ARDS: Monitoring tissue perfusion

NEW MANAGEMENT STRATEGIES IN ARDS

0749–0704/02 $15.00
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ARDS Monitoring Tissue Perfusion Stephan M. Jakob, MD, PhD, and Jukka Takala, MD, PhD

Inadequate tissue perfusion contributes to the pathogenesis and clinical course of organ failure in critically ill patients. The techniques available for monitoring and assessing circulation focus largely on systemic blood flow and pressure and on various aspects of cardiac function and ischemia. In contrast to the major advances in diagnostics and monitoring of cardiac function and perfusion, a clinical evaluation of the adequacy of systemic perfusion or the perfusion of organs other than the heart still must be based largely on indirect assessment and data integration. Tissue perfusion is a risk in acute respiratory distress syndrome (ARDS) for several reasons: metabolic demands often are increased, hemodynamic instability is common, and arterial hypoxemia may limit the delivery of oxygen to the tissues if the cardiovascular reserves are compromised and cannot compensate for the reduced arterial oxygen content. The interaction between mixed venous oxygenation and arterial oxygenation is particularly relevant in ARDS, because in the presence of increased shunting (a hallmark of ARDS), alterations in mixed venous oxygenation also will influence the arterial oxygenation. Hence, acute increases in oxygen consumption (VO2) or decreases in cardiac output will worsen the hypoxemia. Although clinical monitoring in ARDS often focuses on arterial oxygenation, interventions aimed at improving arterial oxygenation actually may impair cardiac output and reduce the delivery of oxygen to the tissues. Normal systemic hemodynamic parameters do not guarantee adequate regional tissue perfusion.16, 27 Impaired tissue oxygenation, especially in the splanchnic region,

From the Department of Intensive Care Medicine, University Hospital Inselspital, Bern, Switzerland

CRITICAL CARE CLINICS VOLUME 18 • NUMBER 1 • JANUARY 2002

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plays a central role in the pathogenesis of multiple organ dysfunction11 and in the development of complications in various groups of intensive care patients.12, 13, 63 This article first briefly reviews the abnormalities in systemic and regional circulation and metabolic demands in ARDS, then discusses the methods available for assessing the adequacy of systemic and regional tissue perfusion, and finally outlines strategies to maintain and improve tissue perfusion in ARDS. SYSTEMIC OXYGEN TRANSPORT IN PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME The delivery of oxygen to the peripheral tissues is the product of blood flow and arterial oxygen content (CaO2), and the arterial oxygen content is determined by arterial partial pressure of oxygen (PaO2), hemoglobin oxygen saturation (SaO2), and hemoglobin concentration (Hb) (Table 1). It is evident that in the clinical setting the variation of blood flow and Hb can be much wider than the variation of SaO2 and PaO2. Hence, the effect of SaO2 (or the degree of hemoglobin oxygen saturation) on systemic oxygen delivery is considerably quantitatively smaller than the potential effect of blood flow and hemoglobin (Tables 1–3). This statement is not meant to overlook or ignore the relevance of monitoring and treating arterial hypoxemia but rather to emphasize the pivotal role of maintaining blood flow and avoiding anemia in patients with or at risk for hypoxemia. As demonstrated in Tables 2 and 3, arterial oxygenation is related directly to cardiac output and Hb and is related inversely to VO2 and the degree of mixed venous oxygenation. Similarly, mixed venous oxygenation is related directly to cardiac output, and Hb and is related inversely to VO2 and the degree of venous admixture. In patients with normal lungs, this interaction between arterial and mixed venous oxygenation, cardiac output, VO2, and Hb is quantitatively negligible because the venous admixture is so small. In contrast, when the venous admixture is large (a hallmark of ARDS), the effect of these variables on arterial oxygenation is magnified significantly (Tables 2, 3). Because of the large physiologic shunt in ARDS, the arterial oxygenation is modified by the effects of cardiac output, VO2, and Hb on mixed venous oxygen saturation (SvO2) and mixed venous oxygen content (CvO2). (A detailed discussion is provided in Marshall et al.43) METABOLIC AND HEMODYNAMIC PATTERNS IN ACUTE RESPIRATORY DISTRESS SYNDROME Acute respiratory distress syndrome is associated with systemic and pulmonary inflammation. It is therefore not surprising that hypermetabolism is typical for patients with ARDS. The degree of hypermetabolism, approximately 30% above the predicted energy expenditure, is

