Purpose: Respiratory variation in inferior vena cava (ΔIVC) has been extensively studied in predicting fluid responsiveness, but the results are conflicting. We performed a systemic review and meta-analysis of studies aiming at investigating the diagnostic accuracy of Δ IVC in predicting fluid responsiveness. Methods: MEDLINE, EMBASE, Cochrane Database and Web of Science were screened for relevant original and review articles from inception to July 2016. The meta-analysis determined the pooled sensitivity, specificity, diagnostic odds ratio (DOR) and area under the ROC curve (AUROC). In addition, subgroup analyses were performed in mechanically ventilated patients and spontaneously breathing patients. Results: A total of 20 studies involving 635 patients were included. Cutoff values of Δ IVC varied from 12% to 42%, the pooled sensitivity and specificity was 0.68 (0.62 - 0.75) and 0.80 (0.75 - 0.85), respectively. The DOR was 14.2 (6.0 - 33.6) and the AUROC was 0.86 (0.78 - 0.93). Subgroup analysis showed better diagnostic performance in patients on mechanical ventilation than in spontaneously breathing patients with higher sensitivity (0.75 vs. 0.56), specificity (0.82 vs. 0.78), DOR (22.9 vs. 7.9) and AUROC (0.90 vs. 0.80). The best threshold of Δ IVC in patients on mechanical ventilation was IVC distensibility index ( Δ IVC ≥ 17% ± 4%), compared to IVC collapsibility index ( Δ cIVC ≥ 33% ± 12%) in spontaneously breathing patients. Conclusion: Δ IVC is not an accurate predictor of fluid responsiveness in patients with acute circulatory failure. In patients on mechanical ventilation, the predicting ability of Δ IVC was moderate with acceptable sensitivity and specificity; in spontaneously breathing patients, the specificity remains acceptable but its sensitivity is poor.
Hypovolemia is a very frequent clinical situation in the intensive care unit (ICU) and is primarily treated with volume expansion (VE). The only goal of VE is to improve the cardiac output (CO) of the patients especially those with acute circulatory failure [
Bedside point-of-care ultrasonography has gained considerable attention because of noninvasiveness, rapid diagnosis and low cost [
Following the first study demonstrating the accuracy of the ΔIVC, it has been extensively investigated for its usefulness. In 2014, a meta-analysis pooling eight studies published at that time confirmed that ΔIVC is of great value in predicting fluid responsiveness [
In order to clarify these mixed results and assess the ability of ΔIVC to predict fluid responsiveness, we conducted a systemic review of all these studies and performed a meta-analysis, with hypothesis that ΔIVC performs well in predicting fluid responsiveness.
The clinical research question was: What is the sensitivity and specificity of the ΔIVC when using it to predict fluid responsiveness?
The PICO statement is as the following:
P-patient, problem or population: patients with acute circulatory failure in whom the effect of volume expansion (VE) is unknown and needs to be predicted.
I-intervention: Inferior vena cava (IVC) diameter was examined subcostally and measured in M-mode or 2D mode, 2 cm before the IVC joined the right atrium. The IVC respiratory variation (ΔIVC) was calculate by recordingthe largest and smallest IVCdiameter at end-inspiration or end-expiration.
C-comparison, control, and comparator: Fluid responsiveness was defined as a significant increase of stroke volume (SV), cardiac output (CO) or other surrogates during a VE.
O-outcomes: Ability of the △IVC to predict fluid responsiveness.
Our aim was to identify all studies evaluating the ability of the ΔIVC to predict fluid responsiveness compared to the increase in SV, CO or other surrogates induced by subsequent VE.
We searched the MEDLINE, EMBASE, Cochrane and Web of Science databases for relative studies published in English from inception to July 2016. The key words we used consist of term related to IVC (“inferior vena cava”, “caval index”, “collapsibility” and “distensibility”) and terms related to volume status (“fluid or volume or preload responsiveness”, “fluid or preload challenge”, “preload dependence or independence or dependency or independency”, “functional haemodynamic monitoring” and “fluid therapy or management”). These key words were searched separately by two groups using different combination strategy. We also looked for relevant articles cited in review articles, commentaries and editorials. The search was performed repeatedly until no new studies could be found.
