Oral dextrose gel for the treatment of hypoglycaemia in newborn infants

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine whether oral dextrose gel in hypoglycaemic newborn infants is more effective than placebo or no treatment or other active treatments in:

  • correcting hypoglycaemia;

  • reducing long-term neurodevelopmental impairment.

Background

Description of the condition

Neonatal hypoglycaemia is a common condition affecting 5 to 15% of infants in the immediate postnatal period (Cornblath 2000; McGowan 2006; Hay 2009). Neonatal hypoglycaemia is important because it is associated with brain injury in newborn infants (Koh 1988; Lucas 1988; Kerstjens 2012). The incidence is likely to be increasing as factors that predispose infants to hypoglycaemia are increasing, including prematurity (Blencowe 2012), maternal diabetes (Wild 2004), and obesity (Doherty 2006). There are known risk factors for neonatal hypoglycaemia, and specific groups of infants are routinely targeted for screening (infants of diabetic mothers, large or small for postmenstrual age, low birth weight, preterm, and those with poor feeding). Less common causes include hyperinsulinism and disorders of beta-oxidation of fatty acids. Neonatal hypoglycaemia is reported to be more common in maternity hospitals in resource-poor settings (Anderson 1993). Screening is usually performed using capillary heel-lance blood samples, as the associated clinical signs are not diagnostically helpful. The accuracy of screening blood tests depends on the method of measurement, with point-of-care testing systems having a greater error range than laboratory systems using glucose oxidase methods (Beardsell 2010).

The definition of hypoglycaemia remains controversial (Hay 2009), with different publications using definition thresholds ranging from 1.7 to 2.6 mM (Pildes 1967; Lubchenco 1971; Sexson 1984; Holtrop 1993; Anderson 1993; Hume 1999; Agrawal 2000; Maayan-Metzger 2009). Several clinical thresholds for treatment have been suggested (Cornblath 2000), but currently a blood glucose concentration of < 2.6 mM is widely accepted as the definition of hypoglycaemia (Harris 2009), based on observations that concentrations below this may be associated with altered brain function and delayed development (Koh 1988; Lucas 1988).

Once diagnosed, infants are frequently managed with increased feeding, supplemental infant formula, or intravenous (IV) dextrose. Supplemental infant formula may disrupt the establishment of breast feeding (Blomquist 1994). IV treatment is expensive, requires separation of the mother and baby, and is not always available in resource-poor settings (Graz 2008), or in settings of lower levels of perinatal care.

Breast feeding is recommended by the World Health Organization (WHO) for all babies up to six months of age (WHO 2008), and the health benefits of breast feeding for both the mother and baby are well recognised. The WHO definitions of breast feeding are available. Human studies have shown breast milk volume in the first 24 hours post-partum is low and progressively increases by day 3 (Kulski 1981; Saint 1984; Le Huerou-Luron 2010). The concentration of lactose within breast milk is also low in the first 24 hours (Kulski 1981; Saint 1984) and steadily increases over the first three days. Therefore, at-risk babies may be at increased risk of severe and prolonged episodes of hypoglycaemia if they are solely breast fed.

One prospective study sought to reduce the incidence of neonatal hypoglycaemia by establishing breast feeding within 30 minutes of delivery (Chertok 2009). Blood glucose concentrations were measured at three hours of age in 84 term infants born to women with gestational diabetes, and showed less hypoglycaemia in babies who were breast fed early. Therefore, it is possible early feeding may reduce the incidence of neonatal hypoglycaemia.

Formula milk is often given to hypoglycaemic infants, although there have been no reported studies of this treatment. The carbohydrate content of breast milk on the first day, in terms of both volume and concentration, is low (Saint 1984). Therefore, formula milk may be more effective as a treatment for neonatal hypoglycaemia than breast milk.

Two studies from India aimed to prevent hypoglycaemia in both small and large for gestational age infants by feeding. Babies with a blood glucose concentration of ≤ 30 mg/dl (1.6 mmol/L) measured by Dextrostix® (Ames Dextrometer) at less than 30 minutes of age were randomised to be fed either formula alone or formula plus added powdered sugar (1.5 g per 30 ml). In both studies hypoglycaemia was reduced four-fold in the group who received additional sugar (Singhal 1991; Singhal 1992).

