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Interventions for treatment of neonatal hyperglycemia in very low birth weight infants

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Authors

Marcela Bottino1, Richard M Cowett2, John C Sinclair3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1(Formerly, Fellow, Division of Neonatology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada), Rio de Janeiro, Brazil [top]
2Neonatal Resource Services, Complex Medical Conditions, Optum, UnitedHealth Group, Lisle, Illinois, USA [top]
3Departments of Pediatrics and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada [top]

Citation example: Bottino M, Cowett RM, Sinclair JC. Interventions for treatment of neonatal hyperglycemia in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD007453. DOI: 10.1002/14651858.CD007453.pub3.

Contact person

Marcela Bottino

(Formerly, Fellow, Division of Neonatology, Department of Pediatrics
McMaster University, Hamilton, Ontario, Canada)
Avenida Senador Danton Jobim
150/404 Barra da Tijuca
22631-060 Rio de Janeiro
Brazil

E-mail: mabottino@hotmail.com

Dates

Assessed as Up-to-date: 28 June 2011
Date of Search: 11 April 2011
Next Stage Expected: 28 June 2013
Protocol First Published: Issue 4, 2008
Review First Published: Issue 1, 2009
Last Citation Issue: Issue 10, 2011

What's new

Date / Event Description
19 May 2011
Updated

This is an update of the review first published in the Cochrane Database of Systematic Reviews, Issue 1, 2009 (Bottino 2009).

Literature searches were updated to April 30, 2011.

19 May 2011
New citation: conclusions not changed

No new eligible included trials were found. One possibly eligible trial (Hawk 2009) published only in abstract form was classed as Studies Awaiting Classification.

The results and conclusions of the review are unchanged.

History

Date / Event Description
06 May 2009
Amended

Minor amendment. Order of the authors in a cited publication changed.

29 January 2009
Amended

This is a minor amendment, adding two additional excluded studies.

Abstract

Background

Early neonatal hyperglycemia is common among very low birth weight (VLBW) neonates. Increased risks for death and major morbidities have been observed among VLBW neonates who develop hyperglycemia. It is uncertain whether the hyperglycemia per se is a cause of adverse clinical outcomes or whether the incidence of adverse outcomes can be reduced by treatment.

Objectives

To assess the effects on clinical outcomes of interventions for treating neonatal hyperglycemia in the VLBW neonate receiving total or partial parenteral nutrition.

Search methods

We searched The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4 of 12, 2011), MEDLINE (1966 to April 2011), EMBASE (1980 to April 2011) and CINAHL (1982 to July 2008). We searched for abstracts submitted for the annual meetings of Pediatric Academic Societies 2000 to 2011 and The European Society for Pediatric Research 2005 to 2010.

Selection criteria

Randomized or quasi-randomized trials of interventions for the treatment of hyperglycemia in hyperglycemic VLBW neonates were eligible for inclusion in this review.

Data collection and analysis

Two review authors independently selected studies for eligibility and extracted data on study design, methodology, clinical features, and treatment outcomes. Additional information on study design and outcomes was obtained from the lead investigator of each of the two included trials. The included trials were assessed for blinding of randomization, blinding of caretakers to the intervention, completeness of follow-up, and blinding of outcome measurement. The treatment effect measures for categorical outcomes were relative risk (RR) and risk difference (RD) with their 95% confidence intervals (CI); for continuous outcomes the measure was mean difference and 95% CI.

Results

Only two eligible trials were found (Collins 1991; Meetze 1998). Both were randomized but of very small size (24 and 23 neonates randomized in each trial, respectively).

No trial compared reduction versus no reduction of glucose infusion.

Collins 1991 compared insulin infusion with standard care. Insulin infusion had no significant effect on death or bacterial sepsis; effects on other major morbidities were not assessed. Insulin infusion resulted in significant increases in non-protein energy intake, glucose intake, and short-term weight gain.

Meetze 1998 compared insulin infusion with reduction of glucose infusion. Insulin infusion had no significant effects on death, severe intraventricular hemorrhage, retinopathy of prematurity, bacterial sepsis, fungal sepsis, or necrotizing enterocolitis; effects on other major morbidities were not assessed. Insulin infusion resulted in significant increases in glucose intake and total energy intake.

Authors' conclusions

Evidence from randomized trials in hyperglycemic VLBW neonates is insufficient to determine the effects of treatment on death or major morbidities. It remains uncertain whether the hyperglycemia per se is a cause of adverse clinical outcomes or how the hyperglycemia should be treated. Much larger randomized trials in hyperglycemic VLBW neonates that are powered on clinical outcomes are needed in order to determine whether, and how, the hyperglycemia should be treated.

Plain language summary

Interventions for treatment of neonatal hyperglycemia in very low birth weight infants

Higher-than-normal blood sugar levels are frequently seen in babies born very early (before 32 weeks gestation) or with very low birth weight (< 1500 grams) and who are fed totally or partially by vein. Several types of adverse outcomes have been associated with high blood sugar levels, including increased risks for death, infections, eye problems, and bleeding into the brain. It is not known if treatment to lower the baby's blood sugar helps to prevent those complications and, if so, which treatment is best. These treatment options include decreasing the amount of sugar delivered by vein to nourish the baby or administration of insulin. This review of trials found no evidence of significant effects of these treatments on the risks of death or major complications. However, the studies reviewed were very small. There is a need for larger trials to answer these questions.

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Background

Description of the condition

In the very low birth weight neonate (VLBW, < 1500 g at birth), an elevated blood glucose concentration occurs frequently, especially during the first weeks after birth when glucose is administered as part of parenteral nutrition. The extremely low birth weight neonate (ELBW, < 1000 g at birth) is especially vulnerable to this occurrence. The increasing survival of this population and the use of early and aggressive parenteral nutrition have resulted in an increased frequency of hyperglycemia in the NICU. Hays 2006 reported that among 82 ELBW neonates studied in the first week after birth, the average daily prevalence of infants with at least one measurement of blood glucose concentration above 8.3 mM/L (> 150 mg/dL) was 57%; above a threshold of 13.9 mM/L (> 250 mg/dL), it was 32%. The risk for hyperglycemia is inversely related to gestational age and birth weight (Blanco 2006; Falcão 1998) and increases with the severity of accompanying illnesses (Louik 1985).

There is no uniform agreement about the definition for hyperglycemia in the VLBW or ELBW neonate. Irrespective of the precise definition, adverse clinical outcomes have been associated with an elevated neonatal blood glucose concentration in these neonates. Adverse outcomes include death (Hays 2006; Kao 2006; Heimann 2007), intraventricular hemorrhage (IVH) grades 3 and 4 (Hays 2006), late onset bacterial infection (Kao 2006), fungal infection (Rowen 1995; Manzoni 2006), retinopathy of prematurity (ROP) (Garg 2003; Blanco 2006; Ertl 2006) and necrotizing enterocolitis (NEC) (Kao 2006). The threshold for hyperglycemia used in these analyses varied: > 8.3 mM/L (> 150 mg/dL) (Hays 2006; Blanco 2006; Heimann 2007), > 8.5 mM/L (> 153 mg/dL) (Ertl 2006), > 10.0 mM/L (> 180 mg/dL) (Kao 2006) or > 12.0 mM/L (> 216 mg/dL) (Manzoni 2006). Several of these studies noted a particularly strong association with adverse outcomes when the hyperglycemia was prolonged (Rowen 1995; Hays 2006; Kao 2006; Heimann 2007). Length of hospital stay (LOS) was reported to be greater when hyperglycemia was sustained, especially when combined with an increased oxygen requirement, which could be related to bronchopulmonary dysplasia (Hays 2006).

