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Intensive Care Nephrology 2000 |
Department of Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Carus Medical Faculty, Technical University Dresden, Harvard Medical International Associated Institution, Dresden, Germany.
Correspondence to Dr. Thea Koch, Department of Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Carus, Fetscherstrasse 74, D-01307 Dresden, Germany. Phone: 49-351-4583453; Fax: 49-351-4584336; E-mail: tkoch{at}rcs.urz.tu-dresden.de
Abstract
Abstract. Sepsis and systemic inflammatory response syndrome—induced severe disruption of microcirculation and consecutive tissue hypoxia is considered a key factor in the development of organ dysfunction and multiple organ failure. The conventionally measured global variables such as lactate or macrohemodynamic parameters using a pulmonary artery catheter do not adequately mirror microcirculatory disturbances. Evaluation of the severity of microcirculatory distress and the effectiveness of resuscitation strategies requires new clinical technologies aimed at the microcirculation. It is anticipated that novel techniques such as optical spectroscopy and intelligent biosensors will play a major role in the development of new monitoring systems. In general, the current monitoring of organ dysfunction is characterized by a trend from invasive to noninvasive and "safe" techniques, which provide bedside or even on-line monitoring and allow a more precise and earlier detection of organ dysfunction. Techniques for the assessment of regional perfusion and microcirculatory bioenergetics to direct therapeutic procedures are expected to refine and optimize clinical treatment of critically ill patients in the future. This article addresses the question of which variables should be monitored, what is feasible, and what is valid for therapeutic consequences. Recent developments in monitoring of macro- and microcirculation and organ-specific dysfunction, e.g., lung, kidney, are described with respect to their advantages and limitations, and future directions are outlined.
Inflammation and infection, resulting in systemic inflammatory response syndrome (SIRS), continue to be major causes of organ dysfunction and organ failure, with high mortality rates (ranging from 30 to 80%, depending on the number of failing organs). Considering recent exciting findings and new technologies that contribute to patient care, the crucial questions are as 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 directed by specific monitoring decreasing?
When published data for some years are compared, a decrease in the mortality rate for patients with severe organ failure and decreasing frequencies of renal failure and acute respiratory distress syndrome after trauma, stress gastrointestinal bleeding, and abdominal abscesses are suggested. There are a number of novel therapies that help certain patients without improving the overall survival rates for sepsis and SIRS. These controversies challenge investigators to focus on more sensitive and valid diagnostic tools and monitoring techniques, to identify risk factors for multiple organ failure and to provide early intervention.
This article addresses the questions of which variables should be monitored, what monitoring is feasible, and what findings are pertinent to therapeutic effects. Recent developments in the monitoring of macro- and microcirculation and organ-specific (lung and kidney) dysfunctions are described with respect to their advantages and limitations. Future directions are also outlined.
Pathophysiologic Aspects
Insight into the mechanisms involved in sepsis and SIRS induction of acute organ dysfunction is essential for the development of diagnostic tools and monitoring techniques to detect organ dysfunction. During severe infection and sepsis/SIRS, a wide array of endogenous humoral and cellular mediator systems are activated, including the complement, coagulation, and fibrinolytic systems, with the release of cytokines and lipid mediators such as eicosanoids, platelet-activating factor, and endothelin-1. The inflammatory response involves the activation of endothelial cells, platelets, macrophages, monocytes, and neutrophils, generating oxygen and nitrogen radicals. Also, activation of the sympathoadrenal axis (with increased levels of norepinephrine), activation of the renin-angiotensin-aldosterone system (with increased levels of angiotensin II), and increases in vasopressin levels are often part of the host response. These mechanisms are largely responsible for the clinical manifestations of sepsis, including specific hemodynamic alterations that are characterized by systemic vasodilation, hyperdynamic macrocirculation, and microcirculatory changes that contribute to inefficient oxygen extraction. Macrocirculatory dysfunction, complicated by inhomogeneous redistribution of regional blood flow and microcirculatory dysfunction, finally leads to tissue hypoxia, which represents the common pathway of organ dysfunction.
