J Am Soc Nephrol 12: S53–S59, 2001 Monitoring of Organ Dysfunction in Sepsis/Systemic Inflammatory Response Syndrome: Novel Strategies

THEA KOCH, STEFAN GEIGER, and MAX J. R. RAGALLER Department of Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Carus Medical Faculty, Technical University Dresden, Harvard Medical International Associated Institution, Dresden, Germany.

Abstract. Sepsis and systemic inflammatory response syn- of organ dysfunction is characterized by a trend from invasive drome–induced severe disruption of microcirculation and con- to noninvasive and “safe” techniques, which provide bedside secutive tissue hypoxia is considered a key factor in the de- or even on-line monitoring and allow a more precise and earlier velopment of organ dysfunction and multiple organ failure. detection of organ dysfunction. Techniques for the assessment The conventionally measured global variables such as lactate of regional perfusion and microcirculatory bioenergetics to or macrohemodynamic parameters using a pulmonary artery direct therapeutic procedures are expected to refine and opti- catheter do not adequately mirror microcirculatory distur- mize clinical treatment of critically ill patients in the future. bances. Evaluation of the severity of microcirculatory distress This article addresses the question of which variables should be and the effectiveness of resuscitation strategies requires new monitored, what is feasible, and what is valid for therapeutic clinical technologies aimed at the microcirculation. It is antic- consequences. Recent developments in monitoring of macro- ipated that novel techniques such as optical spectroscopy and and microcirculation and organ-specific dysfunction, e.g., intelligent biosensors will play a major role in the development lung, kidney, are described with respect to their advantages and of new monitoring systems. In general, the current monitoring limitations, and future directions are outlined.

