better than concomitant brachial measurements.11CASP can be calculated using applanation tonometry-derived peripheral pulse waveforms and associated software.Loss of normal nocturnal systolic blood pressure dipping is prevalent in chronic kidney disease (CKD) and likely contributes to cardiovascular disease.15There have been calls for the routine use of ambulatory blood pressure monitoring (ABPM) in clinical studies of CKDA non-invasive wrist watch-like device, BPro with A-Pulse CASP software  was recently approved by the US Food and Drug Administration (FDA: K072593) for the measurement of CASP as well as ambulatory blood pressure. It is a small, wrist watch-like, cuffless monitor which obtains radial pressure waveforms by applanation tonometry. BPro has the ability to measure ambulatory CASP and although not yet commercially available, the manufacturer is able to convert data into ambulatory CASP using the same software.As part of a recently published study on vascular calcification,The study was approved by the Research Ethics Committee of the University of Cape Town, South Africa. The full methodology has been published elsewhere,Patients were excluded if they were pregnant or planning a pregnancy, had sustained arrhythmias or prior coronary stenting or bypass. One patient was excluded due to loss to follow up so the final case sample was 74 participants. Clinical and demographic data were collected and ethnicity was self-reported.in vivo at the aortic root, using a Millar’s SPC–454D tonometer .17Ambulatory and office blood pressure monitoring: the BPro® radial pulse wave acquisition device and A-pulse CASP® software  system uses an N-point moving-average method to non-invasively derive CASP from the radial arterial pressure waveform. It has been validated against a generalised transfer function method using CAFE study data as well as central aortic pressures recorded For blood pressure determination, the BPro™ has been validated against the Association for the Advancement of Medical Instrumentation and European Society of Hypertension (ESH) protocols and passed both validations.Practically, the device was applied on the non-dominant arm or that which did not contain an AVF on the inter-dialytic day for haemodialysis patients or at a routine visit for prevalent dialysis patients. The device was then calibrated to office blood pressure – brachial blood pressure obtained via use of the MC3000 oscillometric device  according to the recommended ESH protocol.Cardiac CT and coronary calcium score: images were acquired using the Philips Brilliance 64-slice MDCT scanner. A standard protocol was used as follows: tube voltage, 120 kV; tube current, 55 mAs; detector collimation, 40 × 0.625 mm; gantry rotation, 400 ms. CT data were transferred to the Philips Extended Brilliance Workstation Version 4.0.2.145 for analysis and coronary calcium score was calculated with the Agatston algorithm.Abdominal X-ray and abdominal aortic calcium score: a standard technique of exposing the lateral lumbar spine in the standing position  was used. Calcific deposits in the abdominal aorta were scored as described by Kaupilla,2 in males and > 110 g/m2 in females as per ESH guidelines.Echocardiography: assessment of the left ventricular mass was done via use of M-mode echocardiography and this was calculated using the Penn convention.t-test and Mann–Whitney test as appropriate. Dichotomous data are presented as percentages and compared with chi-square tests. All analyses were conducted using Stata 12.0 statistical software .Normality was determined with the Shapiro–Wilk test. Continuous variables are expressed as mean ± SD or median and inter-quartile range (IQR) and compared with the two-tailed independent Student’s Table 1 shows the baseline characteristics of all patients. Overall, only 27 patients (38.6%) in the cohort had a coronary calcium score ≥ 1, and 26 (35.6%) had an abdominal aortic calcium score ≥ 1. The median coronary calcium score in those with coronary calcification was 141 (IQR = 55–619) and in those with abdominal aortic calcification, the median abdominal aortic calcium score was 6 (IQR = 1–10). Table 2 shows the baseline characteristics for all subjects with and without coronary and/or abdominal aortic calcification.p = 0.2 and 0.4, respectively). There was no difference when the ratio was compared in those with the highest versus lowest quartiles of coronary and aortic calcification (p = 0.2). Furthermore, there was no difference in the absolute difference between ambulatory systolic blood pressure and CASP values between those with and without coronary calcification .Both coronary and aortic calcium presence failed to show any association with CASP (r = 0.90).This was an observational study of 75 consecutive patients undergoing dialysis in a South African public sector unit. The cohort was young with a low level of co-morbidity due to stringent criteria for the selection of dialysis patients.A key finding in this study was that both coronary and abdominal aortic calcification was not associated with a higher CASP relative to the brachial systolic blood pressure. This ratio was used to control for systolic blood pressure, which would otherwise make comparison between groups difficult. Since the study