The mechanisms of the hyperglycemia that is commonly seen in the parenterally fed VLBW/ELBW infant in the early neonatal period are probably multifactorial. In order to provide energy and support growth until full enteral feeding is established, these neonates are usually given a parenteral nutrition regimen that delivers glucose at a rate substantially higher than the endogenous glucose production rate of 4 to 7 mg/kg/min that was reported for VLBW infants by Bier 1977 and Sunehag 1993. Unlike the non-pregnant and non-diabetic adult, the preterm neonate does not completely suppress endogenous glucose production in response to a parenteral glucose infusion administered at a rate comparable to the rate of endogenous glucose production (Cowett 1983; Sunehag 1994). In comparison to older infants and children, the VLBW/ELBW neonate may also have a reduced tolerance for intravenous glucose administration due to a limited amount of insulin-dependent tissue (specifically fat and muscle) and a limited insulin secretory response to glucose (Mitanchez-Mokhtari 2004).

Description of the intervention

Interventions that might be used to treat hyperglycemia in the parenterally fed VLBW/ELBW neonate include:

  1. reducing the rate of parenteral glucose infusion with or without any change in the other energy components of the infusate;
  2. treating with insulin, primarily by intravenous infusion.

How the intervention might work

Reducing the rate of parenteral glucose infusion: Cowett 1979 reported that 10 VLBW neonates who received a three hour infusion of glucose at 14.0 mg/kg/min all developed hyperglycemia, defined as a plasma glucose concentration > 8.3 mM/L (> 150 mg/dL). When glucose was infused in 16 infants at a rate of 11.2 mg/kg/min, half of them developed hyperglycemia; but among nine infants infused at a rate of 8.1 mg/kg/min, none developed hyperglycemia. In a retrospective survey of 86 ELBW neonates in one NICU over a one-year period, Cowett 1997 reported a direct linear association between plasma glucose concentration and the glucose infusion rate. These observations can be interpreted to suggest that simply reducing the glucose infusion rate may be effective in treating hyperglycemia. However, the potential nutritional risk of a reduction in the glucose infusion rate is of concern. In the early postnatal period, many VLBW/ELBW infants cannot be fed enterally and must rely on parenteral feeding, either in whole or in part, in order to grow. The parenterally fed neonate needs an energy intake of at least 80 to 90 kcal/kg/day in order to grow at the intrauterine rate (Zlotkin 1981; Heird 1992). The energy requirement for adequate growth may not be met at a reduced parenteral glucose intake depending on the amount of energy provided by the other components of the parenteral feeding regimen.

Sunehag 1999 showed that when the glucose infusion rate is reduced, the VLBW neonate canuse part of the energy supplied by non-carbohydrate sources, including glycerol and amino acids, to sustain the blood glucose concentration. Chacko 2011 reported a study in seven ELBW neonates, post-natal age 3 to 4 days, who were receiving parenteral glucose, amino acids and lipid. In this short-term study, glucose infusion rate was reduced by 60% while the supply of parenteral amino acids and lipid was maintained at pre-study rates. In response to the reduction in the glucose infusion rate the blood glucose concentration was reduced but remained within the normal range, mainly due to ongoing gluconeogenesis. Moreover, the reduced exogenous glucose supply did not increase proteolysis. It is possible that a reduction in the glucose infusion rate, if accompanied by sufficient energy supplied as parenteral amino acids and lipid, might allow some reduction in blood glucose concentration while reducing the risk of energy deficit. Nevertheless, early and/or rapid advancement of lipid infusion in the preterm infant should be carefully monitored for potential side effects, including lipid intolerance with lipemia and hypertriglyceridemia, increased free bilirubin concentration, impaired pulmonary function and interference with immune and platelet function (Thureen 1999). Similar concerns apply for amino acids, in response to which the neonate might develop metabolic acidosis, hyperammonemia and/or azotemia.

Treating with insulin: Insulin acts on cells throughout the body to stimulate uptake, utilization and storage of glucose. In particular, insulin stimulates the liver to store glucose in the form of glycogen and facilitates the entry of glucose into muscle and adipose tissue. However, there appear to be important developmental differences between VLBW infants and older subjects in regard to the role of insulin in regulating blood glucose concentration. In proportion to body weight, the VLBW neonate has a relatively small mass of muscle and fat, but a larger brain (Bier 1977). Insulin facilitates the import of glucose into muscle and fat via the glucose transporter GLUT 4, but has no role in the uptake of glucose by the brain. Since the brain is the major glucose-utilizing organ, these considerations suggest that insulin may have a relatively restricted role in regulating glucose utilization in the VLBW neonate. Moreover, Mitanchez-Mokhtari 2004 reported that extremely preterm infants with hyperglycemia during the first week of life had a very high concentration of proinsulin, although insulin concentration did not differ significantly from that noted in normoglycemic controls. This suggested that proinsulin processing to mature insulin was partially defective. Mitanchez-Mokhtari 2004 also found that the hyperglycemic neonate responded to exogenous insulin infusion, but needed higher doses to achieve normoglycemia. These data suggest the possibility that insulin resistance is of physiological/biochemical importance in the VLBW neonate.

There have been several observational studies, principally case series, suggesting that exogenous insulin administration can safely reduce glucose concentration in the hyperglycemic VLBW or ELBW neonate (e.g. Vaucher 1982; Binder 1989; Thabet 2003). Usually, a starting insulin infusion rate of 0.02 to 0.10 units/kg/h was administered. The insulin is typically administered in a small volume of isotonic saline delivered by an infusion pump (Ostertag 1986). It has been recommended to first flush the intravenous tubing with the insulin solution in order to saturate binding sites on the tubing so that the insulin does not adhere (Fuloria 1998) or to administer the insulin with a protein solution of 0.25% salt poor albumin (Cowett 1987). Frequent glucose monitoring, with adjustments of the rates of insulin and/or glucose infusion, is required. With careful monitoring and dosage adjustments, hypoglycemia occurred very infrequently in these studies.

Why it is important to do this review

The association of neonatal hyperglycemia with adverse clinical outcomes in the VLBW neonate, described previously in observational studies, does not necessarily mean that the hyperglycemia causes these sequelae. It is possible that it is the sicker neonate, who is at higher risk for adverse clinical outcomes, who is more prone to hyperglycemia because of stress or metabolic injury to vital organs, especially the brain. It is also possible that it is hyperglycemia per se that is a cause of adverse clinical outcomes, especially if hyperglycemia is severe enough to cause significant plasma hyperosmolality resulting in fluid shifts from the intracellular to the extracellular fluid compartment. This is of particular concern with respect to the risk of cerebral bleeding (Finberg 1967). There is also some evidence of an adverse effect of severe hyperglycemia on neurologic outcome following cerebral ischemia in both animals and adult humans as well as the neonate (Efron 2003). Thus, in the VLBW/ELBW neonate with hyperglycemia, it is important to determine the benefits and risks of treating the hyperglycemia by either reducing the rate of glucose infusion or by administering exogenous insulin. We have systematically reviewed the evidence from randomized controlled trials of these interventions in this population. We are not aware of any previous systematic review of randomized trials of treatments for hyperglycemia in the VLBW/ELBW neonate. However, Raney et al recently reported a systematic review, including both observational studies and randomized trials, of insulin infusion for the treatment of VLBW neonates with hyperglycemia (Raney 2008).

In a separate review, the evidence from randomized trials of interventions for the prevention of hyperglycemia in VLBW neonates has been systematically reviewed (Sinclair 2009).

Objectives

Primary Objective:

To assess the effects of interventions for treating neonatal hyperglycemia in the very low birth weight neonate receiving total or partial parenteral nutrition. Specific interventions that were reviewed are:

  1. reduction of the rate of parenteral glucose infusion with or without any increase in the provision of parenteral lipids or amino acids (compared with no reduction of the rate of parenteral glucose infusion);
  2. insulin infusion (compared with no reduction of the rate of parenteral glucose infusion);
  3. insulin infusion (compared with reduction of the rate of parenteral glucose infusion).

