Chapter 91: Cardiac Output Measurement

The management of hemodynamically unstable patients requires an assessment of the cardiac output (CO) and the patients’ intravascular volume status (cardiac preload). In most instances the absolute value of the CO is less important than the response of the CO to a therapeutic intervention. In limited circumstances, most notably in the perioperative setting, optimization of CO has been associated with improved patient outcomes. This chapter will review the role of CO monitoring in the ICU and operating room. The most common methods of monitoring CO will be reviewed followed by the utility of CO monitoring.

Pulmonary Artery Catheter

Adolph Fick described the first method of CO estimation in 1870.¹ Fick described how to compute an animal’s CO from arterial and venous blood oxygen measurements. Fick’s original principle was later adapted in the development of Stewart’s indicator-dilution method in 1897,² and Fegler’s thermodilution method in 1954.³ The introduction of the PAC in 1970 and its subsequent use in performing thermodilution measurements in humans translated the ability to measure CO from the experimental physiology laboratory to multiple clinical settings.⁴ The direct Fick method was the reference standard by which all other methods of determining CO were evaluated until the introduction of the PAC. Currently the PAC is considered the “gold standard” against which other devices are compared. Remarkably, the accuracy of the CO measurements as determined by the PAC has never been established. Furthermore, electromagnetometry and ultrasound using aortic flowprobes most closely represent a true “gold standard” for determination of CO but can only be performed in instrumented animals.^5,6,7 Despite the ubiquitous use of the PAC remarkably few studies have investigated the accuracy of the CO measurements as determined by thermodilution. A number of studies have compared the thermodilution CO with that measured by the Fick technique. These studies have reported a percentage error of between 56% and 83% (with < 30% being clinically acceptable).^8,9,10 Philips at al compared thermodilution CO with surgically implanted ultrasonic flow probes in an ovine model.⁵ The percentage bias and precision was –17% and 47%, respectively; the PAC under-measured dobutamine-induced CO changes by 20% (relative 66%) compared with the flow probe. This study found that the PAC was an inaccurate measure of CO and was unreliable for detection of CO changes less than 30%. Critchely et al¹¹ using a similar methodology in pigs reported a precision of 26%. These studies suggest that the true CO has to change by at least 25% to be detected by the PAC. Furthermore, the required change may be as high as 100% depending on the monitor being used.¹² It is likely that multiple factors interact to affect the accuracy of the thermodilution CO calculation.¹³ Occult warming of cold indicator before injection can produce indicator loses leading to overestimation of CO. Several physical variables additionally influence the extent of indicator loss through the catheter.¹⁴ In addition, cold indicator losses to surrounding tissue occur during intravascular transit, particularly during low flow states.¹⁵ For thermodilution CO measurements to be “accurate,” complete mixing of the thermal indicator must occur in the setting of unidirectional flow within the right ventricle. Incomplete mixing of cold injectate due to tricuspid regurgitation will lead to recirculation of indicator, increased total are under the thermodilution curve and underestimation of CO.^7,16,17 This finding is important as the incidence of tricuspid regurgitation is about 15% in the general population increasing to greater than 70% in elderly patients.^18,19,20

Transpulmonary Thermodilution

Transpulmonary thermodilution (TPTD) similar to the PAC calculates the CO by the indicator dilution method using the modified Stewart–Hamilton equation. With this method a known quantity of cold injectate is delivered via a central venous catheter and mixing of the thermal indicator occurs as it passes through the right atrium and ventricle, pulmonary circulation, left atrium, ventricle and aorta. A thermistor-tipped arterial line quantifies the change in temperature over time in a large proximal artery (femoral artery). A monoexponential transformation of the curve with extrapolation of a truncated descending limb back to baseline allows calculation of area under the curve for CO measurement. TPTD suffers from many of the errors and limitations associated with CO determined by the PAC. Compared with PAC thermodilution, the greater transit time and distance between injectate delivery and measurement with TPTD will tend to increase the error associated with conductive loss and recirculation while reducing the potential for the measured CO to be unrepresentative of its true value over the entire respiratory cycle. Nevertheless, several studies have validated the CO measurements obtained by TPTD with the Fick method.^21,22 In addition, the reproducibility of the CO measurements by TPTD appears significantly better than that of the PAC with a precision of about 7% (compared to 25% for the PAC).²³