Table 1. OXYGEN TRANSPORT EQUIVALENTS Oxygen Transport Variable

Equation

Arterial oxygen content (CaO2) Mixed venous oxygen content (CvO2) Systemic oxygen delivery (DO2) Oxygen consumption (VO2) Oxygen extraction

CaO2 (mL/L) CvO2 (mL/L) DO2 (mL/min/m2) VO2 (mL/min/m2) O2 extraction

      

[1.34  Hb (g/L)  SaO2]
[0.2325  PaO2 (kPa)] [1.34  Hb (g/L)  SvO2]
[0.2325  PvO2 (kPa)] CI (L/min/m2)  CaO2 (mL/L) CI (L/min/m2)  [CaO2 (mL/L)  CvO2 (mL/L)] VO2 (mL/min/m2)/DO2 (mL/min/m2) [CaO2 (mL/L)  CvO2 (mL/L)]/CaO2 (mL/L) 1  [CvO2 (mL/L)/CaO2 (mL/L)

If the contribution of the dissolved oxygen is ignored: Oxygen extraction

O2 extraction

 [SaO2  SvO2 ]/SaO2  1  [SvO2 /SaO2]

Hb  hemoglobin concentration; SaO2  arterial oxygen saturation; SvO2  mixed venous oxygen concentration; PaO2  arterial oxygen partial pressure; PvO2  mixed venous oxygen partial pressure; CI  cardiac index

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146 Table 2. EQUATIONS FOR INTERPRETATION OF ARTERIAL OXYGENATION Variables and Explanations Venous admixture or physiologic shunt (QsQt) Arterial oxygenation and Qs/Qt Because The equation for CaO2 can be rewritten as If the contribution of the dissolved oxygen is ignored Assuming full saturation of end-capillary blood in normally ventilated and perfused alveoli

Equation Qs/Qt CaO2 (mL/L) CvO2 (units) CaO2 (mL/L) CaO2 (mL/L)

    

[CcO2  CaO2 (mL/L)]/[CcO2  CvO2] CcO2  [(1  Qs/Qt)]
[(CvO2  Qs/Qt)] CaO2 (mL/L)  VO2 (mL/min/m2)/CI (L /min/m2) CcO2  [VO2 (mL/min/m2)/CI(L/min/m2)  (Qs/Qt)/[1  (Qs/Qt)] SaO2  1.34 Hb (g/L)

CcO2 (mL/L) SaO2

 1.34 Hb (g/L)  1 {[VO2 (mL/min/m2)/C (L/min/m2)]  [Hb (g/L)  1.34 (Qs/Qt)/1  (Qs/Qt)]}

CcO2  pulmonary venous capillary oxygen content in normally ventilated and perfused alveoli; CaO2  arterial oxygen content; CvO2  mixed venous oxygen content; VO2  oxygen consumption; CI  cardiac index; Hb  hemoglobin concentration

Table 3. EQUATIONS FOR INTERPRETATION OF MIXED VENOUS OXYGENATION Variables and Explanations Oxygen consumption (VO2) Mixed venous oxygen content (CvO2) If the contribution of the dissolved oxygen is ignored Mixed venous oxygenation and Qs/Qt because the equation can be rewritten as rewritten as Assuming full saturation of endcapillary blood in normally ventilated and perfused alveoli

Equation VO2 (mL/min/m ) CvO2 (mL/L) SvO2 1.34  Hb (g/L) SvO2 2

   

 CaO2 (mL/L) CaO2 (mL/L)  CvO2 (mL/L)
[VO2 (mL/L)/CI]   Cv˙O2 CvO2 CvO2 CcO2 SvO2

   

CI  [CaO2 (mL/L)  CvO2 (mL/L) CaCO2 (mL/L)  [VO2 (mL/min/m2)/CI] SaO2  1.34  Hb (g/L)  [VO2 (mL/min/m2)/CI] SaO2  [VO2 (mL/min/m2)]/[1.34  Hb (g/L)  CI] CvO2 (mL/L)
[VO2 (mL/min/m2)/CI] CcO2  [VO2 (mL/min/m2)  (Qs/Qt)/(1  Qs/Qt)]  VO2/CI CcO2  [VO2 (mL/min/m2)/CI]  (Qs/Qt)/(1  Qs/Qt) CcO2  [VO2 (mL/min/m2)/CI]  (Qs/Qt)/(1  Qs/Qt)  VO2/CI CcO2  [VO2 (mL/min/m2)/CI]  (1
Qs/Qt)/(1  Qs/Qt) CcO2  [VO2 (mL/min/m2)/CI]  (1
Qs/Qt)/(1  Qs/Qt) 1.34  Hb (g/L) {1  [VO2 (mL/min/m2)/CI]  Hb (g/L)  1.34}  (1
Qs/Qt)/ (1  Qs/Qt)

