Respiratory changes of the inferior vena cava diameter predict fluid responsiveness in spontaneously breathing patients with cardiac arrhythmias

Acute circulatory failure (ACF) occurs in more than one third of ICU patients [1]. Volume expansion (VE) remains the first treatment provided when ACF of infectious origin is suspected [2, 3]. VE consists of a rapid fluid infusion that aims to increase cardiac output and consequently oxygen transport to tissues. However, cardiac output increase in response to VE, or fluid responsiveness, only occurs when the heart is preload dependent. Increasing evidence of the deleterious effects of inappropriate fluid administration encourages the development of variables predicting fluid responsiveness [4‐6], but few have been validated in spontaneously breathing patients, and only exceptionally in patients with irregular cardiac rhythm, frequently excluded from studies [7]. Yet, approximately 25% of septic patients present atrial arrhythmia at ICU admission [8].

The fluid challenge test is the standard reference test although not specifically validated in arrhythmic patients [2]. However, positive response to VE only occurs half a time when the decision is based on clinical criteria, leading to potentially harmful fluid infusion [9]. Thus, the use of tests that do not require fluid infusion remains safer. Because static estimates of preload (e.g., right atrial pressure, pulmonary artery occlusion pressure) do not accurately predict fluid responsiveness, dynamic variables have been developed [7]. Analysis of stroke volume index (SVI) variations or surrogates like arterial pulse pressure variations in response to respiratory-related preload changes is strictly impossible when cardiac rhythm is irregular. Conversely, passive leg raising-induced change in SVI is an accurate variable validated in spontaneously breathing patients with cardiac arrhythmia [10], but may be either technically nonfeasible or unreliable under specific conditions (e.g., pregnancy [11] or intra-abdominal hypertension [12]).

The ability of respiratory-induced variations of the inferior vena cava (IVC) diameters to predict fluid responsiveness has been repeatedly evaluated in spontaneously breathing patients and is still debated because of the potential impact of deep inspiratory movements on the IVC collapsibility [13‐15]. In patients without standardization of respiratory efforts, IVC collapsibility (cIVC) predicts fluid responsiveness with high specificity but low sensitivity [13‐15]. When assessed during a standardized inspiratory maneuver, cIVC accurately predicts fluid responsiveness in infection-related ACF [15]. However, all patients enrolled in these studies had regular sinus rhythm with no or few chronic cardiac failure or pulmonary hypertension. The arrhythmic cardiac rhythm per se may not interfere with the performances of cIVC to predict fluid responsiveness. Nevertheless, because arrhythmic patients often are older patients with more cardiovascular and respiratory comorbidities, the hemodynamic response to a deep inspiration may change [8, 16, 17]. This study sought to assess the reliability of cIVC to predict preload dependence in the specific population of arrhythmic patients.

We hypothesized that not only cIVC but also the inspiratory diameter of the IVC (iIVC) could predict fluid responsiveness in spontaneously breathing patients with infection-related ACF and irregular cardiac rhythm. We studied the ability of cIVC and iIVC assessed during a standardized inspiratory maneuver to predict fluid responsiveness in these patients. To help the interpretation of the primary outcome, we sought to compare the difference between responders and nonresponders in the IVC diameters variations induced by the variations of the inspiratory effort.

To our knowledge, this is the first work reporting the interest of iIVC-st as a potential predictor of response to VE. An iIVC-st < 11 mm predicts fluid responsiveness with a specificity of 88%, a sensitivity of 83% and a negative predictive value of 84%. The gray zone of iIVC-st ranges from 9 to 13 mm. The present study validates that cIVC-st is an accurate predictor of fluid responsiveness in the particular population of spontaneously breathing patients with cardiac arrhythmia during ACF related to infection. A cIVC-st ≥ 39% predicts response to VE with a specificity of 88%, a sensitivity of 93% and a negative predictive value of 93%. The gray zone of cIVC-st is restricted from 39 to 48%. Eventually, both cIVC-st and iIVC-st show good diagnostic accuracy with 95% CI of their area under ROC curve > 0.80.