Pulse Contour Analysis

The concept of pulse contour analysis is based on the relation between blood pressure, stroke volume (SV), arterial compliance, and systemic vascular resistance (SVR).²⁴ If arterial compliance remains unchanged the area under the systolic portion of the arterial waveform is proportional to the stroke volume. The SV or CO can be calculated from the arterial pressure waveform if the arterial compliance and SVR is known. Although the pulse contour systems which are commercially available use different pressure–volume conversion algorithms, they are based on this basic principle. These systems can be divided into 3 categories:

1. pulse contour analysis requiring an indicator dilution CO measurement to calibrate the pulse contour, that is, the LiDCO system (LiDCO, Cambridge, UK) and the PiCCO system (Pulsion, Munich, Germany)

2. pulse contour analysis requiring patient demographic and physical characteristics for arterial impedance estimation, that is, the FloTrac system (Edwards Lifesciences, Irvine, California, USA)

3. pulse contour analysis that does not require calibration or preloaded data, that is, the MostCare system (Vyetech Health, Padua, Italy).

Clinical data suggests that only those pulse contour devices that are calibrated to an external method have acceptable clinical accuracy (vascular compliance is measured rather than calculated using predictive algorithms). Furthermore, these devices should be recalibrated when vascular tone changes (eg, use of a vasoconstrictor or vasodilator). The Flotrac^TM system has found popular appeal as the system is operator independent, easy to use, needs no external calibration, and only requires a peripheral arterial line (usually radial artery). The accuracy of the first, second, and third generations of this device have been evaluated in over 45 studies; these studies have determined the accuracy of this device to be “clinically unacceptable.”²⁵ This device is particularly inaccurate in patients with a low SVR (eg, sepsis or liver failure). More problematic is the fact that the system does not accurately track changes in SV following a volume challenge or following the use of vasopressors. These limitations significantly restrict the clinical utility of this device.²⁵

Esophageal Doppler

The esophageal Doppler technique measures blood flow velocity in the descending aorta by means of a Doppler transducer placed at the tip of a flexible probe. The probe is introduced into the esophagus of sedated, mechanically ventilated patients and then rotated so that the transducer faces the descending aorta and a characteristic aortic velocity signal is obtained. The CO is calculated based on the diameter of the aorta (measured or estimated), the distribution of the CO to the descending aorta and the measured flow velocity of blood in the aorta. As esophageal Doppler probes are inserted blindly, the resulting waveform is highly dependent on correct positioning. The clinician must adjust the depth, rotate the probe and adjust the gain to obtain an optimal signal.²⁶ Poor positioning of the esophageal probe tends to underestimate the true CO. There is a significant learning curve in obtaining adequate Doppler signals and the correlations are better in studies where the investigator is not blinded to the results of the CO obtained with a PAC.²⁷

Bioreactance

Due to the limitations of bioimpedance devices newer methods of processing the impendence signal have been developed. The most promising technology to reach the marketplace is the NICOM device (Cheetah Medical, Portland, OR), which measures the bioreactance or the phase shift in voltage across the thorax. Phase Shifts occur only as a result of pulsatile flow; therefore, the NICOM signal is correlated almost wholly with aortic flow. Furthermore, as the underlying level of thoracic fluid is relatively static, neither the underlying levels of thoracic fluid, nor their change induce any phase shift and do not contribute to the NICOM signal. NICOM is totally noninvasive; the system consists of a high-frequency (75 kHz) sine wave generator and four dual electrode “stickers” that are used to establish electrical contact with the body.²⁸ Within each sticker, one electrode is used by the high-frequency current generator to inject the high-frequency sine wave into the body, while the other electrode is used by the voltage input amplifier. The system’s signal processing unit determines the relative phase shift (ΔΦ) between the input and output signals. Unlike bioimpedance, bioreactance-based CO measurements do not use the static impedance and do not depend on the distance between the electrodes for the calculations of SV, both factors reducing the reliability of the result.²⁸ NICOM averages the signal over one minute therefore allowing “accurate” determination of CO in patients with arrhythmias. The CO as measured by bioreactance has been shown to be correlated with flow on cardiac bypass²⁸ as well as that measured by the Direct Fick method, thermodilution, pulse contour analysis, and carotid Doppler.^{10,29,30,31,32,33} Importantly, the device tracks changes in CO closely.^{10,29,30,31,32,33}