CI  cardiac index; CaO2  arterial oxygen content; SvO2  mixed venous oxygen concentration; Hb  hemoglobin concentration; SaO2  arterial oxygen saturation; CcO2  pulmonary venous capillary oxygen content in normally ventilated and perfused alveoli; Qs/Qt  venous admixture

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comparable with the hypermetabolism typical for severe sepsis.33 The increased metabolic demand also has direct implications for gas exchange and ventilatory management and monitoring. The increased carbon dioxide production, in association with the increased physiologic dead space to tidal volume ratio (another characteristic of ARDS33, 77), means that protective lung ventilation entails a risk for hypercapnia. The increased VO2 in association with the high physiologic shunt accentuates mixed venous desaturation and worsens arterial hypoxemia. Maintenance of normal SvO2 (or systemic oxygen extraction) requires hyperdynamic circulation. If the patient is unable to maintain hyperdynamic circulation, severe arterial hypoxemia will ensue. Paradoxically, therapeutic interventions aimed at improving pulmonary gas exchange (e.g., increased airway pressure or tidal volume, positive end-expiratory pressure [PEEP], or prolonged inspiration) are likely to decrease cardiac output. Hence, any benefits to systemic oxygen delivery from improved pulmonary gas exchange may be offset or reduced by concomitant decreases in cardiac output. Although opening the lung and keeping it open is likely to help limit further lung injury, the potential adverse circulatory effects should be weighed against the benefits of improved gas exchange. The physiologic response to acute hypoxemia is an increase in cardiac output. In ARDS, a hyperdynamic circulatory status is common (Fig. 1) and is consistent with the normal physiologic response to increased metabolic demands and acute hypoxemia. The cardiovascular reserves, however, may not be able to compensate for further worsening of hypoxemia or for the cardiovascular effects of interventions aimed at improving gas exchange. Figure 2 demonstrates the remarkably constant hyperdynamic circulatory status in patients with severe ARDS that does not alter despite worsening arterial and mixed venous hypoxemia.77 Hepatosplanchnic Perfusion in Patients with Systemic Inflammation Acute respiratory distress syndrome is one of several presentations of a systemic inflammatory disease with organ failure. In patients with generalized inflammation or sepsis, inadequate tissue perfusion may be a cause or a consequence of systemic inflammation, or both. The metabolic demand for oxygen in the splanchnic region is increased in inflammatory states.11–13, 57, 63 The increased metabolic demands are caused in part by an increased hepatic metabolism.13, 57 In patients with normal or hyperdynamic hemodynamics, total splanchnic blood flow is also higher than normal. The increase in VO2 is disproportionate to the increase in blood flow, however, and requires high oxygen extraction. Vasoactive drugs, which frequently are used to treat patients with inflammation and cardiovascular instability, may modify splanchnic tissue perfusion and metabolic demands. These drugs may differ in their effects on hepatosplanchnic blood flow and distribution in sepsis or

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Figure 1. Systemic blood flow in patients with severe ARDS. Shaded bar  at onset; solid bar  at worst; open bar  recovery, death, or extracorporeal membrane oxygenation (ECMO). (Data adapted from Valta, P, Uusaro A, Nunes S, et al: Acute respiratory distress syndrome: Frequency, clinical course, and costs of care. Crit Care Med 27:2367–2374, 1999; with permission.)

100

Oxygen Saturation (%)

90

80

70

60

50 Survivors

Nonsurvivors

Arterial Oxygenation

Survivors

Nonsurvivors

Mixed Venous Oxygenation

Figure 2. Patterns of oxygenation in patients with severe acute respiratory distress syndrome (ARDS). Shaded bar  at onset; solid bar  at worst; open bar  recovery, death, or extracorporeal membrane oxygenation (ECMO). (Data adapted from Valta P, Uusaro A, Nunes S, et al: Acute respiratory distress syndrome: Frequency, clinical course, and costs of care. Crit Care Med 27:2367–2374, 1999; with permission.)

