Real-Time Continuous Glucose Monitoring Reduces the Duration of Hypoglycemia Episodes: A Randomized Trial in Very Low Birth Weight Neonates

<div><p>Objectives</p><p>Hypoglycemia is frequent in very low birth weight (VLBW) neonates and compromises their neurological outcome. The aim of this study was to compare real-time continuous glucose monitoring system (RT-CGMS) to standard methods by intermittent capillary blood glucose testing in detecting and managing hypoglycemia.</p><p>Study design</p><p>Forty-eight VLBW neonates were enrolled in this prospective study. During their 3 first days of life, their glucose level was monitored either by RT-CGMS (CGM-group), or by intermittent capillary glucose testing (IGM-group) associated with a blind-CGMS to detect retrospectively missed hypoglycemia. Outcomes were the number and duration of hypoglycemic (≤50mg/dl) episodes per patient detected by CGMS.</p><p>Results</p><p>Forty-three monitorings were analyzed (IGM n = 21, CGM n = 22), with a median recording time of 72 hours. In the IGM group, blind-CGMS revealed a significantly higher number of hypoglycemia episodes than capillary blood glucose testing (1.2±0.4 vs 0.4±0.2 episode/patient, p<0.01). In the CGM-group, the use of RT-CGMS made it possible (i) to detect the same number of hypoglycemia episodes as blind-CGMS (1.2±0.4 episode/patient), (ii) to adapt the glucose supply in neonates with hypoglycemia (increased supply during days 1 and 2), and (iii) to significantly reduce the duration of hypoglycemia episodes per patient (CGM 44[10–140] min versus IGM 95[15–520] min, p<0.05). Furthermore, it reduced the number of blood samples (CGM 16.9±1.0 vs IGM 21.9±1.0 blood sample/patient, p<0.001).</p><p>Conclusion</p><p>RT-CGMS played a beneficial role in managing hypoglycemia in VLBW neonates by adjusting the carbohydrate supply to the individual needs and by reducing the duration of hypoglycemia episodes. The clinical significance of the biological differences observed in our study need to be explored.</p></div

Daily carbohydrate supplies in IGM- and CGM-group.

<p>Results, expressed as mean ± SE, represent daily carbohydrate supplies during the first 4 days of life in IGM versus CGM-group (A), and in patients with (HYPO) versus without (NORMO) hypoglycemia in each group (B and C); *p<0.05.</p

Characteristics of the 48 very low birth weight newborns with intermittent (IGM) or continuous glucose monitoring (CGM).

<p>Results are expressed as number of patients (%) or median [min-max].</p><p>*p<0.05</p><p>Characteristics of the 48 very low birth weight newborns with intermittent (IGM) or continuous glucose monitoring (CGM).</p

Comparison between IGM- and CGM-group: number of heel pricks, number and duration of hypoglycemic episodes per patient.

<p>Number of heel pricks per patient for capillary blood glucose testing (A), number (B) and duration (C) of hypoglycemic episodes per patient. Results are expressed as mean ± SE (A and B) or as median, 25% and 75% percentiles (box) and extreme values (whisker) (C) *p<0.05, ***p<0.001.</p

Computer simulation of the effects of LCAC on I_KR and the human ventricular action potential.

<p><b>A</b>, families of currents mimicking I_KR with or without acyl-CARs. <b>B</b>, action potential profile in the absence of acylcarnitine(black line) or the presence of a physiological concentration of 3 µM LCAC (red line).</p

Effect of 3 µM C16-CAR on I_KS.

<p><b>A</b>,I_KS-V curves of the current at the end of the pulse (<b>Aa</b>) and peak tail current (<b>Ab</b>)<b>. B,</b> Typical examples of families of currents in the absence (<b>Ba</b>) and presence of C16-CAR (<b>Bb</b>).</p

Effect of application of intra- or extracellular acyl-CARs on I_hERG deactivation time constants.The hERG current was fitted to a two exponential function (see Methods for details).

<p>The values of tau1 and tau2 are given in ms. Values were obtained when the membrane potential returned to −55 mV after stepping to −10 mV for 5s. *p<0.05, ** p<0.01.</p

Effect of extracellular C18-CAR on hERG activation and availability.

<p><b>A</b>. Activation curve in PSS (squares): V_½  =  −20.3±0.1 mV (n = 10); in the presence of 1 µM C18-CAR (circles): −22.8±0.1 mV (n = 8); in the presence of 3 µM C18-CAR (diamonds): −30.0±0.3 mV (n = 8) and in the presence of 10 µM C18-CAR (triangles): −31.9±0.9 mV (n = 4). <b>B</b>. Availability curve in PSS (squares): V_½  =  −40.9±2.3 mV (n = 8); in the presence of 1 µM C18-CAR (circles): V_½ =  −36.2±3.1 mV (n = 8); in the presence of 3 µM C18-CAR (triangles): V_1/2 =  −34.8±1.4 mV (n = 8) and in the presence of 10 µM C18-CAR (diamonds): V_1/2 =  −35.6±2.1 mV.</p

Effect of C16-CAR on I_K1.

<p><b>A</b>, mean current measured at −120 mV and normalized to the current in PSS (n = 7 cells). <b>B</b>, typical example of I_K1 elicited by a ramp of voltage between −120 and +40 mV, with (red) or without (black) 10µM C16-CAR.</p

Effect of extracellularacyl-CARs on I_hERG.

<p>I_hERG-V relationships,in all graphs, the filled squares represent the current in the absence of acyl-CAR in the pipette (control, n = 12 cells). <b>Aa</b>, effect of 3 µM C8-CAR (empty circles, n = 8 cells) or 3 µM C10-acyl-CAR (filled circles, n = 7 cells); <b>Ab</b>, typical example of C8-CAR (red) compared with PSS (black). <b>Ba,</b> effect of 3 µM C18-CAR (filled circles, n = 9 cells) on I_hERG-V relationship. The inset shows the effect of 3 µM C18-CAR on end-pulse hERG current elicited by a depolarisation to −10 mV from a holding voltage of −70 mV, obtained on a representative cell (the arrows indicate the current obtained at −10 mV during an IV protocol, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041686#s2" target="_blank">Methods</a>), ***, p<0.001. **, p<0.01.<b>Bb</b>, typical example of C18-CAR (red) compared with PSS (black).</p