Determining Fluid and Inotrope Responsiveness

The measurement of SV and CO is fundamental to the hemodynamic management of critically ill patients in the ICU and unstable patients in the operating room. Fluid resuscitation is generally regarded as the first step in the resuscitation of hemodynamically unstable patients. Fundamentally, the only reason to give a patient a fluid challenge is to increase stroke volume (volume responsiveness). If the fluid challenge does not increase stroke volume, volume loading serves the patient no useful benefit (may be harmful). Clinical studies, however, have demonstrated that only about 50% of hemodynamically unstable patients are volume responsive.³⁴ According to the Frank–Starling principle as the preload increases left ventricular (LV) stroke volume increases until the optimal preload is achieved at which point the stroke volume remains relatively constant. Once the left ventricle is functioning near the “flat” part of the Frank–Starling curve fluid loading has little effect on the stroke volume. This implies that the measurement of SV and its change with a preload challenge is essential in all patients undergoing fluid resuscitation. Similarly, the use of an ionotropic agent is based on the assumption that these agents will increase CO. CO monitoring is therefore essential when inotropic agents are being used to allow titration of the drug to the desired effect. Previously static pressure measurements, namely the pulmonary capillary wedge pressure (PCWP) and the central venous pressure (CVP), have been used to guide fluid therapy. However, studies performed over the last 2 decades demonstrate that these techniques are unable to accurately assess volume status or fluid responsiveness.³⁵ Therefore, both fluid challenges and the use of inotropic agent should be based on the response of the SV to either of these challenges.

While a number of definitions exist, an increase in stroke volume (or cardiac output) > 10% to 15% has been used to define volume responsiveness. Interestingly, this rather arbitrary definition was based on the precision of the PAC from studies performed in the 1980s (which we now know are incorrect).³⁶ Furthermore, although the volume of the fluid bolus has not been well standardized, a volume of between 500 and 1000 mL (or 10 mL/kg) of crystalloid solution has been most studied.³⁴ As an operational definition we use a > 10% increase in stroke volume following a 500 mL crystalloid bolus (over 10 minutes) as an indicator of fluid responsiveness. Fluid boluses of greater than 500 mL should be avoided as this may lead to volume overload. More importantly, large fluid boluses may acutely increase cardiac filling pressures. Increased cardiac filling pressures trigger the release of natriuretic peptides. Natriuretic peptides cleave membrane-bound proteoglycans and glycoproteins (most notably syndecan-1 and hyaluronic acid) off the endothelial glycocalyx.^37,38 The endothelial glycocalyx plays a major role in regulating endothelial permeability.³⁹ Therefore, excessive volume expansion increases the release of natriuretic peptides which in turn damages the endothelial glycocalyx and this is followed by a rapid shift of intravascular fluid into the interstitial space leading to a marked increase in lung water and tissue edema.^37,38 In most circumstances, it would therefore be desirable to determine whether the patient will be fluid responsive without actually administering a fluid bolus. In this regard, the passive leg raising maneuver has received the most attention. Lifting the legs passively from the horizontal position induces a gravitational transfer of blood from the lower limbs toward the intrathoracic compartment. Beyond its ease of use, this method has the advantage of reversing its effects once the legs are tilted down (reversal of the effects on cardiac filling pressures). Therefore, PLR may be considered a reversible “autotransfusion.” A recent meta-analysis, which pooled the results of eight studies, confirmed the excellent value of PLR to predict fluid responsiveness in critically ill patients with a global area under the ROC curve of 0.95.⁴⁰ It should, however, be noted that intra-abdominal hypertension (an intra-abdominal pressure of > 16 mm Hg) impairs venous return and reduces the ability of PLR to detect fluid responsiveness.⁴¹ Similarly, it is likely (although it has not been studied) that patient’s with very thin legs from loss of muscle mass may have a limited “autotransfusion” following a PLR maneuver (and a false negative test). When performing the PLR maneuver, it is important that the method be standardized. The lower limbs should be elevated to 45° (automatic bed elevation or wedge pillow) while at the same time placing the patient in the supine from a 45° semirecumbent position. Starting the PLR maneuver from a total horizontal position may induce an insufficient venous blood shift to significantly elevate cardiac preload.⁴² By contrast, starting PLR from a semirecumbent position induces a larger increase in cardiac preload as it induces the shift of venous blood not only from both the legs but also from the abdominal compartment.⁴³ Since the maximal hemodynamic effects of PLR occur within the first minute of leg elevation,⁴⁴ it is important to assess these effects with a method able to track changes in cardiac output or stroke volume on a real-time basis, that is, pulse contour analysis (calibrated), esophageal Doppler, or bioreactance. While the change in SV may be detected within the first minute of the PLR maneuver with pulse contour analysis it may take up to 3 minutes for this change to be detected by bioreactance.

