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• W1966356742 abstract "Despite recent controversies regarding its safety and efficacy, pulmonary artery catheterization (PAC) remains a widely used tool for the management of patients with cardiovascular instability. In addition to providing measurements of cardiac output (CO), several other potentially useful pieces of data can be obtained, including estimates of preload, afterload, and oxygen utilization. However, many practitioners feel that CO is the most useful parameter obtained with PAC.The desire to measure CO without the risks of PAC has driven the search for other, less invasive measurement methods, such as esophageal Doppler measurements, lithium dilution, and carbon dioxide-based techniques. Esophageal Doppler monitoring involves inserting a flexible probe, similar to an esophageal stethoscope, into the midthoracic esophagus. A pulse-wave Doppler transducer in the probe tip calculates blood flow velocity from the Doppler frequency shift of RBCs in the descending aorta. By entering the age, gender, height, and weight of the patient, the aortic diameter can be estimated. From this and the blood flow velocity, aortic blood flow is calculated, representing approximately 70% of the total CO. Estimates of preload and afterload can be derived from the shape of the velocity waveforms. Modifications of this technique allow for the actual measurement of aortic diameter using M-mode ultrasound, eliminating the error associated with nomogram-based estimates. The resulting values for aortic blood flow correlate well with those of thermodilution CO,1Cariou A Monchi M Joly LM et al.Noninvasive cardiac output monitoring by aortic blood flow determination: evaluation of the Sometec Dynemo-3000 system.Crit Care Med. 1998; 26: 2066-2072Crossref PubMed Scopus (93) Google Scholar2Boulnois JLG Pechoux T Non-invasive cardiac output monitoring by aortic blood flow measurement with the Dynemo 3000.J Clin Monit Comput. 2000; 16: 127-140Crossref PubMed Scopus (48) Google Scholar but the limits of agreement between the two methods are fairly wide.2Boulnois JLG Pechoux T Non-invasive cardiac output monitoring by aortic blood flow measurement with the Dynemo 3000.J Clin Monit Comput. 2000; 16: 127-140Crossref PubMed Scopus (48) Google ScholarLithium dilution CO, a relatively new technique, is less invasive than PAC but requires central venous and intra-arterial catheters. This method involves the injection of a small dose of the indicator lithium chloride through a central venous catheter. The arterial plasma concentration curve then is measured by a specialized sensor connected to the arterial line, and the CO is calculated. Comparing lithium dilution and thermodilution with electromagnetic flowmetry as the “gold standard,” lithium dilution showed higher correlation with electromagnetic flowmetry as well as better limits of agreement when compared with thermodilution.3Kurita T Morita K Kato S et al.Comparison of the accuracy of the lithium dilution technique with the thermodilution technique for measurement of cardiac output.Br J Anaesth. 1997; 79: 770-775Crossref PubMed Scopus (105) Google Scholar Although the accumulation of lithium with repeated dosing is a potential concern, a once-daily lithium dilution may be used with pulse contour analysis to allow the continuous beat-to-beat analysis of CO, stroke volume, and systemic vascular resistance.CO2-based techniques provide a noninvasive measure of CO in patients receiving mechanical ventilation. This method, which is based on the Fick principle, involves transient partial rebreathing of CO2 and the measurement of changes in CO2 elimination and end-tidal CO2 (a measure of arterial CO2). Based on these values, the CO component participating in gas exchange is calculated. Total CO then is calculated by estimating the shunt fraction (based on pulse oximetry and inspired oxygen concentration) and by adding this value to the initial value obtained. The CO2 technique has been shown to be quite accurate when compared to thermodilution CO.4Guzzi L Jaffe MB Orr JA Clinical evaluation of a new noninvasive method of cardiac output measurement: preliminary results in CABG patients [abstract].Anesthesiology. 1998; 89: A543Crossref PubMed Google Scholar Like other noninvasive techniques, the CO2 Fick method does not provide for the measurement of preload indexes.In this issue of CHEST (see page 990), Dhingra and colleagues compare CO obtained using oxygen consumption ( V˙o2), which is called the oxygen Fick method, with the method of thermodilution. By measuring V˙o2 through indirect calorimetry and dividing this value by the arteriovenous oxygen content difference (obtained by the analysis of arterial and mixed venous samples), the CO is derived. The group found that the accuracy of the oxygen Fick method was fair only when using thermodilution as the standard, limiting the usefulness of the method. Their approach also is limited by the need to measure mixed venous oxygen saturation. As opposed to CO2 Fick methods, using easily measured expired CO2 values, the oxygen Fick method requires the sampling of mixed venous blood, necessitating the insertion of a PAC. This defeats the major purpose of most alternative methods of measuring CO, which is to use a less invasive method than the pulmonary artery catheter. However, the authors are to be applauded both for the study and for their statistical analysis of the technique. Instead of using a correlation coefficient to show the agreement between the two methods, the authors measured the bias and precision of the Fick method compared to thermodilution. This approach gives a much more discriminating evaluation of the new method, as two methods can have a high correlation coefficient but can have limited agreement between sets of measurements.5Bland JM Altman DG Statistical methods for assessing agreement between two methods of clinical measurement.Lancet. 