EBNEO COMMENTARY: Dextrose gel for neonates at risk with asymptomatic hypoglycemia: a randomized clinical trial
MANUSCRIPT CITATION
Gupta K, Amboiram P, Balakrishnan U, C A, Abiramalatha T, Devi U. Dextrose Gel for Neonates at Risk With Asymptomatic Hypoglycemia: A Randomized Clinical Trial. Pediatrics. 2022 Jun 1;149(6):e2021050733. doi: 10.1542/peds.2021-050733. PMID: 35582897.
REVIEWED BY
Daniela Dinu, M.D.
Associate Professor
Baylor College of Medicine, Houston, TX, United States
Email: daniela.dinu@bcm.edu
Ganga Gokulakrishnan, M.D.
Associate Professor
Medical Director Texas Children’s West Tower NICU
Baylor College of Medicine, Houston, TX, United States
E-mail: gokulakr@bcm.edu
Corresponding author
Daniela Dinu, M.D.
Associate Professor
Baylor College of Medicine, Houston, TX, United States
Email: Daniela.dinu@bcm.edu
TYPE OF INVESTIGATION
Prevention/Treatment
QUESTION
In term and late preterm infants at risk with asymptomatic hypoglycemia (P) does dextrose gel followed by breastfeeding (I) compared with breastfeeding alone (C) decrease the need for intravenous fluids (O) in the first 48 hours of life (T)?
METHODS
- Design: stratified, randomized controlled trial
- Allocation: a computer generated variable block randomization with 1:1 allocation ratio. The patients were stratified in three groups based on risk factors: small for gestational age (SGA) and intrauterine growth retardation (IUGR), infant of diabetic mothers (IDM) and large for gestational age (LGA) and late preterm. If one newborn had more than one risk factors they were stratified using the previous order.
- Blinding: the primary investigator and the primary care physician were not blinded due to unavailability of similar looking products.
- Follow-up period: at risk newborns were followed starting at 1 hour of life every 3 hours until 48 hours of life (HOL). If hypoglycemia developed by 48 HOL, then monitoring was continued until 2 consecutive glucoses were ≥ 60 mg/dL.
- Setting: a 3b tertiary neonatal care unit in South India. The study period was from October 2017 to January 2019.
- Patients:
Inclusion criteria: all inborn patients ≥ 35 weeks who were at risk of hypoglycemia and developed asymptomatic hypoglycemia in the first 48 hours of life. Newborns at risk were considered: SGA and IUGR, LGA and IDM, and late preterm. Hypoglycemia was defined using the 2011 American Academy of Pediatrics guidelines during the 3 periods: 0 to 4 HOL glucose < 25 mg/dL, 4 to 24 HOL glucose <35 mg/dL, and 24 to 48 HOL glucose <45 mg/dL.
Exclusion criteria: newborns who required resuscitation at birth, those who needed intravenous fluids and those admitted to NICU for any other reason within 48 hours of life.
- Intervention:
All babies had capilary glucose measurement at 1 HOL, 4 HOL, then every 3h until 48 HOL. The newborns enrolled in the intervention group received dextrose gel and direct breastfeeding and those enrolled in the control group received breastfeeding alone. Oral dextrose gel (40%) was administered at a dose of 200mg/kg (0.5 mL/kg) and was followed by breastfeeding and glucose monitoring 30 minutes later. Up to two consecutive doses of dextrose gel were given for an episode of hypoglycemia and a maximum of 6 doses were given within 48 HOL. All samples were capillary and analyzed using a bedside glucometer (Freestyle Optimum Neo), unless there was treatment failure, at which point venous samples were drawn for blood glucose estimation (enzyme method).
- Outcomes:
Primary outcome: to analyze the rate of treatment failure in the treatment group compared to the control group.
Secondary outcomes: to compare the proportion of neonates discharged from the hospital on exclusive breastfeeding.
