The collapsibility index of inferior vena cava (cIVC) is widely used to decide fluid infusion in spontaneously breathing intensive care unit patients. The authors hypothesized that high inspiratory efforts may induce false-positive high cIVC values. This study aims at determining a value of diaphragmatic motion recorded by echography that could predict a high cIVC (more than or equal to 40%) in healthy volunteers.
The cIVC and diaphragmatic motions were recorded for three levels of inspiratory efforts. Right and left diaphragmatic motions were defined as the maximal diaphragmatic excursions. Receiver operating characteristic curves evaluated the performance of right diaphragmatic motion to predict a cIVC more than or equal to 40% defining the best cutoff value.
Among 52 included volunteers, interobserver reproducibility showed a generalized concordance correlation coefficient (ρc) above 0.9 for all echographic parameters. Right diaphragmatic motion correlated with cIVC (r = 0.64, P < 0.0001). Univariate analyses did not show association between cIVC and age, sex, weight, height, or body mass index. The area under the receiver operating characteristic curves for cIVC more than or equal to 40% was 0.87 (95% CI, 0.81 to 0.93). The best diaphragmatic motion cutoff was 28 mm (Youden Index, 0.65) with sensitivity of 89% and specificity of 77%. The gray zone area was 25 to 43 mm.
Inferior vena cava collapsibility is affected by diaphragmatic motion. During low inspiratory effort, diaphragmatic motion was less than 25 mm and predicted a cIVC less than 40%. During maximal inspiratory effort, diaphragmatic motion was more than 43 mm and predicted a cIVC more than 40%. When diaphragmatic motion ranged from 25 to 43 mm, no conclusion on cIVC value could be done.
In 52 spontaneously breathing healthy adults, respiratory variation of collapsibility of central vena cava (cIVC) was associated with inspiratory effort and diaphragmatic motion. This study identified a gray zone of the diaphragmatic motion ranging from 25 to 43 mm for predicting cIVC more than or equal to 40%. This study suggests, although not tested, inaccuracy of cIVC for determining fluid responsiveness when the diaphragmatic motion is more than 25 mm.
Collapsibility of central vena cava is commonly used for assessing fluid responsiveness in spontaneously breathing subjects
We know little about influence of magnitude of inspiratory efforts on the collapsibility of central vena cava
In 52 spontaneously breathing healthy adults, respiratory variation of collapsibility index of inferior vena cava (cIVC) was associated with inspiratory effort and diaphragmatic motion
This study identified a gray zone of the diaphragmatic motion ranging from 25 to 43 mm for predicting cIVC more than or equal to 40%
This study suggests, although not tested, inaccuracy of cIVC for determining fluid responsiveness when the diaphragmatic motion is more than 25 mm
THE inferior vena cava (IVC) crosses the diaphragm and the liver in front of the bodies of the 12th thoracic and the 1st lumbar vertebrae. Due to these close anatomic relations, respiratory movement and diaphragmatic contraction could theoretically affect IVC diameter. Sonography easily assesses diaphragmatic motion, which correlates to vital capacity and inspiratory workload.1–4 To our knowledge, only one study focused on the impact of diaphragmatic motion on IVC diameter.5 In this study, during constant inspiratory effort, the reduction in IVC diameter was related to diaphragmatic excursion, suggesting that the IVC may be compressed through descent of the diaphragm. Nevertheless, the influence of increasing standardized inspiratory efforts on IVC diameter variations was never studied.
The variation of IVC diameter depends on the compliance of the vessel, the central venous pressure (CVP; a surrogate of right atrial pressure [RAP]), and the intrathoracic and abdominal pressures. Therefore, heart–lung interactions and blood volume status also affect IVC diameter.6–12 In spontaneously breathing subjects, the lower the CVP is, the more the IVC diameter decreases and the more the IVC becomes collapsible during the inspiratory time.13 These form the basis of two clinically related transthoracic echocardiographic practices. Cardiologists and critical care physicians use the diameter of the IVC and its collapsibility with respiration to assess RAP and predict fluid responsiveness, if collapsibility index of inferior vena cava (cIVC) is more than 40%.14–16 However, for the latter purpose, studies never considered the magnitude of inspiratory effort and diaphragmatic motion as a confounding factor for cIVC analysis.