Secondary Objectives:

Data permitting, subgroup analyses were to be carried out according to population:

  1. Birth weight 500 to 749 g; 750 to 999 g; 1000 to 1499 g;
  2. Criterion for hyperglycemia at study entry: 8.3 to 13.8 mM/L (150 to 250 mg/dL); > 13.8 mM/L (> 250 mg/dL);
  3. Associated morbidity at study entry: high/low morbidity score or as reported by author.

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Methods

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized trials with parallel groups that randomize individual patients. Randomized crossover trials were to be excluded. Unpublished trials or trials reported only in abstract form were eligible.

Types of participants

Neonates with birth weight < 1500 g or gestational age < 32 weeks, postnatal age up to 28 days, on full or partial parenteral feeding, and with documented hyperglycemia, defined as whole blood or plasma glucose concentration > 8.3 mM/L (> 150 mg/dL).

Types of interventions

  1. Reduction of the rate of parenteral glucose infusion with or without any increase in the provision of parenteral lipids or amino acids.
    Reduction of the rate of glucose infusion was defined as a stepwise or one-time decrease resulting in either a 25% or greater total decrease or a decrease to a rate of less than 7 mg/kg/min, or other reduction as defined by the authors. Duration of intervention was as defined by the authors. An eligible increase in the provision of parenteral lipids or amino acids was any increase up to but not exceeding that required to replace the deficit in energy intake caused by the reduction in the rate of glucose infusion.
  2. The comparison was no reduction of glucose infusion rate. No reduction was defined as a decrease of less than 10% or other adjustment as defined by author.
  3. Insulin infusion (any dose, any dose adjustment protocol, any duration).
  4. The comparison was no reduction of glucose infusion rate as defined above.
  5. Insulin infusion (any dose, any dose adjustment protocol, any duration).
  6. The comparison was reduction of glucose infusion rate, as defined above.

Types of outcome measures

Primary outcomes
  1. All-cause mortality up to 36 weeks postmenstrual age or as defined by authors.
  2. Neurodevelopmental impairment, defined as presence of one or more of the following: cerebral palsy, MDI or PDI < 70, blindness or deafness assessed either between 18 and 24 months postmenstrual age or the latest assessment up to 24 months postmenstrual age.
  3. Severe intraventricular hemorrhage (IVH) defined as grade 3 or 4 by Papile classification.
  4. Incidence of retinopathy of prematurity (ROP): a) any stage; b) requiring treatment.
  5. Proportion of neonates with one or more episodes of bacterial sepsis defined as a positive culture for bacteria in blood, urine or cerebrospinal fluid up to 36 weeks postmenstrual age or as reported by authors.
  6. Proportion of neonates with one or more episodes of fungal sepsis defined as a positive culture for fungus in blood, urine or cerebrospinal fluid up to 36 weeks postmenstrual age or as reported by authors.
Secondary outcomes
  1. Time to resolve hyperglycemia defined as hours to achieve plasma or blood glucose concentration < 8.3 mM/L (< 150 mg/dL) or as defined by authors.
  2. Number of episodes of recurrent hyperglycemia per patient and/or proportion of neonates having one or more episodes; defined as plasma or blood glucose concentration > 8.3 mM/L (> 150 mg/dL) or as defined by authors.
  3. Number of episodes of hypoglycemia per patient and/or proportion of neonates having one or more episodes; defined as plasma or blood glucose concentration < 2.5 mM/L (< 45 mg/dL), or as defined by authors.
  4. Caloric intake assessed as kcal/kg/d in a one week period or longer, or as reported by the authors.
  5. Incidence of necrotizing enterocolitis (NEC) defined as stage 2 or above by the Bell classification.
  6. Duration of mechanical ventilation.
  7. Incidence of chronic lung disease (CLD) at 36 weeks postmenstrual age (Jobe 2001).
  8. Length of hospital stay defined as number of days until discharge home, or as reported by authors.

Search methods for identification of studies

The standard search strategy of the Neonatal Review Group, as outlined in the Cochrane Library, was used. The following sources were searched for eligible reports in any language:

Electronic searches

Electronic databases that were searched included: The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, Issue 4 of 12, 2011; MEDLINE (1966 to April 2011); EMBASE (1980 to April 2011); and CINAHL (1982 to July 2008).

The search string for searching CENTRAL and MEDLINE via PubMed included the following terms: (glucose/administration and dosage OR glucose infusion OR parenteral glucose OR intravenous glucose OR energy intake OR insulin/administration and dosage) AND (hyperglycemia OR hyperglycemic OR glucose intolerance OR glucose intolerant) AND (infant, very low birth weight OR very low birth weight OR VLBW OR extremely low birth weight OR ELBW OR preterm). To limit to clinical trials, we used the maximum sensitivity methodologic filter for questions of therapy, implemented in PubMed Clinical Queries (Haynes 2005).

We used a similar search string for searching EMBASE and CINAHL via Ovid, adapting the search terms to the structured vocabulary and syntax required for those databases; and adapting the limits according to what is available in those databases.

Searching other resources

We searched for abstracts presented at the annual meetings of the Pediatric Academic Societies 2000 to 2011 and the European Society for Pediatric Research 2005 to 2010, from the journal Pediatric Research and abstracts on line.

On-going trials were searched in April 2011 at the following websites: ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy.

Using Web of Science, we did a citation search of Collins (Collins 1991) and Meetze (Meetze 1998) in July 2008.

Data collection and analysis

Selection of studies

The titles and abstracts of reports that were detected by the described search strategies were assessed independently by two review authors (MB and JS) to determine their eligibility for inclusion in this review. Eligibility for inclusion was judged according to the criteria listed under "Criteria for considering studies". If there was uncertainty as regards inclusion/exclusion, the full report was obtained in order to make a decision regarding eligibility. Any disagreement was resolved by discussion. Unresolved disagreements were to be referred to RC for arbitration.

Data extraction and management

For included studies, data were extracted concerning study design, methodology, clinical features of the population, interventions and outcomes, and treatment effects, using specially designed data collection forms. For studies that were initially considered possibly eligible for inclusion but which were excluded after reading the full report, the reason for exclusion was documented. All data were extracted independently by two review authors (MB and JS), compared, and any discrepancies resolved by discussion or, if necessary, through contact with the primary investigators. Unresolved disagreements were to be referred to RC for arbitration. Outcomes that were categorical were expressed as the negative outcome, e.g. death, not survival. We attempted to obtain data sets that were as complete as possible. If necessary, we requested any unreported data on study outcomes from the primary investigators. To the extent possible, we extracted outcome data on all patients randomized.

Assessment of risk of bias in included studies

Two review authors (JS and MB) independently assessed the risk of bias for each study, in general accordance with the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion.

Each trial was assessed for blinding of randomization, blinding of intervention(s), complete follow-up, and blinding of outcome(s) measurement, using a 3-category scale: Yes (low risk of bias); No (high risk of bias); Can't tell (unclear risk of bias). The risk of bias arising from selective reporting could not be assessed in this review because no included study prospectively registered or published the protocol.

Measures of treatment effect

For individual trials, effect measures for categorical outcomes included relative risk (RR), and absolute risk difference (RD), each with its 95% confidence interval (CI). For statistically significant effects, the number needed to treat (NNT) or number needed to harm (NNH) were calculated. For continuous outcomes, the effect measure was mean difference (MD) or, if the scale of measurement differed across trials, standardized mean difference (SMD), each with its 95% CI. For any meta-analyses (see below), for categorical outcomes the typical estimates of RR and RD, each with its 95% CI, were to be calculated; and for continuous outcomes the weighted mean difference (WMD) or a summary estimate for SMD, each with its 95% CI, were to be calculated.

Unit of analysis issues

We did not anticipate any unit of analysis issues. Crossover trials were not eligible. Cluster randomized trials were not expected in this field. For episodes of hypoglycemia and episodes of recurrent hyperglycemia, we planned to analyze the data as number of episodes per neonate and/or proportion of neonates having one or more episodes.