1986; 1: 307-310Abstract PubMed Scopus (38880) Google ScholarHowever, several other factors may have explained their findings. The improved agreement between the oxygen Fick method and the thermodilution method in patients with lower CO (ie, < 50% of the patients studied in this series) is not surprising. Patients with higher CO or severe liver dysfunction often present with an altered oxygen extraction ratio (O2ER) from a lack of O2 utilization or severe systemic/pulmonary shunts, narrowing the arterial-mixed venous oxygen content difference. In this situation, any errors in the calculation of the concentration and arterial O2 content (CaO2) or the concentration and mixed venous O2 content (CvO2) will result in a larger error in CO that is calculated with the oxygen Fick equation, when compared with thermodilution, than in patients with a low CO state. Furthermore, previous studies6Walsh TS Hopton P Lee A A comparison between the Fick method and indirect calorimetry for determining oxygen consumption in patients with fulminant hepatic failure.Crit Care Med. 1998; 26: 1200-1207Crossref PubMed Scopus (34) Google Scholar confirm the limitations of the V˙o2 Fick method compared to V˙o2 calorimetry, with an estimated error of up to 31%.In the “Materials and Methods” section of the article by Dhingra et al, withdrawal of care was performed first with the removal of pressors. It is not clear whether this process was gradual or abrupt. A thermogenic effect of catecholamine has been described in animals7Boorstein SM Hirschl RB Riley MK et al.The effect of norepinephrine infusion on oxygen delivery and consumption in the canine model.J Surg Res. 1994; 56: 251-255Abstract Full Text PDF PubMed Scopus (5) Google Scholar as well as in human volunteers.8Sjostrom L Schutz Y Gudinchet F et al.Epinephrine sensitivity with respect to metabolic rate and other variables in women.Am J Physiol. 1983; 245: E431-E442PubMed Google Scholar The importance of the effect of withdrawing treatment with vasopressors and inotropes on metabolic rate could be particularly important in critically ill patients, in whom a complete exhaustion of endogenous catecholamines is likely to occur.Finally, it is difficult to estimate the degree of error that results from lung metabolic activity in the group of patients with sepsis and multisystem organ failure because the intensity of lung inflammation does not correlate with lung V˙o2.9Jolliet P Thorens JB Nicod L et al.Relationship between pulmonary oxygen consumption, lung inflammation, and calculated venous admixture in patients with acute lung injury.Intensive Care Med. 1996; 22: 277-285Crossref PubMed Scopus (27) Google Scholar10deBoisblanc BP McClarity E Lord K Oxygen consumption in the intensive care unit: indirect calorimetry is the way to go, but where?.Crit Care Med. 1998; 26: 1153-1154Crossref PubMed Scopus (13) Google ScholarToday, therefore, CO calculation by thermodilution catheter remains the clinical “gold standard.” An additional advantage of PAC over other methods of measuring CO is the ability to assess pulmonary pressures and preload. As is known, the pulmonary capillary wedge pressure is not a measure of preload (ie, left ventricular end-diastolic volume) but, instead, is a pressure measurement. The relationship between the pressure and volume is defined by compliance and will vary from patient to patient. Indeed, in the critically ill patient, pulmonary capillary wedge pressure correlates poorly with CO. This raises obvious questions about, for example, our consensus definition of ARDS, with which we cannot deal here.11Bernard GR Artigas A Brigham KL et al.The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.Am J Respir Crit Care Med. 1994; 149: 818-824Crossref PubMed Scopus (5254) Google Scholar Newer catheters that allow the calculation of right ventricular end-diastolic volume demonstrate a better correlation between preload (ie, right ventricular end-diastolic volume) and CO, and, more importantly, between preload and preload-recruitable stroke work.12Calvin L Driedger AA Sibbald WJ Does the pulmonary capillary wedge pressure predict left ventricular preload in critically ill patients?.Crit Care Med. 1981; 9: 437-443Crossref PubMed Scopus (156) Google Scholar13Diebel LN Wilson RF Tagett MG et al.End-diastolic volume: a better indicator of preload in the critically ill.Arch Surg. 1992; 127: 817-821Crossref PubMed Scopus (161) Google ScholarInstead of asking which monitor is best for measuring CO, we might query why, in any event, CO is important to measure. CO is used in critical care medicine to calculate the amount of oxygen delivered to the tissues per minute, using the following formula: DO2=CO×O2content (CaO2)where CaO2 = hemoglobin (g/L) × 1.39 × Sao2 + (0.003 × Pao2) [where Sao2 is arterial oxygen saturation]. V˙o2 represents a global measurement of tissue aerobic generation of adenosine triphosphate and can be measured by indirect calorimetry or calculated using the following formula: V˙O2=CO×(Hgb×1.39×[Sao2-Sv¯o2])where Hgb is hemoglobin and S v¯o2 is mixed venous saturation.In a normal situation, the ratio between V˙o2 and DO2, the O2ER ([ V˙o2 ÷ DO2] × 100), is between 25% and 30%. Thus, the progressive reduction of DO2 and changes in O2ER can be measured in the ICU and can be secondary to ischemic hypoxia (ie, decreased CO), hypoxic hypoxia (ie, decreased Pao2), anemic hypoxia (ie, decreased hemoglobin), or distributive hypoxia (ie, increased O2ER) with decreased oxygen utilization, a condition that is commonly called dysoxia. In an anesthetized healthy animal, the reduction of DO2 from a baseline of 25 mL/kg/min to approximately 10 mL/kg/min increases the O2ER by approximately 100%, to 50 to 60%. Below this level of DO2, O2ER cannot increase further, and V˙o2 decreases. This level of oxygen delivery is called DO2critical and generally correlates well with the anaerobic metabolism and systemic lactic acidosis.14Cain SM Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia.J Appl Physiol. 1977; 42: 228-234Crossref PubMed Scopus (356) Google Scholar However, when dysoxia, or the primary alteration of O2ER, is present, the level of DO2 critical cannot be identified easily. The measurement of DO2 presents several other limitations. While DO2 defines the bulk movement of oxygen to the tissues in general, in many critically ill patients, cellular oxygen delivery is affected by complex interactions of neurohumoral, anatomic, and pharmacologic factors, and typically is subjected to maldistribution among different organ districts.15Leach RM Treacher DF Oxygen transport 2: tissue hypoxia.BMJ. 1998; 317: 1370-1373Crossref PubMed Scopus (109) Google ScholarData obtained from critically ill patients16Ronco JJ Fenwick JC Tweeddale MG et al.Identification of the critical oxygen delivery for anaerobic metabolism in critically ill septic and nonseptic humans.JAMA. 1993; 270: 1724-1730Crossref PubMed Scopus (282) Google Scholar17Van Woerkens EC Trouwborst A van Lanschot JJ Profound hemodilution: what is the critical level of hemodilution at which oxygen delivery-dependent oxygen consumption starts in an anesthetized human?.Anesth Analg. 1992; 75: 818-821Crossref PubMed Google Scholar during the discontinuation of life support, and from Jehovah's Witnesses, show the DO2 critical level to be approximately half (ie, 2 to 3 mL/kg/min) that of healthy animals (4 to 5 mL/kg/min). However, these data differ remarkably from previous studies of healthy anesthetized and critically ill patients in which data were obtained from multiple patients that identified DO2 critical as being between 8 and 21 mL/kg/min.18Shibutani K Komatsu T Kubal K et al.Critical level of oxygen delivery in anesthetized man.Crit Care Med. 1983; 11: 640-643Crossref PubMed Scopus (272) Google Scholar19Mohsenifar Z Goldbach P Tashkin DP et al.Relationship between O2delivery and O2consumption in the adult respiratory distress syndrome.Chest. 1983; 84: 267-271Crossref PubMed Scopus (144) Google ScholarIt is, therefore, no surprise that data comparing the “coupling” of DO2 with V˙o2 below DO2 critical in both animal and human studies are discordant, especially when DO2 and V˙o2 are measured by independent methods (ie, thermodilution and indirect calorimetry).20Nelson DP Beyer C Samsel RW et al.Pathological supply dependence of O2uptake during bacteremia in dogs.J Appl Physiol. 1987; 63: 1487-1492PubMed Google Scholar21Phang PT Cunningham KF Ronco JJ et al.Mathematical coupling explains dependence of oxygen consumption on oxygen delivery and uptake in septic shock.Crit Care Med. 1995; 23: 1962-1970Crossref Scopus (72) Google Scholar This controversial issue remains unclear due to the lack of controlled experiments in humans and the difficulty in obtaining multiple data points over a wide range of DO2 values while maintaining a constant oxygen demand. Dhingra and colleagues obtained patient data during the withdrawal of care. Although the authors satisfied the requirements of obtaining multiple data points on both the oxygen delivery and oxygen dependence curves, their patients may not represent the pathophysiology of a hyperdynamic critically ill patient, in whom DO2 critical seems to be set at a point higher than that in healthy patients.22Friedman G De Backer D Shahla M et al.Oxygen supply dependency can characterize septic shock.Intensive Care Med. 1998; 24: 118-123Crossref PubMed Scopus (75) Google Scholar Finally, despite the widespread use of invasive monitoring in the ICU, which allows the easy measurement of DO2, V˙o2, and O2ER in critically ill patients, none of these parameters have been reliable in predicting outcome.23Bakker J Coffernils M Leon M et al.Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock.Chest. 1991; 99: 956-962Abstract Full Text Full Text PDF PubMed Google ScholarAre there any alternatives to the hemodynamic and oximetric measurement in critically ill patients? Conventional clinical parameters of resuscitation (eg, BP, heart rate, and urine output) seem to be generally unreliable.24Kowalenko T Stern S Dronen S et al.Improved outcome with hypotensive resuscitation of uncontrolled hemorrhagic shock in a swine model.J Trauma. 