had an 80% power to detect a difference of > 3% in CASP, it was unlikely that there would be a clinically meaningful difference between CASP values with and without calcification.The reasons for these findings are unclear but may be that vascular calcification is not directly responsible for aortic stiffening and the association of calcification with PWV is not causative. There are many other factors such as elastin fragmentation, endothelial dysfunction and advanced glycation that affect aortic stiffness other than calcification.11Alternatively, since vascular micro-calcifications may be present in uraemic subjects without radiologically visible calcium,Unfortunately, we were unable to measure PWV. As left ventricular mass index is strongly determined by CASP,Non-dipping was particularly prevalent, as in other studies of CKD,Both inter-dialytic office blood pressure and CASP correlated well with ambulatory blood pressure measurements. This has important implications since the FDA has called for the inclusion of CASP into clinical studies of blood pressure.32There were several limitations to our study. First, the patients in our cohort were young and one cannot be certain whether these findings would be reproduced in an older cohort. Second, we were not able to measure PWV in our study and it would have been useful to do this in attempting to reconcile the lack of effect of vascular calcification on central aortic pressures. It remains to be determined in this cohort whether vascular calcification occurs independently of changes in pulse-wave velocity. Third, CASP was indirectly measured, although a recent publication showed excellent correlation of BPro with direct measurement of CASP.17Coronary and abdominal aortic calcification was not associated with changes in central aortic systolic pressure or dipping status in young South African dialysis patients. Inter-dialytic office blood pressure and central aortic systolic pressure, when measured according to ESH standards, correlated very well with ambulatory measurements.


Ambulatory blood pressure monitoring is regarded as the gold standard for monitoring nocturnal blood pressure (NBP) and is usually performed out of office. Currently, a novel method for monitoring NBP is indispensible in the inpatient setting. The widely used manual BP monitoring procedure has the potential to monitor NBP in the hospital setting. The feasibility and accuracy of manual sphygmomanometer to monitor NBP has not been explored widely.A cross-sectional study was conducted at the cardiology department of a university-affiliated hospital to study patients with mild-to-moderate essential hypertension. One hundred and fifty-five patients were recruited to compare BP derived from a manual device and ambulatory BP monitoring (ABPM). The manual BP measurement was performed six times at 22:00, 02:00, 06:00, 10:00, 14:00 and 18:00 h. The measurements at 22:00, 02:00 and 06:00 h were defined as night-time and the others as daytime. ABPM was programmed to measure at 30-min intervals between measurements.All-day, daytime and night-time BP did not differ significantly from 24-h ambulatory systolic BP [all-day mean difference −0.52±4.67 mmHg, 95% confidence interval (CI) –1.26 to 0.22, P=0.168; daytime mean difference 0.24±5.45 mmHg, 95% CI −0.62 to 1.11, P=0.580; night-time mean difference 0.30±7.22 mmHg, 95% CI −0.84 to 1.45, P=0.601) rather than diastolic BP. There was a strong correlation between clinical and ambulatory BP for both systolic and diastolic BP. On the basis of ABPM, 101 (65%) patients were classified as non-dippers, compared with 106 (68%) by manual sphygmomanometer (P<0.001).Traditional manual sphygmomanometer provides similar daytime and night-time systolic BP measurements in hospital. Moreover, the detection of non-dippers by manual methods is in good agreement with 24-h ABPM. Further studies are required to confirm the clinical relevance of these findings by comparing the association of NBP in the hospital ward assessed by manual monitoring with preclinical organ damage and cardiovascular and cerebrovascular outcomes. In recent decades, although out-of-office blood pressure (BP) monitoring using ambulatory or home measurement techniques has evolved rapidly -3, cliniHowever, in clinical practice, particularly in hospital wards, BP mainly derived from traditional office blood pressure measurement is one of the most important vital signs . In thisUnfortunately, ABPM is regarded as the gold standard for monitoring NBP and is usually performed out of office . CurrentTo date, research exploring the feasibility and accuracy of manual sphygmomanometer to monitor NBP has been rare. The present study compared 24-h ABPM with traditional manual techniques and used standard sphygmomanometer for the assessment of NBP and non-dippers among patients with essential hypertension in a ward setting.This was a cross-sectional study in adults with essential hypertension who were attending the cardiology department of a university-affiliated hospital. The chief complaint of all recruited patients was dizziness, and they attended the hospital to establish the reasons for this dizziness. None of the participants had any acute lesions that influenced BP. Diagnosis and stratification