Dealing with missing data

If some outcome data remained missing despite our attempts to obtain complete outcome data, we performed an available-case analysis based on the numbers of patients for whom outcome data were known. For primary outcomes, if there were instances of statistically significant effects but with missing data, we were to perform a worst case/best case sensitivity analysis based on imputation, to test whether the effect was sustained or overturned.

Assessment of heterogeneity

Before any meta-analysis was done, we judged whether there was sufficient similarity between the eligible studies in their design features and clinical features (population, interventions) to make pooling for meta-analysis scientifically and clinically credible. If there was sufficient similarity, we planned to proceed to meta-analysis. If not, the results of individual trials were to be described separately.

The amount of heterogeneity of treatment effect across trials in a meta-analysis was to be estimated using the I-squared statistic. Whether heterogeneity was statistically significant was to be tested using the chi-squared statistic. If substantial heterogeneity was present, the source(s) of heterogeneity were to be explored post facto, considering differences in design or clinical features of the trials.

Assessment of reporting biases

We did not anticipate a sufficient number of included trials in this field to permit assessment of possible publication bias and other biases using symmetry/asymmetry of funnel plots.

For included trials, we planned to explore possible selective reporting of study outcomes by comparing the primary and secondary outcomes in the reports with the primary and secondary outcomes nominated at trial registration, using the websites ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy. If such discrepancies were found, we were to contact the primary investigators to try to obtain missing outcome data on outcomes pre-specified at trial registration.

Data synthesis

If meta-analysis was judged to be appropriate, it was to be done using RevMan 5, supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. All meta-analyses were to be done using the fixed effect model. When meta-analysis was judged to be inappropriate, individual trials were to be analyzed and interpreted separately.

Subgroup analysis and investigation of heterogeneity

Data permitting, pre-specified subgroup analyses were planned according to population subgroups as defined in Secondary Objectives. If data were not available to permit a pre-planned subgroup analysis to be done, that was stated as a result in this review. Any post-facto subgroup analyses, e.g. to explore unanticipated sources of heterogeneity, were to be labelled as such. It was not anticipated that a sufficiently large number of eligible trials would be available to permit exploration of heterogeneity of treatment effect using meta-regression.

Sensitivity analysis

As noted previously, in the case of missing outcome data, a worst case/best case analysis was planned to test whether a significant result was sensitive to (i.e. overturned by) imputations according to worst/best case assumptions. There were no other pre-planned sensitivity analyses.

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Results

Description of studies

Results of the search

We detected 22 possibly eligible studies. Of these, 18 were excluded from this review. Excluded studies are listed in the table "Characteristics of Excluded Studies" along with the reason for exclusion. Two studies, Alsweiler 2008 and Hawk 2009, were classed as Awaiting assessment. Two studies were eligible for inclusion in this review: Collins 1991 and Meetze 1998.

Included studies

Neither of the two included trials tested glucose reduction versus no glucose reduction. Both included trials tested insulin infusion; one compared insulin with no glucose reduction (standard care), and the other compared insulin with glucose reduction. Thus, the results of included trials are reported and interpreted separately without meta-analysis.

Comparison 1: Reduction of the rate of parenteral glucose infusion compared with no reduction in parenteral glucose infusion

No trials were found which tested this comparison.

Comparison 2: Insulin infusion compared with no reduction of the rate of parenteral glucose infusion

Collins 1991 compared insulin infusion with standard care in 24 hyperglycemic ELBW neonates. Infants were eligible if they had serum glucose values > 9.9 mM/L (>180 mg/dl), glucosuria, and were receiving non-protein parenteral energy intake < 120 kcal/kg/day. The goal was to attain 120 non-protein kcal/kg/day and to maintain serum glucose concentrations < 9.9 mM/L (< 180 mg/dl). The details of this trial, including a summary of the protocols for the insulin infusion and standard care groups, are given in the Table "Characteristics of Included Studies".

In the insulin infusion arm, insulin was begun at 0.04U/h and adjusted initially to maintain serum glucose concentration between 5.5 and 9.9 mM/L (100 and 180 mg/dl). Insulin doses ranged from 0.04 to 1 U/h. The mean duration of insulin therapy was 14.6 days. The report indicates that in the standard care arm, glucose intolerance was to be treated by reducing the rate of intravenous glucose administration as required to keep serum glucose levels < 9.9 mM/L (< 180 mg/dl). However, figure 1 of the report indicates no actual reduction in the mean rate of glucose infusion in the control group. For this review, this trial was categorized under our comparison 2, insulin infusion compared with no glucose reduction, after consultation with the lead study author, Dr James Collins.

The outcomes reported in this trial included non-protein energy intake (kcal/kg/day), glucose infusion rates (mg/kg/min), weight (g), mean daily weight gain (g/kg/day), sepsis, death, mean days on mechanical ventilation and bronchopulmonary dysplasia (BPD) at 28 days. Additional information about the study design and analysis of this trial was supplied to us by the lead study author, Dr James Collins.

Comparison 3: Insulin infusion compared with reduction of the rate of parenteral glucose infusion

Meetze 1998 compared insulin infusion with reduction of the rate of parenteral glucose infusion in 23 hyperglycemic ELBW neonates. The randomized comparison of these two treatments was nested in a larger study of 61 ELBW neonates, enrolled by 48 hours of age, who were followed prospectively to investigate the incidence of hyperglycemia and the relationship of hyperglycemia to blood levels of insulin-like growth factor (IGF)-I and IGF-II. The criterion for hyperglycemia was a single determination of blood sugar >13.3 mM/L (>240 mg/dl) or repeat blood sugars >8.9 mM/L (>160 mg/dl). Hyperglycemia was diagnosed at a mean postnatal age of 96 ± 10 h.

Hyperglycemic neonates were randomly allocated to treatment with either insulin infusion or reduction of glucose infusion. The details of this trial, including a summary of the protocols for insulin infusion and reduction of glucose infusion, are given in the Table "Characteristics of Included Studies".

In the insulin infusion arm, insulin was begun at 0.1 U/kg/h and titrated to maintain blood sugars between 4.4 and 8.9 mM/L (80-160 mg/dl). The maximum dose that was to be used in any infant was 1.0 U/kg/h, but the maximum dose actually used was 0.4 U/kg/h. The mean duration of insulin therapy was 4.4 days. In the glucose reduction arm, the glucose concentration in the parenteral infusate was initially reduced by 2.5g/dl and was again reduced, as needed, in order to maintain blood sugar between 4.4 and 8.9 mM/L (80-160 mg/dl) or until a minimum glucose infusion rate of 5 mg/kg/min was reached.

The outcomes reported in this trial included energy intake (days to reach at least 60 kcal/kg/day); glucose, protein and fat intakes; prolonged hyperglycemia (remained hyperglycemic > 24h); hypoglycemia (one or more episodes); and treatment failure (failure to achieve blood sugar in the target range using the randomly allocated treatment, and requiring the back-up use of the alternative treatment). Additional information about the study design and outcome data on this trial was supplied by the lead study author, Dr William Meetze.

Excluded studies

See table 'Characteristics of excluded studies'.

Studies awaiting classification

We detected two studies awaiting classification, Alsweiler 2008 and Hawk 2009. See table, 'Characteristics of studies awaiting classification'.

Risk of bias in included studies

Both included trials, Collins 1991 and Meetze 1998, were randomized; however, it was not possible to tell from the reports whether the allocation was concealed and, if so, how. In both studies it was probably not feasible clinically to blind caretakers to the allocated intervention. Blinding of outcome ascertainment was not done in either trial. Follow-up was almost complete in Collins 1991 and was complete in Meetze 1998.

Effects of interventions

Comparison 1: Reduction of the rate of parenteral glucose infusion compared with no reduction of the rate of parenteral glucose infusion

No eligible trials that tested this comparison were detected.

