Low Dosing Norepinephrine Effects on Cerebral Oxygenation and Perfusion During Pediatric Shock

Abstract

Background: Cerebral hypoperfusion and impaired oxygen delivery during pediatric critical illness may result in acute neurologic injury with subsequent long-term effects on neurodevelopmental outcome. Yet, the impact of norepinephrine on cerebral hemodynamics is unknown in children with shock. We aimed to describe the norepinephrine effects on cerebral perfusion and oxygenation during pediatric shock.

Patients and methods: We conducted an observational multicentre prospective study in 3 French pediatric intensive care units. Children <18 years of age excluding traumatic brain injury were included in the study if they need norepinephrine for shock. Systemic and cerebral hemodynamics were compared between the time of initiation of norepinephrine (T₀), and the steady-state (T_ss). Cardiac output (CO) was measured using ultrasound. Cerebral perfusion was assessed on middle cerebral arteries (MCA) using transcranial doppler ultrasound. Cerebral tissue oxygen saturation (rScO₂) was recorded using near infrared spectroscopy, and we calculated cerebral fractional tissue oxygen extraction (cFTOE = SpO₂-rScO₂/SpO₂).

Main results: Fourteen children (median [IQR] age of 3.5[1; 13.5] years) were included. Norepinephrine at 0.2[0.1; 0.32] μg/kg/min significantly increased mean arterial blood pressure (61[56; 73] mmHg at T_ss vs. 49[42;54] mmHg at T₀, p=10^-3) without change of CO. MCA velocities, pulsatility index, rScO₂, and cFTOE did not significantly change between T₀ and T_ss. Some individuals observed variations in estimated CBF, which slightly improved in 7 patients, remained unchanged in 5, and was impaired in 2. No patient experienced significant variations of rScO₂.

Conclusions: Low-dosing norepinephrine, despite a homogeneous and significant increase in arterial blood pressure, had little effects on cerebral perfusion and oxygenation during pediatric shock. This reinforces the need for personalized tailored therapies in this population.

Trial registration: Clinicaltrials.gov, NCT03731104. Registered 6 November, 2018. https://clinicaltrials.gov/ct2/show/NCT03731104.

Keywords: cerebral oxygenation; cerebral perfusion; near infrared spectroscopy; norepinephrine; pediatric intensive care unit.

Figure 1

Evolution of (A) systemic and (B) cerebral hemodynamics during norepinephrine infusion. The central bars and diamonds represent, respectively, the medians and means; the lower and upper ends of the box represent, respectively, the 1st and 3rd quartiles; the T-bars represent the 10th and 90th percentiles; circles are outliers; *p < 0.01. DAP, Diastolic Arterial Pressure; cFTOE, cerebral Fractional Tissue Oxygen Extraction; HR, Heart Rate; MAP, Mean Arterial Pressure; MCA, Middle Cerebral Artery; PI, Pulsatility Index; RI, Resistance Index; SAP, Systolic Arterial Pressure; T₀, beginning of norepinephrine infusion; T_ss, steady-state. Median [IQR] cardiac index was 3.8 [2.8; 5.1] mL/min/m₂ at T₀ and 3.9 [3.2; 6.0] mL/min/m₂ at T_SS. Median [IQR] SAP was 77 [59; 90] mmHg at T₀ and 86 [77; 103] at T_SS. Median [IQR] DAP 35 [31; 44] mmHg at T₀ and 48 [39; 62] mmHg at T_SS. Median [IQR] MAP was 49 [42; 54] mmHgat T₀ and 61 [56; 73] mmHg at T_SS. Median [IQR] HR was 116 [108; 148] bpm at T₀ and 128 [117; 146] at T_SS. Median [IQR] right/left PI was 1.4 [0.8; 1.9]/ 1.3 [0.9; 1.6] at T₀ and 1.3 [0.9; 1.5]/ 1.2 [0.9; 1.6]at T_SS. Median [IQR] right/left mean MCA velocity was 47 [38; 64]/ 52 [45; 62] cm/sec at T₀ and 54 [46; 62]/ 57 [41; 62] cm/sec at T_SS. Median [IQR] right/left rScO₂ was 65 [61; 73]/ 65 [61; 76] % at T₀ and 64 [57; 72]/ 69 [60; 72] % at T_SS. Median [IQR] cFTOE was 34 [24; 37]/ 35 [24; 36] % at T₀ and 34 [27; 44]/ 30 [28; 38] at T_SS.

Figure 2

Individual effects of norepinephrine infusion on (A) cerebral perfusion and (B) cerebral oxygenation. Each line represents one patient. cFTOE, cerebral Fractional Tissue Oxygen Extraction; MCA Vm, Middle Cerebral Artery mean velocity; PI, Pulsatility Index; T₀, beginning of norepinephrine infusion; T_ss: steady-state.