Inflammation and infection, resulting in systemic inflamma- should be monitored, what monitoring is feasible, and what tory response syndrome (SIRS), continue to be major causes of findings are pertinent to therapeutic effects. Recent develop- organ dysfunction and organ failure, with high mortality rates ments in the monitoring of macro- and microcirculation and (ranging from 30 to 80%, depending on the number of failing organ-specific (lung and kidney) dysfunctions are described organs). Considering recent exciting findings and new technol- with respect to their advantages and limitations. Future direc- ogies that contribute to patient care, the crucial questions are as tions are also outlined. follows. Are we really making progress and can we monitor and document it? Are the incidence and mortality rates of multiple organ failure treated using therapeutic interventions Pathophysiologic Aspects Insight into the mechanisms involved in sepsis and SIRS directed by specific monitoring decreasing? induction of acute organ dysfunction is essential for the devel- When published data for some years are compared, a de- opment of diagnostic tools and monitoring techniques to detect crease in the mortality rate for patients with severe organ organ dysfunction. During severe infection and sepsis/SIRS, a failure and decreasing frequencies of renal failure and acute wide array of endogenous humoral and cellular mediator sys- respiratory distress syndrome after trauma, stress gastrointes- tems are activated, including the complement, coagulation, and tinal bleeding, and abdominal abscesses are suggested. There fibrinolytic systems, with the release of cytokines and lipid are a number of novel therapies that help certain patients mediators such as eicosanoids, platelet-activating factor, and without improving the overall survival rates for sepsis and endothelin-1. The inflammatory response involves the activa- SIRS. These controversies challenge investigators to focus on tion of endothelial cells, platelets, macrophages, monocytes, more sensitive and valid diagnostic tools and monitoring tech- and neutrophils, generating oxygen and nitrogen radicals. Also, niques, to identify risk factors for multiple organ failure and to activation of the sympathoadrenal axis (with increased levels provide early intervention. of norepinephrine), activation of the renin-angiotensin-aldoste- This article addresses the questions of which variables rone system (with increased levels of angiotensin II), and increases in vasopressin levels are often part of the host re- sponse. These mechanisms are largely responsible for the Correspondence to Dr. Thea Koch, Department of Anesthesiology and Inten- clinical manifestations of sepsis, including specific hemody- sive Care Medicine, University Hospital Carl Gustav Carus, Fetscherstrasse namic alterations that are characterized by systemic vasodila- 74, D-01307 Dresden, Germany. Phone: 49-351-4583453; Fax: 49-351- 4584336; E-mail: [email protected] tion, hyperdynamic macrocirculation, and microcirculatory 1046-6673/1202-0053 changes that contribute to inefficient oxygen extraction. Journal of the American Society of Nephrology Macrocirculatory dysfunction, complicated by inhomogeneous Copyright © 2001 by the American Society of Nephrology redistribution of regional blood flow and microcirculatory dys- S54 Journal of the American Society of Nephrology J Am Soc Nephrol 12: S53–S59, 2001 function, finally leads to tissue hypoxia, which represents the gies, inhibitors of nitric oxide synthase, and nonspecific neu- common pathway of organ dysfunction. tralization of mediators have been performed. Most of these The great dilemma involves how to measure nutritive organ new therapeutic approaches have failed to provide evidence of perfusion and tissue oxygenation. Global parameters do not improved outcomes. Targeting of a single microbial toxin or reflect specific organ disorders or microcirculatory distur- mediator seems to be insufficient to block the complex inflam- bances. We are barely able to determine perfusion in a few matory host response to infection. Furthermore, the timing of organ-specific vascular beds. These data disregard the inho- therapeutic intervention may be critical, because the relative mogeneous redistribution of blood flow within organs. There- roles of different mediators vary with time. Whether sophisti- fore, tissue hypoxia may occur even when normal organ blood cated monitoring of the immune status could facilitate the flow is detected. What does adequacy of tissue oxygenation selection of patients who could profit from special immuno- mean? Ultimately, this is determined at the mitochondrial modulatory therapy remains to be determined. level, so measurements of tissue bioenergetics would be ex- pected to provide a needed standard. The clinical importance of the microcirculation cannot now be adequately monitored, Monitoring of Global Hemodynamic and because of the difficulty of its detection within tissues, but Oxygen-Related Variables there are promising new technologies under development that To date, therapeutic strategies for sepsis and SIRS have been might make the assessment of tissue oxygenation feasible in directed toward optimization of the variables determining the future. global oxygen delivery (DO2). The pulmonary artery catheter Several new approaches to the prevention and treatment of (PAC), which was introduced by Swan et al. (1) in 1970, is still septic shock, which are based on recognition of the role of considered to be the clinical standard for the monitoring of mediator pathways, are currently under investigation; clinical macrohemodynamic variables such as cardiac output, pulmo- trials using anti-lipopolysaccharide and anti-cytokine strate- nary artery occlusion pressure, mixed venous oxygen satura-

Table 1. Noninvasive measurement of cardiac output

Method Advantages Disadvantages

Doppler echocardiography Continuous, real time Experienced investigator required Noninvasive, atraumatic Exact aortic diameter Myocardial performance Expensive equipment Valve function Soluble gas rebreathing High accuracy (depending on sensor) Expensive equipment (depending on sensor) Pulmonary capillary blood flow measured Disconnection from respirator for measurements

Partial CO2 rebreathing Pulmonary capillary blood flow measured Controlled mechanical ventilation required (cardiac output minus shunt) Disconnection not required Automated measurement Pulse contour analysis Continuous, real time Reference for calibration needed Beat to beat Invalid data with changes in aortic impedance, arrhythmia, cardiac instability Left ventricular output Semi-invasive Less invasive (using common vascular access) Bioimpedance Continuous, real time Invalid data with rapid hematocrit changes Beat to beat Artifacts from damp materials, bleeding, electrical noise, respiratory movement, chest wall edema, pleural effusion, hematothorax, chest tubes Noninvasive Accurate Arterial dilution thermodilution Left ventricular output Special indicator needed indocyanine green Less invasive (using common vascular Limited frequency access) lithium chloride Accurate Indicator costs Semi-invasive J Am Soc Nephrol 12: S53–S59, 2001 Monitoring of Organ Function S55

