Update in Intensive Care and Emergency Medicine - part 2 ppt

creases, the vessel caliber increases to maintain the flow. While the precise vascular mechanism(s) involved remain a matter of debate between the myogenic and the metabolic theory, autoregulation is of particular importance to protect perfusion of organs such as the brain. The Concept of Waterfall The flow within an organ can be seen as a function of the difference between the inflow pressure and the outflow pressure. For a given perfusion pressure, the flow depends on the regional vascular tone or resistance. While this remains true for many organs, especially the musculo-cutaneous territory, it may not be so for others. The above concept is no longer correct when organ vessels are surrounded by a pressure different to atmospheric pressure. If this pressure is positive, it can at least induce vessel collapse. The perfusion pressure/flow relation is then more complex and surrounding pressure has to be integrated. If such external pressure becomes higher than intravascular pressure, the vessel is narrowed, with a re- duced flow. The outflow pressure is not the venous pressure, but the intra-vascu- lar pressure elevated by the positive pressure surrounding the tissue. The waterfall phenomenon occurs in the lung, the heart, the brain, and to a lesser extent the portal vein in the liver. Phasic Blood Flow [1] Arterial flow is a phasic phenomenon, with systolic and diastolic components. At the aortic level, flow is only present during systole, with no flow in diastole. At the microvessel level, flow is more continuous, which is a witness to the buffer role of arterial vessels that transform phasic flow into continuous flow. It is important to note that arterial organ blood flow is phasic, with systolic and diastolic compo- nents that differ from organ to organ (Fig.1) [2]. For example, forearm blood flow is essentially during systole with no flow during diastole, whereas cerebral blood flow is systolo-diastolic, and left coronary blood flow is purely diastolic (Fig. 2) [3]. This implies different determinants for these organ blood flows, according to the systolic and diastolic vascular tone. As for systolic pressure, systolic blood flow depends on aortic stroke volume, vessel compliance, and vascular tone. During an acute situation, compliance modification has a limited impact on the observed variations, because it cannot change in any large extent. The stroke volume and the vascular tone are the major factors of systolic blood flow. Diastolic blood flow is positive mainly in organs with an efficient autoregulation. These organs have a relatively low vascular tone during diastole, allowing a passive diastolic run off. Extravascular compressive forces are markedly different in the right and left ventricle under normal conditions. As a consequence, systolic flow expressed as a fraction of diastolic flow is much greater in vessels that perfuse the right ventricle than the left ventricle [4]. During diastole, coronary vascular tone is low, with a large perfusion pressure, generating a diastolic blood flow. On the right coronary vascular bed, perfusion is present both during systole and diastole. The systolic 34 D. M. Payen flow is positive because of a high systolic perfusion pressure (aortic systolic pressure – systolic pulmonary pressure). As in left side, the diastolic right coro- nary blood flow is positive related to a large perfusion pressure (diastolic aortic pressure – diastolic right ventricular pressure). In intensive care unit (ICU) pa- tients, the determinants of the phasic components of flow should be integrated into the understanding and the therapeutic strategy. Oxygen Supply/Oxygen Demand [5] It is agreed that oxygen deprivation may cause tissue damage directly, owing to exhaustion of ATP and other high energy intermediates needed to maintain cellu- lar structural integrity. In addition, oxygen deprivation may cause damage indi- rectly during reperfusion, when oxygen radical “storms” are formed and destroy Fig. 1. Phasic ascending aortic, brachial, femoral, and carotid blood flows before and after caudal anesthesia in infant [2]. Note the absence of diastolic flow in aorta and skeletal muscle circulation. Note the positive diastolic flow in common carotid blood flow. cell structure and function. The relationship between oxygen transport and