In order to quantify the impact of diaphragmatic motion on cIVC, we decided to study the evolution of cIVC during standardized increasing inspiratory efforts in healthy volunteers.
The main objective of the current study aimed at determining a cutoff value of diaphragmatic motion that can predict a cIVC more than or equal to 40% in healthy volunteers. The second objective was to complement this analysis by a gray zone approach.17
Materials and Methods
As required by the French law, the local ethics committee (Comité de Protection des Personnes “Sud Méditerranée III,” Nîmes, reference number 2012-A00625-38) approved the study protocol, and all healthy subjects signed an informed consent after having received oral and written information. None of them was participating in any other clinical study while this protocol was running.
This study included healthy volunteers younger than 60 yr, free of known cardiovascular diseases (cardiac insufficiency or arrhythmia), chronic obstructive pulmonary disease, or related clinical symptoms (productive cough on the early morning for smokers), and not receiving cardiac medication. For each healthy subject, the following anthropometric and clinical data were collected: sex, age, height (centimeter), weight (kilogram), body mass index (BMI; kilogram per square meter), systolic, diastolic, and mean blood pressure (mmHg); and heart rate (beats/min).
General Design of Protocol
General design of protocol is summarized in figure 1. Examples of cIVC and diaphragmatic motion pattern at low, moderate, and high inspiratory efforts (F0, F5, and F10, respectively) are shown in figure 2.
After a period of briefing for each volunteer, subjects were asked to breathe at three inspiratory effort levels: spontaneous nonforced inspiratory effort (low effort, F0), moderate inspiratory effort (F5), and high inspiratory effort (F10). In order to standardize inspiratory effort for F5 and F10, the intensity of breathing was monitored through a closed noninvasive ventilation (NIV) system connected to a ventilator (EVITA© XL, Dräger, Drägerwerk AG & Co. KGaA, Germany), set without positive airway pressure or pressure support. The subjects were then asked to generate an inspiratory effort in order to obtain a −5 cm H2O pressure (F5) and −10 cm H2O pressure (F10).
All echographic measurements were performed by a trained operator (L.M., L.G.), using a Vivid S6 machine (GE Healthcare, United Kingdom), and a transthoracic probe (1.3 to 3.3 MHz). A second trained operator, blinded to inspiratory efforts, reviewed all measurements at the end of the study.
Cardiac Echographic Measurements.
Echocardiographic examination aimed at detecting a pathologic cardiac profile that would compromise the inclusion of the subject in our study. The global cardiac function was evaluated in a supine position, on a five-chamber apical view. Left ventricular ejection fraction (normal value, more than 55%) was assessed visually,18 and filling pressures were evaluated by recording transmitral early diastolic velocity (E; normal value, more than 70 to 90 cm s−1), E:A ratio, late diastolic filling velocity (A), and early tissue Doppler diastolic velocity (Ea; normal value, 8 to 14 cm s−1) at the lateral mitral annulus.19–21 Right ventricular function was assessed in a four-chamber apical view with the systolic tissue Doppler velocity recorded at the lateral tricuspid annulus (Sa; normal value more than 10 cm s−1).14
Respiratory Variability of Inferior Vena Cava Diameter.
In the supine position, IVC diameter was assessed via a subcostal view. The IVC diameter was measured with M-mode imaging, perpendicular to its long axis, at the junction of the hepatic veins to the IVC, 0.5 to 3 cm from the right atria–IVC junction. Maximum and minimum IVC diameters (Dmax and Dmin) were measured over a single ventilatory cycle; the cIVC was determined as previously reported: cIVC= [Dmax − Dmin]/Dmax, expressed as percentage.10,15 The cIVC measurements were performed on a single respiratory cycle when a stable respiratory state was achieved (i.e., five consecutive respiratory cycles with visually similar diaphragmatic excursions and IVC diameters).