- Analysis and Sample Size: in their unit, the rate of asymptomatic hypoglycemia in neonates at risk was 45%. Of those, 33% needed NICU admission for intravenous dextrose. The aim of the study was to decrease the incidence of NICU admission from 33% to 20%. With an 80% power and 5% precision, sample size was calculated to be 284 infants, with 142 in each group. 700 mothers were eligible for study with 409 excluded: Reasons for exclusion included no consent/withdrew consent, neonates needed for fluids for other reasons, babies did not develop hypoglycemia. A total of 291 babies who developed hypoglycemia were randomized: 147 in the intervention group and 144 in the control group.
- Patient follow-up: the treatment group included 147 patients, all of them had data analyzed, and the control group included 144 patients and were included in final analysis. There were no patients lost to follow up.
MAIN RESULTS
Maternal and neonatal characteristics were similar between the 2 groups (Table 1).
| Table 1. Maternal and Neonatal Baseline Characteristics | ||
| Characteristics | Dextrose gel group
(n = 147) |
Control group
(n = 144) |
| Maternal age, mean ± SD | 29.2 ± 4.56 | 29.5 ± 5.13 |
| Pregnancy induced hypertension, n (%) | 31 (21.1) | 35 (24.3) |
| Gestational diabetes, n (%) | 68 (46.3) | 70 (48.6) |
| Anemia, n (%) | 34 (23.1) | 39 (27) |
| USG Doppler abnormality, n (%) | 9 (6.3) | 6 (4.2) |
| Birth weight, g, mean ± SD | 2802 ± 618 | 2728 ± 573 |
| Male, n (%) | 77 (52.4) | 76 (52.8) |
| Cesarean section delivery, n (%) | 51 (34.7) | 47 (32.6) |
| Need for resuscitation, n (%) | 9 (6.2) | 8 (4.6) |
| Late preterm babies >35 weeks, n (%) | 55 (34.7) | 62 (43.0) |
| SGA and IUGR, n (%) | 56 (38) | 33 (38.1) |
| Infant of diabetic mother, n (%) | 68 (46.3) | 70 (48.6) |
| Median capillary blood glucose mg/dL (interquartile range)
0 – 4 h 4 – 24 h 24 – 48 h |
22 (21 – 24) 29.8 (27.5 – 31) 36 (32.2 – 39.8) |
22.3 (21 – 24.8) 32.5 (26.5 – 34.2) 37.5 (32 – 34) |
Note: 1 mg/dL glucose = 0.055 mmol/L glucose
| Table 2. Primary outcome | ||||||||||||
| Categories | SGA/IUGR | LGA/IDM | Late preterm | Total | ||||||||
| DGG | CG | p | DGG | CG | p | DGG | CG | p | DGG | CG | p | |
| Total number of failures n/N (%) | 6/49
(12.2) |
20/48
(41.6) |
<0.001 | 7/52
(13.4) |
20/46
(43.4) |
<0.001 | 4/46
(8.6) |
18/50
(36) |
<0.001 | 17/147
(11.5) |
58/144
(40.2) |
<0.001 |
| Within 0-4h | 2/21
(9.5) |
6/20
(30) |
0.09 | 2/24
(8.3) |
11/21
(52.3) |
0.001 | 2/21
(9.5) |
7/24
(29.1) |
0.1 | 6/66
(9.1) |
24/65
(36.9) |
<0.001 |
| Within 4-24h | 4/22
(18.1) |
14/27
(51.8) |
0.01 | 5/27
(18.5) |
9/27
(33.3) |
0.214 | 2/26
(7.6) |
11/24
(45.8) |
0.02 | 11/75
(15) |
34/78
(45.3) |
<0.0010/6 |
| Random blood glucose at the time of starting iv fluids (mg/dL)* | 22
(17.5-29) |
21
(18.2-26) |
0.41 | 21
(15-24) |
19.5
(17-29.2) |
0.72 | 20
(16-26)
|
20.5
(17-24) |
0.31 | 21
(16-26) |
21
(17-26) |
0.13 |
DGG dextrose gel group, CG control group, * median (range)
CONCLUSION
The authors conclude that the use of dextrose gel as a treatment for asymptomatic hypoglycemia in newborns at risk (SGA and IUGR, LGA/IDM and late preterm) in first 48 hours of life reduces the need for intravenous dextrose and NICU stay while promoting exclusive breastfeeding and mother-infant bonding.