tissue well-being is of interest to intensivists. As mentioned above for circulatory items, it is useful to separate the macrovascular parameters from the microvascular parameters of tissue oxygenation. Macrovascular parameters commonly used in clinical practice are oxygen uptake or consumption (VO 2 ), oxygen delivery (DO 2 ), and oxygen extraction ratio (O 2 ER). VO 2 is relatively easy to measure since it is the quantity of oxygen consumed by a given tissue per unit time. It is the differ- ence between the quantity of oxygen that enters and that which leaves a given vascular bed: VO 2 = flow × (CaO 2 – CvO 2 ) where CaO 2 and CvO 2 are the oxygen content of arterial and venous blood, respec- tively. DO 2 is the quantity of oxygen flowing into a given tissue and is calculated as: DO 2 = flow × CaO 2 Since only a fraction of DO 2 normally diffuses into cells, the remainder is carried away from the organ in the venous effluent. The fraction of DO 2 that diffuses from capillaries into cells, expressed as per cent of the total, is termed the O 2 ER and is calculated as VO 2 /DO 2 , i.e., O 2 ER = (CaO 2 -CvO 2 )/CaO 2 . Assuming in most circumstances that the hemoglobin concentration is adequate, such a ratio could be simplified as follows: O 2 ER = (SaO 2 -SvO 2 )/SvO 2 in %. The use of regional SvO 2 is currently the only parameter that approaches the O 2 ER [6]. As for circulation parameters, microcirculation parameters for oxygen utiliza- Fig. 2. Phasic left coronary bypass blood flow veloc- ity: top tracing shows pha- sic flow velocity with no systolic flow, with a large diastolic blood flow. The arrow indicates the impact on coronary bypass blood flow velocity of the closing of the chest [3]. 36 D. M. Payen tion differ from macrocirculation parameters. Tissue PO 2 provides information on tissue oxygenation, but varies considerably within a given organ. This has led to the use of PO 2 histograms to better characterize tissue oxygenation. The final determinant of mitochondrial oxidative phosphorylation is mitochondrial PO 2 . The minimum driving oxygen pressure to support oxidative phosphorylation in mitochondria is less than 0.5 mmHg. It depends both on oxygen convection (DO 2 ) and diffusion from capillary to cell. Metabolic parameters can be used to estimate the tissue redox state, such as lactate/pyruvate ratio, β-hydroxybutyrate/aceto/ acetate ratio, and depend both on macro- and microcirculation parameters. If the concept of the whole body DO 2 /VO 2 relationship can be easily manipulated by clinicians, it is not the same at the tissue level. When DO 2 varies over a large range, tissues maintain VO 2 constant, extracting only as much oxygen from the blood as appears needed to maintain vital metabolism. This refers to oxygen supply inde- pendency and is thought to signify tissue well-being. When DO 2 declines to a critical threshold value, VO 2 can no longer be maintained constant, because of the oxygen extraction limitation. Below this threshold, VO 2 declines in proportion to DO 2 , a phenomenon referred to as oxygen supply dependency. The corresponding O 2 ER is approximately 70%. Such a biphasic view of the VO 2 /DO 2 relation has been demonstrated in many organs, at least experimentally. This concept has lost importance in clinical ICU practice, because assumptions must be made which are incorrect for some ICU patients: • Oxygen demand is constant at all DO 2 values • Whole body measurements accurately reflect oxygenation of all organs • All DO 2 is equal for all physiologic conditions Two problems are created by the variations in VO 2 with respect to application of the VO 2 /DO 2 model: • the critical DO 2 varies with the change in VO 2 demand; • increased VO 2 due to increased oxygen demand is normally supported not by an increase in the O 2 ER, but rather by an increase in DO 2 . Thus, when oxygen demand is allowed to vary, the DO 2 -VO 2 relation is no longer biphasic but linear. It is not oxygen supply dependency but oxygen demand dependency (Fig.3). In ICU patients, one can admit that the cardiovascular system provides tissues with twice the critical value of DO 2 needed to support an oxygen supply-independent metabolism. When oxygen demand exceeds this capability of the cardiovascular system, then the O 2 ER increases to supply oxygen demand. The most important limitation for clinicians