If feeding does not improve the blood glucose concentration the next step is commonly admission to the neonatal intensive care unit (NICU) for IV dextrose. A bolus of 200 mg/kg.min of 10% dextrose followed by an IV infusion of 8 mg/kg.min increases the blood glucose concentration within one minute, without causing hyperglycaemia (Lilien 1977; Lilien 1980).

IV dextrose and glucagon (200 mcg/kg) or intragastric medium chain triglycerides (5 ml/kg) have also been assessed in a randomised controlled trial (Hawdon 1993). Both treatments substantially increased the blood glucose concentration in babies already receiving 5 mg/kg.min IV dextrose for hypoglycaemia.

Brain injury as a result of hypoglycaemia may be evident on magnetic resonance imaging (MRI). Whereas early publications focused on the occipital cortex as the prime site of injury (Alkalay 2005), more recent reports have extended the possible sites of injury (Burns 2008). Injury is particularly evident with co-morbidities of hypoxic ischaemic encephalopathy and sepsis (Caksen 2011).

Description of the intervention

Dextrose gel contains dextrose, a simple carbohydrate, in concentrated aqueous solution, which can be administered by direct application to the mucosal surfaces of the mouth, including buccal and lingual surfaces. Specific absorption from these sites may allow rapid access to the circulation. Some proportion of the dose may also be swallowed and absorbed from the gastrointestinal tract.

In infants with hypoglycaemia, the simplicity of treatment with dextrose gel and the potential avoidance of more complex treatments, such as IV dextrose or complementary milks, would be an attractive option, if effective. Dextrose gel is typically available in a 40g/100ml form (40%) and is administered at doses of 200-400 mg/kg. There are two observational studies that suggest it may be helpful in treating hypoglycaemia and do not report any adverse effects (Ang 1990; Bourchier 1992).

How the intervention might work

Dextrose may be absorbed directly from the oral mucosa, bypassing the portal circulation and gaining more rapid access to the circulation. Dextrose is also rapidly absorbed by the gastrointestinal mucosa, since it does not require any digestion, but may then be taken up by the liver via the portal circulation and hence have a more delayed effect on blood glucose concentrations.

Why it is important to do this review

Treatment of hypoglycaemia in the neonate usually involves additional feeding, often with formula milk, with potential adverse impact on the quality and duration of breast feeding. If feeding is not effective, IV dextrose is usually administered, commonly requiring admission to NICU and resulting in separation of mother and baby, impaired initiation of breastfeeding and increased healthcare costs.

Dextrose gel is simple to administer and inexpensive. If it is effective in treating neonatal hypoglycaemia without adverse effects then these problems may be avoided. Further, dextrose gel could be used in resource-poor settings where higher levels of neonatal care are unavailable, and potentially prevent brain damage caused by untreated neonatal hypoglycaemia.

Objectives

To determine whether oral dextrose gel in hypoglycaemic newborn infants is more effective than placebo or no treatment or other active treatments in:

  • correcting hypoglycaemia;

  • reducing long-term neurodevelopmental impairment.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi-RCTs comparing dextrose gel with placebo, no treatment, or other therapies for treatment of neonatal hypoglycaemia. We will include both published and unpublished studies. We will include unpublished studies and studies published only as abstracts if assessment of study quality is possible and if other criteria for inclusion are fulfilled.

Types of participants

Newborn infants, from birth to discharge home, who are hypoglycaemic (blood glucose concentrations below the normal range, investigator defined) for any reason. We will exclude infants who have received prior IV treatment for maintenance glucose control at the time of hypoglycaemia, which will be likely to exclude very preterm infants.

Types of interventions

Dextrose gel, at any dose, given orally compared with placebo, no treatment, or other therapies (including IV bolus), at any postmenstrual age and any postnatal age. The dextrose gel product may be sourced by local preparation or provided commercially.

Types of outcome measures

Primary outcomes
  1. Correction of hypoglycaemia (investigator defined) for each event of hypoglycaemia

  2. Major neurological disability at age 2 years or greater (defined as any of: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay/intellectual impairment (defined as developmental quotient lower than two standard deviations below the mean)

Secondary outcomes
Infant outcomes
  1. The need for IV treatment for hypoglycaemia

  2. Requirement for any medications for hypoglycaemia such as glucagon or corticosteroids

  3. Neonatal seizures

  4. Separation from the mother for treatment of hypoglycaemia (infant being nursed in an environment which is not in the same hospital room as the mother e.g. for NICU admission or the like)