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septic shock. For instance, in an experimental model of septic shock, treatment with dopexamine, epinephrine, or norepinephrine was found to increase systemic but not splanchnic blood flow.66 Epinephrine decreased colonic mucosal pH and was associated with tissue damage in the ileum and the colon. In contrast, only moderate changes were seen in animals receiving dopexamine and norepinephrine. In patients with septic shock, epinephrine caused higher arterial and liver vein lactate concentrations, lower splanchnic blood flow and VO2, and lower gastric mucosal pH than the norepinephrine-dobutamine combination, despite similar changes in systemic hemodynamics.46 In patients with hyperdynamic shock, dopexamine increased mucosal perfusion as reflected by a significant rise in mucosal hemoglobin oxygen saturation.71 Dobutamine infusion in patients with respiratory failure and pancreatitis had no consistent effect on splanchnic blood flow, and changes in splanchnic blood flow were different from changes in splanchnic metabolism.64 In another study, in patients with septic shock who had been stabilized with volume replacement and norepinephrine, dobutamine increased the cardiac index (CI) and splanchnic blood flow to a similar extent, whereas splanchnic oxygen consumption remained unchanged, and hepatic glucose production decreased.57 In these well-resuscitated patients, VO2 therefore did not depend on oxygen delivery, and splanchnic glucose metabolism was not increased by dobutamine. In experimental trials, some,4, 47 but not all22 investigators have found a beneficial, although not selective, effect of dobutamine in the splanchnic region. Mesenteric oxygen delivery was improved, and gastrointestinal mucosal blood flow was preserved14 or increased47 when dobutamine was infused in a porcine model of endotoxic shock. On the other hand, dopamine and dopexamine, but not dobutamine, increased jejunal mucosal tissue oxygenation in a porcine model of endotoxemia.22 Nitric oxide production is enhanced in sepsis and may protect visceral tissue perfusion during septic shock.23, 52, 76 In experimental, fluid-resuscitated septic shock,72 maintaining blood pressure by using a nonselective nitric oxide synthase inhibitor N-omega-monomethyl-Larginine (L-NMMA) increased systemic vascular resistance and decreased cardiac output to preshock values. Liver blood flow and oxygen delivery were increased during norepinephrine but not L-NMMA infusion. Endotoxin infusion resulted in increased resting endogenous glucose production. Glucose production increased further during norepinephrine infusion, whereas L-NMMA restored glucose production nearly to preendotoxin levels. Similarly, replacing norepinephrine by phenylephrine to maintain similar systemic blood pressure in septic shock reduces splanchnic blood flow and oxygen delivery, lactate uptake, and glucose production.58 These results and results from other studies65 suggest that drugs with additional beta-mimetic activity should be used in treating septic shock, because maintenance of systemic blood pressure by nitric oxide synthase inhibitors or phenylephrine may be achieved at the expense of regional blood flow and metabolic functions.

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Liver-lung Interaction in Acute Respiratory Distress Syndrome There are several possible mechanisms by which hepatic function modulates pulmonary function in ARDS. Matuschak has proposed that hepatic performance interacts to affect lung function by four regulatory elements of the acute inflammatory response.45 These regulatory elements include (1) control of systemic endotoxemia, bacteremia, and vasoactive by-products of sepsis and trauma by the gut-liver axis of inflammation, mononuclear phagocytic clearance, and Fc and complement receptor-mediated events; (2) production and export of endogenous cytokines by the hepatic Kupffer’s cells; (3) metabolic inactivation and detoxification of such mediators; and (4) cytokine-driven synthesis of acute-phase proteins that modulate metabolism and inflammation.

Assessment of Systemic Perfusion As pointed out previously, clinical assessment of tissue perfusion must be based largely on indirect assessment and data integration. Clinical monitoring of hemodynamics focuses on blood pressure and, perhaps to a smaller extent, blood flow. In ARDS, much of the monitoring and treatment also is driven by arterial oxygenation. Because hypoxemia is the hallmark symptom of the pathophysiologic process and its severity in ARDS, it is intuitively attractive to focus on correcting this symptom. At the same time, levels of arterial hypoxemia that prompt major therapeutic interventions in the intensive care setting, however, are encountered routinely in daily life (e.g., in airplanes and in the mountains). The physiologic response to hypoxemia is increased cardiac output, whereas the therapeutic interventions used to treat acute hypoxemia tend to decrease cardiac output. The goals of monitoring tissue perfusion in ARDS (and most other conditions in critically ill patients) are prevention and correction of organ dysfunction and tissue injury and evaluation of the need for and the response to therapeutic interventions. Although the goals can be stated easily, attaining them is often difficult. Hypoxemia presents a specific problem: hypoxemia limits oxygen delivery, but attempts to correct it also may limit oxygen delivery because of reduced cardiac output. The following discussion is based on the authors’ clinical experience in assessing what level of tissue perfusion is sufficient or adequate in the clinical setting. It is in no way an evidence-based recommendation. A structured approach is helpful in the clinical assessment and monitoring of tissue perfusion in ARDS. The authors address the following issues: 1. Is there a problem? 2. Is the blood flow low? 3. What is the volume status?