Optimizing Cardiac Output in Elective Surgical Patients

A seminal paper published by Shoemaker et al. in 1982 demonstrated that postoperative patients with an oxygen delivery (DO₂) < 550 mL/min/m² and a cardiac index (CI) < 4.5 L/min/m² were at a significantly greater risk of dying than patients whose DO₂ and CI were above these thresholds.⁴⁵ These authors hypothesized that optimizing postoperative DO₂ using the cardiorespiratory pattern of those who survived (DO₂ > 550 mL/min/m² and cardiac index > 4.5 L/min/m²) would improve the outcome of patients undergoing high-risk surgery.⁴⁶ This study was followed by a pseudorandomized control trial in which 100 patients were “randomized” to achieve these postoperative DO₂ and VO₂ targets (supranormal) or a control group with standard postoperative hemodynamic goals.⁴⁶ The mortality of the control group was 48% compared to 13% in the supranormal group (P < 0.03). In 1988 these authors published a now landmark study in which they measured DO₂ and VO₂ in 100 consecutive patients undergoing high-risk surgical operations.⁴⁷ They calculated the intraoperative and postoperative oxygen debt (VO₂ debt) by subtracting the measured VO₂ from the estimated VO₂ requirements corrected for temperature and anesthesia. The estimated VO₂ during anesthesia was calculated using the following formula: VO₂ (anesthesia) = 10 x kg^0.72.⁴⁷ This unvalidated equation was published in a textbook by Lowe and Ernst.⁴⁸ Shoemaker and colleagues then correlated the calculated VO₂ deficit with the subsequent development of lethal and nonlethal organ failure. In this study the cumulative VO₂ deficit averaged 33.5 ± 36.9 L/m² in nonsurvivors, 26.8 ± 32.1 L/m² in survivors with organ failure, and 8.0 ± 10.9 L/m² in survivors without organ failure (P < 0.05). Shoemaker and colleagues noted that the oxygen debt was incurred almost exclusively during the intraoperative period. Based on these findings, the authors proposed that the greater the oxygen debt incurred (during surgery), the greater the risk of organ failure and death.⁴⁷ This observation was supported by experimental models of hemorrhagic shock in which the magnitude of VO₂ deficit was related to the risk of death of the study animals.⁴⁹ The same year (1988) these authors published the results of two series of patients.⁵⁰ The first series was again a pseudo-randomized study in which a DO₂ > 600 mL/min m² and CI > 4.5 L/min m² were targeted in the postoperative period as compared to standard postoperative hemodynamic targets. The reported mortality was 38% in the control group compared to 21% in the protocol group (P < 0.05). In the second series, patients were randomized preoperatively into one of three treatment groups, namely: (i) a central venous pressure (CVP)-control group, (ii) a pulmonary artery (PAC) control group, and (iii) a PAC protocol group in which “supranormal” hemodynamic and oxygen transport values were used as the goals of care (DO₂ > 600 mL/min m² and CI > 4.5 L/min m². The reported mortality was 23% in the CVP control group, 33% in the PA-control group, and 4% in the PA-protocol group (P < 0.01). Complications were observed less frequently in patients treated by the protocol in both series. Based on the VO₂ debt incurred intraoperatively and the summation of their outcome data, Shoemaker and colleagues recommended that “in the high-risk patient, PA catheterization should be instituted preoperatively and that the important cardiorespiratory values be prophylactically augmented beginning in the preoperative and continued into the intraoperative and immediate postoperative periods.”⁵¹