In the supine position, right and left diaphragmatic motion was recorded according to a previously validated method.1,2,22 The right diaphragm dome was visualized behind the liver on a subcostal view between the anterior and midaxillary lines, where the ultrasound beam is aligned perpendicular to the posterior part of the diaphragm. M-mode imaging was performed and diaphragmatic movement was recorded during a single respiratory cycle when the patient reached the required intensity of breathing. A similar recording was performed on a left subcostal view after visualizing the posterior part of the left diaphragm behind the spleen. Right and left diaphragmatic motions were measured as the maximal excursion (expressed as millimeters) of the diaphragm on the respective M-mode records (E-right and E-left).
Quantitative data were expressed as mean ± SD or median with 25th and 75th percentiles according to the variable distribution. Qualitative variables were expressed as frequency with percentage.
The sample size was previously determined considering a minimal sensitivity of 90% and a minimal specificity of 90% for predicting that 50% of population will demonstrate a cIVC more than or equal to 40%, whatever the breathing intensity.15,16 A minimum sample size of 32 healthy subjects was calculated as being necessary to estimate this parameter with a half precision of the CI equal to 15% and a 5% type 1 error rate, but a bigger number (n = 50) was considered necessary to minimize the risk of nonanalyzable variables. Our group recently reported that the mean cIVC value in stable patients admitted the day before elective surgery was 37%. This was a population with mainly American Society of Anesthesiologists physical status score 1 to 2 patients who could be considered as comparable to healthy volunteers.23
The interobserver variability was estimated through a generalized concordance correlation coefficient (ρc). The relationship between diaphragmatic motions and cIVC was first explored using correlation (with Spearman correlation coefficient, r estimate) and graphically (with a nonparametric local regression smoothing line using the Loess procedure). For the graph, cIVC was normalized with an arcsine square root transformation. Second, univariate analyses were performed to test the association between the cIVC and the following potential cofactors: age, sex, weight, height, and BMI. Third, a logistic mixed regression model was built with a nested data structure for the three levels of inspiratory effort within each patient. Receiver operating characteristic (ROC) curves, and its area under the curve + 95% CI were used to assess the performance of diaphragmatic motions to predict cIVC more than or equal to 40%. The robustness of the model was checked by sensitivity analyses. The accuracy of the results was checked by bootstrapping (1,000 resamples were used). The best diaphragmatic motion cutoff was defined as the one that maximizes the Youden index (sensitivity + specificity − 1).24
Finally, a gray zone approach was used. It determined a range of values for which no conclusion could be obtained when predicting cIVC.17,25 We defined as inconclusive responses the values with sensitivity less than 90% or specificity less than 90% (diagnostic tolerance of 10%). A graphical representation with two curves (sensitivity and specificity) was provided to illustrate this approach.
Correlation (with Spearman correlation coefficient) was used to compare cIVC with right and left diaphragmatic motions. Concordance (with generalized concordance correlation coefficient ρc) was used to compare right with left diaphragmatic motions.
All analyses were performed using SAS version 9.3 (SAS Institute Inc., USA) using a two-sided type 1 error rate of 5% as the threshold for statistical significance.
Among 52 included healthy volunteers, 2 were not analyzable due to a poor acoustic window. The demographic and echocardiographic findings were typical of healthy population: age, 33 ± 9 yr; weight, 67 ± 11 kg; height, 170 ± 7 cm; BMI, 23 ± 3.5 kg m−2; systolic blood pressure, 121 ± 16 mmHg; diastolic blood pressure, 74 ± 11 mmHg; mean blood pressure, 89 ± 11 mmHg; and heart rate, 68 ± 11 bpm. None of the 52 included subjects took a cardiac medication or had a pathologic profile on echocardiographic examination. Mean values for criteria evaluating left cardiac function were as follows: left ventricular ejection fraction, 61 ± 5%; E wave velocity, 77 ± 15 cm s−1; A wave velocity, 49 ± 11 cm s−1; E:A ratio, 1.66 ± 0.46; and Ea, 15 ± 3 cm s−1. Considering the right cardiac function, mean tricuspid S wave velocity was 11 ± 2 cm s−1.