of hypertension were based on recent guidelines . Newly d2). To ensure that evaluation of NBP was as accurate as possible, shift workers were also excluded. Secondary hypertension was ruled out using the procedure suggested in the international literature [Exclusion criteria were severe cardiac, renal or other systemic diseases, insomnia, and arrhythmia that interfere with ABPM devices, as well as patients with morbid obesity  was used to measure daytime and night-time CBP. In the ward, all recruited patients were instructed to go to bed around 22:00 h and arise around 07:00 h. Six manual CBP measurements were obtained from 22:00 h at 4-h intervals between measurements. The actual times of CBP measurement were around 22:00, 02:00, 06:00, 10:00, 14:00 and 18:00 h. All the measurements were carried out by the same trained examiner. Before the monitoring, all patients were informed of the process and during the monitoring none of the participants were deliberately awakened. The desk lamp was switched on for the examiner to identify and write down the readings. Triplicate BP monitoring with at least 1 min between measurements using the same device was performed at the daytime points  after the patients had refrained from exercise, coffee drinking, and smoking, and had relaxed for at least 5 min sitting in a quiet environment, as were the night-time measurements  in the supine position. The inflatable cuff was always placed on the non-dominant upper limb. The mean of the triplicate BP readings was considered for analysis. Two inflatable bladder sizes were available according to the individual’s arm circumference (22 × 12 and 30 × 14 cm).Ambulatory BP was monitored using validated oscillometric automatic-measuring device (A&D 2430) . The ABPTo guarantee that there was no consistent difference of ≥10 mmHg in the measured BP between ABPM devices and manual standard sphygmomanometer, before and after each CBP measurement or ABPM session, the accuracy of the monitors was assessed against a standard mercury sphygmomanometer .CBP values with systolic BP (SBP) <90 mmHg or >200 mmHg and those with diastolic BP (DBP) <40 mmHg or >110 mmHg were considered erroneous and were discarded. If any of the aforementioned six consecutive BP readings was invalidated or the sleeping duration was <4 h, that patient’s data were excluded from the following analysis. Three daytime  and three night-time  CBP readings were averaged to give a single daytime and night-time CBP value per patient. Dipping pattern was defined as follows: dippers had a ≥10% but <20% fall in NBP; non-dippers had an NBP fall <10% but >0%; extreme dippers had an NBP fall ≥20%; and reverse dippers had an NBP increase .The 24-h ABPM data were divided into daytime (07:00–22:00 h) and night-time (22:00–07:00 h) values. ABPM measurements with three consecutive or a total of five invalidated readings were regarded as erroneous and were discarded, as were measurements with SBP <60 mmHg or >250 mmHg and those with DBP <30 mm Hg or >150 mmHg. Erroneous readings and duplicate readings that the software flagged were also discarded. The means of all valid daytime and night-time ABPM readings were to give a single daytime and night-time ABPM value per patient.t test for paired samples was used to compare BP measurements in the same individual and χ2 test was used to compare the categorical variables. Pearson correlation coefficient and intraclass correlation coefficient were used to estimate the association between continuous variables. The κ statistic was used to determine the level of agreement in diagnosis of non-dippers measured by ambulatory blood pressure (ABP) and CBP measurements. Two-tailed values of P<0.05 were considered statistically significant.The data were stored and analyzed using the MS Excel program. The statistical analysis was carried out using SPSS for Windows release 13.0. The 2, CBP 160.79±23.19/90.74±14.46 mmHg, SBP/DBP). Twenty-seven (17.4%) patients had type 2 diabetes mellitus. Sixty-five participants (41.9%) had a history of stroke and 32 (20.6%) had a previous major cardiovascular disease. During the manual measurement of NBP, about one half of participants (46%) were awake.A total of 169 patients were recruited and 14 were excluded because of inadequate ABPM data. Therefore, 155 patients were included in the final analysis  years, body mass index 23.53±2.92 kg/mAll-day CBP did not differ significantly from 24-hour ABP for SBP [mean difference −0.52±4.67 mmHg, 95% confidence interval (CI) –1.26 to 0.22, P=0.168; Figure On the basis of ABPM, 101 (65%) patients were classified as non-dippers, as compared with 106 (68%) by manual sphygmomanometer (P<0.001). When taking ABPM as the reference standard to determine non-dippers, the agreement was 82.58% as compared with CBP . Furthermore, when dividing the circadian rhythm of BP into four groups, 61 participants were classified as reverse-dippers (night-time BP higher than daytime) by ABPM and 62 by CBP . Five patients were defined as extreme-dippers  by ABPM and five by CBP . When non-dippers were assessed separately for SBP and DBP, the diagnostic agreements between ABP and CBP are shown in Table In this study, we compared manual sphygmomanometer monitoring with 24-h ABPM in the inpatient