Effect of etomidate on systemic and regional cerebral perfusion in neonates and infants with congenital heart disease: A prospective observational study

Neonates and infants with congenital heart disease undergoing general anesthesia have an increased risk for critical cardiovascular events. Etomidate produces very minimal changes in hemodynamic parameters in older children with congenital heart disease. There is a lack of studies evaluating the effect of etomidate on systemic and regional cerebral perfusion in neonates and infants with congenital heart disease.


| INTRODUC TI ON
Infants undergoing general anesthesia have an increased risk for severe cardiovascular critical events. 1 Especially in newborns or infants with limited hemodynamic reserve, induction of anesthesia has to be performed very carefully, including a critical, rational choice of the induction agent to be used. Propofol has a rapid onset of sedation and relaxes the oropharyngeal musculature, an effect that facilitates laryngoscopy and tracheal intubation. It remains the induction drug of choice for many older infants in daily routine, but may lead to hypotension. 2,3 Thiopental has fewer cardiovascular effects in neonates 4 and small infants, and is therefore a good alternative for these patient groups, but was recently temporarily not available on the European market. As it is not associated with clinically significant hypotension, etomidate is often used in children with head injury, 5 in the emergency department setting 6 and for induction of children with severe congenital heart disease (CHD). 7 It is important to realize that, especially in neonates and small infants, normal blood pressure does not automatically reflect normal perfusion. 8 After administration of etomidate, cardiac catheterization studies demonstrated only minimal hemodynamic responses in pediatric patients, 9,10 but these data were collected on sedated children during the catheterization procedure and may not reflect the routine induction situation. Furthermore, these studies did not include neonates and infants.
Modern non-invasive techniques for measurement of regional cerebral oxygenation (Near-infrared spectroscopy, NIRS) and cardiac index (electrical cardiometry) can report online on cerebral and systemic perfusion during induction of anesthesia. At our clinic, etomidate is routinely used for induction of neonates and infants with CHD undergoing cardiac surgery. Therefore, we conducted a prospective non-interventional observational study to evaluate the effect of etomidate on blood pressure, regional cerebral oxygen saturation, and cardiac index during a routine induction procedure.
We hypothesized that all three parameters would not change significantly and would remain stable above the predefined lower limits.  Hypotension was defined as MAP lower than 35 mm Hg and cerebral desaturation as regional cerebral oxygen saturation lower than 80% of baseline. 11 In accordance with Hsu et al, 12 a cardiac index above 2.5 L min −1 m −2 was assumed as normal.

| ME THODS
Our sample size considerations were based on the rate of desaturation in infants during general anesthesia (6.1%) published by Michelet et al 13

What is already known
Neonates and infants undergoing general anesthesia have an increased risk of severe cardiovascular critical events.
In these age groups, normal blood pressure does not automatically reflect normal perfusion. According to cardiac catheterization studies, etomidate produces only minimal hemodynamic responses in older children with congenital heart disease.

What this article adds
In neonates and infants with congenital heart disease, etomidate does not impair systemic or regional cerebral perfusion as measured by electrical cardiometry and nearinfrared spectroscopy.
All recorded data were analyzed using MS Excel (

| RE SULTS
A total of 50 infants with CHD were included, 12 (24%) of whom were neonates. One infant was excluded because of established inotropic support (Milrinone) prior to induction. Four infants had to be excluded because of artifact interference in the electrical cardiometry ( Figure 1). Patient characteristics are summarized in Table 1.

| D ISCUSS I ON
In line with our hypothesis, the key findings of this prospective observational study were stable systemic and regional cerebral perfusion with no episodes of hypotension or cerebral desaturation after administration of 0.4 mg kg −1 etomidate in neonates and infants with CHD.
Performing anesthesia in neonates or small infants (even without CHD) is often a challenge, and the risk for severe cardiovascular critical events is high. 1 Avoiding hypotension should always be a major goal in pediatric anesthesia. Michelet et al demonstrated in 60 infants younger than three months that systolic blood pressure variation should be maintained <20% to avoid possible cerebral desaturation. 13 This threshold can easily be exceeded if propofol is used in this age group, and the drug of choice for neonatal intubation remains controversial. 14 Thiopental seems to be more convenient, 4 but, as mentioned in the introduction, it was temporarily not available in Europe.
Infants with CHD have an increased risk for anesthesia-related morbidity and mortality. [15][16][17] Especially in infants with aortic arrest. 16 In case of cyanotic heart disease, a decrease in vascular resistance can increase right-to-left shunt volume and may lead to desaturation. Infants with heart insufficiency and limited cardiac reserve due to high left-to-right shunt volume or cardiomyopathy may be compromised by negative inotropic effects of the chosen induction drug.
Based on these considerations, children with higher ASA classes, CHD of more severity, and expected limited hemodynamic reserve tend to be induced with etomidate, ketamine, or midazolam/fentanyl. 7 Etomidate is a steroid-based carboxylated imidazole derivative that rapidly induces hypnosis following intravenous injection. Offset after a short duration of action is by redistribution. Similar to propofol, younger children require a larger bolus dose of etomidate than older children to achieve equivalent plasma concentrations. 18 In neonates and infants with CHD, the clearance is lower as compared to values for older children without CHD. 19  be demonstrated. 23 The increase in regional cerebral oxygenation after induction is common in hemodynamically stable patients and reflects pre-oxygenation and the reduced oxygen consumption during general anesthesia. Cardiac Index measured by electrical cardiometry should be seen as a trend parameter with limitations in low and high cardiac output states. 21 The results of validation studies on electrical cardiometry are conflicting, which emphasize the need for definitive validation of accuracy and precision. In a recent published review and meta-analysis on accuracy and precision of non-invasive cardiac output monitoring by electrical cardiometry, Sanders M et al demonstrate low bias for both adults and pediatrics, but the mean percentage error was not clinically acceptable. They concluded that electrical cardiometry cannot replace thermodilution and transthoracic echocardiography for the measurement of absolute cardiac output values, but that electrical cardiometry might still be applicable as a trend monitor to measure acute changes in cardiac output, which is relevant for clinical decision-making. 26