1992; 33: 349-353Crossref PubMed Scopus (269) Google Scholar25Nelimarkka O Halkola L Niinikoski J Effect of graded hemorrhage on renal cortical perfusion in dogs.Am J Surg. 1981; 141: 235-239Abstract Full Text PDF PubMed Scopus (10) Google Scholar Nonconventional blood markers have been extensively studied as resuscitation end points in critically ill patients. Lactic acid level correlates well with insufficient oxygen delivery beyond DO2 critical in animal models of hemorrhagic shock. Remarkably, 48-h lactate level trends have been considered to be superior to measurements of oxygen delivery and V˙o2 in determining outcome in patients with septic shock.26Bakker J Coffernils M Leon M et al.Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock.Chest. 1991; 99: 956-962Abstract Full Text Full Text PDF PubMed Scopus (421) Google ScholarA base deficit > −4 is correlated with the onset of multiorgan system failure and mortality in several models of trauma.27Rutherford EJ Morris Jr, JA Reed GW et al.Base deficit stratifies mortality and determines therapy.J Trauma. 1992; 33: 417-423Crossref PubMed Scopus (339) Google Scholar Venoarterial CO2 gap has also been correlated with poor outcome in patients after they experience cardiac arrest28Weil MH Rackow EC Trevino R et al.Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation.N Engl J Med. 1986; 315: 153-156Crossref PubMed Scopus (434) Google Scholar and in those being resuscitatated from hemorrhagic shock.29Ducey JP Lamiell JM Gueller GE Arterial-venous carbon dioxide tension difference during severe hemorrhage and resuscitation.Crit Care Med. 1992; 20: 518-522Crossref PubMed Scopus (33) Google Scholar The production of CO2 by the gut (intramural pH [pHi]) recently has been proposed as an early marker of regional dysoxia. The distribution of flow away from the gut when oxygen delivery is insufficient represents a compensatory mechanism to maintain oxygen delivery to more essential organs. Therefore, dysoxia of the gastric mucosa can represent an earlier estimate of global tissue dysoxia. A pHi of < 7.32 has been associated with a statistical increase in mortality in a heterogeneous group of critically ill patients30Gys T Hubens A Neels H et al.Prognostic value of gastric intramural pH in surgical intensive care patients.Crit Care Med. 1988; 16: 1222-1224Crossref PubMed Scopus (150) Google Scholar31Mythen MG Webb AR Intra-operative gut mucosal hypoperfusion is associated with increased post-operative complications and cost.Intensive Care Med. 1994; 20: 99-104Crossref PubMed Scopus (308) Google Scholar and trauma patients. Furthermore, a pHi of < 7.35 has been a better predictor of sepsis and mortality than DO2 and V˙o2.32Doglio GR Pusajo JF Egurrola MA et al.Gastric mucosal pH as a prognostic index of mortality in critically ill patients.Crit Care Med. 1991; 19: 1037-1040Crossref PubMed Scopus (387) Google ScholarMore recently, a noninvasive, sublingual electrode that is capable of measuring mucosal CO2 has been studied33Marik PE Sublingual capnography: a clinical validation study.Chest. 2001; 120: 923-927Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar as an index of proper resuscitation and correlated to gastric tonometry. A sublingual CO2 of 70 mm Hg has been noted as a critical value that is significant for survival (sensitivity, 0.73; specificity, 1.0) in a subset of critically ill emergency department patients.34Weil MH Nakagawa Y Tang W et al.Sublingual capnometry: a new noninvasive measurement for diagnosis and quantification of severity of circulatory shock.Crit Care Med. 1999; 27: 1225-1229Crossref PubMed Scopus (174) Google Scholar While all these methods aim to indirectly evaluate critical end points of resuscitation, a direct measurement of oxygen transport at the “ultimate frontier” level (ie, mitochondrial oxidative phosphorylation) is now available. Near-infrared light spectroscopy is the only technology allowing the continuous monitoring of cytochrome a,a3 redux status, a reliable index of cell hypoxia. Unfortunately, at the time of this writing its use is only experimental and its cost is prohibitive.While the utility of invasive cardiac monitoring to improve outcome in critically ill patients is still subject to verification, we note that there are at least two studies35Rivers E Nguyen B Havstad S et al.Early goal-directed therapy in the treatment of severe sepsis and septic shock.N Engl J Med. 2001; 345: 1368-1377Crossref PubMed Scopus (7748) Google Scholar36Yu M Burchell S Hasaniya NW et al.Relationship of mortality to increasing oxygen delivery in patients > 50 years of age: a prospective, randomized trial.Crit Care Med. 1998; 26: 1011-1019Crossref PubMed Scopus (86) Google Scholar that appear to confirm this proposition. Furthermore, we emphatically question whether derivative studies37Connors AF Speroff T Dawson NV et al.The effectiveness of right heart catheterization in the initial care of critically ill patients.JAMA. 1996; 276: 889-897Crossref PubMed Google Scholar or suprapharmacologic studies38Hayes MA Timmins AC Yau E et al.Elevation of systemic oxygen delivery in the treatment of critically ill patients.N Engl J Med. 1994; 330: 1717-1722Crossref PubMed Scopus (1228) Google Scholar have added anything to that understanding. While we applaud the attempt of Dhinga and colleagues to deal with this question in a forthright and innovative manner, the increased potential for inaccuracies in patients with high or very low CO makes the calculation of CO by the Fick method in critically ill patients impractical and of questionable use. Finally, the utility of the data extrapolated from terminally ill patients just before death should be carefully considered before applying any conclusions to critically ill