setting, in terms of daytime and night-time BP levels and the detection of BP circadian rhythm. The main conclusions were that: (i) there were no differences between CBP and ABP measurements taking during the daytime and night-time for SBP rather than diastolic BP; and (ii) there was good agreement between CBP and ABP in the detection of non-dippers.Since ABPM was firstly described >40 years ago, it has been generally accepted that it can provide the following three types of information: an estimate of mean BP level; diurnal rhythm of BP; and BP variability , particuA recent study in 40 healthy individuals has provided a direct comparison between night-time home BP monitoring and ABPM. No significant difference was found between the two methods for measurement of NBP . AnotherTo the best of our knowledge, no studies have assessed the potential of manual sphygmomanometer devices to monitor NBP in an inpatient setting. Also, no studies have directly compared NBP obtained by manual sphygmomanometer monitoring and ABPM. BP is one of the vital signs and in hospital wards, it must be taken seriously. Isolated nocturnal hypertension upon ambulatory measurement as a novel clinical entity was first described by Li et al. . Isolaten=3). The current study showed that NBP monitoring performed by manual sphygmomanometer gave similar values compared with ABPM. In contrast, strong correlations were found between CBP and ABP. Despite there being a small difference between ABP and CBP in monitoring of NBP, the two methods appeared to be interchangeable in the detection of NBP in the clinical setting. In our study, the two methods differed significantly between CBP and ABP for DBP. The divergence of SBP and DBP needs further study. Several reasons may explain the divergence. First, manual monitoring or ABPM influence DBP more than SBP. Second, sleep quality may be affected more by DBP than SBP. Finally, there is probably no correlation between night-time DBP using the two methods.In the present study, we compared CBP measured by manual devices with automated ABPM. Regardless of the all-day, daytime or night-time measurements, no significant difference was found between the CBP and ABP for SBP, despite a small number of readings being obtained per night (The most challenging finding of the present study was that there was good agreement in the detection of non-dippers, and moderate and fair agreement for reverse dippers and extreme dippers, respectively. In 155 patients with hypertension, >50% were found to be non-dippers using both methods. Furthermore, about 60 patients were classified as reverse-dippers. This finding warned us that in the clinical setting, nocturnal dipping of BP is much less frequent, and even the NBP is much higher than the daytime BP. It may have been that the patients were under stress, and the percentage of non-dippers was high. Therefore, we should not ignore the NBP in the hospital setting. It could be that the ideal management of BP in the daytime results in abnormal BP at night. The present study showed that traditional widely used manual devices for monitoring BP may give reliable NBP measurement compared with ABPM. It should be noted, however, that there are no other available data to define the non-dippers in clinical settings, regardless of ABPM or other methods. More studies should be performed to investigate the relationship between non-dippers measured by ABPM or CBP monitoring in hospital wards and target organ damage or mortality.The present study must be interpreted within the context of its potential limitations. First, BP measurement was only performed on 2 days, and one type of method was just implemented once. Therefore, the reproducibility could not be analyzed. Second, this study did not evaluate the sleep quality associated with the two methods, which may have seriously influenced NBP. Third, the study fixed the daytime and night-time using an arbitrary range, which may have affected the definition of non-dippers.Our data suggest that traditional manual sphygmomanometer provides similar daytime and night-time SBP in the hospital ward. Moreover, the detection of non-dippers by the manual methods is in good agreement with 24-h ABPM, but moderate and fair agreement for reverse dippers and extreme dippers, respectively. One challenge of the study is that more than half of the patients in the ward had high NBP. Further studies are required to confirm the clinical relevance of these findings by comparing the association of NBP in the hospital ward assessed by manual sphygmomanometer monitoring and ABPM with preclinical organ damage and cardiovascular and cerebrovascular outcomes.1. In the past five years all the authors haven’t received any reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript. 2. All the authors don’t hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript. 3. All the authors don’t hold or currently apply for any patents relating to the content of the manuscript. 4. All the authors don’t have any other financial competing interests. 5. There is a non-financial competing interests related to this manuscript, which I have declared in the acknowledgment. This work was supported by the Provincial Natural Science Foundation of Guangdong.TX performed the survey and wrote the draft of manuscript. YQZ supervised data collection. XRT designed the study, helped interpret the analysis results, and assisted in drafting and modifying the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/13/37/prepub