The great dilemma involves how to measure nutritive organ perfusion and tissue oxygenation. Global parameters do not reflect specific organ disorders or microcirculatory disturbances. We are barely able to determine perfusion in a few organ-specific vascular beds. These data disregard the inhomogeneous redistribution of blood flow within organs. Therefore, tissue hypoxia may occur even when normal organ blood flow is detected. What does adequacy of tissue oxygenation mean? Ultimately, this is determined at the mitochondrial level, so measurements of tissue bioenergetics would be expected to provide a needed standard. The clinical importance of the microcirculation cannot now be adequately monitored, because of the difficulty of its detection within tissues, but there are promising new technologies under development that might make the assessment of tissue oxygenation feasible in the future.
Several new approaches to the prevention and treatment of septic shock, which are based on recognition of the role of mediator pathways, are currently under investigation; clinical trials using anti-lipopolysaccharide and anti-cytokine strategies, inhibitors of nitric oxide synthase, and nonspecific neutralization of mediators have been performed. Most of these new therapeutic approaches have failed to provide evidence of improved outcomes. Targeting of a single microbial toxin or mediator seems to be insufficient to block the complex inflammatory host response to infection. Furthermore, the timing of therapeutic intervention may be critical, because the relative roles of different mediators vary with time. Whether sophisticated monitoring of the immune status could facilitate the selection of patients who could profit from special immunomodulatory therapy remains to be determined.
Monitoring of Global Hemodynamic and Oxygen-Related Variables
To date, therapeutic strategies for sepsis and SIRS have been directed toward optimization of the variables determining global oxygen delivery (DO2). The pulmonary artery catheter (PAC), which was introduced by Swan et al. (1) in 1970, is still considered to be the clinical standard for the monitoring of macrohemodynamic variables such as cardiac output, pulmonary artery occlusion pressure, mixed venous oxygen saturation, DO2, and oxygen consumption (VO2). This invasive technique has been significantly questioned since the report by Connors et al. (2), who described increased mortality rates, longer intensive care unit stays, and increased costs for critically ill patients monitored with PAC, compared with those without PAC. In the past decade, several attempts have been made to develop noninvasive techniques to estimate cardiac output, some of which have been shown to be reliable and sufficiently precise.
Transthoracic or transesophageal bioimpedance monitoring, CO2-rebreathing methods, rebreathing of soluble gases, and Doppler echocardiography are noninvasive methods for the assessment of cardiac output. Advantages and shortcomings are presented in Table 1. The major advantage of Doppler echocardiography is the possibility of observing myocardial performance and valve function. However, it is still more difficult to obtain reliable cardiac output results using Doppler techniques, compared with invasive techniques. High accuracy and precision have been shown for the soluble gas- and CO2-rebreathing methods. CO2-rebreathing measurements do not require extensive technical equipment, and recent changes in hardware and software have improved the validity of this method (3). The development of a clinically applicable monitor (DAVID; MedServ, Leipzig, Germany) by our group allows automated semiquantitative measurements of pulmonary capillary blood flow (which represents cardiac output minus shunting), as an important variable for guiding hemodynamic and ventilator therapy.
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Transpulmonary techniques for cardiac output measurements assess left-heart cardiac output. Several indicators are used, e.g., indocyanine green, lithium chloride, or sodium chloride. These semi-invasive techniques require a central venous catheter and an arterial dilution-detecting device, most commonly located in one of the femoral arteries. The combination of arterial pulse contour analysis (providing continuous cardiac output measurements) and transpulmonary thermodilution (for frequent calibration) is commercially available (PiCCO; Pulsion Medical Systems, Munich, Germany). High correlation and low bias for transpulmonary thermodilution and pulse contour analysis, compared with right ventricular cardiac output (PAC) measurements, have been reported (4).
Effects of Global Hemodynamic and Oxygen-Related Variables in Sepsis/SIRS
In sepsis and SIRS, several strategies have been attempted in past years to avoid the development of oxygen debt, which is defined as inadequacy of tissue oxygenation (5). These strategies involve the improvement of systemic hemodynamics and oxygen-derived parameters.
When DO2 is progressively reduced by either decreases in cardiac output or decreases in arterial oxygen content, the appearance of lactate may be used to characterize critical DO2, which leads to anaerobic metabolism. Critical DO2 was demonstrated to be related to a decrease in VO2 in numerous experimental studies (6,7). The crucial question of whether we should use "supranormal" DO2 values to optimize our treatment of critically ill patients, as proposed by Shoemaker et al. (8), was investigated in various prospective trials (9,10,11). Targeting therapy to achieve supraphysiologic end points in critically ill patients was found to be associated with decreased mortality rates in some studies (8,12), but others did not confirm those results (10,11,13). In conclusion, the results revealed a particular relationship between the ability to increase DO2 and VO2 and treatment outcomes (14). It was demonstrated that the failure to respond to treatment was an indicator of poor prognosis among patients with septic shock and that survivors exhibited significantly greater percentage increases in cardiac index, DO2, and VO2 in response to dobutamine infusion, whereas VO2 was not increased in nonsurvivors (15). Those studies also confirmed that cardiac reserve was significantly reduced in nonsurvivors, suggesting that survival is associated with the ability to increase myocardial performance sufficiently to sustain a hypermetabolic state.