Comparison 2: Insulin infusion compared with no reduction of the rate of parenteral glucose infusion

One trial that tested this comparison was detected (Collins 1991). This was a small trial, with outcome data analyzed for 11 of 12 infants in the insulin group and 12 infants in the comparison group (no glucose reduction).

Primary Outcomes

All-cause mortality

Death before discharge (2.1.1)

Collins 1991 found no significant difference between insulin infusion and no reduction in the rate of parenteral glucose infusion on death before discharge (3/11 versus 2/12). Relative risk (RR) 1.64 (95% CI 0.33 to 8.03). Risk difference (RD) 0.11 (95% CI -0.23 to 0.44).

Neurodevelopmental impairment

Collins 1991 did not report this outcome.

Severe IVH

Collins 1991 did not report this outcome

Incidence of ROP

Collins 1991 did not report this outcome with respect to either: a) any stage or b) requiring treatment.

Bacterial sepsis, one or more episodes (2.2)

Collins 1991 found no significant effect (5/11 versus 9/12). RR 0.61 (95% CI 0.29 to 1.25); RD -0.30 (95% CI -0.68 to 0.09).

Fungal sepsis, one or more episodes

Collins 1991 did not report this outcome.

Secondary Outcomes

Time to resolve hyperglycemia

Collins 1991 did not report this outcome.

Recurrent hyperglycemia

Collins 1991 did not report this outcome.

Hypoglycemia

Collins 1991 reported that in infants treated with insulin fewer than 1% of glucose determinations by reagent strip were < 2.2 mM/L (< 40 mg/dl). The incidence of hypoglycemia in infants treated in the control group was not reported.

Caloric intake

Non-protein energy intake (kcal/kg/d) (2.3.1)

Collins 1991 reported that infants treated with insulin infusion received significantly higher non-protein energy intake, 124.7 ± 18 kcal/kg/d, than infants treated with no glucose reduction, 86.0 ± 6 kcal/kg/d (Mean difference 38.7 kcal/kg/d, 95% CI 27.5 to 49.9).

Glucose infusion rate (mg/kg/min) (2.3.2)

Collins 1991 reported that infants treated with insulin infusion received significantly higher glucose infusion rates, 20.1 ± 2.5 mg/kg/min, than infants treated with no glucose reduction, 13.2 ± 3.2 mg/kg/min (Mean difference 6.9 mg/kg/min, 95% CI 4.6 to 9.2). This outcome was not pre-specified in our protocol.

Weight gain (g/kg/d) (2.4)

Collins 1991 reported that infants treated with insulin infusion had a higher weight gain, 20.1 ± 12.1 g/kg/d, than infants treated with no glucose reduction, 7.8 ± 5.1 g/kg/d (Mean difference 12.3 g/kg/d, 95% CI 4.6 to 20.0). This outcome was not pre-specified in our protocol. Collins 1991 reported no significant differences in gains in length or head circumference.

Necrotizing enterocolitis

Collins 1991 did not report this outcome.

Duration of mechanical ventilation (2.5)

Collins 1991 reported no significant difference in the number of days on mechanical ventilation. Mean difference 4.0 days (95% CI -10.4 to 18.4).

Chronic lung disease

Collins 1991 reported no significant difference in the incidence of BPD at day 28. However, the actual numbers were not reported.

Length of hospital stay

Collins 1991 did not report this outcome.

Comparison 3: Insulin infusion compared with reduction of the rate of parenteral glucose infusion

One trial that tested this comparison was detected (Meetze 1998). This was a small trial, with 12 infants in the insulin group and 11 in the comparison group (glucose restriction).

Primary outcomes

All-cause mortality (3.1)

Meetze 1998 did not report this outcome in the published paper. However, unpublished data were provided to us by the lead study author, Dr William Meetze. The incidence of death to latest follow-up (3.1.1) was 1/12 in the insulin infusion group versus 0/11 in the glucose reduction group, but this difference was not statistically significant. RR 2.77 (95% CI 0.12 to 61.65); RD 0.08 (95% CI -0.12 to 0.29).

Neurodevelopmental impairment

Meetze 1998 did not report this outcome.

Severe IVH (3.2)

Meetze 1998 did not report this outcome in the published paper. However, unpublished data were provided to us by the lead study author, Dr William Meetze. The incidence of severe IVH was 2/12 in the insulin infusion group versus 0/11 in the glucose reduction group, but this difference was not statistically significant. RR 2.71 (95% CI 0.33 to 22.51); RD 0.17 (-0.14 to 0.48). There were no statistically significant differences within birth weight (BW) subgroups (500-749g; 750-999g).

Incidence of ROP (3.3 and 3.4)

Meetze 1998 did not report this outcome, as regards to a) any stage or b) requiring treatment. However, unpublished data were provided to us by the lead study author, Dr William Meetze.The incidence of ROP any stage was 12/12 in the insulin infusion group versus 7/11 in the glucose reduction group, but this difference was not statistically significant. RR 1.49 (95% CI 0.95 to 2.33); RD 0.35 (95% CI 0.00 to 0.70). The incidence of ROP requiring treatment was 2/12 in the insulin infusion group versus 3/11 in the glucose reduction group; the difference was not statistically significant. RR 0.59 (95% CI 0.16 to 2.21); RD -0.15 (-0.47 to 0.17). There were no statistically significant differences within BW subgroups (500 to 749 g; 750 to 999 g).

Bacterial sepsis, one or more episodes (3.5)

Meetze 1998 did not report this outcome in the published paper. However, unpublished data were provided to us by the lead study author, Dr William Meetze.The incidence of bacterial sepsis was 2/12 in the insulin infusion group versus 4/11 in the glucose reduction group, but this difference was not statistically significant. RR 0.46 (95% CI 0.10 to 2.03); RD -0.20 (95% CI -0.55 to 0.16).

Fungal sepsis, one or more episodes (3.6)

Meetze 1998 did not report this outcome in the published paper. However, unpublished data were provided to us by the lead study author, Dr William Meetze.The incidence of fungal sepsis was 0/12 in the insulin infusion group versus 2/11 in the glucose reduction group, but this difference was not statistically significant. RR 0.18 (95% CI 0.01 to 3.47); RD -0.18 (95% CI -0.43 to 0.07).

Secondary outcomes

Time to resolve hyperglycemia

Meetze 1998 did not report this outcome.

Prolonged hyperglycemia (3.7)

Meetze 1998 reported that none of the infants in either group remained hyperglycemic for more than 24 hours.

Recurrent hyperglycemia

Meetze 1998 did not report this outcome.

Treatment failure, need for alternative treatment (3.8)

Meetze 1998 reported that the proportion of infants requiring the alternative treatment for control of glucose levels was 0/12 in the insulin infusion group versus 2/11 in the glucose reduction group, but this difference was not statistically significant. RR 0.18 (95% CI 0.01 to 3.47); RD -0.18 (95% CI -0.43 to 0.07). This outcome was not pre-specified in our protocol.

Hypoglycemia (3.9)

Meetze 1998 found that one infant in the insulin group developed blood glucose < 3.3 mM/L (< 60 mg/dl) and one in the control group. The values were 1.9 and 2.3 mM/L (35 and 41 mg/dl) respectively. The difference in proportion of neonates having an episode of hypoglycemia was not statistically significant. RR 0.92 (95% CI 0.06 to 12.95); RD -0.01 (95% CI -0.24 to 0.22).

Caloric intake (3.10)

Meetze 1998 reported that caloric intake was higher in the insulin infusion group as compared to the glucose reduction group. However, the data were not reported quantitatively in a form permitting analysis in this review.

Days to reach 60 kcal/kg/d

Meetze 1998 reported a significant decrease in the number of days to reach 60 kcal/kg/d in the insulin infusion group, 5.5 ± 2.1 days, as compared to the glucose reduction group, 8.6 ± 4.3 days (Mean difference -3.1 days, 95% CI -5.1 to -0.3). This outcome was not pre-specified in our protocol.