Study identification was performed in two steps. Step 1 comprised screening for titles and abstracts, and step 2, review of full texts of studies obtained in step 1. We only included studies investigating the accuracy of the △IVC that were published in full text or accepted for publication in indexed journals. Excluded criteria were 1) studies using central venous pressure or right atrial pressure as the reference standard, because these static parameters cannot predict fluid responsiveness accurately; 2) studies measuring IVC with techniques other than ultrasonography; 3) studies involving animals and healthy volunteers. Two reviewers process searching independently, disagreement was settled by a third opinion. The quality of the included studies was evaluated by using the QUADAS-2 scale [
Important information was extracted from the included articles using a standardized data form by two reviewers. Extracted data include the name of the first author, publication year, characteristics of the investigated population, sample size, respiratory pattern, the device for IVC measurement, formula for the calculation of ΔIVC, definition of fluid responsiveness and volume challenge strategy, the number of true positives, true negatives, false positives and false negatives, sensitivity, specificity, the area under the receiver operation characteristics curve (AUROC) and the best threshold of ΔIVC which is used to predict the fluid responsiveness.
Included studies were assessed for their quality based on the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) protocol. QUADAS-2 scale [
We performed a meta-analysis in order to determine the pool sensitivity, specificity and diagnostic odds ratio (DOR). In addition, the pooled area under the ROC curve (AUROC) and threshold for ΔIVC as a predictor of fluid responsiveness was also evaluated. To investigate a threshold effect, we calculated the Spearman correlation coefficient between sensitivity and specificity. Homogeneity between studies was tested by the Chi squared test and I2 index. According to heterogeneity, we adopted a random effect model by using the method of DerSimonian-Laird from the Mantel-Haenszel model. We compared studies with ICU setting versus non-ICU setting making the hypothesis that ΔIVC could be more reliable in ICU patients. We compared studies with adults versus children making the hypothesis that ΔIVC could be more reliable in adults. We compared studies with different devices for measuring IVC making the hypothesis that one device is better than the others. We compared studies with three different formulas for the calculation of ΔIVC making the hypothesis that one formula is better than the others. We compared studies with patients on mechanical ventilation versus studies with spontaneously breathing patients, testing the hypothesis that the reliability of ΔIVC is better in patients on mechanical ventilation. We compared studies where fluid responsiveness was defined by an increase in SV, CO or surrogate ≥ 15% versus studies with other definitions of fluid responsiveness, testing the hypothesis that the reliability of ΔIVC is better when fluid responsiveness is defined by a larger increase. We compared studies where SV, CO or surrogate were measured by echocardiography versus studies where they were measured by other methods, testing the hypothesis that the reliability of ΔIVC is better when SV, CO or surrogate were measured by echocardiography. Finally, we compared studies where VE was performed with versus studies where it was performed by colloids, testing the hypothesis that the reliability of ΔIVC is better when VE is performed with colloids. Causes of heterogeneity were also investigated by meta-regression based on the Littenberg and Mose linear model.
Results are expressed as mean (95% confidence interval) or as mean ± standard deviation. The meta analysis was performed with Meta-Disc v.1.4 (Universidad Complutense, Madrid, Spain). The additional statistical analysis was performed with MedCal 15.2.2 (MedCal Software, Mariakerke, Belgium). A two-tailed p < 0.05 was considered to statistical significance.
