Value of respiratory variation of aortic peak velocity in predicting children receiving mechanical ventilation: a systematic review and meta-analysis

Fluid resuscitation is the cornerstone of fluid management wherever in ICU or in perioperative period. Excessive volume expansion increases the risk of pulmonary edema, impairs the cardiac ventricular function, and even causes renal dysfunction [1]. However, hypovolemia could also lead to oxygen deliver disorder in critical organs which poses a great threat to life [2, 3].

Different from adult patients, pediatric patients possess larger ratio of body surface area to weight and higher water quality. Physically, children’s body compositions such as water proportion or muscle proportion are changing as they grow older, especially rapidly changing in preterm and term infants during the first 12 months of life [4]. Moreover, the myocardial structure of the heart, particularly the volume of cellular mass devoted to contractility, is significantly less developed in neonates than in adults. These differences, as well as developmental changes in contractile proteins, produce a leftward displacement of the cardiac function curve and less compliant ventricles. This developmental immaturity of myocardial structures also accounts for the tendency toward bi-ventricular failure, sensitivity to volume loading, poor tolerance of increasing afterload, and heart rate-dependent cardiac output [5, 6]. Due to pediatric patients’ special physical body structure, those deleterious effects caused by inappropriate fluid therapy should be taken more seriously in children. Therefore, physicians need to make a prompt and precise clinical decision in preloading judgment for children.

Considering special physical structure, it is hard to accurately assess children volume state in many situations. Clinically, many monitoring indices are applied to help physicians to assess fluid responsiveness. Traditional static indices, such as blood pressure (BP), central venous pressure (CVP), and pulmonary artery wedge pressure (PAWP), although are important but of limited sensitivity and specificity, especially in intra-abdominal hypertension, one lung ventilation, and prone position [7‐9]. The famous Frank–Starling Law mandates that, in a certain range capability, the heart could adjust ventricular contractility and cardiac ejection to dynamic changes in ventricular filling [10, 11]. According to this, usually, a patient, who has the increment over 15% or 10% from baseline measurements in physiological parameters after volume expansion, is defined as fluid responsiveness positively [12‐14]. Usually, indices which are directive to reflect cardiac ejection, such as stroke volume (SV), cardiac output (CO), cardiac index (CI), were seen as the gold standard indices to judge fluid responsiveness [14]. However, the measurement of the gold standard indices needs invasive operation and expensive monitoring equipments although they are accurate. Over the last decade, hemodynamic parameters, such as stroke volume variation (SVV) or pulse pressure variation (PPV), were reported to have a strong capability to assess fluid responsiveness during ventilation [15‐17]. These hemodynamic parameters are based on heart-lung interaction that, in the air-tight thoracic construction, mechanical ventilation introduces cyclic changes in preload, leading to matched cardiac ejection and pulse pressure variation [18, 19]. However, the expensive equipment and invasive procedure also restrict the widespread application of these parameters.

Recently, noninvasive dynamic indices that calculate variation of peak velocity of the artery during several respiratory cycles measured by ultrasound have become an alternative quick volume assessment method [20, 21]. However, vessels in pediatric patients are thinner and more variable than adults. These distinctions bring challenges to noninvasive ultrasonagraphic techniques in children. Among all the vessels, the aortic artery is the largest and the nearest vessel next to cardiac ejection and is feasible and available to access whenever in ICU or in operating room. A recent review has reported that only respiratory variation in aortic blood flow peak velocity (△VPeak) has the capability to predict fluid responsiveness in children rather than SVV or PPV [22]. In 2015, a meta-analysis of 6 studies concluded that △VPeak showed good diagnostic accuracy in ventilated children [23]. However, it failed to find the optimal △VPeak threshold and potential factors that influence the accuracy of △VPeak due to limited included studies.

Our research was conducted to estimate the diagnostic accuracy of △VPeak as a predictor of fluid responsiveness in ventilated children, explore the potential factors that influence the accuracy of △VPeak, and analyze the most accurate threshold of △VPeak to predict fluid responsiveness in ventilated children.

Our systematic review and meta-analysis found that overall, △VPeak performed well in predicting fluid responsiveness of ventilated children, with pooled sensitivity of 0.85, pooled specificity of 0.89, and AUSROC of 0.91. We synthesized the mean, median, and scatter plot to estimate that the most accurate value of △VPeak for prediction of fluid responsiveness in ventilated children is reliable between 12 and 13%. However, the accuracy of △VPeak decreased in children less than 25 months.