Glucose infusion rate (mg/kg/min)

Meetze 1998 reported that glucose intake was significantly higher in the insulin infusion group than in the glucose reduction group. As indicated graphically in the study report, glucose infusion rate averaged approximately 10.0 mg/kg/min in the insulin infusion group and approximately 7.6 mg/kg/min in the glucose reduction group. However, exact quantitative data are not available for analysis in this review. This outcome was not pre-specified in our protocol.

Necrotizing enterocolitis (3.11)

Meetze 1998 did not report this outcome in the published paper. However, unpublished data were provided by the lead study author, Dr William Meetze.The incidence of NEC was 0/12 in the insulin infusion group versus 1/11 in the glucose reduction group, but this difference was not statistically significant. [RR 0.31 (95% CI 0.01, 6.85); RD -0.09 (95% -0.31 to 0.12)].

Duration of mechanical ventilation

Meetze 1998 did not report this outcome

Chronic lung disease

Meetze 1998 did not report this outcome

Length of hospital stay

Meetze 1998 did not report this outcome.

For our comparison 3, insulin infusion versus glucose reduction, subgroup analyses according to birth weight could be done for the outcomes severe IVH and ROP. The other planned subgroup analyses according to criterion for hyperglycemia and associated morbidity at study entry could not be done for lack of available data.

Discussion

Only two small trials were eligible for inclusion in this review (Collins 1991; Meetze 1998). No trial compared reduction with no reduction of glucose infusion rates in hyperglycemic VLBW neonates. One trial (Collins 1991) compared insulin infusion with no reduction of glucose infusion rate (standard care). One trial (Meetze 1998) compared insulin infusion with reduction of glucose infusion rate.

The included trials provided insufficient evidence to address major objectives of this review, which concerned effects of interventions for treatment of hyperglycemia in VLBW neonates on death and major morbidities. Collins 1991 reported that insulin infusion compared with standard care had no significant effect on either death or bacterial sepsis; effects on other major morbidities were not assessed. Meetze 1998 found that insulin infusion compared with glucose reduction had no significant effects on death, severe IVH, ROP, bacterial or fungal sepsis; effects on other major morbidities were not assessed. Neither of the two eligible trials measured effects on long-term outcomes. The failure of these small trials to find significant effects of treatment on death or major morbidities may well be due to their very low power to detect real effects. Moreover, these small trials are not sufficient to shed light on the underlying question of whether hyperglycemia per se causes important clinical harms in VLBW neonates.

In regard to our secondary outcomes, some significant effects were reported in each trial. Collins 1991 found that insulin infusion compared with standard care resulted in significant increases in non-protein energy intake, glucose intake, and short-term weight gain. Meetze 1998 found that insulin infusion compared with glucose reduction resulted in significant increases in glucose intake and total energy intake. However, the clinical importance of these short-term effects is uncertain.

It is unlikely that a relevant study was not included in this review. The authors performed extensive searches of several databases for reports in any language, including searches for published studies and studies reported only as abstracts. These searches were backed up by citation searches on the two eligible trials, Collins 1991 and Meetze 1998, published 17 and 10 years ago respectively. The primary investigator for each included trial was contacted and responded with additional requested information concerning the design, conduct and outcome data of his trial. Thus, all relevant available information from those trials has been considered and included in this review.

In a systematic review of insulin for the treatment of hyperglycemia in low birth weight neonates, Raney 2008 included eight observational studies as well as the two randomized trials we included in this review. The results of the two randomized trials were reported separately, without meta-analysis, as we did. However, Raney 2008 did not distinguish between Collins 1991 and Meetze 1998 in the nature of the control intervention, nor did they report treatment effects on death or major morbidities in their review. Kairamkonda published an evidence summary with commentary concerning the effects of insulin infusion on control of blood glucose and nutrition in the VLBW neonate (Kairamkonda 2006) and a review concerning the management of hyperglycemia in the ELBW neonate (Kairamkonda 2008). Neither report constituted a systematic review. Earlier, Ashton 2002 reported a review of treatment of hyperglycemia in preterm infants that was not restricted to randomized trials or to neonates of very low birth weight.

Based on the evidence from randomized trials of interventions for the treatment of hyperglycemia in VLBW neonates, it remains uncertain whether the hyperglycemia per se is a cause of the increase in death and important morbidities reported in such neonates or how the hyperglycemia should be treated.

Authors' conclusions

Implications for practice

There is insufficient evidence from randomized controlled trials to determine whether treatments for neonatal hyperglycemia in VLBW neonates reduce mortality and morbidities.

Insulin infusion is associated with increases in energy and glucose intakes and greater short-term weight gain. However, the clinical importance of these findings is unknown.

Implications for research

The available evidence from randomized trials of treatments for neonatal hyperglycemia in VLBW neonates is insufficient to establish clinically important benefits and risks of treatment. Much larger randomized trials in hyperglycemic VLBW neonates are needed, powered on clinical outcomes, in order to determine whether, and how, the hyperglycemia should be treated.

Acknowledgements

We thank Dr James Collins and Dr William Meetze for providing additional information on study design and outcomes for their trials. This review was begun and the early stages completed when Dr Marcela Bottino was a Neonatal Fellow at McMaster University, Hamilton, Canada.

Contributions of authors

All authors contributed to all stages of preparation of both the Protocol and Review.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Collins 1991

Methods

Randomized controlled trial, single centre

Participants

24 hyperglycemic, ELBW and AGA neonates, randomized to insulin infusion (BW 790.4 ± 119.8 g, GA 26.4 ± 1.6 wk) or standard care (BW 755.4 ± 140.0 g, GA 26.1 ± 1.6 wk) between 4 and 14 days of life. Eligibility criteria included all of the following: (i) serum glucose levels > 9.9 mM/L (> 180 mg/dl); (ii) glucosuria; (iii) non-protein parenteral energy intake < 120 kcal/kg/day. The infants entered the study at a mean age of 7.4 ± 3.3 days. All infants received same regimen of parenteral nutrition. Enteral feeding was initiated when the infant was considered to be stable.

Interventions

Insulin infusion (n=12): Insulin begun at 0.04 U/h, and titrated to maintain serum glucose concentrations between 5.5 and 9.9 mM/L (100 and 180 mg/dl). Insulin doses ranged from 0.04 to 1 U/h. The mean duration of therapy was 14.6 days (range 7 to 21 days). Blood glucose values were checked every 1 to 4 hours. The goal was to achieve 120 non-protein kcal/kg/day.

Standard care (n=12): with the same goal to achieve 120 kcal/kg/day, nevertheless, when glucose intolerance developed, intravenous glucose administration was to be reduced to keep serum glucose values < 9.9 mM/L (< 180 mg/dl). However, figure 1 of the report indicates no actual reduction in the mean rate of glucose infusion in the control group. Blood glucose values were checked at least three times a day.

Outcomes

Non-protein energy intake (kcal/kg/day)

Glucose infusion rates (mg/kg/min)

Weight (g)

Daily weight gain (g/kg/day)

Sepsis

Death

Duration of mechanical ventilation (days)

BPD at 28 days

Notes

For this review this trial was categorized under our comparison 2, insulin infusion compared with no reduction of the rate of parenteral glucose infusion, after consultation with the lead study author Dr James Collins

Unpublished outcome data that were potentially eligible for this review were requested from Dr Collins, who informed us that data from his trial are no longer available

One infant allocated to the insulin group never required it, and was excluded from analyses of outcomes (personal communication from Dr James Collins)

Hypoglycemia reported as < 1% of all blood glucose determinations in the insulin group; no comment on the standard care group

Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) Unclear risk

Allocation concealment uncertain

Blinding of participants and personnel (performance bias) High risk

Caretakers not blinded to intervention

Blinding of outcome assessment (detection bias) High risk

Outcome assessors not blinded to group allocation

Incomplete outcome data (attrition bias) Low risk

Complete follow-up except for non-inclusion in outcome analyses of one infant randomized to insulin infusion who never required it

Meetze 1998

Methods

Randomized controlled trial, single centre

Participants

23 hyperglycemic participants, BW 500-1000 g, GA 24-30 wk, randomized to insulin infusion (BW 763 ± 29 g SEM, GA 26.5 ± 0.5 wk). Parenteral nutrition begun at 48-72h. All neonates had received greater than/or equal to 6mg/kg/min of glucose on day three, advanced incrementally to a maximum of 12mg/kg/min on day six. Minimal enteral feeds begun after day three in stable infants. Hyperglycemia (single determination of blood sugar > 13.3 mM/L, > 240 mg/dl, or repeat blood sugars > 8.9 mM/L, > 160 mg/dl) diagnosed at PNA 96 ± 10h (range 13-172 h). Not reported: actual blood sugar at time of diagnosis of hyperglycemia, associated morbidity (score or other).