tion, DO2, and oxygen consumption (VO2). This invasive ment of critically ill patients, as proposed by Shoemaker et al. technique has been significantly questioned since the report by (8), was investigated in various prospective trials (9–11). Tar- Connors et al. (2), who described increased mortality rates, geting therapy to achieve supraphysiologic end points in crit- longer intensive care unit stays, and increased costs for criti- ically ill patients was found to be associated with decreased cally ill patients monitored with PAC, compared with those mortality rates in some studies (8,12), but others did not without PAC. In the past decade, several attempts have been confirm those results (10,11,13). In conclusion, the results made to develop noninvasive techniques to estimate cardiac revealed a particular relationship between the ability to in- output, some of which have been shown to be reliable and crease DO2 and VO2 and treatment outcomes (14). It was sufficiently precise. demonstrated that the failure to respond to treatment was an Transthoracic or transesophageal bioimpedance monitoring, indicator of poor prognosis among patients with septic shock

CO2-rebreathing methods, rebreathing of soluble gases, and and that survivors exhibited significantly greater percentage Doppler echocardiography are noninvasive methods for the increases in cardiac index, DO2, and VO2 in response to assessment of cardiac output. Advantages and shortcomings dobutamine infusion, whereas VO2 was not increased in non- are presented in Table 1. The major advantage of Doppler survivors (15). Those studies also confirmed that cardiac re- echocardiography is the possibility of observing myocardial serve was significantly reduced in nonsurvivors, suggesting performance and valve function. However, it is still more that survival is associated with the ability to increase myocar- difficult to obtain reliable cardiac output results using Doppler dial performance sufficiently to sustain a hypermetabolic state. techniques, compared with invasive techniques. High accuracy and precision have been shown for the soluble gas- and CO2- Lactate Levels in Critically Ill Patients rebreathing methods. CO2-rebreathing measurements do not Blood lactate measurements are considered to be indicators require extensive technical equipment, and recent changes in of anaerobic metabolism associated with tissue dysoxia, but the hardware and software have improved the validity of this real meaning of lactate levels in patients with sepsis remains method (3). The development of a clinically applicable monitor incompletely understood (16). Alternative explanations for lac- (DAVID; MedServ, Leipzig, Germany) by our group allows tic acidosis in patients with resuscitated sepsis include in- automated semiquantitative measurements of pulmonary cap- creased aerobic production, decreased utilization, and pulmo- illary blood flow (which represents cardiac output minus shunt- nary removal and release (in patients with acute lung injuries). ing), as an important variable for guiding hemodynamic and Elevation of serum lactate levels in septic patients results from ventilator therapy. increased peripheral intraorgan production and reduced hepatic Transpulmonary techniques for cardiac output measure- uptake and renal elimination. Abnormal functioning of the ments assess left-heart cardiac output. Several indicators are liver and kidney in septic patients significantly contributes to used, e.g., indocyanine green, lithium chloride, or sodium the development of lactic acidosis. Consideration of causes chloride. These semi-invasive techniques require a central ve- unrelated to tissue hypoxia allows more specific and effective nous catheter and an arterial dilution-detecting device, most treatment of lactic acidosis (Table 2). commonly located in one of the femoral arteries. The combi- Despite its ambiguous meaning, hyperlactatemia during crit- nation of arterial pulse contour analysis (providing continuous ical illnesses serves as an indirect metabolic indicator of cel- cardiac output measurements) and transpulmonary thermodi- lular stress, even if the amount of lactate is not correlated with lution (for frequent calibration) is commercially available the total oxygen debt, the magnitude of hypoperfusion, or the (PiCCO; Pulsion Medical Systems, Munich, Germany). High severity of shock, as previously suggested (17). Numerous correlation and low bias for transpulmonary thermodilution investigators have demonstrated a strong correlation between and pulse contour analysis, compared with right ventricular lactate levels and mortality rates (18,19). Despite the various cardiac output (PAC) measurements, have been reported (4).