is that the whole body VO 2 -DO 2 relationship does not reflect phenomena occurring in individual organs, as illus- trated by many examples. Experimentally, it has been shown that critical DO 2 in different organs differs from the whole body value. This is more true in clinical conditions in which ventilation, especially with positive end-expiratory pressure (PEEP), the type of disease, and the pharmacology of the drugs used could alter the distribution of whole body DO 2 among organs. A septic patient treated with PEEP plus pressors may have a reduced liver blood flow due to PEEP, with an increase in cardiac oxygen demand due to inotropes and chronotropes. It is clear that the DO 2 -VO 2 relationship of the liver and the heart differ from that of the whole body. Determining Effectiveness of Regional Perfusion 37 Another frequent condition in ICU patients limits the applicability of this concept. When an organ is perfused by a stenotic vessel, the poststenotic vascular bed is already maximally dilated. Additional vasodilatation cannot be obtained to in- crease flow and DO 2 . Perfusion in this tissue is then dependent not on whole body and local DO 2 , but rather on arterial blood pressure. At the cerebral level, when autoregulation is abolished, cerebral blood flow is dependent on blood pressure, which then becomes the main determinant of cerebral DO 2 . Finally, there is a third mechanism by which the model of DO 2 -VO 2 is limited in clinical conditions. It is possible that factors other than macrovascular DO 2 determine tissue oxygen supply. Some clinical ICU conditions are characterized by a maldistribution of whole body DO 2 among organs, with overperfusion of some, and underperfusion of others. Oxygen diffusion betweencapillariesandmitochon- dria may differ among organs, because of important interstitial edema, abnormal structural barriers, or abnormal presence of migrating cells from blood (immune cells) within the tissue, trapping oxygen. Practically, in non-septic conditions, the most important determinant of VO 2 -limitation is the convective factor DO 2 .In septic conditions, if DO 2 remains a major determinant at least at the early phase, other factors interfere such as microvascular alterations (obstruction, or shunt), cellular dysoxia, oxygen radical formation. Finally, when hemoglobin concentra- tion is corrected and arterial oxygen saturation is over 95%, it is more DO 2 than oxygen diffusion that determines tissue perfusion. Fig. 3. Left panel: coronary blood flow tracings, with quoting of systole and diastole time (Ts and Td). The right panel shows the impact of dobutamine on phasic coronary bypass flow at three different doses. The lower part shows the oxygenated blood volume entering coronary vessels in relation to dobutamine dose [8]. 38 D. M. Payen Organ Variability of Oxygen Demand In ICU Situations The liver is a good example of VO 2 variations during acute situations. It is known that liver oxygen demand depends on the concentration of substrates reaching the liver: the more elevated the nutritional substrate supply, the more elevated the liver oxygen demand. As a result of this elevated oxygen demand, liver DO 2 has to increase. In sepsis or in systemic inflammation, the liver shifts the metabolism towards the acute phase response. The net effect of this shift on liver oxygen demand is not known, and may differ patient to patient. Kidney blood flow, like most organs (except brain and heart), varies in direct proportion to cardiac output. A reduction in cardiac output by 50% will produce a similar reduction in renal blood flow. However in contrast to other organs, kidney VO 2 decreases dramatically in parallel with a decrease in kidney DO 2 , even in physiological ranges. Since NaCl reabsorption accounts for two thirds of kidney VO 2 , the re- duced VO 2 implies a decreasing demand to reabsorb NaCL. The use of furosemide provides protection against kidney hypoperfusion, since it decreases oxygen de- mand by the drug-induced limitation of NaCl reabsorption. Integration of the Determinants Two separate conditions have to be considered in the analysis of regional perfu- sion determinants: first, when systemic blood flow is not the limiting factor, and second, when systemic blood flow is one of the limiting factors. In these two conditions, the consequences for organ perfusion are different