  5. Breast feeding (any) after discharge

  6. Exclusive breast feeding after discharge (WHO definition)

  7. Exclusive breast feeding at six months of age (WHO definition)

  8. Developmental impairments (investigator-defined)

  9. Abnormal MRI of the brain in the neonatal period

  10. Number of episodes of hypoglycaemia (investigator-defined)

Event outcomes (for any event of hypoglycaemia for which specific management is initiated)
  1. Improvement of blood glucose to greater than 2.6 mM

  2. Rebound hypoglycaemia (occurring within six hours of initial correction))

  3. Increment of blood glucose after treatment (change in blood glucose concentration 30 to 90 mins after treatment)

  4. Duration of hypoglycaemia (time from detection of hypoglycaemia to achieving a blood glucose concentration above the threshold definition)

Search methods for identification of studies

Electronic searches

We will request a search from the Cochrane Neonatal Review Group's Specialised Register. We will also undertake a search of MEDLINE, EMBASE, CENTRAL, CINAHL, and Web of Science from inception of the database to the present. We will undertake a search of registries of clinical trials for any evidence of work in progress, or prior work planned for which there is no published result. We will search in proceedings of relevant scientific meetings. We will not apply any restrictions on language.

We will search using the following key words: hypoglycaemia OR hypogly$, AND neonate OR neonat$, AND dextrose gel. We will also use "*" as a wild card character where appropriate. We will ensure that both American and English spellings are searched.

We will permit the newborn period to refer to those infants admitted at or soon after birth and remaining in their neonatal admission until first discharge home. We will limit to potentially eligible randomised clinical trials using a maximally sensitive methodology filter.

Searching other resources

We will search reference lists of included trials. We will contact known researchers in this clinical area to identify any unpublished or ongoing research.

Data collection and analysis

Selection of studies

Two study authors will independently undertake the following steps:

  1. merge search results using reference management software, and remove duplicate records of the same report;

  2. examine titles and abstracts to remove obviously irrelevant reports;

  3. retrieve full texts of the potentially relevant reports;

  4. link together multiple reports of the same study;

  5. examine full-text reports for compliance of studies with eligibility criteria;

  6. correspond with investigators, where appropriate, to clarify study eligibility, and where possible obtain missing results;

  7. make final decisions on study inclusion and proceed to data collection.

Disagreements will be resolved by a third author.

Data extraction and management

We will develop a data extraction form prior to data gathering, which will enable multiple authors to seek information from the studies. We will extract data such as source details, eligibility assessment, methodological features, participant characteristics, intervention details, and outcome reports. Two authors will independently perform data extraction. We will resolve discrepancies in data extraction by referral to a third author. In the case of the data from the "Sugar Babies Study", the data extraction will be performed by two Cochrane authors not associated with the study. We will enter the data into the Cochrane Collaboration's statistical software, Review Manager 2013, and check for accuracy.

Assessment of risk of bias in included studies

Two authors will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion with a third author.

Random sequence generation (checking for possible selection bias)

For each included study we will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias ( any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.

Allocation concealment (checking for possible selection bias)

For each included study we will describe the method used to conceal allocation to interventions prior to assignment and assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.

Blinding of participants and personnel (checking for possible performance bias)

For each included study we will describe the methods used, if any, to blind study participants and personnel from which intervention a participant received. We will consider studies to be at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

Blinding of outcome assessment (checking for possible detection bias)

For each included study we will describe the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received.

We will assess the methods used to blind outcome assessment as: low, high or unclear risk of bias

Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

For each included study, we will describe the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions are reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusions where reported, and whether missing data are balanced across groups or are related to outcomes. Where sufficient information is reported, we will re-include missing data in the analyses which is undertaken.

We will assess the methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

Measures of treatment effect

We will use the numbers of events in the control and intervention groups of each study to calculate risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We will calculate mean differences (MDs) between treatment groups where outcomes are measured in the same way for continuous data. Standardised mean differences (SMDs) will be used if the outcomes from trials are the same but different methods have been used to collect the data. We will report 95% CIs for all outcomes. We will also report risk differences (RDs) and where a significant effect is found we will calculate the numbers needed to treat to benefit (NNTBs) or the numbers needed to treat to harm (NNTHs).

Unit of analysis issues

For some specific measures (relating to correction of hypoglycaemia), the unit analysed will be the event itself. For other measures that determine the outcome for the baby (such as relating to breast feeding and developmental outcomes), the unit analysed will be the baby.