Effects of Global Hemodynamic and Oxygen- Table 2. Common causes of hyperlactatemia in intensive Related Variables in Sepsis/SIRS care units In sepsis and SIRS, several strategies have been attempted in Inadequate Delivery of Oxygen Unrelated to Tissue Hypoxia past years to avoid the development of oxygen debt, which is Relative to Tissue Requirements defined as inadequacy of tissue oxygenation (5). These strate- Shock Hepatic failure gies involve the improvement of systemic hemodynamics and Cardiac arrest Renal failure oxygen-derived parameters. Hypoxia Sepsis When DO is progressively reduced by either decreases in 2 Anemia Myeloproliferative disease cardiac output or decreases in arterial oxygen content, the Severe exercise Pancreatitis appearance of lactate may be used to characterize critical DO , 2 Diabetes mellitus Short bowel syndrome which leads to anaerobic metabolism. Critical DO was dem- 2 Regional ischemia (e.g., gut) Drug-induced: catecolamines, onstrated to be related to a decrease in VO in numerous 2 biguanides, methanol, experimental studies (6,7). The crucial question of whether we ethanol, ethylene glycol should use “supranormal” DO2 values to optimize our treat- S56 Journal of the American Society of Nephrology J Am Soc Nephrol 12: S53–S59, 2001

factors affecting lactate levels, lactate can still be considered Novel Technologies for the Monitoring of one of the best, most widely available indicators for the as- Tissue Oxygenation and Bioenergetics sessment of global cellular metabolism in critically ill patients. The acceptance of any new technology depends on the Single elevated serum lactate measurements have only poor medical need for that technology, its reliability and accuracy, sensitivity as prognostic indicators. The use of sequential mea- and its potential to improve outcomes and cost/benefit ratios. surements is advocated, because it is not the peak lactate level Because it is extraordinarily difficult and expensive to demon- that can differentiate survivors from nonsurvivors but the abil- strate improvements in outcomes for critically ill patients in a ity to clear circulating lactate in response to therapeutic inter- randomized manner, the suggested advantages of new technol- vention (18). Because lactate concentrations are only nonspe- ogies often remain hypothetical. cific indirect indicators of cellular stress, more sensitive and specific means to guide and optimize therapy for critically ill Direct Measurement of Tissue PO2 patients are desired. Direct measurement of tissue PO2 during sepsis, in both experimental and clinical settings, has been performed primar- ily with the use of polarographic oxygen electrodes (24,25). Gastric Mucosal pH and the Mucosal/Arterial These have included needle and catheter electrodes for inser- CO2 Gradient as Indicators of Regional tion into tissues and arrays of oxygen electrodes for placement Hypoperfusion on organ surfaces. The main limitation of oxygen electrodes is

An increase in gastrointestinal mucosal PCO2 (PmCO2) was their extremely limited area of measurement, with penetration ␮ proposed to be an early marker of inadequate oxygen supply in depths of approximately 15 m. They measure the average PO2 shock states and to indicate the risk of gut epithelial dysfunc- of tissue cells, capillaries, and larger blood vessels in the tion, which may facilitate bacterial translocation and promote vicinity of the electrode and may therefore not detect the organ failure. Gutierrez et al. (20) demonstrated in septic presence of hidden hypoxic areas. Because oxygenation is

patients that a short-term infusion of dobutamine (10 ␮g/kg per highly heterogeneous at this level, PO2 measurements must be min) increased gastric mucosal pH (pHi), i.e., decreased obtained at multiple sites, using an array of electrodes placed PmCO2, whereas VO2 remained unchanged. These results raise on the organ surface or stepwise insertion of a needle electrode the question of whether gastric pHi or PmCO2 is a better into the tissue. The shortcomings of the method and the diffi- indicator of hypoperfusion, compared with related increases in culties in performance do not yet allow the routine clinical use

VO2, for guiding goal-directed therapy. Indeed, several studies of this technique. have shown that gastrointestinal mucosal/arterial CO2 Gradient ⌬ ( PCO2) may be useful for more refined titration of therapeutic Optical Spectroscopy for Measurement of strategies aimed at improving tissue oxygenation. Schlichtig Microcirculatory Oxygenation and Bowles (21) presented convincing evidence that changes in Optical spectroscopic methods (absorption, fluorescence, PmCO2, which mirror changes in VO2 during progressive flow and phosphorescence spectroscopy) are used to examine the stagnation, most likely represent dysoxia. The authors also chemical characteristics of substances by measuring the alter-

observed that PmCO2 values markedly exceeded PCO2 values in ations of light in various parts of the spectrum. They can be portal venous blood when flow was decreased below the crit- used for the assessment of tissue and cellular oxygenation, in ⌬ ical DO2 and that only a maximal mucosal/arterial PCO2 of terms of the oxygen saturation of hemoglobin in the microcir- approximately 25 to 35 mmHg was consistent with aerobic culatory blood, the cellular mitochondrial energy state, and the