Studies focusing specifically on fluid management of arrhythmic patients during sepsis are scarce. Because clinical variables cannot predict fluid responsiveness [9] and because fluid overload could be harmful, there is a need for appropriate hemodynamic variables to assess the response to VE in this specific population. In nonventilated, arrhythmic patients, only the fluid challenge [25] and the passive leg raising tests [26] are validated to predict fluid responsiveness. However, the fluid challenge exposes the patients to the risk of inappropriate fluid infusion, and the passive leg raising cannot be performed with all beds and stretchers, raising the issue of the feasibility in clinical routine [3, 13]. The search for predictive factors of fluid responsiveness in our study population was relevant because VE decided on clinical variables increased VTIao in 53% of patients only. In addition, the very close rate of responders in patients with atrial fibrillation (54%) and frequent extrasystoles (52%) justified to gather these two populations of infected patients in the analysis. With regard to their often older age and greater comorbidities including cardiac insufficiency [8, 16, 17], arrhythmic patients may present an increased risk of deleterious effects induced by inappropriate VE [27‐30]. In case of acute circulatory failure related to an infection, VE is frequently performed even though dynamic tests do not clearly support the decision [3]. Thus, clinicians need tools with high negative predictive value to avoid potentially harmful VE, rather than yet another incentive to initiate VE.

With regard to unstandardized spontaneous ventilation, our data show a high specificity of cIVC-sp but a low sensitivity to predict response to VE, as previously published in infected patients with regular sinus rhythm [13‐15]. Indeed, in patients with regular cardiac rhythm, Muller et al. [13], Airapetian et al. [14] and our team [15] reported that cIVC-sp > 40%, > 42% and > 31% were predictive of fluid responsiveness with high specificity of 80, 97 and 88% but low sensitivity of 70, 31 and 76%, respectively. The similarities in the results from these studies despite different study populations and measurement techniques support the reliability of IVC variations to predict fluid responsiveness with high specificity in septic patients, regardless of their cardiac rhythm. Although the contribution of cIVC-st is small in case of high cIVC-sp values, performing an inspiratory maneuver seems of interest when cIVC-sp values are low. Indeed, in our selected population, using a deep inspiratory maneuver when assessing cIVC to predict fluid responsiveness allows the reduction of false-negative responses (10 in spontaneous unstandardized breathing vs. 2 in standardized inspiration) without creating false positive (4 in spontaneous unstandardized breathing vs. 3 in standardized inspiration). These results suggest that a deep inspiration might significantly improve cIVC sensitivity and negative predictive value to detect fluid responsiveness, without altering specificity in arrhythmic patients. These results are consistent with those of our previous work on cIVC-st in infected critically ills with regular cardiac rhythm [15]. In this population, a cIVC-st ≥ 48% predicted response to VE with a specificity of 90% and a sensibility of 84%, and a gray zone ranging from 39 to 48%. Like cIVC, a deep standardized inspiration maneuver improves fluid responsiveness prediction of iIVC with a 95% CI of its area under ROC curve increasing from < 0.80 to > 0.85.

One limitation frequently discussed about the use of the respiratory changes of the IVC diameter to predict fluid responsiveness in spontaneously breathing patients is the impact of an uncontrolled inspiratory effort on the vessel collapsibility, questioning the reliability of this variable [31]. Based on a physiological study performed on healthy volunteers (i.e., responders to VE [32, 33]), it has been shown that the IVC collapsibility was affected by the inspiratory effort [31] with potential risk of false-negative or false-positive responses when the inspiratory effort is, respectively, insufficient or excessive. In our study, the decrease in false-negative responses with the use of the deep inspiratory maneuver suggests that an insufficient inspiratory effort might actually be responsible for a lack of sensitivity. However, the fact that no false-positive response occurred with the use of the inspiratory maneuver, together with the absence of correlation between the IVC collapsibility and the intensity of the inspiratory effort in nonresponders, may suggest that a deep inspiration might be unlikely to increase the collapsibility of the IVC in nonresponders, contrarily to responders. These specific findings need to be confirmed in larger studies. Similarly, it has been shown in the literature that the IVC collapsibility was dependent on the sampling zone. The IVC percentage collapse at the junction of the right atrium and IVC was dissimilar to the other sites of measurement (hepatic or renal). Thus, it is recommended not to use this proximal sampling zone to assess IVC diameters respiratory variations. Subsequently, all the measurements in our study were performed within 15–20-mm caudal to the hepatic vein–IVC junction, or 30–40 mm to the IVC–right atrium junction [34].