A flow chart of the study selection is provided in
Characteristics of included studies are listed in
Study | Type of patients | Sample size | Setting | Type of device | Method for reference standard | Respiratory pattern | Index formula | reference standard | volume expansion |
---|---|---|---|---|---|---|---|---|---|
Barbier et al. 2004 [ | adults | 20 | ICU | Philips | Echocardiography | Mechanical ventilation (TV = 8.5 ± 1.5 mL/kg; PEEP = 4 ± 2 cm H2O) | (IVCmax − IVCmin)/IVCmin | CI > 15% | 7 ml/kg plasma |
Feissel et al. 2004 [ | adults | 39 | ICU | Not mention | Echocardiography | Mechanical ventilation (TV = 8 - 10 mL/kg) | (IVCmax − IVCmin)/[(IVCmax + IVCmin)/2] | CO > 15% | 8 ml/kg 6% hydroxyethlstarch |
Moretti and Pizzi 2010 [ | adults | 29 | ICU | Esaote MyLab 30 CV | Transpulmonary, thermodilution | Mechanical ventilation (TV = 8 mL/kg; PEEP = 0 cm H2O) | (IVCmax − IVCmin)/IVCmin | CI > 15% | 7 ml/kg 6% hydroxyethlstarch |
Deok et al. 2010 [ | children | 21 | Pediatrics | Acuson Cypress Diagnostic Ultrasound System | Echocardiography | Mechanical ventilation (TV = 10 mL/kg; PEEP = 0 cm H2O) | (IVCmax − IVCmin)/[(IVCmax + IVCmin)/2] | SV > 15% | 10 ml/kg 6% hydroxyethlstarch |
Machare-Delgado 2011 [ | adults | 25 | ICU | M-turbo, Sonosite, Bothell | Echocardiography | Mechanical ventilation (TV = 8.6 mL/kg) | (IVCmax − IVCmin)/IVCmin | SVI > 10% | 500 ml saline |
Corl et al. 2012 [ | adults | 26 | ED | M-turbo, Sonosite, Bothell | ICG | Spontaneously breathing | (IVCmax − IVCmin)/IVCmax | CI > 10% | passive leg raise |
Muller et al. 2012 [ | adults | 40 | ICU | Vivid S6 machine, GE | Echocardiography | Spontaneously breathing | (IVCmax − IVCmin)/IVCmax | VTI > 15% | 500 ml 6% hydroxyethlstarch |
Brun et al. 2013 [ | adults | 23 | Anesthesiology and obstetrics | Philips | Echocardiography | spontaneously breathing | (IVCmax − IVCmin)/[(IVCmax + IVCmin)/2] | SVI > 15% | 500 ml normal saline |
Byon HJ 2013 [ | children | 33 | Operation room | Vivid 7, Pro, GE | Echocardiography | Mechanical ventilation (PEEP = 0 cm H2O) | (IVCmax − IVCmin)/[(IVCmax + IVCmin)/2] | SVI > 10% | 10 ml/kg hydroxyethlstarch |
---|---|---|---|---|---|---|---|---|---|
Baker et al. 2013 [ | adults | 25 | ICU | Philips | Echocardiography | Mechanical ventilation (TV 6 - 8 mL/kg; PEEP 5 - 8 cmH2O | (IVCmax − IVCmin)/IVCmin | SV > 15% | 500 ml colloid |
Lanspa et al. 2013 [ | adults | 14 | ICU | Philips | Echocardiography | Spontaneously breathing | (IVCmax − IVCmin)/IVCmax | CI > 15% | 10 ml/kg crystalloid |
Charbonneau et al. 2014 [ | adults | 44 | ICU | Philips | Echocardiography | Mechanical ventilation (TV = 6.4 - 11.0 mL/kg; PEEP = 5- 12 cm H2O) | (IVCmax − IVCmin)/IVCmin | CI > 15% | 7 ml/kg 6% hydroxyethlstarch |
de Valk et al. 2014 [ | adults | 45 | ED | Zonare, Mountain View | Systolic blood pressure | Spontaneously breathing | (IVCmax − IVCmin)/IVCmax | SBP > 10 mmHg | 500ml 0.9% NaCl |
Sobczyk et al. 2015 [ | adults | 50 | ICU | Philips | Echocardiography | Mechanical ventilation (TV = 8 mL/kg; PEEP = 4.5 cm H2O | (IVCmax − IVCmin)/IVCmin; (IVCmax − IVCmin)/IVCmax | CO > 15% | 2625 ± 778 mL within the first 6 hours |
Lujan,varas et al. 2015 [ | adults | 15 | ICU | Not mention | Picco, Vigileo, Swan-Ganz | Mechanical ventilation (PEEP11.4 ± 3.74) | (IVCmax − IVCmin)/IVCmin | CO > 15% | passive leg raise |