Lactate Levels in Critically Ill Patients
Blood lactate measurements are considered to be indicators of anaerobic metabolism associated with tissue dysoxia, but the real meaning of lactate levels in patients with sepsis remains incompletely understood (16). Alternative explanations for lactic acidosis in patients with resuscitated sepsis include increased aerobic production, decreased utilization, and pulmonary removal and release (in patients with acute lung injuries). Elevation of serum lactate levels in septic patients results from increased peripheral intraorgan production and reduced hepatic uptake and renal elimination. Abnormal functioning of the liver and kidney in septic patients significantly contributes to the development of lactic acidosis. Consideration of causes unrelated to tissue hypoxia allows more specific and effective treatment of lactic acidosis (Table 2).
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Despite its ambiguous meaning, hyperlactatemia during critical illnesses serves as an indirect metabolic indicator of cellular stress, even if the amount of lactate is not correlated with the total oxygen debt, the magnitude of hypoperfusion, or the severity of shock, as previously suggested (17). Numerous investigators have demonstrated a strong correlation between lactate levels and mortality rates (18,19). Despite the various factors affecting lactate levels, lactate can still be considered one of the best, most widely available indicators for the assessment of global cellular metabolism in critically ill patients. Single elevated serum lactate measurements have only poor sensitivity as prognostic indicators. The use of sequential measurements is advocated, because it is not the peak lactate level that can differentiate survivors from nonsurvivors but the ability to clear circulating lactate in response to therapeutic intervention (18). Because lactate concentrations are only nonspecific indirect indicators of cellular stress, more sensitive and specific means to guide and optimize therapy for critically ill patients are desired.
Gastric Mucosal pH and the Mucosal/Arterial CO2 Gradient as Indicators of Regional Hypoperfusion
An increase in gastrointestinal mucosal Pco2 (Pmco2)
was proposed to be an early marker of inadequate oxygen supply in shock states
and to indicate the risk of gut epithelial dysfunction, which may facilitate
bacterial translocation and promote organ failure. Gutierrez et al.
(20) demonstrated in septic
patients that a short-term infusion of dobutamine (10 µg/kg per min)
increased gastric mucosal pH (pHi), i.e., decreased
Pmco2, whereas VO2 remained unchanged. These results
raise the question of whether gastric pHi or Pmco2 is a
better indicator of hypoperfusion, compared with related increases in
VO2, for guiding goal-directed therapy. Indeed, several studies
have shown that gastrointestinal mucosal/arterial CO2 Gradient
(
Pco2) may be useful for more refined titration of
therapeutic strategies aimed at improving tissue oxygenation. Schlichtig and
Bowles (21) presented
convincing evidence that changes in Pmco2, which mirror changes in
VO2 during progressive flow stagnation, most likely represent
dysoxia. The authors also observed that Pmco2 values markedly
exceeded Pco2 values in portal venous blood when flow was decreased
below the critical DO2 and that only a maximal mucosal/arterial
Pco2 of approximately 25 to 35 mmHg was consistent with
aerobic CO2 metabolism in an animal model. From these data, it was
assumed that, above this value, an additional increase in mucosal/arterial
Pco2 would be consistent with mucosal dysoxia. These results
obtained in animal models were confirmed in human subjects using
microlight-guided reflectance spectrophotometry for direct assessment of
microvascular hemoglobin oxygen saturation; the findings indicated the
occurrence of abnormal microcirculatory oxygenation in the gastrointestinal
tract, despite more than normal systemic oxygen-derived parameters during
septic shock (22). According
to recent studies, the mucosal/arterial Pco2 should be
maintained below 25 mmHg to avoid severe gastrointestinal hypoperfusion and
associated dysoxia. The routine use of treatment directed by pHi
remains questionable because, in a prospective, randomized, controlled
clinical study (23), no
significant improvement in intensive care unit mortality rates could be
observed after resuscitation of critically ill patients on the basis of
gastric tonometric results.