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Because of the increased permeability of pulmonary capillaries in ARDS, avoiding high pulmonary capillary pressures (e.g., following strict criteria for volume loading) has a high priority throughout the assessment, monitoring, and treatment procedures. The bedside clinical assessment should detect the possible presence of a major problem in tissue perfusion rapidly. The prerequisites for sufficient systemic perfusion are that the heart is pumping blood to the aorta and that enough blood is returning to the heart. If these prerequisites are fulfilled, the clinical status of central organ and peripheral tissue perfusion should be evaluated clinically. The clinical indicators of central organ perfusion are cerebral (neurologic) status and coronary perfusion, as assessed indirectly with electrocardiography. In mechanically ventilated patients, assessment of neurologic status as an indicator of adequacy of perfusion often is confounded by concomitant use of sedative and analgesic drugs. In any case, neurologic symptoms as a sign of inadequate systemic perfusion are a preterminal finding. Assessment of peripheral tissue perfusion is based on observing the temperature of the skin and the status of capillary perfusion and refill in the periphery. Urine output is a further indicator of the adequacy of perfusion. Finally, abnormal blood pressure gives additional information. Signs of reduced peripheral perfusion (cold skin, reduced capillary filling, reduced diuresis), alone or together with signs of poor central perfusion, suggest that the blood flow is low. The next step is to evaluate the volume status. This assessment also is based on clinical evaluation of peripheral tissue perfusion in combination with assessment of peripheral venous filling in the extremities and central venous filling (neck veins). These simple, objective evaluations can be performed rapidly at the bedside. Further information can be obtained by analysis of blood gases (to determine acidosis) and lactate levels. Finally, when there are severe gas exchange abnormalities in ARDS, inserting a pulmonary artery catheter and measuring SvO2 (intermittently or, preferably, continually) indicates the overall adequacy of oxygen supply. Although normal or even high SvO2 alone does not guarantee adequate systemic perfusion, low SvO2 (high oxygen extraction) indicates that systemic oxygen transport is inadequate for the metabolic demand. A pulmonary artery catheter also allows access to intravascular pressures and measuring cardiac output, information useful in evaluating the response to therapeutic interventions. Cardiac output can be monitored with less invasive means as well (e.g., by ultrasonography).79 Mixed venous oxygenation is probably the best single indicator of the adequacy of systemic perfusion and oxygen transport, because the SvO2 represents the amount of oxygen left after perfusion of the capillary beds. As such, it represents the oxygen reserve, or the balance between oxygen supply and demand. It is the flow-weighted average oxygen content of the venous effluents from various tissues. Mixed venous oxygen saturation, however, has a significant limitation in monitoring tissue perfusion: severe tissue hypoxia in a tissue bed receiving only a small proportion of cardiac output will

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have little effect on SvO2 if the rest of the tissues are well perfused. The changes in SvO2 in response to therapy are more important than single values. In particular, a rapidly decreasing SvO2 should alert the physician to an impending catastrophe. Techniques in the Assessment of Regional Perfusion Brinkmann et al9 provide a detailed review of techniques used to assess regional perfusion. Indocyanine Green Dye Extraction In critically ill patients, splanchnic blood flow estimation often is based on hepatic uptake of substances that are distributed in the plasma and metabolized by the liver.7, 39, 73 Indocyanine green (ICG) dye is used most often, but there is a poor correlation between estimated hepatic blood flow calculated from systemic indocyanine green clearance and blood flow obtained with hepatic vein catheterization and the Fick principle.39 The accuracy can be improved greatly by pharmacokinetic modeling, but only if liver function is normal. Variability of ICG extraction, acute changes in ICG extraction, and extrapolation of zero-time dye concentration may act as confounding factors. Vasoactive drugs may change the hepatic extraction of ICG acutely and invalidate the use of noninvasive methods. The dye extraction methods have been used mostly for research, and their applicability to clinical monitoring is questionable. Nevertheless, these methods have revealed the poorly predictable response of splanchnic blood flow to treatments routinely used. Mucosal Laser Doppler Flowmetry The reflection of light projected into tissue consists of a Dopplershifted component from moving objects (e.g., red blood cells) and an unshifted component. The interaction of these two components on a photodetector creates beat frequencies. The magnitude of the obtained signal is related to the product of the number of moving cells and their velocity and is an estimation of mucosal blood flow.41, 68 Laser Doppler flowmetry uses a laser-produced monochromatic beam and a low spatial resolution for estimating mucosal blood flow. Relative changes in mucosal perfusion can be assessed reliably.1, 68 The method has been used in animals, in healthy volunteers,2, 41 and in patients.49 Drawbacks are the small tissue volume for which mucosal perfusion can be estimated and technical difficulties (e.g., maintaining an appropriate tissue contact). Seventeen mechanically ventilated patients were studied to assess the association between various estimates of mucosal perfusion.17 Patients with low gastric mucosal pH (n  6) had lower mucosal blood flow (laser Doppler flowmetry), Hb, and hemoglobin saturation than patients