CO2 metabolism in an animal model. From these data, it was oxygen pressure in the plasma, using oxygen-dependent optical assumed that, above this value, an additional increase in mu- properties of tissue, blood, or extrinsic diagnostic dyes (26). ⌬ cosal/arterial PCO2 would be consistent with mucosal dysoxia. Measurements of intermediates in the mitochondrial respira- These results obtained in animal models were confirmed in tory chain, e.g., the fluorescence intensity of endogenous mi- human subjects using microlight-guided reflectance spectro- tochondrial NADH measured in situ, can thus be used as direct photometry for direct assessment of microvascular hemoglobin measures of tissue bioenergetics. These techniques have the oxygen saturation; the findings indicated the occurrence of advantage of being noninvasive and can indicate the heteroge- abnormal microcirculatory oxygenation in the gastrointestinal neity of oxygenation. A limitation is the inability to make tract, despite more than normal systemic oxygen-derived pa- quantitative measurements. rameters during septic shock (22). According to recent studies, ⌬ the mucosal/arterial PCO2 should be maintained below 25 Orthogonal Polarization Spectral Imaging mmHg to avoid severe gastrointestinal hypoperfusion and as- Orthogonal polarization spectral (OPS) imaging (27) is a sociated dysoxia. The routine use of treatment directed by pHi novel method that can be used to make quantitative measure- remains questionable because, in a prospective, randomized, ments of diameter, flow velocity, and functional capillary controlled clinical study (23), no significant improvement in density in a wide variety of tissues (28). With this technique, intensive care unit mortality rates could be observed after high-quality, transillumination-like images can be produced resuscitation of critically ill patients on the basis of gastric from thick solid tissues without the use of fluorescence dyes. tonometric results. The OPS optical system has been incorporated into a small, J Am Soc Nephrol 12: S53–S59, 2001 Monitoring of Organ Function S57 easy-to-use probe that must simply be placed on the tissue to be Monitoring of Renal Function imaged. This device (CYTOSCAN; Cytometrics Inc., Phila- Sepsis and particularly septic shock are important risk fac- delphia, PA) is much more portable and easy to use than tors for the development of acute renal failure (ARF). Recent conventional intravital microscopes. Clinical applications are clinical trials with patients with sepsis demonstrated an inci- possible in easily accessible sites such as the mouth. The OPS dence of ARF at the time of study entry that varied between 9 system can be used to produce excellent images of the sublin- and 40%, depending on the case mixture, the severity of gual microcirculation, with the probe placed under the tongue illness, and the definitions used to characterize ARF (34). ARF like a thermometer. The changes in microvascular perfusion in sepsis is generally part of multiple organ dysfunction syn- during hemorrhagic shock that occur in internal organs such as drome, which may complicate sepsis, indicating that similar the intestine and liver can also be demonstrated in the sublin- mechanisms are operative in inducing dysfunctions of various gual vascular bed (29). Therefore, OPS imaging could be used organ systems. Both systemic and local renal mediators and to monitor perfusion changes in internal organs in a noninva- mechanisms are involved in the pathogenesis of septic ARF. sive manner, which could have important diagnostic implica- Renal hypoperfusion, ultimately resulting in renal ischemic tions. Because quantitative measurements of tissue perfusion injury, is considered to be a major factor in the pathogenesis of are possible, the technology could be used to monitor the ARF. However, in experimental models of sepsis and in septic progression and development of diseases that affect the micro- patients, renal blood flow (RBF) varies widely (35). In general, circulation, as well as to directly monitor the success or failure RBF is difficult to predict from systemic hemodynamic vari- of treatments. ables, in part because of BP-maintaining compensatory mech- anisms (e.g., sympathetic activity and the renin-angiotensin- aldosterone system) in sepsis. Furthermore, redistribution of Online Monitoring of Gas Exchange to Monitor blood flow within the kidney itself, favoring the juxtaglomer- Lung Function ular and medullary areas at the expense of outer cortical flow, To date, there is no method available to replace arterial may occur even if global RBF is relatively normal. Experi- blood gas sampling. Despite significant advances in pulse mental animal studies and in vitro studies have shown that oximetry and capnography, both techniques provide only lim- endotoxin decreases the glomerular plasma flow and GFR in ited information. Pulse oximetry requires the presence of a superficial nephrons, with an increase in total renal arteriolar pulsed blood flow and does not detect impaired tissue oxygen- resistance and a decrease in filtration fraction (34,36). As a ation attributable to a leftward shift of the oxygen-hemoglobin result of the markedly reduced GFR, effective tubular sodium dissociation curve. Breathing and circulation are ensured if the reabsorption (the main energy-consuming process in the kid- characteristic fluctuations in end-tidal carbon dioxide tension ney) is decreased, indicating a relative VO2 excess. Therefore, are present. However, the end-tidal PCO2 may not accurately determination of fractional sodium excretion may be a clinical reflect the arterial PCO2 in patients with acute lung diseases tool for the detection of inadequate renal perfusion before the (e.g., increased alveolar dead space) or patients in hemody- manifestation of organ failure in terms of anuria, hyperkalemia, namically unstable condition. The need