Novel Technologies for the Monitoring of Tissue Oxygenation and Bioenergetics
The acceptance of any new technology depends on the medical need for that technology, its reliability and accuracy, and its potential to improve outcomes and cost/benefit ratios. Because it is extraordinarily difficult and expensive to demonstrate improvements in outcomes for critically ill patients in a randomized manner, the suggested advantages of new technologies often remain hypothetical.
Direct Measurement of Tissue Po2
Direct measurement of tissue Po2 during sepsis, in both
experimental and clinical settings, has been performed primarily with the use
of polarographic oxygen electrodes
(24,25).
These have included needle and catheter electrodes for insertion into tissues
and arrays of oxygen electrodes for placement on organ surfaces. The main
limitation of oxygen electrodes is their extremely limited area of
measurement, with penetration depths of approximately 15 µm. They measure
the average Po2 of tissue cells, capillaries, and larger blood
vessels in the vicinity of the electrode and may therefore not detect the
presence of hidden hypoxic areas. Because oxygenation is highly heterogeneous
at this level, Po2 measurements must be obtained at multiple sites,
using an array of electrodes placed on the organ surface or stepwise insertion
of a needle electrode into the tissue. The shortcomings of the method and the
difficulties in performance do not yet allow the routine clinical use of this
technique.
Optical Spectroscopy for Measurement of Microcirculatory
Oxygenation
Optical spectroscopic methods (absorption, fluorescence, and
phosphorescence spectroscopy) are used to examine the chemical characteristics
of substances by measuring the alterations of light in various parts of the
spectrum. They can be used for the assessment of tissue and cellular
oxygenation, in terms of the oxygen saturation of hemoglobin in the
microcirculatory blood, the cellular mitochondrial energy state, and the
oxygen pressure in the plasma, using oxygen-dependent optical properties of
tissue, blood, or extrinsic diagnostic dyes
(26). Measurements of
intermediates in the mitochondrial respiratory chain, e.g., the
fluorescence intensity of endogenous mitochondrial NADH measured in
situ, can thus be used as direct measures of tissue bioenergetics. These
techniques have the advantage of being noninvasive and can indicate the
heterogeneity of oxygenation. A limitation is the inability to make
quantitative measurements.
Orthogonal Polarization Spectral Imaging
Orthogonal polarization spectral (OPS) imaging
(27) is a novel method that
can be used to make quantitative measurements of diameter, flow velocity, and
functional capillary density in a wide variety of tissues
(28). With this technique,
high-quality, transillumination-like images can be produced from thick solid
tissues without the use of fluorescence dyes. The OPS optical system has been
incorporated into a small, easy-to-use probe that must simply be placed on the
tissue to be imaged. This device (CYTOSCAN; Cytometrics Inc., Philadelphia,
PA) is much more portable and easy to use than conventional intravital
microscopes. Clinical applications are possible in easily accessible sites
such as the mouth. The OPS system can be used to produce excellent images of
the sublingual microcirculation, with the probe placed under the tongue like a
thermometer. The changes in microvascular perfusion during hemorrhagic shock
that occur in internal organs such as the intestine and liver can also be
demonstrated in the sublingual vascular bed
(29). Therefore, OPS imaging
could be used to monitor perfusion changes in internal organs in a noninvasive
manner, which could have important diagnostic implications. Because
quantitative measurements of tissue perfusion are possible, the technology
could be used to monitor the progression and development of diseases that
affect the micro-circulation, as well as to directly monitor the success or
failure of treatments.