Dealing with missing data

We will note levels of attrition. We will carry out analyses using an intention-to-treat basis, where possible, for all of the outcomes. We will analyse all participants where possible in the treatment group to which they were randomised, regardless of the actual treatment received. We will contact the original investigators to request missing data whenever possible. We will make explicit the assumptions of any methods used to cope with missing data. Sensitivity analyses may be performed to assess how sensitive results are to reasonable changes in the assumptions that are made. We will address the potential impact of missing data on the finding of the review in the discussion section.

Assessment of heterogeneity

We will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta-analysis to provide a clinically meaningful summary. This will be done by assessing statistical heterogeneity using the Chi2 test and the I2 statistic. An I2 measurement greater than 50% and a low P value (< 0.10) in the Chi2 test for heterogeneity will be taken to indicate substantial heterogeneity (Higgins 2011). Where substantial heterogeneity is detected, we will explore possible explanations in sensitivity/subgroup analyses. Statistical heterogeneity will be taken into account when interpreting the results, especially if there is any variation in the direction of effect.

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results. Some types of reporting bias (e.g. publication bias, multiple publication bias, language bias) reduce the likelihood that all studies eligible for a review will be retrieved. If all eligible studies are not retrieved, the review may be biased. We aim to conduct a comprehensive search for eligible studies and will be alert for duplication of data. We will assess publication bias by visual inspection of a funnel plot, if there are enough studies (10 or more trials) to make such an inspection valid.

Two authors will examine the methods of each study for pre-specified outcomes. If all pre-specified outcomes are reported in the results, the study will carry a low risk of bias. If any pre-specified outcome is not reported in the results, the study will be considered to carry a higher risk of bias. If the authors uncover reporting bias that could, in the opinion of the authors, introduce serious bias, a sensitivity analysis is planned to determine the effect of including and excluding these studies in the analysis.

Data synthesis

We will evaluate studies for potential clinical diversity, and restrict meta-analysis to where clinical consistency is apparent. We will evaluate studies for bias, as above, and restrict meta-analysis if bias would be compounded. We will use a fixed-effect meta-analysis for combining data where it is reasonable to assume that studies were estimating the same underlying treatment effect. If there is evidence of clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will undertake sensitivity and subgroup analyses to attempt to explain the heterogeneity.

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup and sensitivity analyses. We will consider whether an overall summary is meaningful and if it is, we will use a random-effects model to analyse it. We plan to carry out the following subgroup analyses.

Infant factors
  • Reason for risk of hypoglycaemia (infant of diabetic mother, preterm, small, large, other)

  • Method used to measure blood glucose concentration (reliable instrument using glucose oxidase method versus less reliable cot-side approaches)

  • Treatment of first episode of hypoglycaemia versus any other subsequent episodes

  • Dextrose gel as the only intervention versus dextrose gel administered as a co-intervention (e.g. in addition to formula feeds)

Event factors
  • Method of feeding at the time of the event (formula versus breast feeding versus mixed versus nil versus other)

  • Method of administration of gel (buccal mucosa versus lingual mucosa versus other)

  • Dose of dextrose per administration (≤ 200 mg/kg versus > 200 mg/kg)

  • Maximum number of doses for treatment of a single episode of hypoglycaemia (1 versus > 1)

Sensitivity analysis

We will conduct sensitivity analysis by examining only those trials considered to have a low risk of bias.

Acknowledgements

We acknowledge the support of the editorial base in assisting with the title application, and Professor Caroline Crowther for her early advice and support in the initiation of this review.

Contributions of authors

PW and DH will independently perform data extraction. Discrepancies in data extraction will be resolved by referral to a third author (MB). Discrepancies in determining study inclusion will be referred to a further author (JHa). In the case of the data from the "Sugar Babies Study", the data extraction will be performed by two Cochrane authors not associated with the study (JHe, JB).

PW and DH will examine the methods of each study for pre-specified outcomes.

Declarations of interest

Deborah Harris, Phil Weston, and Jane Harding have designed and conducted an RCT called the "Sugar Babies Study" comparing dextrose gel and placebo in the treatment of neonatal hypoglycaemia.

Sources of support

Internal sources

  • Waikato District Health Board, New Zealand.

    Clinical salaries for Phil Weston and Deborah Harris

  • Auckland District Health Board, New Zealand.

    Clinical salaries for Malcolm Battin and Jo Hegarty

  • Liggins Institute, Auckland University, New Zealand.

    University appointments for Julie Brown and Jane Harding

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

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