Metabolic Fluid Responsiveness in Children

Acute circulatory failure, defined as a mismatch between oxygen delivery and consumption, is a frequent but serious condition in children after cardiac surgery. Fluid expansion is the cornerstone of acute circulatory failure treatment, but several studies have highlighted the adverse effects of excessive fluid expansion. Therefore, it is crucial to assess the individual benefit-risk ratio before each fluid expansion. Currently, finding fluid responsiveness tests is a major issue in intensive care. Usually, fluid responsiveness is defined as a significant improvement in stroke volume after fluid expansion. However, this is an intermediate objective, as the ultimate goal of the treatment is to restore an adequate balance between oxygen delivery and consumption. In adults, a significant proportion of hemodynamically successful volume expansions (i.e. resulting in a significant increase in stroke volume) are in fact metabolically ineffective, as they do not result in a significant increase in VO2. Certain biological parameters indicating anaerobiosis, such as the Pv-aCO2/CavO2 ratio, could be predictive of metabolic fluid responsiveness (e.g. a significant increase in VO2) in these patients. This has never been investigated in children.

The main objective of this study will be to evaluate the diagnostic accuracy of the Pv-aCO2/DAVO2 ratio at baseline for the diagnosis of metabolic fluid responsiveness, in children hospitalized in intensive care after cardiac surgery, for whom a fluid expansion was prescribed by the physician in charge.

The investigators will conduct a non-interventional, multicentric diagnostic accuracy study in French pediatric intensive care units. VO2 will be measured at baseline (e.g. before fluid expansion) and within 1h after fluid expansion by the combination of echocardiographic assessment and both arterial and venous blood gas. Blood gas are routinely measured, in patients already implanted with arterial and central line, to help manage acute circulatory failure. Echocardiography assessment, which is noninvasive and nonradiative, is also a common practice in this situation. Additional simple demographic, hemodynamic and clinical data will be collected at baseline and within 1 hour after fluid expansion, if monitored. No supplemental blood test or invasive parameter will be collected. These data will be collected from standard monitoring and/or from the patient's medical record.

The primary outcome is the diagnostic accuracy (measured by the area under the receiver operating characteristics curve) of the index test (Pv-aCO2/DAVO2 ratio at baseline) for the diagnostic of metabolic fluid responsiveness, defined as a 15% increase in VO2 after fluid expansion compared to baseline (gold standard test).

• VO2 (ml/min/m2) will be measured as follow, at baseline and within 1h after fluid expansion: VO2=(10.CO.DAVO2)/(Body Surface Area)
• DAVO2: difference between arterial and venous oxygen content (measured by blood gas analysis)
• CO: cardiac output, measured by transthoracic echocardiography as the product of heart rate, left ventricular outflow tract surface (from a parasternal long axis view) and left ventricular outflow tract velocity-time integral (from an apical 5-chambers view).

The secondary outcomes are:

• Diagnostic accuracy (AUROC, %) of the following index tests for the diagnosis of metabolic fluid responsiveness: arterial lactate, central venous oxygen saturation, Pv-aCO2.
• Association between fluid expansions induced tissular oxygen saturation variation and metabolic fluid responsiveness.
• Association between metabolic fluid responsiveness and hemodynamic profile (4 categories, depending on the increase of mean arterial pressure and/or stroke volume after fluid expansion)
• Subgroup analysis of the primary outcome: age, type of fluid expansion, circulatory physiology
• Association between baseline clinical data and metabolic fluid responsiveness Study design: non-interventional study of diagnostic accuracy (non-interventional, prospective, multi center). After a prescription of 10 ml/kg volume expansion by the physician in charge, screening for inclusion and exclusion criteria will be performed by an investigator physician. If the patient is included, volume expansion will be delayed for a few minutes (<5 min) while VO2 and the index test are measured. Within one hour after volume expansion, VO2 will be measured once again to evaluate the metabolic response to fluid expansion (gold-standard test).

Inclusion criteria

Age between 0 days and 15 years old; Patient hospitalized in an intensive care unit after cardiac surgery; Prescription of a 10ml/kg fluid expansion by the physician in charge; Prescription of arterial and venous blood gas before and after the volume expansion to help manage acute circulatory failure; Patient implanted with a functioning arterial line; Patient implanted with a functioning central venous line in the superior vena cava territory Exclusion criteria: Patient less than 37 weeks' corrected gestational age; Hemodynamic instability making the delay necessary for any test dangerous; Supine position contraindicated or deleterious; Impairment of echocardiographic acoustic window or restless patient making ultrasonography impossible; Opposition to participate expressed by the patient or by a parent or legal guardian Number of subjects: One hundred and ten patients are needed. This was calculated with the Obuchowski method, with an alpha risk of 0.05, a statistical power of 80%, a ratio "responder/non-responder" of 3, a predicted area under the receiver operating characteristics curve of 0.85 (based on previous studies) with a confidence interval greater than 0.75 which is a classic threshold for clinical pertinence.

Statistical analysis: Comparisons between metabolic "responders" and "non-responders" (to fluid expansion) will be performed with Student's t-test or Mann-Whitney test for continuous variables; or with the Chi-2 test or Fisher's exact test for categorical variables.

Metabolic fluid responsiveness represents the gold standard test. Patients will be classified as metabolic fluid responders in case of at least 15% increase in VO2 after fluid expansion, compared to baseline.

Diagnostic accuracy of the index tests will be explored. As multiple cut-offs of theses index tests can be defined, the investigators will report a receiver operating characteristic (ROC) curve which graphically represents the combination of sensitivity and specificity for each possible test positivity cut-off. The area under the ROC curve informs in a single numerical value about the overall diagnostic accuracy of the index test. The Youden index will also be calculated. The ROC curves of all index tests will be compared using a DeLong test.

A p value less than 0.05 will be considered statistically significant.

Inclusion criteria

• Age less than or equal to 15 years old
• Hospitalization in a pediatric intensive care unit after cardiac surgery
• Prescription by the attending physician of a fluid expansion of 10ml/kg
• Prescription of arterial and venous blood gas before and after the volume expansion to help manage acute circulatory failure
• Patient implanted with a functioning arterial line
• Patient implanted with a functioning central venous line in the superior vena cava territory

Exclusion criteria

• Patient less than 37 weeks' corrected gestational age
• Hemodynamic instability making the delay necessary for any test dangerous
• Supine position contraindicated or deleterious
• Impairment of echocardiographic acoustic window or restless patient making ultrasonography impossible
• Opposition to participate expressed by the patient or by a parent or legal guardian