As we all know, each cardiac contraction brings a stroke volume from the left ventricle, and the blood flow passes through the vessel tract at different speed depending on the amount of blood ejection, the diameter of the tract, and blood velocity. In fact, △VPeak measured by ultrasound is similar to SVV, but it transforms invisible stroke volume to digital speed as an alternation. According to Rudnick’s theory, the closer the measurement position to cardiac ejection, the more accurate the prediction for hemodynamic indices to reflect central perfusion [41]. In our study, △VPeak showed a strong ability to predict fluid responsiveness in ventilated children, with AUSROC more than 0.9 and high sensitivity and specificity.

Desgranges et al. [23] first performed a six study systematic review and meta-analysis, but it failed to find optimal threshold value for △VPeak to predict fluid responsiveness in ventilated children due to extent variation of △VPeak cutoff value and inadequate data. However, more studies were published in the recent years, and comparing with demonstrating △VPeak is capable for predicting fluid responsiveness of ventilated children, acquiring optimal △VPeak threshold value of prediction possesses more clinical value. In a similar meta-analysis of respiratory variation in inferior vena cava diameter (△IVC), Si et al. [42] directly calculated the mean cutoff value of △IVC with only six studies in subgroups as the optimal threshold value of △IVC. In our scatter pot of △VPeak cutoff value, we observed that the cutoff value of △VPeak distributed symmetrically around the value of 12 to 13% [43]. And excluding several extreme studies, most data were centered between 12 and 13%. Combining mean and medium values, we estimated the most accurate value of △VPeak for prediction of fluid responsiveness in ventilated children is between 12 and 13%.

The extreme △VPeak cutoff values in our systematic review were 7% and 20%. Renner [32] performed volume expansion and △VPeak measurement after induction of anesthesia and before surgery. Without any fluid loss and hemodynamic alteration induced by surgery, such as trauma [44] and incision evaporation, patients possessed a stable volume state, and we observed a smaller value of △VPeak in Renner’s study than in other included studies, with 10.1% and 5.2% separately in responsive and non-responsive group before fluid loading, which could be the reason for only 7% cutoff value of △VPeak. Besides, fluid time is defined as the time of fast volume expansion with colloid 400–600 ml or crystalloid 300–1000 ml, usually within 30 min [45], while Renner’s study did not clarify fluid time of volume expansion. Recent evidence indicated that fluid responsive proportion decreased as fluid time extended [14], which could be a mixed factor for the cutoff value of △VPeak in Renner’s study. In another extreme condition, Choi et al. [31] got a 20% cutoff value for △VPeak. Compared to other included studies, Choi chose 1 h after arriving at ICU as measurement time point in cardiac surgery children. However, not only blood loss caused absolute inadequate volume state, trauma and stress could also rise plant nerve disorder, leading to relative hypovolemia [46, 47]. What is more, 1-h treatment in ICU may also increase variations in the hemodynamic state. Evidence shows that postoperative hemorrhage is a frequent complication after cardiac surgery [48], and patients after cardiac surgery represent a challenging high-risk population with specific requirements in catecholamine and fluid therapy in face of compromised cardiac performance and pronounced systemic inflammatory response after cardiopulmonary bypass [49]. Considering reasons above, patients were in high degree hypovolemia state before volume expansion, and we indeed observed a larger value of △VPeak in both groups, which could finally rise for large cutoff value of △VPeak.