for continuous intra- acidemia, and azotemia. Imaging techniques used for ARF, vascular arterial blood gas monitoring for these patients is such as grayscale ultrasonography; duplex ultrasonography, obvious. In recent years, tremendous progress has been made and magnetic resonance imaging, do not provide specific in- in the miniaturization of fiberoptic blood gas and pH sensors, formation regarding acute prerenal failure in sepsis/SIRS (37). which is a required criterion for intravascular sensors. Absor- Diuresis and creatinine clearance currently represent the clin- bance sensors and fluorescence sensors (optodes) are the two ically most important variables for global renal function existing types of optical sensors. Simplistically, these sensors monitoring. operate via illumination of a sample chamber containing a dye In summary, the sepsis-induced systemic activation of var- located on a fiberoptic probe (30). Compared with conven- ious mediator systems and compensatory mechanisms affects tional electrodes, optodes are impervious to electrical interfer- systemic and renal perfusion. Both vasoconstrictive and vaso- ence, exhibit no drift, and do not consume the analyte (because dilating mediators are generated within the kidney, and their the reactions are reversible). Disadvantages are the marginal balance dictates renal hemodynamics, often resulting in renal signal/noise ratio, the instability of chemical dyes, and the hypoperfusion, which is considered to be a major factor in the requirement for sophisticated optic and electronic equipment. development of renal injury and failure. In addition, toxic The reliability and accuracy, particularly of PO2, remain to be products resulting from neutrophil-endothelium interactions, improved. Reliability is decreased because of probe failures, endothelial damage, reperfusion injury, and microvascular pressure damping, wall effects, and reduced flow at the mea- thrombosis in the kidney contribute to renal dysfunction during surement site (usually the radial artery). Clinical evaluation of severe sepsis. continuous arterial blood gas monitoring suggests that the intravascular system may be used to monitor trends in highly selected patients, such as those undergoing lung transplantation Conclusion (31–33). Extravascular, on-demand, optode-based systems cir- Sepsis and SIRS induce severe disruption of the microcir- cumvent all intravascular patient-probe interface problems and culation, and resultant tissue hypoxia is considered a key factor function well, but none are currently available. in the development of organ dysfunction and multiple organ S58 Journal of the American Society of Nephrology J Am Soc Nephrol 12: S53–S59, 2001 failure. Conventionally measured global variables such as lac- 12. Boyd O, Grounds RM, Bennett ED: The beneficial effect of tate levels and macrohemodynamic parameters measured using supranormalization of oxygen delivery with dopexamine hydro- a PAC do not adequately reflect microcirculatory disturbances. chloride on perioperative mortality. JAMA 270: 2699–2707, To evaluate the severity of microcirculatory distress and the 1993 effectiveness of resuscitation strategies, new clinical technol- 13. Tuchschmidt J, Fried J, Astiz M, Rackow E: Elevation of cardiac ogies aimed at the microcirculation must be developed. It is output and oxygen delivery improves outcome in septic shock. anticipated that novel techniques such as optical spectroscopy Chest 102: 216–220, 1992 14. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, and the use of intelligent biosensors will play a major role in Watson D: Elevation of systemic oxygen delivery in the treat- the development of new monitoring systems. In general, the ment of critically ill patients. N Engl J Med 330: 1717–1722, monitoring of organ dysfunction is currently characterized by 1994 a trend from invasive to noninvasive “safe” techniques, which 15. Rhodes AR, Lamb FJ, Malagon I, Newman PJ, Grounds RM, provide bedside or even online monitoring, allowing more Bennett ED: A prospective study of the use of a dobutamine precise and earlier detection of organ dysfunction. Techniques stress test to identify outcome in patients with sepsis, severe for the assessment of regional perfusion and microcirculatory sepsis, or septic shock. Crit Care Med 27: 2361–2366, 1999 bioenergetic parameters, to direct therapeutic procedures, are 16. Kirschenbaum LA, Astiz ME, Rackow EC: Interpretation of expected to refine and optimize the clinical treatment of criti- blood lactate concentrations in patients with sepsis. Lancet 352: cally ill patients in the future. 921–922, 1998 17. Mizock BA, Falk JL: Lactic acidosis in critical illness. Crit Care Med 20: 80–93, 1992 References 18. Abramson D, Scalea TM, Hitchcock R, Trooskin SZ, Henry SM, 1. Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Chonette Greenspan J: Lactate clearance and survival following injury. D: Catheterization of the heart in man with use of a flow-directed J Trauma 35: 584–588, 1993 balloon-tipped catheter. N Engl J Med 283: 447–451, 1970 19. Rashkin MC, Bosken C, Baughman RP: Oxygen delivery in 2. Connors AF Jr, Speroff T, Dawson NV, Thomas C, Harrell FE Jr, critically ill patients: Relationship to blood lactate and survival. Wagner D, Desbiens N, Goldman L, Wu AW, Califf RM, Fulk- Chest 87: 580–584, 1985 erson WJ Jr, Vidaillet H, Broste S, Bellamy P, Lynn J, Knaus 20. Gutierrez G, Clark C, Brown SD, Price K, Ortiz L, Nelson C: WA: The effectiveness of right heart catheterization in the initial Effect of dobutamine on oxygen consumption and gastric muco- care of critically ill patients. JAMA 276: 889–897, 1996 sal pH in septic patients. Am J Respir Crit Care Med 150: 3. Gama de Abreu M, Quintel M, Ragaller M, Albrecht DM: Partial 324–329, 1994 carbon dioxide rebreathing: A reliable technique for noninvasive 21. Schlichtig R, Bowles SA: Distinguishing between aerobic and