Online Monitoring of Gas Exchange to Monitor Lung Function
To date, there is no method available to replace arterial blood gas sampling. Despite significant advances in pulse oximetry and capnography, both techniques provide only limited information. Pulse oximetry requires the presence of a pulsed blood flow and does not detect impaired tissue oxygenation attributable to a leftward shift of the oxygen-hemoglobin dissociation curve. Breathing and circulation are ensured if the characteristic fluctuations in end-tidal carbon dioxide tension are present. However, the end-tidal Pco2 may not accurately reflect the arterial Pco2 in patients with acute lung diseases (e.g., increased alveolar dead space) or patients in hemodynamically unstable condition. The need for continuous intravascular arterial blood gas monitoring for these patients is obvious. In recent years, tremendous progress has been made in the miniaturization of fiberoptic blood gas and pH sensors, which is a required criterion for intravascular sensors. Absorbance sensors and fluorescence sensors (optodes) are the two existing types of optical sensors. Simplistically, these sensors operate via illumination of a sample chamber containing a dye located on a fiberoptic probe (30). Compared with conventional electrodes, optodes are impervious to electrical interference, exhibit no drift, and do not consume the analyte (because the reactions are reversible). Disadvantages are the marginal signal/noise ratio, the instability of chemical dyes, and the requirement for sophisticated optic and electronic equipment. The reliability and accuracy, particularly of Po2, remain to be improved. Reliability is decreased because of probe failures, pressure damping, wall effects, and reduced flow at the measurement site (usually the radial artery). Clinical evaluation of 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 (31,32,33). Extravascular, on-demand, optode-based systems circumvent all intravascular patient-probe interface problems and function well, but none are currently available.
Monitoring of Renal Function
Sepsis and particularly septic shock are important risk factors for the development of acute renal failure (ARF). Recent clinical trials with patients with sepsis demonstrated an incidence of ARF at the time of study entry that varied between 9 and 40%, depending on the case mixture, the severity of illness, and the definitions used to characterize ARF (34). ARF in sepsis is generally part of multiple organ dysfunction syndrome, which may complicate sepsis, indicating that similar mechanisms are operative in inducing dysfunctions of various organ systems. Both systemic and local renal mediators and mechanisms are involved in the pathogenesis of septic ARF. Renal hypoperfusion, ultimately resulting in renal ischemic injury, is considered to be a major factor in the pathogenesis of ARF. However, in experimental models of sepsis and in septic patients, renal blood flow (RBF) varies widely (35). In general, RBF is difficult to predict from systemic hemodynamic variables, in part because of BP-maintaining compensatory mechanisms (e.g., sympathetic activity and the renin-angiotensin-aldosterone system) in sepsis. Furthermore, redistribution of blood flow within the kidney itself, favoring the juxtaglomerular and medullary areas at the expense of outer cortical flow, may occur even if global RBF is relatively normal. Experimental animal studies and in vitro studies have shown that endotoxin decreases the glomerular plasma flow and GFR in superficial nephrons, with an increase in total renal arteriolar resistance and a decrease in filtration fraction (34,36). As a result of the markedly reduced GFR, effective tubular sodium reabsorption (the main energy-consuming process in the kidney) is decreased, indicating a relative VO2 excess. Therefore, determination of fractional sodium excretion may be a clinical tool for the detection of inadequate renal perfusion before the manifestation of organ failure in terms of anuria, hyperkalemia, acidemia, and azotemia. Imaging techniques used for ARF, such as grayscale ultrasonography; duplex ultrasonography, and magnetic resonance imaging, do not provide specific information regarding acute prerenal failure in sepsis/SIRS (37). Diuresis and creatinine clearance currently represent the clinically most important variables for global renal function monitoring.
In summary, the sepsis-induced systemic activation of various mediator systems and compensatory mechanisms affects systemic and renal perfusion. Both vasoconstrictive and vasodilating mediators are generated within the kidney, and their balance dictates renal hemodynamics, often resulting in renal hypoperfusion, which is considered to be a major factor in the development of renal injury and failure. In addition, toxic products resulting from neutrophil-endothelium interactions, endothelial damage, reperfusion injury, and microvascular thrombosis in the kidney contribute to renal dysfunction during severe sepsis.
Conclusion
Sepsis and SIRS induce severe disruption of the microcirculation, and resultant tissue hypoxia is considered a key factor in the development of organ dysfunction and multiple organ failure. Conventionally measured global variables such as lactate levels and macrohemodynamic parameters measured using a PAC do not adequately reflect microcirculatory disturbances. To evaluate the severity of microcirculatory distress and the effectiveness of resuscitation strategies, new clinical technologies aimed at the microcirculation must be developed. It is anticipated that novel techniques such as optical spectroscopy and the use of intelligent biosensors will play a major role in the development of new monitoring systems. In general, the monitoring of organ dysfunction is currently characterized by a trend from invasive to noninvasive "safe" techniques, which provide bedside or even online monitoring, allowing more precise and earlier detection of organ dysfunction. Techniques for the assessment of regional perfusion and microcirculatory bioenergetic parameters, to direct therapeutic procedures, are expected to refine and optimize the clinical treatment of critically ill patients in the future.
References
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