as is the impact of therapy. Such differences are amplified by metabolic stimulation. If an organ has an elevated oxygen demand, sudden hypoperfusion will induce more cellular damage and organ dysfunction than in an organ at rest. As an extreme example, a patient having a cardiac arrest when at rest has a better chance of being success- fully resuscitated than if the heart is stressed. Few sportsmen having a cardiac arrest have been successfully resuscitated compared to patients experiencing a cardiac arrest when at rest. It should be noted in cardiopulmonary trials that some patients were successfully resuscitated. Among the survivors, those having a good neurologic score had a long delay for cardiopulmonary (CPR) intervention (>10 min) [7]. This confirms the ability of cardiac and brain cells to turn off the metabolism maintaining only essential functions, when in a pre-arrest condition the organ was not being stimulated. The duration of poor organ perfusion is an additional factor to be taken into account. This factor allows vascular or cardiac surgery to be preformed during which every effort is made to reduce oxygen demand, and to limit the duration of absence of organ perfusion: short duration of aortic clamping, cooling of the heart during bypass, use of diuretics and or manni- tol to protect the kidney, participate in preventing post procedure organ failure. The tolerance of hypoperfusion varies among organs: 5 to 7 min for brain total ischemia, 15 min for heart, 2 to 3 hours for the liver, 8 hours for skeletal muscle. Determining Effectiveness of Regional Perfusion 39 Determinants of Regional Perfusion when Systemic Circulation is not the Limiting Factor When the organ is not ischemic, the situation is close to physiological and the determinants depend on organ characteristics. Heart perfusion: Myocardial perfusion is provided by coronary vessels. The distri- bution of flow depends on three major vessels, with frequent efficient anastomoses within territories. The main characteristic of this circulation is that coronary blood flow is the adapting factor to cater for myocardial metabolic demand, since coro- nary circulation oxygen extraction is physiologically sub-maximal [4]. Any change in myocardial metabolic demand will be immediately followed by an adapted flow. More precisely, the energy consumed during one contraction has to be covered during the next diastole [8]. The greater the cost of one contraction, such as extrasystole, the more elevated should be the flow for the next diastole. It becomes clear why heart rate is the most important determinant of myocardial metabolic demand. Each contraction consumes energy that has to be covered by diastolic perfusion. That explains why β blocking agents are so powerful in reducing the imbalance between myocardial demand and supply. The limited diastolic time during tachycardia may reduce the capacity of the diastolic oxygenated blood volume to cover the metabolic demand [8]. This has to be kept in mind when using inotropes, which are also chronotrope drugs, in ICU patients. Patients with a limited coronary blood flow adaptation related to coronary disease and/or severe anemia, may suffer during inotrope treatment as it can induce myocardial is- chemia. In ICU patients, additional arterial hypotension may participate in ampli- fication of myocardial ischemia, in relation to a decrease in diastolic left coronary perfusion pressure. During resuscitation, fluid loading may also participate in myocardial ischemia, sinceitcan increase the end-diastolic ventricularvolume and the wall tension. Such effect could in turn change the intra-myocardial pressure, which becomes the back pressure of coronary blood flow. Myocardial tissue pres- sure seems to be largely higher than coronary vein pressure. It has been shown that the zero flow pressure in the coronary vascular bed is close to 30 to 40 mmHg [9]. Any increase in such a pressure may participate in the deterioration of perfusion pressure, and consequently in a reduction in blood flow, despite a higher demand. For the right coronary blood flow, since the perfusion is both systolic and diastolic, determinants for perfusion involve the two components [4]. For systolic perfusion, the concepts are grossly the same as those of the left ventricle. It should be mentioned that it is better preserved on the rightthanon