Diaphragmatic Motions to Predict cIVC
Data related to diaphragmatic motions and cIVC are summarized in table 1. Measurements of left diaphragmatic motions were not possible to perform in 13 to 31 of 50 volunteers. Cardiac, diaphragmatic, and IVC echographic measurements showed a good interobserver reproducibility with a ρc more than 0.9 for all echographic parameters. Univariate analyses did not show any significant association between cIVC and age, sex, weight, size, or BMI. Thus, no adjustment was necessary for the model. There was a significant correlation between right and left diaphragmatic motions (millimeter) and cIVC (%; r = 0.64, P < 0.0001 and r = 0.61, P < 0.0001, respectively).
The cIVC and right diaphragmatic motion for the three levels of inspiratory effort are represented in figure 3 (for the graph, cIVC has been normalized with an arcsine square root transformation). At rest (F0), the mean (±SD) maximal and minimal IVC diameter values were 19 (±4) and 16 (±4) mm, respectively. Considering the principal objective (cIVC more than or equal to 40%), the logistic mixed regression model found an association to diaphragmatic motions corresponding to an odds ratio (95% CI) of 1.09 (1.06 to 1.12) for an excursion of 10 mm, 1.30 (1.19 to 1.41] for excursion of 30 mm, and 1.54 (1.33 to 1.78) for an excursion of 50 mm (P < 0.0001). The area under the curve of the ROC curve of diaphragmatic motion to predict cIVC more than 40% was 0.87 (0.81 to 0.93; fig. 4), with a best cutoff value of 28 mm (Youden Index, 0.65; sensitivity, 89%; and specificity, 77%). Considering a gray zone approach, diaphragmatic motions between 25 and 43 mm were inconclusive with sensitivity or specificity less than 90%, as represented in figure 5.
This study showed a significant correlation between IVC diameter variation and diaphragmatic motion in healthy volunteers breathing spontaneously. During standardized inspiratory efforts, the deeper the breathing, the larger the diaphragmatic excursion and collapsibility of IVC were. We found that when diaphragmatic excursion exceeded 28 mm, cIVC was likely to be more than or equal to 40%. Moreover, maximal inspiratory efforts (F10) were strongly associated with a total IVC collapse (cIVC = 100%). Finally, the gray zone approach determined a range of diaphragmatic values between 25 and 43 mm, where no clinical conclusion could be done in terms of cIVC prediction.
This study showed that respiratory variations of IVC diameter might only be due to inspiratory efforts in healthy subjects. It was already demonstrated that diaphragmatic motion could help to quantify inspiratory efforts and work of breathing.1–3 The current report highlighted the fact that breathing pattern was a critical element of IVC diameter respiratory variations. In case of F0, diaphragmatic excursions were moderate and cIVC was minimally affected. At F0, the mean value of cIVC (18% [±14]) was below the critical value of 40% (table 1).15,16 This means that without significant inspiratory effort, the IVC is not collapsible. During high respiratory efforts (F5 and F10), diaphragmatic excursions were maximal and cIVC exceeded 40% for F5 and was nearly 100% for maximal effort (F10). Therefore, a high value of cIVC was only due to inspiratory efforts and not due to a decrease of blood volume in this healthy population. In a recent study, Kimura et al.5 showed that forced spontaneous inspiration was positively correlated to cIVC, suggesting that the IVC may be compressed through descent of the diaphragm. A median diaphragmatic excursion of 34 mm was associated with high cIVC. These findings were similar to those of the current study, which included a greater number of subjects (n = 50 vs. 19).