Interventions

Insulin infusion (n=12): Insulin begun at 0.1 U/kg/h, and titrated to maintain blood sugar between 4.4 and 8.9 mM/L (80 to 160 mg/dl). Maximum dose to be used in any infant was 1.0 U/kg/h, but maximum dose actually required was 0.4 U/kg/h. When insulin was begun, blood sugar was measured at least hourly until stable in the desired range, at least every 4h thereafter while on insulin. Parenteral glucose intake initially maintained at the same prescribed level. However, if maximum permitted insulin dose was reached and the neonate remained hyperglycemic ("treatment failure"), glucose intake was to be reduced while maintaining insulin infusion.

Glucose reduction (n=11): Glucose concentration in the parenteral infusate was initially reduced by 2.5 g/dl. If this did not reduce blood sugar within 4h, infused glucose concentration was again reduced, as needed, in order to maintain blood sugar between 4.4 and 8.9 mM/L (80-160 mg/dl), or until a minimum intake of 5 mg/kg/min was reached. In neonates who remained hyperglycemic on 5 mg/kg/min ("treatment failure"), insulin infusion was to be started.

Outcomes

Energy intake (days to reach 60 kcal/kg/day)

Glucose, protein, fat intakes (g/kg/day)

Prolonged hyperglycemia (remained hyperglycemic for more than 24h)

Hypoglycemia (one or more episodes)

Treatment failure (failure to achieve blood sugar in target range using the randomly allocated treatment, which required back-up use of the alternative treatment)

Notes

This randomized trial in 23 hyperglycemic neonates was nested in a larger study of 61 ELBW infants enrolled by 48 hours and followed prospectively for the development of hyperglycemia. Among these 61 infants, there were 5 post-entry withdrawals from the study, but none of these withdrawals were among the hyperglycemic neonates who were participants in the randomized trial (personal communication from the lead investigator, Dr William Meetze). Among the 56 remaining infants, 23 developed hyperglycemia and were treated with insulin infusion or reduced glucose intake according to which treatment for hyperglycemia had been randomly assigned. Only these 23 neonates were eligible for inclusion in this review.

Two neonates allocated to glucose reduction required back-up use of insulin, but were (appropriately) analyzed in the glucose reduction group. These two neonates were analyzed in the glucose reduction group in this review, as well.

Dr Meetze provided us with previously unpublished outcome data concerning death, severe IVH, ROP, bacterial and fungal sepsis and NEC. Although Meetze 1998 reported that none of the 12 insulin-treated neonates developed hypoglycemia, Dr Meetze stated to us that in fact one neonate in the insulin-treated group had an episode of hypoglycemia while on insulin (single blood sugar reading of 1.9 mM/L [35 mg/dl]) that was missed when writing the published report. Dr Meetze also reported to us that two neonates in the glucose reduction group had an episode of low blood sugar while on glucose reduction, 2.3 mM/L (41 mg/dl) in one and 2.5 mM/L (45 mg/dl) in the other. The neonate having a blood sugar value of 2.3 mM/L was hypoglycemic by the definition we adopted for this review.

Risk of bias table
Bias Authors' judgement Support for judgement
Allocation concealment (selection bias) Unclear risk

Allocation concealment uncertain

Blinding of participants and personnel (performance bias) High risk

Caretakers not blinded to intervention

Blinding of outcome assessment (detection bias) High risk

Outcome assessors not blinded to group assignment

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Beardsall 2007

Reason for exclusion

Participants not hyperglycemic at study entry

(Protocol for RCT of insulin for prevention of hyperglycemia)

Beardsall K 2007

Reason for exclusion

Participants not hyperglycemic at study entry

(Pilot study for RCT of insulin for prevention of hyperglycemia)

Becerra 2002

Reason for exclusion

Participants not hyperglycemic at study entry

Not very low birth weight infants

Berces 2006

Reason for exclusion

Case series of 64 hyperglycemic infants, < 26 wk GA, treated with insulin infusion

Binder 1989

Reason for exclusion

Insulin for hyperglycemic very low birth weight infants, non-randomized controls

Ditzenberger 1999

Reason for exclusion

Retrospective chart review of insulin for control of hyperglycemia

Fuloria 2002

Reason for exclusion

Comparison of two modes of insulin delivery in hyperglycemic extremely low birth weight infants

Goldman 1980

Reason for exclusion

Case series of insulin infusion for glucose intolerance in extremely low birth weight infants

Heron 1988

Reason for exclusion

Case series of insulin for glucose intolerant preterm infants < 1250g

Kanarek 1991

Reason for exclusion

Not RCT

Ng 2005

Reason for exclusion

Case series of insulin infusion for hyperglycemic very low birth weight infants

Ostertag 1986

Reason for exclusion

Case series of insulin infusion for hyperglycemic very low birth weight infants

Patil 2006

Reason for exclusion

Case series of insulin infusion for hyperglycemic very low birth weight infants

Pollak 1978

Reason for exclusion

Non-randomized paired comparison of insulin infusion versus placebo, at mid-point of steady-state hyperglycemia induced by glucose infusion at 14 mg/kg/min.

Sparks 1982

Reason for exclusion

Galactose was an ineligible intervention for this review

Tejera Ramírez 1998

Reason for exclusion

Case series of insulin infusion in hyperglycemic VLBW neonates

Thabet 2003

Reason for exclusion

Case series of insulin infusion for hyperglycemic very low birth weight infants

Vaucher 1982

Reason for exclusion

Case series of insulin infusion for hyperglycemic very low birth weight infants.

Characteristics of studies awaiting classification

Alsweiler 2008

Methods

Randomised controlled trial, parallel group. Central randomization by computer, stratified by gender and birth weight for gestational age (> or < 10th centile). Open (masking not used). Target sample size 88

Participants

Babies < 30 weeks gestation or < 1500 g, postnatal age from birth up to 36 weeks post-menstrual age, with hyperglycemia (two consecutive blood glucose measurements > 8.5 mM/L, at least 4 h apart

Interventions

Experimental: Continuous intravenous insulin infusion starting at 0.05 units/kg/hour, titrated to maintain blood glucose level from 4 - 6 mM/L

Contol: Insulin started only in hyperglycemic babies > 3 days old who have persistently elevated blood glucose levels > 10 mM/L, and are unable to tolerate 100 kcal/kg/day. Insulin dose titrated to maintain blood glucose level from 8 - 10 mM/L

Outcomes

Primary: Lower leg growth rate, assessed twice a week until 36 weeks postmenstrual age

Secondary: Number of episodes of sepsis; number of blood transfusions; myocardial hypertrophy; levels of cortisol, insulin-like growth factor 1, insulin; incidence of hypoglycemia

Notes

This study has been completed, awaiting publication

Hawk 2009

Methods

Randomized controlled trial, single centre

Participants

35 VLBW infants, 24 hours postnatal age at study entry; abstract contains no mention of whether or not participants were hyperglycemic at study entry

Interventions

Experimental: Continuous infusion of insulin 1 U/kg/day titrated to target blood glucose range of 4.4 - 6.1 mM/L (80 - 100 mg/dL)

Control: Conventional management with target blood glucose range < 10.0 mM/L (< 180 mg/dL)

Outcomes

Blood glucose concentrations, episodes of hypoglycemia, growth, death, severe ROP, severe IVH, CLD, NEC

Notes

Insufficient information in abstract to judge whether eligible as included study for this review. Awaiting full report.