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with normal gastric mucosal pH. The authors concluded that intramucosal acidosis reflected mucosal hypoperfusion in these patients. Despite the limited clinical experience, laser Doppler flowmetry is a promising method for clinical monitoring of local splanchnic perfusion. Remission Spectrophotometry Remission spectrophotometry determines intracapillary hemoglobin molecular oxygen (O2) saturation. It is therefore a measure of microcirculatory O2 availability. The Erlanger Micro-lightguide Photometer (University of Erlanger, Germany) projects light from a xenon lamp into tissues and collects the remitted light by means of a recipient light conductor.19, 36 To measure mucosal hemoglobin O2 saturation, the fibercontaining tube is inserted through the operating channel of an endoscope. Clinical experience with this device is limited. Problems related to its use include possible interference with other pigments (e.g., bilirubin), movement artifacts, and difficulties in handling the device. In healthy controls and in patients with hyperdynamic septic shock, effects of dopexamine on gastrointestinal mucosal hemoglobin O2 saturation and pH were studied.56 Baseline hemoglobin O2 saturation and mucosal pH were lower in septic patients than in controls despite increased systemic O2 delivery. Dopexamine caused a significant rise in hemoglobin saturation in septic patients, but mucosal pH did not change. This study demonstrates the potential clinical applicability of this method for monitoring the effect of therapeutic interventions. Tonometry and Venous-arterial Partial Pressure of Carbon Dioxide Gradients Tonometry—and the use of venous-arterial PCO2, gradients in the assessment of perfusion—is based on the almost linear relationship between PCO2 and the corresponding CO2 concentration. Carbon dioxide concentration assesses the relation between metabolism (CO2 production) and blood flow. Therefore, mucosal or venous PCO2 gradients are an indirect measure of the adequacy of the mucosal or regional blood flow. Changes in VO2, hemoglobin, and pH induce changes in the relation between PCO2 and CO2, however, making the interpretation difficult.28, 30 In addition, gastric mucosal PCO2 gradients may not reflect small bowel PCO2 gradients during splanchnic ischemia4 because of the different vascular reflex responses of the celiac trunk and superior mesenteric artery59 and possibly because of the hepatic arterial buffer response.37 Data from clinical studies indicate that dissociation between changes in total splanchnic and mucosal blood flow may occur.50, 74 Recently, the use of nitric oxide tonometry has been investigated in animal research. Decreased production of nitric oxide during critical reductions of gastrointestinal perfusion has been associated with events leading to failure of the mucosal barrier function.34, 35 Tonometry can be applied easily in clinical monitoring. Its main limitations are related to the difficulty of interpretation. Recently, the gastric mucosal end-tidal PCO2 difference