As cIVC is also influenced by blood volume status, we chose to study healthy volunteers. We hypothesized that they would have a normal blood volume. The absolute value of blood volume can vary from a healthy volunteer to another and can also vary over time in a given subject, according to hydration status and/or fasting. In a previous study, we showed that an 8-h fasting period did not alter echocardiographic parameters of blood volume or fluid responsiveness.23 In the current study, the duration of protocol was about 45 min. Over such a short period of time, we can assume that blood volume could not significantly vary in a given subject. Therefore, we hypothesized that blood volume remained constant during the study period and that IVC diameter variations were mainly due to inspiratory efforts.
Cardiologists routinely use cIVC to assess RAP in order to calculate pulmonary artery pressure in spontaneously breathing patients. According to guidelines,14 the absolute IVC diameter and its change with a sniff maneuver are used to estimate CVP (or RAP): 3 mmHg (range, 0 to 5) if IVC diameter is less than or equal to 21 mm and cIVC is more than 50% and 15 mmHg (range, 10 to 20) if more than 21 mm and less than 50%, respectively. Indeterminate findings are used to estimate a CVP of 8 mmHg (range, 5 to 10). In the current study, the mean (±SD) IVC diameter measured at F0 (shallow respiration) was 19 mm (±4) and cIVC value was 18% at baseline. Such value argues against significant hypovolemia and reinforces the hypothesis that the included volunteers probably had a normal blood volume.
Inferior vena cava collapsibility is widely used in intensive care unit patients to assess fluid responsiveness. A high cIVC value (more than or equal to 40%) is usually associated with fluid responsiveness in ventilated and nonventilated patients.6,15,16 However, in spontaneously breathing critically ill patients, high inspiratory efforts are frequent due to respiratory failure and/or circulatory failure and/or lactic acidosis. Therefore, one clinical implication is that high inspiratory efforts should be taken into account when evaluating cIVC in clinical practice. Such hypothesis must be verified in future studies including critically ill patients. The corollary is that respiratory variations of IVC are not always due to blood volume status but can be related to maximal inspiratory effort.
Collapsibility of IVC is a dynamic index of fluid responsiveness. Dynamic indices are based on the idea that, during mechanical ventilation, cyclic intrathoracic positive pressure may induce cyclic variation of cardiac output in case of hypovolemia. The use of a dynamic index is then restricted to mechanically ventilated patients. Therefore, the use of cIVC in spontaneous ventilation could appear to be a weak physiologic concept.26 However, numerous studies showed that cIVC became a popular way to assess volume status during circulatory failure, especially in the emergency department.9,11,12,27 The brief learning curve was probably the main reason for the widespread use of cIVC. Despite the weak accuracy of dynamic indices to predict fluid responsiveness in spontaneously breathing patients,28,29 cIVC was used to assess blood volume in both ventilated and nonventilated patients.9,11,12,27 We recently showed that, in spontaneously breathing patients, a cIVC more than or equal to 40% was associated with fluid responsiveness.15 For lowest values, fluid responsiveness could not be predicted (risk of false negative). We also reported that some nonresponding patients paradoxically exhibited high cIVC values (false positive). Our current results supported the hypothesis that a high cIVC value could be induced by the breathing pattern and not only by hemodynamic status. Again, this hypothesis must be confirmed by a clinical study including critically ill patients.
As in many studies, we used a ROC curve methodology to assess the discriminative power of diaphragmatic excursion for predicting cIVC more than or equal to 40%. However, the threshold of 28 mm (Youden Index, 0.65) provides a “yes or no” binary answer that could be too stringent for clinical decision. Therefore, we chose to complement the analysis with a gray zone approach that fits better to the clinical practice.17 This produces two cutoffs that constitute the border of the gray zone. The first one, a diaphragmatic excursion below 25 mm, predicted a cIVC less than 40%. The second one, a diaphragmatic excursion over 43 mm, predicted cIVC more than 40%. For diaphragmatic motion values ranging from 25 to 43 mm, cIVC could not be predicted.
These thresholds should not be directly extrapolated from healthy volunteers to critically ill patients. Nevertheless, the current results suggested that the impact of diaphragmatic motion on cIVC should be studied in spontaneously breathing critically ill patients. If the current results are verified, the coupled assessment of cIVC and diaphragmatic motion could become the rule.