the left, since pressures on the right side are largely lower than on the left. It will then be relatively independent of systemic pressure, but largely dependent on pulmonary hyperten- sion. In presence of chronic pulmonary hypertension, the systolic perfusion pres- sure is reduced, inducing a flow pattern identical to that observed on the left ventricle. With regard the diastolic perfusion pressure, this is very well maintained since diastolic aortic pressure is largely higher than the end-diastolic right ven- tricular pressure. We can conclude that without systemic circulatory failure, the right ventricle is particularly well protected from ischemia. The oxygen demand of 40 D. M. Payen the right ventricle is increased by right ventricular afterload. The blood flow has then to increase to cover such an increase in requirements. The vascular tone is reduced and flow increases if perfusion pressure is adequate. The organis ischemic: Thisis a frequent conditioninthe ICU because of agerelated co-morbidity such as coronary artery disease. Downstream of the coronary stenosis, the resistance is low, related to the metabolic demand of myocardium. This implies that a further dilatation will be limited if it is required to improve flow supply. This is a major concept in coronary reserve impairment. This reserve can be tested dynamically by inotropes, such as dobutamine. The stress test induces an increase in myocardial demand that has to be covered by flow. The coronary stenosis may limit this flow increase, leading to myocardial ischemia and dysfunc- tion. The vasodilatation leads to a flow dependency on perfusion pressure. If for any reason, systemic pressure is low, flow decreases in parallel, adding another is- chemic factor. Finally, anemia limiting oxygen transport to the myocardium, may also worsen myocardial ischemia. To summarize, left coronary perfusion depends on perfusion pressure, i.e., mainly diastolic aortic pressure. In some circumstances, the back flow pressure, i.e., the left ventricular pressure, could limit the flow in the presence of diastolic overload, especially if there is low diastolic aortic pressure. The main determinants of myocardial demand are: heart rate, afterload, and inotropism. The presence of a stenosis induces a post stenotic vasodilatation, causing the flow to be pressure dependent. This limited coronary reserve creates a high-risk of ischemia for the left myocardium. Regarding right coronary blood flow, in relation to the territory supplied, the flow is both systolic and diastolic. It is relatively well protected from left side modifications, but depends essentially on the right side pressures: pulmo- nary arterial pressure, right ventricular end-diastolic pressure. With an abnormal systemic circulation, with hypotension, tachycardia, and anemia, myocardial per- fusion can be compromised leading to ischemia and/or necrosis. It is then crucial to evaluate the tolerance to the circulatory conditions and the impact of treatment by dynamic tests such as: fluid loading and/or pressors, or inotropes with careful evaluation of S-T segment, troponin I, or echocardiography to quickly detect myocardial ischemia. Determinants of Regional Perfusion when The Systemic Circulation is the Limiting Factor Even when the coronary circulation is intact, there are some critical circumstances during which myocardial perfusion is compromised. In the association of severe hypotension, as during shock, with a reflex and therapeutic tachycardia and ane- mia, all the conditions are created to induce ischemia. Hemorrhagic shock may induce severe myocardial ischemia in coronary disease patients. Septic shock seems to be less dangerous, since myocardial ischemia has been demonstrated rarely. However, the co-existence of severe coronary stenosis and septic shock may lead to ischemia as assessed by elevated tropinin I. For the right circulation, Determining Effectiveness of Regional Perfusion 41 frequently challenged in ICU situations, the reasoning is different. The main determinant of right ventricular myocardial demand is the afterload, i.e, the pulmonary pressure. When pulmonary hypertension occurs with systemic hypo- tension, right ventricular ischemia may be observed. This is mainly important in septic shock, when systolic aortic pressure falls and systolic pulmonary pressure rises, reducing coronary