As previously described, 16 (29%) patients were unable to reach the predefined inspiratory pressure threshold of − 5 mmHg [15]. A smaller inspiratory target (e.g., − 3 mmHg) may be proposed for clinical use, as only 5 (9%) patients were unable to reach this threshold value. Interestingly, 2 of the 3 patients unable to reach an inspiratory pressure below − 3 mmHg were classified as false negative with the cIVC-st test. Similarly, 3 patients over the 6 classified as false negative with the iIVC-st test did not reach the − 3 mmH2O threshold. Thus, negative results of cIVC-st and iIVC-st should be carefully interpreted in patients unable to perform an adequate inspiratory effort. These results highlight the importance of an adequate inspiratory maneuver, meaning a deep (< − 3mmH20), brief (< 5 s), continuous and regular inspiratory strain to enhance the diagnostic performance of cIVC and iIVC.

Interestingly, although not statistically significant, the nonresponders show a trend toward older age and higher severity with regard to SAPS2 values and norepinephrine infusion, compared to the responders. However, these criteria were not discriminant enough to help in the prediction of fluid responsiveness. The reasons for this trend remain unknown and cannot be explained by any data collected in this work.

This study has several limitations. First, fifty-five patients were included, instead of the 90 anticipated in sample size calculation. This could be at least partly explained by a lower frequency of patients meeting the inclusion criteria than expected, and the need for an available operator on site to perform the inclusion and the initial echocardiography. Nevertheless, the areas under ROC curve of cIVC-st and iIVC-st were greater than those anticipated in the sample size calculation. Thus, the final sample size had enough power to demonstrate that cIVC-st and iIVC-st before VE have a good diagnostic accuracy to predict fluid responsiveness with 95% CI of their areas under ROC curve > 0.80. However, the representativity of the population could be questioned as only a small number of patients has been included and does not allow any generalization of the conclusions to other populations. For these reasons, this study may rather be considered as a pilot study, especially for the iIVC variable that has never been studied before. Second, the assessment of our dynamic variables has been performed in a very selected population, as only patients with infection-related ACF, with no or low-dose of norepinephrine, for whom VE has already been decided by the physician in charge, were enrolled. Plus, patients with perturbations of intra-abdominal pressure observed in active exhalation, abdominal compartment syndrome, pregnancy and other specific conditions that alter sonographic images like obesity or abdominal surgery which could have interfered with cIVC accuracy were excluded from the study. Therefore, our results cannot be generalized to an unselected critically ill population. Concerning patients’ inclusion or exclusion criteria, tachycardia might be poorly appropriate to detect ACF in arrhythmic patients, and other nonclinical markers, like lactate, pCO₂ gap or central venous oxygenation, could have been helpful to refine the screening of the patients, although requiring adequate arterial and central venous catheter which are not always available. Likewise, assessing the intra-abdominal pressure along with clinical examination might have been more appropriate to detect intra-abdominal hypertension. Third, IVC diameters were not measurable in 15% of the patients because of a lack of echogenicity, raising the question of the practical application of these variables to all patients. Fourth, although all the efforts have been made to maintain the operators blind, some of the operators may have remembered some clinical or echocardiographic data. Fifth, we arbitrarily defined the positive response to VE as an increase in VTIao of ≥ 10% with rapid fluid loading. This threshold value seems clinically relevant and is more than twice as high as the value of the intra-observer variability of the VTIao measured in this study. Eventually, for feasibility reasons, we did not assess intra-abdominal and central venous pressures, which would have been highly helpful to understand the underlying physiological mechanisms involved in the respiratory variations of the IVC. Last, although IVC diameter changes throughout the cardiac cycle [35], IVC measurements were not taken with electrocardiogram synchronization to detect tele–diastole as usually recommended. This uncertainty in the end-diastolic measurement of the expiratory diameter of the IVC possibly impairs the diagnostic accuracy of cIVC but improves clinical feasibility.

In a small and selected population of spontaneously breathing patients with cardiac arrhythmia, the collapsibility index and the inspiratory diameter of the IVC accurately predict fluid responsiveness during infection-related acute circulatory failure. A standardized, deep inspiration might improve their sensitivity to detect fluid responsiveness without altering their specificity. The simplicity and rapidity of the measurement of the inspiratory diameter of the IVC may make it a useful tool for fluid management at patients’ bedside. However, the several limitations raised in this work should lead to a cautious interpretation of the results, which need to be confirmed in a larger-scale study before considering any clinical application.