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has been proposed as a way of continuously monitoring splanchnic perfusion.75 Monoethylglycinexylidide Production Monoethylglycinexylidide (MEGX) is produced from lidocaine mainly but not exclusively by the liver, through N-de-ethylation by the cytochrome P-450 enzyme complex. Because of the high first-pass effect in the normal liver, the amount of lidocaine available for metabolization is a function of total liver blood flow. In advanced liver disease the flow dependency of MEGX production is lost because of (1) reduced liver blood flow, (2) the changed distribution volume of lidocaine, (3) reduced functional liver tissue, and (4) uneven flow distribution in functional liver tissue. Measurement of arterial MEGX concentrations has been used as a quantitative dynamic measure of liver function in critically ill patients. Furthermore, changes in arterial MEGX concentrations after bolus injection of lidocaine have been extrapolated and interpreted as changes in splanchnic blood flow. The relation between total liver blood flow and MEGX production may, however, be altered even if liver function is not reduced grossly, mainly because the distribution volume for lidocaine can change. Also, concentrations of ␣1-acid glycoprotein, the compound to which lidocaine is bound and with which lidocaine is transported in blood, may vary. In patients with sepsis, low arterial MEGX concentrations do not reflect a low splanchnic blood flow.29 Intestinal Mucosal Permeability Measuring intestinal permeability is a noninvasive method of assessing intestinal damage. Intestinal permeability is not a measure of the adequacy of mucosal blood flow.60 It involves the estimation of the urinary recovery of single or multiple probes that have been administered orally. Dual-sugar tests are used to estimate intestinal permeability and function. Quantifying the absorption of two sugars of different sizes is more useful than using single probes. Urinary recovery of these probes expressed as a ratio is a particularly sensitive measure. The ratio reflects the contrasting effects of decreased absorption of monosaccharides (e.g., rhamnose or mannitol) because of the reduced surface area and increased permeability by larger disaccharides (e.g., lactulose or cellobiose) because of the opening of intracellular pathways. A further advantage of this ratio is the elimination of confounding, nonmucosal factors such as gastric emptying, intestinal transit, impairment of renal function, and incompleteness of urinary collection. These factors should affect both sugars equally. Recently, the effects of fluid administration on renal excretion of intravenously injected sugar probes were examined.26 In this experimental study, fluid administration increased urinary lactulose but not rhamnose recovery, and the lactulose–rhamnose ratio increased.

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Liver Vein Oxygen Saturation The measurement of liver vein O2 saturation (ShO2) is a clinically feasible method of assessing the relationship between splanchnic O2 delivery and VO2. The gradient between ShO2 and SvO2 reflects a mismatch between splanchnic O2 delivery and O2 consumption.11 This gradient was not altered by dopamine or dobutamine in patients after cardiac surgery, in patients with septic shock, or in patients with respiratory failure.62 The usefulness of the O2 saturation gradient between pulmonary artery and liver vein blood has been addressed recently.15 In septic patients with an oxygen saturation gradient of more than 10%, splanchnic O2 consumption increased with dobutamine-induced increase in splanchnic O2 delivery. This finding may suggest that in these patients O2 consumption depends on O2 delivery. Lactate Exchange Splanchnic ischemia leads to intestinal lactate production with consequently increased portal and liver vein lactate concentrations, unless the liver is capable of fully extracting the excess lactate.48, 67 In addition, increased aerobic metabolism or impaired ability of the gut to extract oxygen may cause intestinal lactate production. Overall, hepatosplanchnic lactate production suggests that splanchnic tissue oxygenation is at risk. Effects of Hypercarbia on Systemic and Regional Blood Flow and on Intracranial Pressure Because increased metabolism is combined with severely impaired lung function, arterial hypercarbia is sometimes unavoidable in patients with ARDS. In addition, to decrease the probability of potentially deleterious barotraumas, these patients often are ventilated with low tidal and minute volumes. The effect of hypercarbia and its correction with sodium bicarbonate has been studied experimentally (Table 4).10 Extensive hypercarbia (arterial PCO2 [PaCO2] of 80 mm Hg) was associated with increased systemic and regional (mesenteric, renal, carotid arterial) blood flow and with increased intracranial pressure. If the arterial pH was corrected, these changes were reversed. Effects of Strategies to Improve Oxygen Transport in Acute Lung Injury and Acute Respiratory Distress Syndrome Effects of Positive End-expiratory Pressure on Hepatic and Mesenteric Perfusion Positive end-expiratory pressure is used in patients with ARDS to improve arterial oxygenation and to restore functional residual capacity.

Table 4. EFFECTS OF THERAPEUTIC INTERVENTIONS ON SYSTEMIC AND HEPATOSPLANCHNIC OXYGEN DELIVERY

Systemic O2 delivery Splanchnic O2 delivery

Increasing Arterial PCO2

Increasing Hematocrit

⇑ ⇑

⇑ ⇑, (⇒)

PEEP

PEEP  Dopamine

PEEP  Dobutamine

PEEP  Dopexamine

PEEP  Enteral Feeding

⇓, ⇒ ⇓, ⇒

⇑ ⇑, ⇒

⇑ ⇒

⇒ ⇑

⇒ ⇑

O2  oxygen; PEEP  positive end-expiratory pressure; ⇑  increase; ⇓  decrease; ⇒  no change.