perfusion pressure. The right systolic coronary blood flow decreases limiting the adequate supply for an elevated myocardial demand. This ischemia may induce right ventricular systolic dysfunction. Pulmonary em- bolism is also a good example. The huge increase in afterload, and consequently in myocardial demand, imposes a large increase in coronary blood flow. If this increase is not sufficient, right myocardial ischemia may occur, precipitating the collapse. The cerebral circulation: The cerebral blood flow is normally independent of systemic circulatory conditions [10]. The brain conditions determine the cerebral blood flow. The basic principle agreed by neurophysiologists is that the cerebral blood flow is coupled to cerebral oxygen consumption. Each modification of cerebral metabolic demand is followed by modification ofcerebralblood flow.This implies that for the clinician to have some indication of brain metabolic state will require specific explorations. Among these, seizure detection is the most obvious. In the absence of any clear modification in brain metabolism, the blood saturation in the jugular vein (SjO 2 ) can help. If SjO 2 is low (<70%), we can suppose that cerebral blood flow is not adequate for some reason. Multimodal monitoring is then of interestto provide a spectrum ofitemsto diagnosethemost probable causal mechanism. For a given cerebral metabolic rate, brain perfusion depends on several factors: the cerebral perfusionpressureaccording to the autoregulation concept,thepartial pressure of CO 2 (PCO 2 ), and the tissue oxygenation. Figure 4 shows the flow modifications observed in relation to the cerebral perfusion pressure. In normal brain conditions, autoregulation works to maintain the flow within a large range of cerebral perfusion pressure values. However, because of peripheral pattern modifications, this regulation can be overcome. For example, acute hyper- capnia, a frequent situation in ICU patients, leads to cerebral vasodilatation, increased cerebral blood flow, and increased cerebral blood volume. With normal intracranial pressure (ICP), the consequences are negligible. When ICP is elevated, in conditions that increase cerebral blood flow and also cerebral blood volume, ICP increases because of lack of space in a rigid box. This situation may inducesecondarybrain ischemia [10]. That is thereasonwhy, during brain injury, multimodal monitoring allows the diagnosis of brain hypoperfusion and determinationof themechanism ofthedecrease incerebral perfusionpressure. If ICP elevation relates to hypercapnia-induced cerebral vasodilatation, it has to be controlled by ventilation. If the perfusion is limited because of anemia despite a significant cerebral blood flow, transfusion is the appropriate treatment. After correcting PaCO 2 and hemoglobin level, if ICP remains elevated it is the combina- tion between all the parameters given by monitors that will provide a mechanism: • pure cerebrospinal fluid (CSF) control problem: CSF derivation has to be per- formed. 42 D. M. Payen • Brain parenchyma edema: osmotherapy, craniectomy, in rare cases, lumbar puncture • Elevated cerebral blood volume: several means can be used. – Use of autoregulation in the remaining reactive areas by increasing cerebral perfusion pressure with norepinephrine – Reduction of cerebral blood flow by acute hypocapnia or PaCO 2 decrease – Reduction of cerebral oxygen demand by anesthetic drugs that reduce meta- bolic induced dilatation. Transcranial Doppler associated with SjO 2 provides perfusion/oxygenation infor- mation [6]. Since cerebral blood flow is autoregulated, the phasic cerebral blood flow velocity has a large diastolic component. This diastolic flow velocity depends on parenchymal resistance: high resistance induces low diastolic velocity. The typical example is the brain dead patient, who is characterized by an absence of cerebral blood flow, and a zero diastolic blood flow velocity [11]. When diastolic Fig. 4. Schematic repre- sentation of cerebral autoregulation on involved parameters. CPP: cerebral perfussion pressure; CBF: cerebral blood flow; CBV: cerebral blood volume Determining Effectiveness of Regional Perfusion 43 [...]