measurement of nonshunted pulmonary capillary blood flow. anaerobic appearance of dissolved CO2 in intestine during low Crit Care Med 25: 675–683, 1997 flow. J Appl Physiol 76: 2443–2451, 1994 4. Sakka SG, Reinhart K, Meier-Hellmann A: Comparison of pul- 22. Temmesfeld-Wollbruck B, Szalay A, Mayer K, Olschewski H, monary artery and arterial thermodilution cardiac output in crit- Seeger W, Grimminger F: Abnormalities of gastric mucosal ically ill patients. Intensive Care Med 25: 843–846, 1999 oxygenation in septic shock: Partial responsiveness to dopexam- 5. Connett RJ, Honig CR, Gayeski TE, Brooks GA: Defining hyp- ine. Am J Respir Crit Care Med 157: 1586–1592, 1998 oxia: A systems view of VO2, glycolysis, energetics, and intra- 23. Gomersall CD, Joynt GM, Freebairn RC, Hung V, Buckley TA, cellular PO2. J Appl Physiol 68: 833–842, 1990 Oh TE: Resuscitation of critically ill patients based on the results 6. Schlichtig R, Pinsky MR: Defining the hypoxic threshold. Crit of gastric tonometry: A prospective, randomized, controlled trial. Care Med 19: 147–149, 1991 Crit Care Med 28: 607–614, 2000 7. Chapler CK, Cain SM: The physiologic reserve in oxygen car- 24. Boekstegers P, Weidenhofer S, Kapsner T, Werdan K: Skeletal rying capacity: Studies in experimental hemodilution. Can muscle partial pressure of oxygen in patients with sepsis. Crit J Physiol Pharmacol 64: 7–12, 1986 Care Med 22: 640–650, 1994 8. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS: 25. Vallet B, Lund N, Curtis SE, Kelly D, Cain SM: Gut and muscle Prospective trial of supranormal values of survivors as therapeu- tissue PO in endotoxemic dogs during shock and resuscitation. tic goals in high-risk surgical patients. Chest 94: 1176–1186, 2 J Appl Physiol 76: 793–800, 1994 1988 9. Vallet B, Chopin C, Curtis SE, Dupuis BA, Fourrier F, Mehdaoui 26. Ince C, Sinaasappel M: Microcirculatory oxygenation and shunt- H, LeRoy B, Rime A, Santre C, Herbecq P: Prognostic value of ing in sepsis and shock. Crit Care Med 27: 1369–1377, 1999 the dobutamine test in patients with sepsis syndrome and normal 27. Groner W, Winkelman JW, Harris AG, Ince C, Bouma GJ, lactate values: A prospective, multicenter study. Crit Care Med Messmer K, Nadeau RG: Orthogonal polarization spectral imag- 21: 1868–1875, 1993 ing: A new method for study of the microcirculation. Nat Med 5: 10. Hayes MA, Timmins AC, Yau EH, Palazzo M, Watson D, Hinds 1209–1212, 1999 CJ: Oxygen transport patterns in patients with sepsis syndrome 28. Harris AG, Langer S, Messmer K: The study of the microciru- or septic shock: Influence of treatment and relationship to out- lation using orthogonal polarization spectral imaging. In: Year- come. Crit Care Med 25: 926–936, 1997 book of Intensive Care and Emergency Medicine 2000, edited by 11. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Vincent JL, Berlin, Springer, 2000, pp 705–713 Fumagalli R: A trial of goal-oriented hemodynamic therapy in 29. Jin X, Weil MH, Sun S, Tang W, Bisera J, Mason EJ: Decreases