Airapetian et al. 2015 [ | adults | 59 | ICU | Philips | Echocardiography | Spontaneously breathing | (IVCmax − IVCmin)/IVCmax | CO > 10% | 500 ml saline |
Weber et al. 2015 [ | children | 31 | PICU | Vivid S6; GE | Echocardiography | Mechanical ventilation (TV = 7.9 ± 3.8 mL/kg; PEEP = 6.8 ± 1.8 cm H2O) | (IVCmax − IVCmin)/IVCmin | SVI > 10% | 10 ml/kg 6% hydroxyethlstarch |
Achar et al. 2016 [ | children | 42 | Operation room | Vivid e; GE | Echocardiography | Mechanical ventilation (TV = 10 mL/kg; PEEP = 0 cm H2O) | (IVCmax − IVCmin)/IVCmin | SVI > 15% | 10 ml/kg 1% dextrose Ringer’s lactate |
---|---|---|---|---|---|---|---|---|---|
Sobczyk et al. 2016 [ | adults | 35 | ICU | Philips | Echocardiography | Mechanical ventilation (TV = 8 mL/kg; PEEP = 4.5 cm H2O) | (IVCmax − IVCmin)/IVCmin | CO > 15% | 250 ml saline |
de Oliveira et al.2016 [ | adults | 20 | ICU | Samsung Medison | Echocardiography | Mechanical ventilation (TV = 8 mL/kg; PEEP = 5 - 6 cm H2O) | (IVCmax − IVCmin)/IVCmin | VTI > 15% | 500 crystalloid |
IVCmax and IVCmin = maximum and minimum diameter of inferior vena cava during a complete respiratory cycle; CI = cardiac index; CO = cardiac output; VTI = velocity-time index; SV = stroke volume; SVI = stroke volume index; SBP = systolic blood pressure; TV = tidal volume.
small, ranging from 14 to 50 patients. A total of 635 patients were included. 16 studies [
The diagnostic performance of ΔIVC in each study is showed in
Study | TP | FP | FN | TN | Cutoff value | Sensitivity (%) | Specificity (%) | AUROC (95% CI) |
---|---|---|---|---|---|---|---|---|
Barbier et al. 2004 | 9 | 1 | 1 | 9 | 18% | 90.00 | 90% | 0.91 (0.84, 0.98) |
Feissel et al. 2004 | 14 | 1 | 2 | 22 | 12% | - | - | - |
Moretti and Pizzi 2010 | 12 | 0 | 5 | 12 | 16% | 70.59% | 100% | 0.902 (0.733, 0.979) |
Deok et al. 2010 | - | - | - | - | - | - | - | 0.85 (0.69, 1.00) |
Machare-Delgado 2011 | 8 | 8 | 0 | 9 | 12% | 100.00 | 53% | 0.81 (0.64, 0.99) |
Corl et al. 2012 | - | - | - | - | - | - | - | 0.46 (0.21, 0.71) |
Muller et al. 2012 | 14 | 4 | 6 | 16 | 40% | 70 | 80% | 0.77 (0.60, 0.88) |
Brun et al. 2013 | - | - | - | - | - | - | - | 0.57 (0.32, 0.82) |
Byon HJ 2013 | - | - | - | - | - | - | - | 0.369 (0.156, 0.582) |
Baker et al. 2013 | - | - | - | - | - | - | - | 0.46 (0.22 - 0.69) |
Lanspa et al. 2013 | 5 | 3 | 0 | 6 | 15% | 100 | 66.66% | 0.83 (0.58 - 1.0) |
Charbonneau et al. 2014 | 10 | 7 | 16 | 11 | 21% | 38 | 61% | 0.43 (0.25, 0.61) |
de Valk et al. 2014 | 10 | 11 | 2 | 22 | 36.5 | 83 | 67% | 0.741 |
Sobczyk et al. 2015 | - | - | - | - | - | - | - | - |
Lujan, varas et al. 2015 | 2 | 2 | 1 | 10 | 18% | - | - | - |
Airapetian et al. 2015 | 9 | 1 | 20 | 29 | 42% | 31 | 97% | 0.62 ± 0.07 (0.49 - 0.74) |
Weber et al. 2015 | - | - | - | - | - | - | - | 0.502 (0.29, 0.71) |
Achar et al. 2016 | 22 | 2 | 2 | 16 | 23.5% | 91 | 89% | 0.94 |
Sobczyk et al. 2016 | 20 | 3 | 4 | 8 | 18%- | 82.35%- | 72.72%- | 0.739 |
de Oliveira et al. 2016 | 6 | 0 | 3 | 11 | 16% | 66.67 | 100% | 0.84 ± 0.10 (0.63 - 1.0) |
TP = true positive; FP = false positive; FN = false negative; TN = true negative; AUROC = area under the receiver operating characteristic curve; CI = confidence interval.
sensitivity and specificity was reported in 14 studies [
The Spearman correlation coefficient between sensitivity and specificity was 0.323 (p = 0.260), indicating no threshold effect. The heterogeneity Chi-squared was 56% for sensitivity and 39% for specificity. The I2 statistics was 77% for sensitivity, 66% for specificity.
