Non-invasive assessment of fluid responsiveness by changes in partial end-tidal CO₂ pressure during a passive leg-raising maneuver

The passive leg-raising (PLR) maneuver provides a dynamic assessment of preload dependence inducing a transient and reversible increase in cardiac preload. The abrupt transfer of blood contained in the venous reservoir of the legs and splanchnic compartment while moving the patient from a semirecumbent to supine position with legs elevated increases cardiac preload as a 'self-volume challenge' and, when both ventricles are operating in the steep part of the Frank-Starling curve, also improves cardiac output (CO) [1]. This maneuver has been demonstrated to predict fluid responsiveness in many studies over a wide population, including clinical situations in which other parameters of fluid responsiveness have failed, such as patients with cardiac arrhythmias or with spontaneous breathing [1‐3]. However, since the hemodynamic effects of PLR are usually sudden and transient, a fast-response continuous CO monitor is required to detect these changes and to characterize fluid responder patients accurately [4‐6]. In this regard, several monitoring techniques have been proposed for this purpose: echocardiography [2, 3, 7], arterial pulse contour analysis [8, 9], bioreactance [10], esophageal Doppler [1, 11, 12], and so on. Nevertheless, the need for measuring CO usually limits the widespread application of this test to a specific group of patients requiring expensive, burdensome or invasive hemodynamic monitoring systems.

The relationship between CO and partial end-tidal CO₂ pressure (PETCO₂) has been known for decades [13, 14], so measurement of PETCO₂ has been proposed to confirm the restoration of spontaneous circulation in patients with cardiac arrest [15], but also as a quantitative indicator of hemodynamic effectiveness of precordial compression during cardiopulmonary resuscitation [16]. Moreover, since PETCO₂ is mainly determined by tissue CO₂ production (VCO₂), alveolar ventilation and CO (that is, pulmonary blood flow) [17], when stable metabolic conditions are assumed and minute ventilation is kept constant, acute changes in PETCO₂ have been shown to correlate strongly with changes in CO in experimental [18‐24] and clinical [25, 26] settings. Thus, PETCO₂ has been suggested as a noninvasive alternative for continuous assessment of CO in different shock states [20].

The aim of the present study, therefore, was to assess whether PETCO₂ monitoring can track changes in CO induced by PLR and can be used as a noninvasive surrogate for predicting fluid responsiveness in mechanically ventilated patients with acute circulatory failure requiring fluid administration.

This study was prospectively conducted in a 17-bed adult multidisciplinary Intensive Care Unit of the Hospital del SAS Jerez de la Frontera. The study protocol was approved by the Institutional Ethics Committee of the Hospital Jerez of the Andalusian Health Service and endorsed by the Scientific Committee of the Spanish Society of Intensive Care, Critical and Coronary Units (SEMICYUC). Written informed consent was obtained from each patient's next of kin.

The main finding of this study is that, under fixed minute ventilation and assuming a constant tissue CO₂ production, acute changes in partial end-tidal CO₂ pressure during the passive leg-raising maneuver are strongly correlated with changes in cardiac output measured by an esophageal Doppler and could provide a reliable and non-invasive method for predicting fluid responsiveness in mechanically ventilated patients with acute circulatory failure.

Although intravascular volume therapy remains a keystone in the treatment of patients with acute circulatory failure, the benefits of fluid administration seem to be defined within relatively narrow boundaries: on the one hand, excessive fluid therapy appears to be associated with higher morbimortality in critical ill patients and, on the other hand, inadequate fluid resuscitation could aggravate tissue hypoperfusion and organ dysfunction [37]. Furthermore, for physiological reasons, the hemodynamic response to a fluid challenge is not easily predictable, since the expected improvement in CO is only observed in half the patients [35]. In this regard, the PLR maneuver has been proposed as a reliable method for predicting fluid responsiveness, challenging the cardiovascular system to a reversible and transient increase in cardiac preload by mobilizing venous blood contained in the lower limbs and abdominal compartment toward the intrathoracic vessels. Only if both ventricles are operating in the steep part of the cardiac function curve will this increment in preload result in a significant increase in CO and, therefore, in a similar response after volume administration [6].

Our results confirm the ability of the PLR maneuver to detect preload dependence and the strong relationship between changes induced by PLR and VE-induced increases in CO [6, 34]. Moreover, the ΔCO_PLR cutoff for predicting fluid responsiveness is also consistent with previous studies in which esophageal Doppler was employed [1, 11] and similar to the recommended threshold value for interpretation of PLR maneuver effects [6, 34]. Accordingly, when CO increased above 12%, 95% of the studied patients increased their CO after fluid administration.

Exhaled or end-tidal CO₂ is mainly determined by pulmonary blood flow (that is, CO), metabolic CO₂ production (VCO₂) and alveolar ventilation; so PETCO₂ varies directly with VCO₂ and CO and inversely with alveolar ventilation [17]. Therefore, assuming that during PLR the systemic metabolic rate remained relatively constant (and minute ventilation was kept unchanged), then changes in PETCO₂ should predominantly reflect variations in pulmonary blood flow and thus, indirectly, changes in CO. The strong relationship observed between changes in PETCO₂ and CO during PLR supports this hypothesis and it is also in agreement with numerous studies performed under similar conditions [18‐26]. For this reason, the measurement of PETCO₂ has been advocated as a simple and noninvasive parameter of the circulatory status for monitoring the resumption of spontaneous circulation and the efficacy of chest compressions during cardiac arrest [15] but also as a prognostic indicator in cardiopulmonary resuscitation [38] and emergency trauma surgery [39].