Our results were consistent. First, our study showed a good interobserver variability. Second, ultrasonography was previously shown as a reproducible method for assessing diaphragmatic movement in healthy volunteers as in critically ill patients.1,3,4,30 The normal lower limit for diaphragmatic excursion values was 9 mm for women and 10 mm for men during quiet breathing, 16 mm for women and 18 mm for men during voluntary sniffing, and 37 mm for women and 47 mm for men during deep breathing.1 These previous results were consistent with the current findings, confirming the accuracy of our methodology. The current study also confirmed that recording diaphragmatic motion was difficult at the left side, probably because of the small size of the spleen, as compared to the liver.
Some limitations should be acknowledged:
As the current study involved only healthy volunteers, the current findings should not be directly extrapolated to critically ill patients. Specific studies are needed to validate if these results are applicable to intensive care unit patients.
In this study, we assumed that blood volume was normal and stable over the study period, but this issue remains a hypothesis. Some volunteers could be slightly dehydrated and hypovolemic. Moreover, blood volume could theoretically vary even over a short period of time.
The current study did not measure transdiaphragmatic pressure (by recording esophageal and gastric pressures) to evaluate diaphragmatic function.31 We postulated that such technique could be badly tolerated in healthy volunteers.
The cIVC was measured over one respiratory cycle, not averaged over 5 respiratory cycles.
Finally, it could be argued that the diaphragm is not predominantly involved in dyspnea and deep inspiratory efforts. Indeed, not only in chronic obstructive pulmonary disease or asthma patients, but also in healthy volunteers during exercise, contribution of extradiaphragmatic muscles can be dominant for providing inspiratory efforts.32,33 Moreover, some patients breathing predominantly with intercostal muscles could not benefit from neurally adjusted ventilator assist, emphasizing the fact that diaphragm can sometimes not be the main determinant of inspiratory muscular effort.34 However, in the current study, the greater the inspiratory effort, the greater the diaphragmatic motion. Thus, in case of deep respiratory efforts associated with high diaphragmatic excursion, the risk of false diagnosis of hypovolemia exists. In such patients, diaphragmatic echography could avoid the risk of deleterious fluid challenge.
The current study showed a correlation between IVC diameter respiratory variation, inspiratory effort, and diaphragmatic motion in spontaneously breathing healthy volunteers. When diaphragmatic value was below 25 mm, cIVC was likely to be less than 40%, whereas when it exceeded 43 mm, cIVC was likely to be more than 40%. When diaphragmatic motion ranged from 25 to 43 mm, the cIVC value could not be predicted.
The authors thank Loubna Elotmani (Departments of Anesthesiology and Critical Care, CHU Caremeau, Nîmes, France), Sophie Lloret (Departments of Anesthesiology and Critical Care, CHU Caremeau), Audrey Ayral (Departments of Anesthesiology and Critical Care, CHU Caremeau), and Gilbert Saissi, M.D. (Departments of Anesthesiology and Critical Care, CHU Caremeau), for their help in data management and data collection. They also thank AzuRea group for its collaboration. See appendix for a listing.
Supported by The Nîmes University Hospital, Nîmes, France.
The authors declare no competing interests.
Appendix. AzuRea Group Members
Jean Michel Constantin, M.D., Ph.D., Department of Anesthesiology and Critical Care, University Hospital of Estaing, Clermont-Ferrand, France.
Carole Ichaï, M.D., Ph.D., Department of Anesthesiology and Critical Care, University Hospital of Nice, Nice, France.
Jean-Yves Lefrant, M.D., Ph.D., Department of Anesthesiology and Critical Care, University Hospital of Nîmes, Nîmes, France.
Bernard Allaouchiche, M.D., Ph.D., Department of Anesthesiology and Critical Care, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
Marc Leone, M.D., Ph.D., Department of Anesthesiology and Critical Care, Hospital Nord, University Hospital of Marseille, Marseille, France.