Meta-regression shows none of the covariates included were the significant source of heterogeneity. However, the comparison between studies with mechanical ventilation versus studies with spontaneously breathing, and between
studies with different devices and formulas for the calculation of ΔIVC had influence on sensitivity and specificity. Diagnostically, ΔIVC performed better in patients on mechanical ventilation than in spontaneously breathing patients with higher sensitivity (0.75 vs.0.56), specificity (0.82 vs. 0.78), DOR (22.9 vs. 7.9), and AUROC (0.9 vs.0.8) (
This meta-analysis including 20 studies with a combined total of 635 patients concluded that ICU staff must be cautious of using ΔIVC, which was not so excellent to predict fluid responsiveness with pooled sensitivity (0.68) and specificity (0.80).In patients on mechanical ventilation, ΔIVC could predict fluid responsiveness moderately with acceptable pooled sensitivity (0.75) and specificity (0.82). The pooled AUROC was 0.90 (0.80 - 0.99) and the average of threshold was ΔIVC ≥ 17% ± 4%. However, in spontaneously breathing patients, ΔIVC predict fluid responsiveness with poor sensitivity (0.56) and acceptable specificity (0.78).
Point-of-care ultrasonography is a reliable monitoring technique and is becoming increasingly popular in the ICU. The IVC diameter is easily examined from a subcostal view in a longitudinal section, varying during the respiratory cycle due to the changes in intrathoracic pressure during inspiration and expiration. This variation is expressed as the △IVC. Recent years, ΔVC has been developed to
Setting | Total number of studies | Sensitivity (95% CI) | Specificity (95% CI) | Diagnostic odds ratio (95% CI) | Positive likelihood ratio (95% CI) | Negative likelihood ratio (95%CI) | AUROC |
---|---|---|---|---|---|---|---|
Overall | 14 | 0.68 (0.62 - 0.75) | 0.80 (0.75 - 0.85) | 14.2 (6.0 - 33.6) | 3.3 (2.1 - 5.1) | 0.34 (0.21 - 0.54) | 0.86 (0.78 - 0.93) |
Mechanical ventilation | 9 | 0.75 (0.67 - 0.82) | 0.82 (0.74 - 0.88) | 22.9 (5.6 - 93.4) | 4.3 (2.0 - 9.4) | 0.27 (0.13 - 0.54) | 0.90 (0.80 - 0.99) |
Spontaneous breathing | 5 | 0.56 (0.45 - 0.68) | 0.78 (0.70 - 0.86) | 7.9 (3.5 - 18.1) | 2.7 (1.8 - 4.0) | 0.50 (0.29 - 0.86) | 0.80 (0.71 - 0.89) |
accurately predict fluid responsiveness in clinical practice. The consensus on circulatory shock and hemodynamic monitoring published by task force of the European Society of Intensive Care Medicine in 2014 recommended that ΔIVC as dynamic variables were available to predict fluid responsiveness [
To our knowledge, in 2014, Zhang and co-workers performed a systematic review and meta-analysis that included eight studies investigating the diagnostic performance of ΔIVC [
Our meta-analysis is inconsistent with the meta-analysis performed by Zhang et al. and concluded that ICU staff must be cautious of using ΔIVC to test fluid responsiveness. Based on the results from a large number of patients, we found that ΔIVC was not so excellent to predict fluid responsiveness with poor sensitivity (0.68) and acceptable specificity (0.80). The pooled AUROC was 0.86 but not close to each other. In addition, the threshold values for ΔIVC varied across studies, ranging from 12% to 42%, which reinforce our conclusion.