... Webster NR (20 03) The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis Crit Care Med 31 :25 74 25 78 21 Di Giantomasso D, May CN, Bellomo R (20 03) Norepinephrine and vital organ blood flow during experimental hyperdynamic sepsis Intensive Care Med 29 :1774–1781 22 Baskurt OK, Temiz A, Meiselman... availability and regional blood flow during endotoxic shock Arch Surg 131:767–774 35 Siegemund M, van Bommel J, Ince C (20 00) Influence of NO donor SIN-1 on the gut oxygenation in a normodynamic, porcine model of low-dose endotoxaemia Intensive Care Med 26 :S3 62 36 Buwalda M, Ince C (20 02) Opening the microcirculation: can vasodilators be useful in sepsis? Intensive Care Med 28 : 120 8– 121 7 37 Avontuur JA, Bruining... 7:359–373 28 van Iterson M, Sinaasappel M, Burhop K, Trouwborst A, Ince C (1998) Low-volume resuscitation with a hemoglobin-based oxygen carrier after hemorrhage improves gut microvascular oxygenation in swine J Lab Clin Med 1 32: 421 –431 29 Siegemund M, racovitza I, Ince C (20 02) The rationale for vasodilator therapy in sepsis In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine Springer,... prostacyclin when no further increase in DO2 could be obtained by volume resuscitation and dobutamine infusion Gastric intramucosal pH (pHi) improved after starting prostacyclin, suggesting an increase in splanchnic blood flow [57] Bihari et al found that, after increasing DO2 with the vasodilator prostacyclin, all patients survived when the increase in DO2 did not coincide with an increase in VO2, whereas... resuscitation and restored to baseline values in the SIN-1 group DO2 and VO2 increased in response to fluid therapy alone and were significantly higher than in the SIN-1 group Arterial and mesenteric lactate increased Superior mesenteric artery blood flow decreased together with µPO2 of the ileal mucosa and serosa This decrease was accompanied by an increase in the intestinal PCO2 gap Administering fluids... together with SIN-1 increased flow and mucosal µPO2 to baseline levels SIN-1 produced a significantly higher serosal µPO2 and normalization of the intestinal PCO2 gap These findings support the notion that therapy including vasodilators can recruit shunted microcirculatory units and improve tissue oxygenation while maintaining systemic hemodynamic parameters above shock values In a recent study in pigs,... microcirculation In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine Springer Verlag, Heidelberg, pp 23 3 24 5 52 Mathura KR, Vollebregt KC, Boer K, De Graaff JC, Ubbink DT, Ince C (20 01) Comparison of OPS imaging and conventional capillary microscopy to study the human microcirculation J Appl Physiol 91:74–78 53 Mathura KR, Bouma GJ, Ince C (20 01) Abnormal microcirculation in brain tumours during... (20 01) Hemodynamic support in septic shock Intensive Care Med 27 (Suppl 1):S80–S 92 41 Kaplan LJ, McPartland K, Santora TA, Trooskin SZ (20 01) Start with a subjective assessment of skin temperature to identify hypoperfusion in intensive care unit patients J Trauma 50: 620 – 627 42 Rivers E, Nguyen B, Havstad S, et al (20 01) Early goal-directed therapy in the treatment of severe sepsis and septic shock N Engl... dysfunction in sepsis Microcirculation 7:83–101 18 Albuszies G, Bruckner UB (20 03) Antioxidant therapy in sepsis Intensive Care Med 29 :16 32 1636 19 Rank N, Michel C, Haertel C, et al (20 00) N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study Crit Care Med 28 :3799–3807 20 Paterson RL, Galley HF, Webster NR (20 03)... oxygenation and perfusion in patients with systemic sepsis Crit Care Med 29 :1343–1349 26 Sinaasappel M, van Iterson M, Ince C (1999) Microvascular oxygen pressure in the pig intestine during haemorrhagic shock and resuscitation J Physiol 514 :24 5 25 3 27 Bateman RM, Sharpe MD, Ellis CG (20 03) Bench-to-bedside review: microvascular dysfunction in sepsis–hemodynamics, oxygen transport, and nitric oxide Crit Care . i.e., O 2 ER = (CaO 2 -CvO 2 )/CaO 2 . Assuming in most circumstances that the hemoglobin concentration is adequate, such a ratio could be simplified as follows: O 2 ER = (SaO 2 -SvO 2 )/SvO 2 in %. The. change in VO 2 demand; • increased VO 2 due to increased oxygen demand is normally supported not by an increase in the O 2 ER, but rather by an increase in DO 2 . Thus, when oxygen demand is allowed. as a noninvasive method for brain death diagnosis: a prospective study. Anesthesiology 72: 222 22 9 12. Berre J, De Backer D, Moraine JJ, Melot C, Kahn RJ, Vincent JL (1997) Dobutamine increases cerebral