COMMENTARY
Hypoglycemia is the most common metabolic derangement, with 5-15% of all newborns and almost 50% of those considered at risk experiencing at least one episode of low blood glucose in the first few days of life.1 Dextrose gel 40% has emerged as a safe, inexpensive and efficient method to prevent further episodes of hypoglycemia. A recent meta-analysis concluded that 40% oral dextrose gel used as treatment in late preterm and term newborns probably increases correction of hypoglycemic events and reduces separation from the mother.2 Additionally, studies have shown a decrease in NICU admissions after implementation of a dextrose gel protocol for hypoglycemia treatment.1, 3-5 However, when used prophylactically, dextrose gel has not decreased the rate of NICU admission in a multicenter trial.6
In the current study by Gupta and colleagues, the authors investigated the efficacy of dextrose gel 40% in decreasing the need for intravenous (IV) fluids. At risk newborns were stratified in three groups: small for gestational age (SGA) and intrauterine growth-restriction (IUGR), infants of diabetic mothers (IDM) and large for gestational age (LGA), and late preterms (LPT), followed by randomization in two groups: the intervention group received dextrose gel followed by breastfeeding (DGG), and the control group (CG} received only breastfeeding. The glucose threshold for successful treatment was defined as a blood or serum glucose > 45 mg/dL 30 minutes after intervention, with maximum two consecutive interventions. Overall, there was a decrease in treatment failure (need for IV fluids) in the DGG (11.5%) compared to CG (40.2%) with an absolute risk reduction of 0.29 and a number needed to treat (NNT) of 3.5. The mean number of doses used was 1.3-1.5, similar to previous studies1. The late preterm group had the lowest rate of treatment failure (8.6%) compared with SGA/IUGR (12.2%) and LGA/IDM (13.4%).
More newborns developed hypoglycemia between 4-24 hours (h) (153) compared to 0-4 h (131) which might be explained by higher glucose values used as treatment threshold. Not surprinsigly, in the SGA category, rate of failure between 4-24h was much higher than in the first 4 hours for both groups. There were no episodes of hypoglycemia after 24 h.
One limitation was the lack of blinding. There was a high incidence of NICU admission (40.2% in CG) compared with previous trials1,3possibly due to the lack of formula use, since studies have shown that dextrose gel use in combination with formula leads to higher increase in mean glucose values compared to gel use followed by breastfeeding.7
The most striking finding of this study is the significant reduction in NICU admissions in the first 48 hours after birth following dextrose gel use in a neonatal population being exclusively breastfed. While the use of dextrose gel has been studied extensively in resource rich settings, this is the first study conducted in a resource limited setting where an inexpensive treatment such as dextrose gel has the potential to make a significant impact by decreasing NICU admission, minimizing mother infant separation, and promoting breastfeeding with a very promising NNT.
REFERENCES
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2. Edwards T, Liu G, Battin M, Harris DL, Hegarty JE, Weston PJ et al. Oral dextrose gel for the treatment of hypoglycaemia in newborninfants.Cochrane Database of Systematic Reviews 2022, Issue 3
3.Rawat M, Chandrasekharan P, Turkovich S, Barclay N, Perry K, Schroeder E, et al. Oral Dextrose Gel Reduces the Need for Intravenous Dextrose Therapy in Neonatal Hypoglycemia. Biomed Hub. 2016 Sep-Dec;1(3):1–9. doi: 10.1159/000448511. Epub 2016 Sep 10. PMID: 27840813; PMCID: PMC5104273.
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6. Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial. PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. PMID: 33507929; PMCID: PMC7842885.
7. Gregory K, Turner D, Benjamin CN, Monthe-Dreze C, Johnson L, Hurwitz S, Wolfsdorf J, Sen S. Incorporating dextrose gel and feeding in the treatment of neonatal hypoglycaemia. Arch Dis Child Fetal Neonatal Ed. 2020 Jan;105(1):45-49. doi: 10.1136/archdischild-2018-316430. Epub 2019 May 11. PMID: 31079067.