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Positive end-expiratory pressure has important circulatory side effects: the increased intrathoracic pressure decreases venous return and thereby decreases cardiac output. Despite improved arterial oxygenation, such effects can decrease tissue oxygen delivery (Table 4).18, 55 Positive endexpiratory pressure may reduce cardiac output and also influence its distribution.55, 61 In experimental trials, lung injury per se reduces hepatic blood flow and oxygen delivery, and this reduction is aggravated by increasing PEEP levels,54 but these findings are controversial.3, 8, 20, 21, 44, 54 The volume state may modify effects of PEEP on systemic blood flow: in rats, PEEP-induced reduction of cardiac output but not mesenteric blood flow is restored by volume application.40 Under isovolemic conditions, PEEP-induced reduction in splanchnic perfusion does not cause increased lactate concentrations.5 Lung injury and PEEP reduce MEGX production as a measure of hepatic function, however.53 In critically ill patients, reduced splanchnic blood flow is associated with impaired hepatic function, and substantial reductions in splanchnic blood flow may even produce liver and gut ischemia. Splanchnic tissue perfusion therefore may be inadequate in patients with ARDS and PEEP, and impaired splanchnic tissue perfusion may be a cofactor in the high morbidity and mortality rates in patients requiring mechanical ventilation.24, 25, 51 In critically ill patients, the effect of PEEP depends on the actual PEEP level and on the presence of lung injury. Unlike patients without acute lung injury,5, 6, 78 in patients with acute lung injury establishing clinically relevant PEEP levels does not influence cardiac output, splanchnic blood flow, or gastric mucosal-arterial PCO2 gradients if the patients are ventilated within the linear part of the pressure–volume curve.32 In such patients the effect of increased airway pressure on splanchnic perfusion is likely to be modified by reduced transmission of airway pressure to intrathoracic and intra-abdominal structures and by heart-lung interaction.61 Effects of Feeding on Hepatosplanchnic Perfusion In an animal model of acute lung injury, gastric bolus feeding reversed PEEP-induced impairment of hepatic blood flow and oxygen delivery.54 In this model, hepatic oxygen delivery and consumption increased to the same extent during feeding, indicating supply-dependent oxygen consumption in the liver or increased oxygen demand induced by feeding itself (see Table 4). Effect of Increasing Hematocrit on Regional Oxygen Delivery and Extraction A mechanism that may be partly responsible for multiple organ failure and the high mortality rates in patients with ARDS is tissue hypoxia in organs rendered supply dependent and therefore vulnerable by high metabolic demands. Alternatively, to increase oxygenation, PEEP may reduce cardiac output. By increasing right ventricular afterload,

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inotropic drugs often fail to increase cardiac output. It therefore seems reasonable to increase hemoglobin so as to increase oxygen delivery. The effects of increasing hematocrit on regional oxygen delivery, consumption, and extraction were studied in an experimental model of ARDS in which cardiac output and pulmonary artery occlusion pressure (PAOP) were not affected by the changes in hematocrit (see Table 4).42 A progressive increase in hematocrit up to 40% caused a corresponding increase in systemic oxygen delivery associated with a decrease in oxygen extraction. Renal, hepatic, and splanchnic oxygen delivery, however, did not increase after a threshold hematocrit of 35%. Neither systemic nor regional oxygen consumption increased. An increase in hematocrit to greater than 35% may decrease blood flow or oxygen availability as a consequence of increased blood viscosity. Effects of Vasoactive Drugs on Hepatosplanchnic Perfusion Portal blood flow and gut oxygen delivery decreased and gut oxygen extraction increased during PEEP in an animal model of acute lung injury (see Table 4).31 The values returned to near baseline with lowdose dopamine (5 ␮g/kg/minute for 1 hour). The increase in portal venous blood flow was more pronounced than the increase in systemic blood flow. Hepatic arterial blood flow did not increase. In rats, neither dopamine nor dobutamine corrected PEEP-induced depression of mesenteric blood flow, although they corrected partly impaired cardiac output.38 Dopexamine, but not dopamine, blocked the depressive effects of PEEP on mesenteric blood flow in a rat model of acute lung injury.70 SUMMARY A clinically feasible method for assessing regional splanchnic perfusion is still lacking. Methods used for research purposes demonstrate that the effects of current therapies on splanchnic perfusion are not predictable in intensive care patients with and without ARDS. Tonometry, laser Doppler flowmetry, and spectrophotometry have been used to assess splanchnic perfusion. Combining the available methods in different parts of the gastrointestinal tract may help assess splanchnic perfusion more accurately in the near future.

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