patients. Despite recent controversies regarding its safety and efficacy, pulmonary artery catheterization (PAC) remains a widely used tool for the management of patients with cardiovascular instability. In addition to providing measurements of cardiac output (CO), several other potentially useful pieces of data can be obtained, including estimates of preload, afterload, and oxygen utilization. However, many practitioners feel that CO is the most useful parameter obtained with PAC. The desire to measure CO without the risks of PAC has driven the search for other, less invasive measurement methods, such as esophageal Doppler measurements, lithium dilution, and carbon dioxide-based techniques. Esophageal Doppler monitoring involves inserting a flexible probe, similar to an esophageal stethoscope, into the midthoracic esophagus. A pulse-wave Doppler transducer in the probe tip calculates blood flow velocity from the Doppler frequency shift of RBCs in the descending aorta. By entering the age, gender, height, and weight of the patient, the aortic diameter can be estimated. From this and the blood flow velocity, aortic blood flow is calculated, representing approximately 70% of the total CO. Estimates of preload and afterload can be derived from the shape of the velocity waveforms. Modifications of this technique allow for the actual measurement of aortic diameter using M-mode ultrasound, eliminating the error associated with nomogram-based estimates. The resulting values for aortic blood flow correlate well with those of thermodilution CO,1Cariou A Monchi M Joly LM et al.Noninvasive cardiac output monitoring by aortic blood flow determination: evaluation of the Sometec Dynemo-3000 system.Crit Care Med. 1998; 26: 2066-2072Crossref PubMed Scopus (93) Google Scholar2Boulnois JLG Pechoux T Non-invasive cardiac output monitoring by aortic blood flow measurement with the Dynemo 3000.J Clin Monit Comput. 2000; 16: 127-140Crossref PubMed Scopus (48) Google Scholar but the limits of agreement between the two methods are fairly wide.2Boulnois JLG Pechoux T Non-invasive cardiac output monitoring by aortic blood flow measurement with the Dynemo 3000.J Clin Monit Comput. 2000; 16: 127-140Crossref PubMed Scopus (48) Google Scholar Lithium dilution CO, a relatively new technique, is less invasive than PAC but requires central venous and intra-arterial catheters. This method involves the injection of a small dose of the indicator lithium chloride through a central venous catheter. The arterial plasma concentration curve then is measured by a specialized sensor connected to the arterial line, and the CO is calculated. Comparing lithium dilution and thermodilution with electromagnetic flowmetry as the “gold standard,” lithium dilution showed higher correlation with electromagnetic flowmetry as well as better limits of agreement when compared with thermodilution.3Kurita T Morita K Kato S et al.Comparison of the accuracy of the lithium dilution technique with the thermodilution technique for measurement of cardiac output.Br J Anaesth. 1997; 79: 770-775Crossref PubMed Scopus (105) Google Scholar Although the accumulation of lithium with repeated dosing is a potential concern, a once-daily lithium dilution may be used with pulse contour analysis to allow the continuous beat-to-beat analysis of CO, stroke volume, and systemic vascular resistance. CO2-based techniques provide a noninvasive measure of CO in patients receiving mechanical ventilation. This method, which is based on the Fick principle, involves transient partial rebreathing of CO2 and the measurement of changes in CO2 elimination and end-tidal CO2 (a measure of arterial CO2). Based on these values, the CO component participating in gas exchange is calculated. Total CO then is calculated by estimating the shunt fraction (based on pulse oximetry and inspired oxygen concentration) and by adding this value to the initial value obtained. The CO2 technique has been shown to be quite accurate when compared to thermodilution CO.4Guzzi L Jaffe MB Orr JA Clinical evaluation of a new noninvasive method of cardiac output measurement: preliminary results in CABG patients [abstract].Anesthesiology. 1998; 89: A543Crossref PubMed Google Scholar Like other noninvasive techniques, the CO2 Fick method does not provide for the measurement of preload indexes. In this issue of CHEST (see page 990), Dhingra and colleagues compare CO obtained using oxygen consumption ( V˙o2), which is called the oxygen Fick method, with the method of thermodilution. By measuring V˙o2 through indirect calorimetry and dividing this value by the arteriovenous oxygen content difference (obtained by the analysis of arterial and mixed venous samples), the CO is derived. The group found that the accuracy of the oxygen Fick method was fair only when using thermodilution as the standard, limiting the usefulness of the method. Their approach also is limited by the need to measure mixed venous oxygen saturation. As opposed to CO2 Fick methods, using easily measured expired CO2 values, the oxygen Fick method requires the sampling of mixed venous blood, necessitating the insertion of a PAC. This defeats the major purpose of most alternative methods of measuring CO, which is to use a less invasive method than the pulmonary artery catheter. However, the authors are to be applauded both for the study and for their statistical analysis of the technique. Instead of using a correlation coefficient to show the agreement between the two methods, the authors measured the bias and precision of the Fick method compared to thermodilution. This approach gives a much more discriminating evaluation of the new method, as two methods can have a high correlation coefficient but can have limited agreement between sets of measurements.5Bland JM Altman DG Statistical methods for assessing agreement between two methods of clinical measurement.Lancet. 