According to previous observations [22, 25], the increase in PETCO₂ induced by PLR could be explained at least by two mechanisms. First, if PLR increases venous return and pulmonary blood flow, then CO₂ delivery to the lungs (that is, pulmonary arterial CO₂ content) and CO₂ removal should be increased. Second, by increasing pulmonary perfusion pressure, PLR could recruit previous collapsed pulmonary vessels and reduce alveolar spaces with high ventilation-to-perfusion mismatch or alveolar dead space. This latter phenomenon could be particularly striking in patients with severely impaired pulmonary perfusion pressure, as seen in deep hemorrhagic shock [18, 19, 21, 23] or patients with alveolar overdistension due to high levels of PEEP [40]. In this latter regard, a recent study by Fougéres et al. [41] demonstrated that in patients with ARDS who were ventilated with high levels of PEEP, the PLR maneuver improved the cardiac index but also was associated with a decrease in pulmonary vascular resistance, which suggested that by increasing central blood volume, PLR decreased PEEP-induced West zones 1 with subsequent decrease in alveolar dead space. Unfortunately, since we did not measure arterial CO₂ pressure, we cannot estimate the relative influence of changes in dead space during PLR. In any case, according to the above explanation, whatever the underlying mechanism, the increase in PETCO₂ is determined ultimately to an effective increase in pulmonary blood flow and improved efficiency of alveolar CO₂ excretion [22, 25].

Although the relationship between CO and PETCO₂ was initially described as linear [14, 22, 24, 25], other authors have suggested that a logarithmic function better defines this association [18, 20, 21]. According to the latter, in low-flow states (as during cardiac arrest or severe hemorrhagic shock), for a given change in CO a larger variation in PETCO₂ should be expected [18, 20, 21]. This marked reduction in PETCO₂ at low CO values might be attributed not only to limited CO₂ elimination, but also to changes in metabolic CO₂ production during oxygen supply dependency [21‐23]. In contrast, at high CO values, pulmonary blood flow would not be the limiting factor for PETCO₂, and thus, changes in PETCO₂ would not reflect its variations but mainly the adequacy of alveolar ventilation [18, 20]. Although our study was not designed to address this specific issue, the strong association observed during PLR between fractional changes in CO and PETCO₂ suggests that, under the conditions described by the study protocol, this relationship remains valid over the wide range of studied CO values. Furthermore, the moderate magnitude of transient changes in CO produced by PLR (in contrast with marked and sustained decreases induced in some studies [18‐21]) and the timing between PETCO₂ and CO measurements [25] may also have contributed to the observed findings in our study. When perturbations in CO were produced over a brief period of time and PETCO₂ measurements were performed within a relatively short time frame, similar results have been observed in previous studies [22, 25].

Before drawing conclusions from our results, some considerations should be mentioned. First, the assessment of fluid responsiveness using PETCO₂ variations should potentially share the same limitations as interpreting CO changes during PLR, since in this context the former is in essence just a surrogate for the latter. Therefore, any condition that could affect the ability of PLR to predict fluid responsiveness (for example, intraabdominal hypertension) [12] should also be considered when analyzing PETCO₂ changes. Second, to prevent fluctuations in minute ventilation, all the patients were mechanically ventilated in volume control mode, deeply sedated and fully adapted to the ventilator with no inspiratory efforts. Consequently, in spontaneously breathing patients, the unpredictable variations in alveolar ventilation could make the analysis of changes in PETCO₂ more difficult. For this reason, this population was deliberately excluded from the study and extrapolation of our results to this clinical condition cannot be recommended. Third, the assessment of PETCO₂ variations is also based in the assumption that no significant changes in metabolic CO₂ production have been produced while performing the PLR maneuver. If the metabolic rate varies considerably (for example, during shivering, fever, and so on), the observed changes in PETCO₂ could not be attributed solely to modifications in CO and thus the ability of PETCO₂ variations to predict fluid responsiveness could be diminished. However, the maximum hemodynamic effects of PLR take place primarily during the first minute [6], so it is very unlikely that this phenomenon will occur in such a short period of time. By contrast, since infusion time was significantly longer, this assumption is more difficult to sustain and could be one of the reasons for the weaker relationship between changes in CO and PETCO₂ after fluid administration. However, even under these circumstances, the VE-induced increase in CO still accounted for more than 50% of the observed changes in PETCO₂. Finally, the 5% cutoff found for changes in PETCO₂ represents an increase of no more than 2 mmHg, which a priori could be attributed to a low signal-to-noise ratio and easily interpreted as a measurement error. Nonetheless, we effectively confirmed that this value is almost three times the LSC for PETCO₂ measurement, so under the same conditions, an increase above this threshold should represent an actual increase in PETCO₂ and the presence of fluid responsiveness. Despite these considerations, PETCO₂ measurement could offer an easily available, totally noninvasive method for the assessment of fluid responsiveness with similar performance as measuring CO, but without the need of any hemodynamic monitoring device, when similar clinical conditions are present (uniform alveolar ventilation and constant VCO₂).

In our study we demonstrated that PETCO₂ effectively tracked changes in CO during the PLR maneuver and predicted fluid responsiveness in patients with acute circulatory failure with fixed minute ventilation, assuming a constant tissue CO₂ production.