There is good stability in MMP-2 and sTNF-R1 levels in a followup study of patients with stable hypertension. As a consequence, assessment of its concentrations may be a useful tool for monitoring the follow-up of these patients. Measured variations in MMP-2 and sTNF-R1 levels, exceeding 8.2% and 11.3%, respectively, may indicate an increase in cardiovascular risk, thus, could be used to optimizing treatment than blood pressure control alone.The aim of this study is to analyze MMP-2 and sTNF-R1 variability, potent predictors of cardiovascular events, in stable hypertensive patients during a 12-month followup. 234 asymptomatic patients  out of 252 patients with essential hypertension were followed up. MMP-2 and sTNF-R1 were measured at baseline and after 12 months (stage I). To compare MMP-2 and sTNF-R1 levels over time interval, we used the statistical method of Bland-Altman. MMP-2 and sTNF-R1 reproducibility was good in our patients for the two intervals with a coefficient of reproducibility of 8.2% and 11.3%, respectively. The percentages of patients within 1.96 × standard deviation of the mean were 93.6% and 92.7%. An elevated coefficient of correlation was obtained for MMP-2, basal versus stage I ( Sustained hypertension (HT) may cause left ventricular hypertrophy (LVH), alterations in cardiac function, and heart failure (HF) . Cardiomα is observed in patients with pressure overload states and cardiac dilation. Evidence supports that circulating sTNF-R1 levels are increased in patients with HF [The soluble tumor necrosis factor receptor 1 (sTNF-R1) represent the classical death signal of the apoptotic process , 5. Over with HF –8, being with HF . In addi with HF . Changes in the composition of the extracellular matrix (ECM) are known to occur in HT , 12, andIn a recent study, our group has found a good stability of amino-terminal propeptide of B type natriuretic peptide (NT-proBNP) levels , a powerWe hypothesized that inflammatory and fibrosis markers levels may change over time even in patients with clinically stable HT. Therefore, the aims of the present study were to analyze MMP-2 and sTNF-R1 variability during a 12-month followup, in a cohort of stable hypertensive patients.The study was on 252 Caucasian asymptomatic consecutive out-patients with mild hypertension (mean (SD) age 60 (13) years, 136 male), from 11 participating hospitals. All patients underwent a routine physical examination, electrocardiogram, echo-Doppler study, and laboratory analyses. Physicians using a standardized protocol measured systolic and diastolic blood pressure in the left arm of seated subjects between 08:00 and 11:00 AM, following the recommendations of The American Heart Association. Of the Patients analyzed in this study met these inclusion criteria: a previous diagnosis of hypertension, as defined by the “seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure” . Furtherβ-blockers 21%, statins 26%, and calcium-channel blockers 19%. There were not statistically significant changes in the different drugs administered during followup. None of the 234 patients finally studied presented cardiovascular events  [2. Glomerular filtration rate was calculated using the modified diet in renal disease equation [All patients were on stable medical therapy for at least 2 months before study enrollment with angiotensin II receptor antagonist 50%, diuretics 45%, angiotensin-converting enzyme inhibitors 32%, r death) . Body maVenous blood was taken by venipuncture into pyrogen-free vacuum tubes containing EDTA, and serum was obtained by gel clotter tubes, from subjects in sitting position between 8:00 and 11:00 AM. Samples were centrifuged immediately, frozen at −80°C, and only thawed once. Plasma concentrations of MMP-2 and sTNF-R1 were determined at central laboratory by specific commercial sandwich enzyme-linked immunosorbent assay . The MMP-2 and sTNF-R1 tests have limits of detection of 0.1 ng/mL and 25 pg/mL, respectively. Our intra-assay and interassay coefficients of variation were 5.9 and 6.2% for MMP-2, and 26.5 and 9.1% for sTNF-R1.The examinations were performed using standard systems equipped with 2.5–4 MHz transducers. The echocardiographic examinations were performed using the standard apical and parasternal long axis views were obtained in all echocardiographic studies and analyzed by a computerized system . M-Mode and two-dimensional images, Doppler spectrum and color Doppler were measured and averaged for each Doppler variable. For each patient, four consecutive beats were measured and averaged for each Doppler variable.2.7 due to the high prevalence of obese and overweight patients, defining LVH as LVM index >46.7 g/m2.7 in women and >49.2 g/m2.7 in men [Left ventricular ejection fraction (LVEF) was calculated with the area-length method . The E/A7 in men . t-test and categorical variable changes were compared using the McNemar test. Continuous variables are presented as mean ± SD and categorical variables as a number of patients or percentage. Results for