1986; 1: 307-310Abstract PubMed Scopus (38880) Google Scholar However, several other factors may have explained their findings. The improved agreement between the oxygen Fick method and the thermodilution method in patients with lower CO (ie, < 50% of the patients studied in this series) is not surprising. Patients with higher CO or severe liver dysfunction often present with an altered oxygen extraction ratio (O2ER) from a lack of O2 utilization or severe systemic/pulmonary shunts, narrowing the arterial-mixed venous oxygen content difference. In this situation, any errors in the calculation of the concentration and arterial O2 content (CaO2) or the concentration and mixed venous O2 content (CvO2) will result in a larger error in CO that is calculated with the oxygen Fick equation, when compared with thermodilution, than in patients with a low CO state. Furthermore, previous studies6Walsh TS Hopton P Lee A A comparison between the Fick method and indirect calorimetry for determining oxygen consumption in patients with fulminant hepatic failure.Crit Care Med. 1998; 26: 1200-1207Crossref PubMed Scopus (34) Google Scholar confirm the limitations of the V˙o2 Fick method compared to V˙o2 calorimetry, with an estimated error of up to 31%. In the “Materials and Methods” section of the article by Dhingra et al, withdrawal of care was performed first with the removal of pressors. It is not clear whether this process was gradual or abrupt. A thermogenic effect of catecholamine has been described in animals7Boorstein SM Hirschl RB Riley MK et al.The effect of norepinephrine infusion on oxygen delivery and consumption in the canine model.J Surg Res. 1994; 56: 251-255Abstract Full Text PDF PubMed Scopus (5) Google Scholar as well as in human volunteers.8Sjostrom L Schutz Y Gudinchet F et al.Epinephrine sensitivity with respect to metabolic rate and other variables in women.Am J Physiol. 1983; 245: E431-E442PubMed Google Scholar The importance of the effect of withdrawing treatment with vasopressors and inotropes on metabolic rate could be particularly important in critically ill patients, in whom a complete exhaustion of endogenous catecholamines is likely to occur. Finally, it is difficult to estimate the degree of error that results from lung metabolic activity in the group of patients with sepsis and multisystem organ failure because the intensity of lung inflammation does not correlate with lung V˙o2.9Jolliet P Thorens JB Nicod L et al.Relationship between pulmonary oxygen consumption, lung inflammation, and calculated venous admixture in patients with acute lung injury.Intensive Care Med. 1996; 22: 277-285Crossref PubMed Scopus (27) Google Scholar10deBoisblanc BP McClarity E Lord K Oxygen consumption in the intensive care unit: indirect calorimetry is the way to go, but where?.Crit Care Med. 1998; 26: 1153-1154Crossref PubMed Scopus (13) Google Scholar Today, therefore, CO calculation by thermodilution catheter remains the clinical “gold standard.” An additional advantage of PAC over other methods of measuring CO is the ability to assess pulmonary pressures and preload. As is known, the pulmonary capillary wedge pressure is not a measure of preload (ie, left ventricular end-diastolic volume) but, instead, is a pressure measurement. The relationship between the pressure and volume is defined by compliance and will vary from patient to patient. Indeed, in the critically ill patient, pulmonary capillary wedge pressure correlates poorly with CO. This raises obvious questions about, for example, our consensus definition of ARDS, with which we cannot deal here.11Bernard GR Artigas A Brigham KL et al.The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.Am J Respir Crit Care Med. 1994; 149: 818-824Crossref PubMed Scopus (5254) Google Scholar Newer catheters that allow the calculation of right ventricular end-diastolic volume demonstrate a better correlation between preload (ie, right ventricular end-diastolic volume) and CO, and, more importantly, between preload and preload-recruitable stroke work.12Calvin L Driedger AA Sibbald WJ Does the pulmonary capillary wedge pressure predict left ventricular preload in critically ill patients?.Crit Care Med. 1981; 9: 437-443Crossref PubMed Scopus (156) Google Scholar13Diebel LN Wilson RF Tagett MG et al.End-diastolic volume: a better indicator of preload in the critically ill.Arch Surg. 1992; 127: 817-821Crossref PubMed Scopus (161) Google Scholar Instead of asking which monitor is best for measuring CO, we might query why, in any event, CO is important to measure. CO is used in critical care medicine to calculate the amount of oxygen delivered to the tissues per minute, using the following formula: DO2=CO×O2content (CaO2)where CaO2 = hemoglobin (g/L) × 1.39 × Sao2 + (0.003 × Pao2) [where Sao2 is arterial oxygen saturation]. V˙o2 represents a global measurement of tissue aerobic generation of adenosine triphosphate and can be measured by indirect calorimetry or calculated using the following formula: V˙O2=CO×(Hgb×1.39×[Sao2-Sv¯o2])where Hgb is hemoglobin and S v¯o2 is