The concept of deliberate perioperative supranormal oxygen delivery was subsequently tested in a true randomized controlled clinical trial by Boyd and colleagues published in 1993.⁵² In this study 107 high-risk surgical patients were randomized to a control group or a protocol group in which DO₂ was increased to greater than 600 mL/min m² by the use of a dopexamine hydrochloride infusion. The mortality was 5.7% in the protocol group compared to 22.2% (P = 0.01) in the control group with half the number of complication in the protocol group as compared to the control group (P = 0.008). Patients enrolled in this RCT were followed for 15 years following randomization to ascertain their length of survival after surgery.⁵³ Remarkably 20.7% of the goal directed therapy patients versus 7.5% of the control group were alive at 15 years. The authors concluded that short-term goal directed therapy in the perioperative period may improve long-term outcome, in part due to is ability to reduce the number of perioperative complications. The study of Boyd and colleagues has been followed by at least 30 RCTs which have studied perioperative hemodynamic optimization in a variety of settings using various goals and techniques of hemodynamic optimization.^54,55,56 The initial preemptive hemodynamic studies used the PAC and targeted the Shoemaker “supranormal” goals while more recent studies have “optimized” CO using esophageal Doppler or dynamic indices of fluid responsiveness. Meta-analyses of these studies have demonstrated that both approaches reduce surgical mortality and morbidity.^54,55,56 Furthermore, while mortality was reduced only in the high-risk patients’ morbidity was reduced across all risk groups. In addition, these meta-analyses have demonstrated that the PAC has been largely replaced by less invasive hemodynamic monitoring techniques.

The original goal directed therapy (GDT) study by Shoemaker et al published in 1982 demonstrated the benefit of achieving postoperative supranormal hemodynamic targets.⁴⁶ Following their 1988 study in which they demonstrated that the oxygen debt was incurred intraoperatively,⁴⁷ they recommended preemptive perioperative (preoperative or intraoperative) hemodynamic optimization.⁵⁰ The studies that followed demonstrated that this approach reduced surgical morbidity and mortality.^54,55,56 In their 1988 paper Shoemaker and colleagues were unable to determine “which of these influences are operative” to explain the intraoperative oxygen debt.⁴⁷ Furthermore, as already mentioned the VO₂ deficit was calculated using a formula that had not been validated.⁴⁸ At face value it would appear to be counterintuitive that anesthesia would result in an oxygen debt. General anesthesia and neuromuscular blockade reduce metabolic rate and oxygen consumption while DO₂ remains largely unchanged.^57,58 Hypothermia occurs frequently during anesthesia which further reduces metabolic oxygen requirements.^59,60 Indeed, in Shoemaker’s pivotal paper VO₂ fell during the intra-operative period reaching a nadir and the end of surgery.⁴⁷ In this study VO₂ increased sharply after surgery reaching the pre-operative VO₂ at 1 hour with the VO₂ peaking at 4 hours. It is therefore difficult to understand how anesthesia induces an oxygen debt. This apparent contradiction is best resolved by an analysis of the time course of the mixed venous oxygen saturation (SmvO₂) or central venous oxygen saturation (ScvO₂) during the perioperative period. SmvO₂ (or ScvO₂) is a reflection of the balance between DO₂ and VO₂; in patients who incur an oxygen debt the SmvO₂ should fall. A number of studies have monitored the SmvO₂/ScvO₂ in the perioperative period.^61,62,63,64 These studies have reproducibly demonstrate that the SmvO₂/ScvO₂ remains stable or increases slightly during anesthesia and surgery but falls sharply in the immediate post-anesthesia period. This data suggests that the oxygen debt is incurred postoperatively with the withdrawal of anesthesia (and NMB) and with the development of postoperative pain, agitation, shivering, and increased sympathetic tone. Furthermore, those patients with limited cardiac reserve and most likely to have the largest postoperative fall in SmvO₂/ScvO₂ and incur the largest oxygen debt. Indeed, these are the patients that have been demonstrated to be at the greatest risk of death and postoperative morbidity.^62,64 This would suggest that optimization of CO and DO₂ in the immediate postoperative period should be as effective as initiating hemodynamic optimization preoperatively or during the intraoperative period. Meta-analyses have confirmed the benefit of hemodynamic optimization whether initiated pre, intra, or postoperatively.^54,55