In subgroup analysis, our study indicated that in patients on mechanical ventilation, ΔIVC predict fluid responsiveness with acceptable pooled sensitivity (0.75) and specificity (0.82), which are less accurate than meta-analysis performed by Zhang et al., however. This is likely due to high PEEP and/or low tidal volume invalidating the diagnostic performance of ΔIVC. High PEEP has been demonstrated to elevate right atrial pressure (RAP) and IVC pressure, while simultaneously reducing venous return, introducing an increase IVC size and false negative of ΔIVC [
An important point that must be paid more attention to is the formula of calculation of ΔIVC. ΔIVC is usually expressed as the difference between expiratory IVC diameter and inspiratory IVC diameter divided by the expiratory IVC diameter, multiplied by 100%. However, in spontaneous respiration or mechanical ventilation, the changes of IVC diameter are opposite because of opposite changes of intrathoracic pressure during inspiration. In patients on mechanical ventilation, ΔIVC is calculated by (IVCmax − IVCmin)/IVCmin defined as IVC distensibility index (ΔdIVC), while in spontaneously breathing patients, it is calculated by (IVCmax − IVCmin)/IVCmax defined as IVC collapsibility index (ΔcIVC). In our meta-analysis, the best threshold of ΔIVC in patients on mechanical ventilation was ΔdIVC ≥ 17% ± 4%, compared to ΔcIVC ≥ 33% ± 12% in spontaneously breathing patients. Nowadays, the clinical use of ΔIVC is in chaos regardless of its physiology, leading to misjudgment, which need to be more accurate define and recognition.
There are some limitations that should be noted for interpreting the results. First, the heterogeneity of the included studies existed with respect to patient population, respiratory pattern, calculation formula, definition of index test and fluid responsiveness. Nevertheless, no threshold effect was detected. Furthermore, both the subgroup analyses and meta-regression were opposed to the influence of heterogeneity on the results. Second, although we performed subgroup analysis, the number of studies and sample size in each subgroup was small, the conclusion needs to be validated in future trials. Third, we did not include studies not in English, non-full-text and unpublished studies, which may increase the risk of reporting bias.
In conclusion, our meta-analysis indicated that ΔIVC is not an excellent predictor of fluid responsiveness in patients with acute circulatory failure. The predicting ability of ΔIVC was moderate in patients on mechanical ventilation, while it was poor in spontaneously breathing patients. Thus, intensivist must be cautious of using ΔIVC.
The authors declare no conflicts of interest regarding the publication of this paper.
Si, X., Cao, D.Y., Xu, H.L. and Guan, X.D. (2018) Meta-Analysis of Ventilated versus Spontaneously Breathing Patients in Predicting Fluid Responsiveness by Inferior Vena Cava Variation. International Journal of Clinical Medicine, 9, 760-777. https://doi.org/10.4236/ijcm.2018.910063