critically ill patients: SvO2 Collaborative Group. N Engl J Med in organ blood flows associated with increases in sublingual PCO2 333: 1025–1032, 1995 during hemorrhagic shock. J Appl Physiol 85: 2360–2364, 1998 J Am Soc Nephrol 12: S53–S59, 2001 Monitoring of Organ Function S59

30. Mahutte CK, Gallacher TS: Blood gas monitoring with optodes. quential lung transplantation. J Cardiothorac Vasc Anesth 13: In: Yearbook of Intensive Care and Emergency Medicine 2000, 253–257, 1999 edited by Vincent JL, Berlin, Springer, 2000, pp 726–727 34. Thijs A, Thijs B: Pathogenesis of acute renal failure during 31. Venkatesh B, Clutton Brock TH, Hendry SP: A multiparameter sepsis. Kidney Int 53[Suppl 66]: S34–S37, 1998 sensor for continuous intra-arterial blood gas monitoring: A 35. Groeneveld ABJ: Pathogenesis of acute renal failure during prospective evaluation. Crit Care Med 22: 588–594, 1994 sepsis. Nephrol Dial Transplant 9: 47–51, 1994 32. Abraham E, Gallagher TJ, Fink S: Clinical evaluation of a 36. Camussi G, Ronco C, Montrucchia G, Piccoloi G: Role of multiparameter intra-arterial blood-gas sensor. Intensive Care soluble mediators in sepsis and renal failure. Kidney Int 53[Suppl Med 22: 507–513, 1996 66]: 38–42, 1998 33. Myles PS, Buckland MR, Weeks AM, Bujor M, Moloney J: 37. Mucelli RP, Bertolotto M: Imaging techniques in acute renal Continuous arterial blood gas monitoring during bilateral se- failure. Kidney Int 53[Suppl 66]: 102–105, 1998