Optimizing Cardiac Output in Trauma Patients

Patients who suffer severe traumatic injuries with blood loss incur an oxygen debt. The early increases in CO and DO₂ following resuscitation of trauma patients is considered compensation in order to replenish the oxygen debt. It has therefore been postulated that hemodynamic optimization following trauma targeting supranormal goals would decreases the incidence of multiple organ failure and death.^65,66 Bishop and coworkers pseudo-randomized 115 patients who had suffered from severe traumatic injuries to normal or supranormal hemodynamic goals (using a PAC) on admission to the SICU.⁶⁷ In this study patients in the supranormal group had significantly fewer organ failures and a lower risk of death. Furthermore, the CI and DO₂ of the survivors were significantly higher than those of the patients who died. McKinley and colleagues randomized 36 patients following traumatic shock to a protocol that aimed to achieve a DO₂ > 600 mL/min/m² or a protocol that aimed for a DO₂ of about 500 mL/min/m².⁶⁸ The patients in the 500 mL/min/m² group received less fluid and blood; however, there was no difference in outcomes between the groups. Velmahos et al randomized 75 severely injured patients to normal or supranormal hemodynamic goals in the pre-ICU period.⁶⁹ Survival rates were identical between the normal and supranormal groups. However, patients from either group who achieved supranormal values had improved survival rates compared with patients who did not. In this study patients in the supranormal group who could not achieve supranormal values had a higher death rate than similar patients in the control group. These findings support the argument that achieving supranormal values is an indicator of physiologic reserve rather than being a useful endpoint of resuscitation. Patients who have the inherent ability to respond to trauma by increasing their CO and oxygen transport capacity beyond normal levels are more likely to eliminate the existing oxygen deficit, avoid organ failure, and survive. Furthermore, attempts to optimize patients who do not have the necessary physiologic reserve may be detrimental. Based on the assimilation of these studies it would appear that targeting supranormal DO₂ does not improve the outcome of patients who have suffered traumatic injuries and that the most appropriate hemodynamic goals would be a MAP > 65 mm Hg with a normal cardiac index (> 2.5 L/min/m²).

Optimizing Cardiac Output in Medical Patients

It is widely believed that patients with sepsis, particularly those with an increased lactate concentration, have an oxygen debt (due to increased oxygen demand) and that increasing oxygen delivery will increase oxygen consumption and improve patient outcome.⁷⁰ This concept was popularized by Edwards et al⁷¹ and Astiz et al⁷² in the late 1980s. There is, however, scant evidence that in patients with sepsis tissue hypoxia occurs. Hotchkiss and Karl in a seminal review published by over 20 years ago demonstrated that cellular hypoxia and bioenergetic failure do not occur in sepsis.⁷³ Using phosphorus 31 NMR spectroscopy to monitor concentrations of high-energy phosphates, Song et al, demonstrated normal concentrations of ATP in the leg muscle of septic rats.⁷⁴ Jepson et al confirmed these findings.⁷⁵ Similarly, Solomon et al demonstrated that sepsis-induced myocardial depression was not due to bioenergetic failure.⁷⁶ Using the hypoxic marker [¹⁸F]Fluoromisonidazole, Hotchkiss et al were unable to demonstrate evidence of cellular hypoxia in the muscle, heart, lung, and diaphragm of septic rates.⁷⁷ Additional studies support these findings. In a porcine peritonitis model, Regueira et al demonstrated a significant increase in arterial lactate concentration yet there was no significant change in hepatic and muscle mitochondrial oxidative function.⁷⁸