mixed venous saturation. In a normal situation, the ratio between V˙o2 and DO2, the O2ER ([ V˙o2 ÷ DO2] × 100), is between 25% and 30%. Thus, the progressive reduction of DO2 and changes in O2ER can be measured in the ICU and can be secondary to ischemic hypoxia (ie, decreased CO), hypoxic hypoxia (ie, decreased Pao2), anemic hypoxia (ie, decreased hemoglobin), or distributive hypoxia (ie, increased O2ER) with decreased oxygen utilization, a condition that is commonly called dysoxia. In an anesthetized healthy animal, the reduction of DO2 from a baseline of 25 mL/kg/min to approximately 10 mL/kg/min increases the O2ER by approximately 100%, to 50 to 60%. Below this level of DO2, O2ER cannot increase further, and V˙o2 decreases. This level of oxygen delivery is called DO2critical and generally correlates well with the anaerobic metabolism and systemic lactic acidosis.14Cain SM Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia.J Appl Physiol. 1977; 42: 228-234Crossref PubMed Scopus (356) Google Scholar However, when dysoxia, or the primary alteration of O2ER, is present, the level of DO2 critical cannot be identified easily. The measurement of DO2 presents several other limitations. While DO2 defines the bulk movement of oxygen to the tissues in general, in many critically ill patients, cellular oxygen delivery is affected by complex interactions of neurohumoral, anatomic, and pharmacologic factors, and typically is subjected to maldistribution among different organ districts.15Leach RM Treacher DF Oxygen transport 2: tissue hypoxia.BMJ. 1998; 317: 1370-1373Crossref PubMed Scopus (109) Google Scholar Data obtained from critically ill patients16Ronco JJ Fenwick JC Tweeddale MG et al.Identification of the critical oxygen delivery for anaerobic metabolism in critically ill septic and nonseptic humans.JAMA. 1993; 270: 1724-1730Crossref PubMed Scopus (282) Google Scholar17Van Woerkens EC Trouwborst A van Lanschot JJ Profound hemodilution: what is the critical level of hemodilution at which oxygen delivery-dependent oxygen consumption starts in an anesthetized human?.Anesth Analg. 1992; 75: 818-821Crossref PubMed Google Scholar during the discontinuation of life support, and from Jehovah's Witnesses, show the DO2 critical level to be approximately half (ie, 2 to 3 mL/kg/min) that of healthy animals (4 to 5 mL/kg/min). However, these data differ remarkably from previous studies of healthy anesthetized and critically ill patients in which data were obtained from multiple patients that identified DO2 critical as being between 8 and 21 mL/kg/min.18Shibutani K Komatsu T Kubal K et al.Critical level of oxygen delivery in anesthetized man.Crit Care Med. 1983; 11: 640-643Crossref PubMed Scopus (272) Google Scholar19Mohsenifar Z Goldbach P Tashkin DP et al.Relationship between O2delivery and O2consumption in the adult respiratory distress syndrome.Chest. 1983; 84: 267-271Crossref PubMed Scopus (144) Google Scholar It is, therefore, no surprise that data comparing the “coupling” of DO2 with V˙o2 below DO2 critical in both animal and human studies are discordant, especially when DO2 and V˙o2 are measured by independent methods (ie, thermodilution and indirect calorimetry).20Nelson DP Beyer C Samsel RW et al.Pathological supply dependence of O2uptake during bacteremia in dogs.J Appl Physiol. 1987; 63: 1487-1492PubMed Google Scholar21Phang PT Cunningham KF Ronco JJ et al.Mathematical coupling explains dependence of oxygen consumption on oxygen delivery and uptake in septic shock.Crit Care Med. 1995; 23: 1962-1970Crossref Scopus (72) Google Scholar This controversial issue remains unclear due to the lack of controlled experiments in humans and the difficulty in obtaining multiple data points over a wide range of DO2 values while maintaining a constant oxygen demand. Dhingra and colleagues obtained patient data during the withdrawal of care. Although the authors satisfied the requirements of obtaining multiple data points on both the oxygen delivery and oxygen dependence curves, their patients may not represent the pathophysiology of a hyperdynamic critically ill patient, in whom DO2 critical seems to be set at a point higher than that in healthy patients.22Friedman G De Backer D Shahla M et al.Oxygen supply dependency can characterize septic shock.Intensive Care Med. 1998; 24: 118-123Crossref PubMed Scopus (75) Google Scholar Finally, despite the widespread use of invasive monitoring in the ICU, which allows the easy measurement of DO2, V˙o2, and O2ER in critically ill patients, none of these parameters have been reliable in predicting outcome.23Bakker J Coffernils M Leon M et al.Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock.Chest. 1991; 99: 956-962Abstract Full Text Full Text PDF PubMed Google Scholar Are there any alternatives to the hemodynamic and oximetric measurement in critically ill patients? Conventional clinical parameters of resuscitation (eg, BP, heart rate, and urine output) seem to be generally unreliable.24Kowalenko T Stern S Dronen S et al.Improved outcome with hypotensive resuscitation of uncontrolled hemorrhagic shock in a swine model.J Trauma. 1992; 33: 349-353Crossref PubMed Scopus (269) Google Scholar25Nelimarkka O Halkola L Niinikoski J Effect of graded hemorrhage on renal cortical perfusion in dogs.Am J Surg. 1981; 141: 235-239Abstract Full Text PDF PubMed Scopus (10) Google Scholar Nonconventional blood markers have been extensively studied as resuscitation end points in critically ill patients. Lactic acid level correlates well with insufficient oxygen delivery beyond DO2 critical in animal models of hemorrhagic shock. Remarkably, 48-h lactate level trends have been considered to be superior to measurements of oxygen delivery and V˙o2 in determining outcome in patients with septic shock.26Bakker J Coffernils M Leon M et al.Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock.Chest. 1991; 99: 956-962Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar A base deficit > −4 is correlated with the onset of multiorgan system failure and mortality in several models of trauma.27Rutherford EJ Morris Jr, JA Reed GW et al.Base deficit stratifies mortality and determines therapy.J Trauma. 1992; 33: 417-423Crossref PubMed Scopus (339) Google Scholar Venoarterial CO2 gap has also been correlated with poor outcome in patients after they experience cardiac arrest28Weil MH Rackow EC Trevino R et al.Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation.N Engl J Med. 1986; 315: 153-156Crossref PubMed Scopus (434) Google Scholar and in those being resuscitatated from hemorrhagic shock.29Ducey JP Lamiell JM Gueller GE Arterial-venous carbon dioxide tension difference during severe hemorrhage and resuscitation.Crit Care Med. 1992; 20: 518-522Crossref PubMed Scopus (33) Google Scholar The production of CO2 by the gut (intramural pH [pHi]) recently has been proposed as an early marker of regional dysoxia. The distribution of flow away from the gut when oxygen delivery is insufficient represents a compensatory mechanism to maintain oxygen delivery to more essential organs. Therefore, dysoxia of the gastric mucosa can represent an earlier estimate of global tissue dysoxia. A pHi of < 7.32 has been associated with a statistical increase in mortality in a heterogeneous group of critically ill patients30Gys T Hubens A Neels H et al.Prognostic value of gastric intramural pH in surgical intensive care patients.Crit Care Med. 1988; 16: 1222-1224Crossref PubMed Scopus (150) Google Scholar31Mythen MG Webb AR Intra-operative gut mucosal hypoperfusion is associated with increased post-operative complications and cost.Intensive Care Med. 1994; 20: 99-104Crossref PubMed Scopus (308) Google Scholar and trauma patients. Furthermore, a pHi of < 7.35 has been a better predictor of sepsis and mortality than DO2 and V˙o2.32Doglio GR Pusajo JF Egurrola MA et al.Gastric mucosal pH as a prognostic index of mortality in critically ill patients.Crit Care Med. 1991; 19: 1037-1040Crossref PubMed Scopus (387) Google Scholar More recently, a noninvasive, sublingual electrode that is capable of measuring mucosal CO2 has been studied33Marik PE Sublingual capnography: a clinical validation study.Chest. 2001; 120: 923-927Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar as an index of proper resuscitation and correlated to gastric tonometry. A sublingual CO2 of 70 mm Hg has been noted as a critical value that is significant for survival (sensitivity, 0.73; specificity, 1.0) in a subset of critically ill emergency department patients.34Weil MH Nakagawa Y Tang W et al.Sublingual capnometry: a new noninvasive measurement for diagnosis and quantification of severity of circulatory shock.Crit Care Med. 1999; 27: 1225-1229Crossref PubMed Scopus (174) Google Scholar While all these methods aim to indirectly evaluate critical end points of resuscitation, a direct measurement of oxygen transport at the “ultimate frontier” level (ie, mitochondrial oxidative phosphorylation) is now available. Near-infrared light spectroscopy is the only technology allowing the continuous monitoring of cytochrome a,a3 redux status, a reliable index of cell hypoxia. Unfortunately, at the time of this writing its use is only experimental and its cost is prohibitive. While the utility of invasive cardiac monitoring to improve outcome in critically ill patients is still subject to verification, we note that there are at least two studies35Rivers E Nguyen B Havstad S et al.Early goal-directed therapy in the treatment of severe sepsis and septic shock.N Engl J Med. 2001; 345: 1368-1377Crossref PubMed Scopus (7748) Google Scholar36Yu M Burchell S Hasaniya NW et al.Relationship of mortality to increasing oxygen delivery in patients > 50 years of age: a prospective, randomized trial.Crit Care Med. 1998; 26: 1011-1019Crossref PubMed Scopus (86) Google Scholar that appear to confirm this proposition. Furthermore, we emphatically question whether derivative studies37Connors AF Speroff T Dawson NV et al.The effectiveness of right heart catheterization in the initial care of critically ill patients.JAMA. 1996; 276: 889-897Crossref PubMed Google Scholar or suprapharmacologic studies38Hayes MA Timmins AC Yau E et al.Elevation of systemic oxygen delivery in the treatment of critically ill patients.N Engl J Med. 1994; 330: 1717-1722Crossref PubMed Scopus (1228) Google Scholar have added anything to that understanding. While we applaud the attempt of Dhinga and colleagues to deal with this question in a forthright and innovative manner, the increased potential for inaccuracies in patients with high or very low CO makes the calculation of CO by the Fick method in critically ill patients impractical and of questionable use. Finally, the utility of the data extrapolated from terminally ill patients just before death should be carefully considered before applying any conclusions to critically ill patients." @default.
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