In a subgroup analysis, compared to total data analysis, the prediction accuracy of △VPeak decreased in the younger age group (mean age < 25 months) and increased in the older age group (mean age > 25 months), indicating that clinicians should be cautious to apply △VPeak in younger children, especially children under 25 months, which was not mentioned in the previous study. Compared to Desgranges et al. [23], studies that gave a lower area under the curve of ROC (less than 0.8) emerged only in new studies published in recent years, and we have reasons to believe age is a potential factor to predictive accuracy of △VPeak. We consider inaccurate prediction of △VPeak could be relative to anatomical variation in younger children due to distinctive development, especially in children with congenital heart defects [50]. Studies reported that cardiac function in the immature left ventricle might be characterized by a higher basal contractile state, reduced compliance, and greater sensitivity to changes in afterload [51‐53]. Moreover, Wolf et al. [53] found the neonatal myocardium is less responsive to preload and is vulnerable to overfilling. Due to limited data in different months phase, we failed to conclude the exact age group that optimally suitable for △VPeak. But children more than 3 years old could be more reliable on clinical work because of mature organs of the heart and vessels. With respect to the measurement tool of △VPeak, we are interested to find all younger group studies included in our research measured △VPeak by transthoracic or transoesophageal echocardiography. So far, no direct evidences have shown the distinction between transthoracic and transoesophageal echocardiography or the two methods could substitute for each other, but the closer measurement position to cardiac ejection, the more accurate to reflect central perfusion [41], and the two measurement methods both take close position to cardiac ejection. We concluded transoesophageal echocardiography had similar or slightly higher accuracy. Vasoactive drugs could activate α and β receptors in the heart and vessels, augment heart rate, and increase cardiac afterload, which could influence volume state and velocity of cardiac ejection. However, Sakai et al. [54] examined the effects of adrenaline administration on changes in circulatory dynamics and cardiac function in rats pretreated with chlorpromazine, and consequently found SV did not change significantly, and SVV significantly reduced at 1 and 2 min after treatment with adrenaline, but returned back to baseline thereafter. In our study, seven included studies used vasoactive drugs, and the vasoactive group yielded an area under SROC of 0.92, which was similar to total data, indicating vasoactive drugs had no significant impact on △VPeak.

In our study, overall data Cochran’s Q and I² statistical analysis shown no significant heterogeneity, but significant heterogeneity for sensitivity existed and we still cannot rule out any potential heterogeneity. The threshold effect is one of the main causes of heterogeneity in diagnostic tests due to different cutoff values used in different studies to determine a positive (or negative) result. The Spearman correlation coefficient value in our study was 1, which meant the heterogeneity could be fully explained by the threshold effect [55, 56], which has not been explained in Desgranges’ study [23].

There are some limitations in our study. Firstly, sample size and study numbers in our meta-analysis were limited, although they were twice the number than previous studies. We included 11 diagnostic tests distributed between 2008 and 2018, with only 302 sample sizes, which were much smaller than the similar scale meta-analysis [42]. We attributed this phenomenon to the fact that ventilated children requiring △VPeak measurement were most critical or severe trauma, such as cardiac surgery, neurosurgery, or complicated diseases hospitalized in ICU. This population was rather small and each clinical study included in our meta-analysis collected limited samples. However, even under this condition, a meta-analysis still provided valuable information on the diagnostic accuracy until proven by larger or better-conducted studies [57]. Secondly, time of volume expansion was different or not clarified in our included studies. In the recent years, Toscani and colleagues [14] conducted a large sample meta-analysis finding that responsive proportion of population had no significant correlation with the type and volume of fluid but decreased with long infusion time, especially more than 30 min. Although most included studies in our meta-analysis restricted infusion time less than 20 min, we still could not exclude infusion time as a factor for △VPeak accuracy. Thirdly, except Favia et al. [38] using the peripheral artery wave contour analysis technique, the gold standard index was measured by transthoracic or transoesophageal echocardiography. To our knowledge, the closer measurement position to cardiac ejection, the more accurate prediction for hemodynamic indices to reflect central perfusion [41]. However, we failed to find difference after excluding Favia’s study (see Additional file 2), but we still could not rule out reference index measurement as a potential factor that influence accuracy of △VPeak, and more studies in the future could bring different results. Fourthly, included studies picked different time to start fluid challenge and △VPeak measurement, such as after anesthesia, during surgery, sternum closure, or even arriving at ICU. However, complicated operating procedure could rise variable hemodynamic state in different measurement points, which could not be neglected to our meta-analysis. Lastly, in subgroup analysis, we found age was a factor that influenced △VPeak accuracy. However, due to included studies providing a mean value of age rather than a limited scale of age, we only found a decline tendency of prediction accuracy of △VPeak rather than giving an accurate value of age that △VPeak should be recommended applied in. Therefore, more new studies are needed to be done in the future.

Overall, △VPeak has a good ability in predicting fluid responsiveness of children receiving mechanical ventilation and the optimal threshold value of △VPeak to predict fluid responsiveness is reliable between 12 and 13%. However, we observed that this ability decreased in younger children, especially mean age less than 25 months; thus, we expect more studies to make a statistic treatment in the future.