While sepsis is considered to be hypermetabolic condition oxygen consumption and energy expenditure are broadly comparable to that of normal people, with energy expenditure decreasing with increasing sepsis severity.^79,80,81 Therefore, there is no requirement that oxygen delivery increase with sepsis. Ronco and colleagues determined the critical oxygen delivery threshold for anaerobic metabolism in septic and nonseptic critically ill humans while life support was being discontinued.⁸² In this study there was no difference in the critical oxygen delivery threshold between septic and nonseptic patients. The critical oxygen delivery threshold was 3.8 ± 1.5 mL/min/kg (266 mL/min in a 70 kg patient); assuming a hemoglobin concentration of 10 g/L translates into a cardiac output of approximately 2 L/min. It is likely that only preterminal moribund patients with septic shock would have such a low cardiac output.

Several studies performed over four decades ago provide strong evidence that hyperlactacidemia noted during shock states was unlikely to be caused by tissue hypoxia.^83,84 It has now been well established that epinephrine released as part of the stress response in patients with shock stimulates Na⁺ K⁺ ATPase activity. Increased activity of Na⁺ K⁺ ATPase leads to increased lactate production under well-oxygenated conditions in various cells, including erythrocytes, vascular smooth muscle, neurons, glia, and skeletal muscle.^85,86 This concept was confirmed by Levy and colleagues, who in patients with septic shock demonstrated that skeletal muscle was the leading source of lactate formation as a result of exaggerated aerobic glycolysis through Na⁺ K⁺ ATPase stimulation.⁸⁷ Selective inhibition of Na⁺ K⁺ ATPase with ouabain infusion stopped over-production of muscle lactate and pyruvate. In summary, these data suggest that oxygen requirement are not increased in patients with sepsis, that an oxygen debt does not exist in patients with sepsis, and that lactate is produced aerobically as part of the stress response. This would suggest that increasing oxygen delivery would not be a useful exercise. In a pivotal study published in 1994, Hayes and colleagues randomized 109 fluid resuscitated critically ill patients to receive dobutamine titrated to achieve a DO₂ > 600 mL/min/m² or a control group who received dobutamine only if the CI < 2.8 L/m².⁸⁸ During treatment there was no difference between groups in the MAP or VO₂, despite a significantly higher CI and DO₂ in the treatment group. The in-hospital mortality was significantly higher in the treatment group (34% vs 54%, P = 0.04). In a follow-up publication limited to those patients with sepsis, these authors demonstrated that those patients with normal hemodynamics and those who reached the supranormal DO₂ goal spontaneously (fluid alone) had a significantly lower morality than those in whom the DO₂ goals were achieved with dobutamine.⁸⁹ The findings of this study are in keeping with the studies in trauma patients which suggest that attempts at driving up oxygen delivery in patients with limited cardiac reserve is not beneficial and maybe potentially harmful. This concept is supported by the study by Gattinoni and colleagues.⁹⁰ These authors randomized 762 critically ill patients to three groups, namely (i) a control group, (ii) a group with a target cardiac index > 4.5 L/min/m² (supranormal group), and (iii) a group with a target SmvO₂ > 70%. In this study there was no difference in outcome between any of the groups.

In conclusion, fluid challenges and the use of inotropic agents should be guided by the change in cardiac output following these interventions. Perioperative optimization of cardiac output with targeted fluid challenges reduces postoperative complications and mortality. Targeting supranormal hemodynamic targets in patients with traumatic injuries and those with sepsis does not improve outcome and may be harmful. Similarly, in patients with sepsis attempting to increase oxygen delivery in response to an increased lactate concentration is illogical and potentially harmful.

The author has no financial interest in any of the products mentioned in this paper.