each variable were tested for normality using the Kolmogorov Smirnov method. MMP-2 and sTNF-R1 concentrations exhibit a nonnormal distribution and were presented as the median and interquartile range and log transformed  before parametric correlation analysis by Pearson's coefficient. Temporal changes in molecule levels and clinical characteristics were analyzed using the paired student's To compare MMP-2 and sTNF-R1 levels over time interval , we used the statistical method of Bland-Altman , 31. In Furthermore, a multivariate linear regression analysis was performed using log transformed MMP-2 and sTNF-R1 as dependent variables and included gender, blood pressure, body mass index, LVMI and known HT duration, and treatment as independent variables. The discrimination of the best model was based on the principle of least mean square and higher R-square. P value <0.05 was considered significant for all measures. All statistical analyses were performed using the SPSS 11.5 statistical software package .A P < 0.05, and for sTNF-R1 basal stage, 385 (290–541) pg/mL, stage I, 394 (289–576) pg/mL, with no significant differences.The baseline characteristics of the 234 hypertensive patients included in the study in the two stages are shown in r = 0.55, P < 0.0001) and sTNF-R1 .We obtained good reproducibility for MMP-2 and sTNF-R1 measurements for the whole study comparing stage I-basal stage. P < 0.0001), with LVMI (P < 0.0001), and with BMI (P = 0.005). We also found a correlation between sTNF-R1 and the same parameters, with E/A (P < 0.0001), with LVMI (P < 0.0001), and with BMI (P = 0.016). The correlation between MMP-2 and sTNF-R1 was P < 0.0001. When we related both molecules with cholesterol neither MMP-2 nor sTNF-R1 were significantly correlated.When we correlated MMP-2 with well-established parameters, we found a significant correlation with E/A ratio  above 8.2% and for sTNF-R1, values over 11.3% may be considered of potential clinical value when monitoring hypertensive patients. Although there are differences in the average of MMP-2 levels compared with stage I versus basal stage, with the Bland-Altman analysis we can observe that this molecule is one of the most stable and has the lowest coefficient of reproducibility, indicating that these variations in the average do not affect its stability as a marker of in hypertensive disease development. Furthermore, good correlation was obtained between MMP-2 and sTNF-R1 concentrations at the two stages over the entire study, the correlation coefficients being higher for the sTNF-R1 levels of hypertensive patients.In our 234 patients with clinically and functionally stable HT there were neither cardiovascular events nor differences in ventricular function. Moreover, we found significant differences for values of blood pressure and total cholesterol of these variables decreasing over time probably as a consequence of the treatment. At first we might think that these changes in blood pressure values may affect the molecules concentrations during followup and thus alter its intrinsic variability and limit the purpose of the study. However, through the simple correlations and the multivariate linear regression analysis carried out we can confirm that neither blood pressure nor total cholesterol levels were independent predictors of these molecule levels in hypertensive patients, as other authors have pointed out , 35, 36.One limitation of this study is that our patients were on medication and it is known that these molecule values could be affected by treatment with diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or beta-blockers –40. NeveAn important consideration is that we selected patients with clinically stable HT without clinical or functional changes, but we cannot rule out the possibility of subtle changes in neurohormonal and immunology systems that might potentially influence the variability of the molecule levels. In some studies, the increase of apoptotic markers was associated with comparable changes of other cytokine levels, indicating that the activation of this system is also associated with autoimmune-inflammatory reactions , 42. HowAnother potential limitation is that although echocardiography-standardized techniques have been shown to be a more sensitive tool for detecting LVH than for electrocardiographic measurements, the variability of this technique is higher than the variability using magnetic resonance imaging. However, in this study a specialized, blinded, single cardiologist performed the echocardiographic analysis to minimize variability of the measurements. Moreover, it would have been interesting to get the filling pressures, but the methodology used in our asymptomatic patients did not include this measure. This study shows that there is good stability in MMP-2 and sTNF-R1 levels in a 12-month follow-up study of asymptomatic patients with clinically and functionally stable hypertension. Measured variations in MMP-2 exceeding 8.2% in a 12-month followup and for sTNF-R1, values over 11.3% may indicate an increase in cardiovascular risk. The low variability of these molecules suggest that their levels could be used to monitor hypertensive patients and optimizing medical treatment rather than blood pressure control alone.