Characteristics of ongoing studies

  • None noted.

Additional tables

  • None noted.

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References to studies

Included studies

Collins 1991

Collins JW, Hoppe M, Brown K, Edidin DV, Padbury J, Ogata ES. A controlled trial of insulin infusion and parenteral nutrition in extremely low birth weight infants with glucose intolerance. The Journal of Pediatrics 1991;118:921-7.

Meetze 1998

Meetze W, Bowsher R, Compton J, Moorehead H. Hyperglycemia in extremely-low-birth-weight Infants. Biology of the Neonate 1998;74:214-21.

Excluded studies

Beardsall 2007

Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Ahluwalia JS, Vanhole C, Palmer C, Midgley P, Thompson M, Cornette L, Weissenbruch M, Thio M, de Zegher F, Dunger D. A randomised controlled trial of early insulin therapy in very low birth weight infants, "NIRTURE" (neonatal insulin replacement therapy in Europe). BMC Pediatrics 2007;7:29.

Beardsall K 2007

Beardsall K, Ogilvy-Stuart AL, Frystyk J, Chen JW, Thompson M, Ahluwalia J, Ong KK, Dunger DB. Early elective insulin therapy can reduce hyperglycemia and increase insulin-like growth factor-I levels in very low birth weight infants. The Journal of Pediatrics 2007;151:611-7.

Becerra 2002

Becerra M, Cifuentes J, Saldias MI, Galvez MC, Fernandez P, Aguila A. Continuous gastric drip versus intravenous fluids in low birthweight infants. Acta Paediatrica 2002;91:430-3.

Berces 2006

Berces M, Polonkai E, Horvath Z, Katona N, Kovacs-Paszthy B, Kovacs J, Balla G. Continuous insulin infusion in extremely-low-birth-weight newborns under 26 weeks of gestational age. European Journal of Pediatrics 2006;165(Suppl 1):272.

Binder 1989

Binder ND, Raschko PK, Benda GI, Reynolds JW. Insulin infusion with parenteral nutrition in extremely low birth weight infants with hyperglycemia. Journal of Pediatrics 1989;114:273-80.

Ditzenberger 1999

Ditzenberger GR, Collins SD, Binder N. Continuous insulin intravenous infusion therapy for VLBW infants. Journal of Perinatal and Neonatal Nursing 1999;13:70-82.

Fuloria 2002

Fuloria M, Beisswanger A, Hansell BJ, Morgan TM, Aschner JL. Randomized trial comparing two modes of insulin delivery to extremely low birth weight infants with hyperglycemia. In: Pediatric Academic Societies Conference Proceedings. 2002:Abstract 2355.

Goldman 1980

Goldman SL, Hirata T. Attenuated response to insulin in very low birthweight infants. Pediatric Research 1980;14:50-3.

Heron 1988

Heron P, Bourchier D. Insulin infusions in infants of birthweight less than 1250g and with glucose intolerance. Australian Paediatric Journal 1988;24:362-5.

Kanarek 1991

Kanarek KS, Santeiro ML, Malone JI. Continuous infusion of insulin in hyperglycemic low-birth weight infants receiving parenteral nutrition with and without lipid emulsion. Journal of Parenteral & Enteral Nutrition 1991;15:417-20.

Ng 2005

Ng SM, May JE, Emmerson AJ. Continuous insulin infusion in hyperglycaemic extremely-low-birth-weight neonates. Biology of the Neonate 2005;87:269-72.

Ostertag 1986

Ostertag SG, Jovanovic L, Lewis B, Auld PAM. Insulin pump therapy in the very low birth weight infant. Pediatrics 1986;78:625-30.

Patil 2006

Patil S, Cayabyab R, Sardesai S, Siassi B, Seri I, Ramanathan R. Management of transient hyperglycemia in very low birth weight (VLBW) infants with continuous insulin infusion and its. Effect on serum lactate levels. In: Pediatric Academic Societies Conference Proceedings. 2006:Abstract 5571.431.

Pollak 1978

Pollak A, Cowett RM, Schwartz R, Oh W. Glucose disposal in low-birth-weight infants during steady-state hyperglycemia: effects of exogenous insulin administration. Pediatrics 1978;61:546-549.

Sparks 1982

Sparks JW, Avery GB, Fletcher AB, Simmons MA, Glinsmann WH. Parenteral galactose therapy in the glucose-intolerant premature infant. The Journal of Pediatrics 1982;100:255-9.

Tejera Ramírez 1998

Tejera Ramírez C, Siles Quesada C, Bonnet Delgado D, González Azpeitia G, Reyes Santana D. Continuous insulin perfusion in preterm infants with weight less than 1, 500 grams who receive parenteral nutrition [Perfusión continua de insulina en RN pretérminos con peso inferior a 1.500 gramos que reciben nutrición parenteral]. Anales Españoles de Pediatria 1998;49:213-5.

Thabet 2003

Thabet F, Bourgeois J, Guy B, Putet G. Continuous insulin infusion in hyperglycaemic very-low-birth-weight infants receiving parenteral nutrition. Clinical Nutrition 2003;22:545-7.

Vaucher 1982

Vaucher EY, Walson PD, Morrow G 3rd. Continuous insulin infusion in hyperglycemic, very low birth weight infants. Journal of Pediatric Gastroenterology and Nutrition 1982;1:211-7.

Studies awaiting classification

Alsweiler 2008

Alsweiler J, Bloomfield F, Harding J. Randomized controlled trial on the effect of tight glycaemic control with insulin in hyperglycaemic very low birth weight (VLBW) preterm neonates on growth (The HINT Trial). Completed study, awaiting publication.

Hawk 2009

Hawk BJ, Ternes RL, Wilson BJ. Tiny infant glycemic hypothesis trial: TIGHT glucose control in VLBW infants. In: Pediatric Academic Societies Conference Proceedings. 2009:Abstract 5508.149.

Ongoing studies

  • None noted.

Other references

Additional references

Ashton 2002

Ashton J. Hyperglycaemic premature infants: Insulin infusion versus alternative treatment. Journal of Neonatal Nursing 2002;8:70-75.

Bier 1977

Bier DM, Leake RD, Haymond MW, Arnold KJ, Gruenke LD, Sperling MA, Kipnis DM. Measurement of "true" glucose production rates in infancy and childhood with 6, 6-dideuteroglucose. Diabetes 1977;26:1016-23.

Binder 1989

Binder ND, Raschko PK, Benda GI, Reynolds JW. Insulin infusion with parenteral nutrition in extremely low birth weight infants with hyperglycemia. The Journal of Pediatrics 1989;114:273-80.

Blanco 2006

Blanco CL, Baillargeon JG, Morrison RL, Gong AK. Hyperglycemia in extremely low birth weight infants in a predominantly Hispanic population and related morbidities. Journal of Perinatology 2006;26:737-41.

Chacko 2011

Chacko SK, Ordonez J, Sauer PJJ, Sunehag AL. Gluconeogenesis is not regulated by either glucose or insulin in extremely low birth weight infants receiving total parenteral nutrition. The Journal of Pediatrics 2011;158:891-6.

Cowett 1979

Cowett RM, Oh W, Pollack A, Schwartz R, Stonestreet BS. Glucose disposal of low birth weight infants: steady state hyperglycemia produced by constant intravenous glucose infusion. Pediatrics 1979;63:389-96.

Cowett 1983

Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the neonate. Journal of Clinical Investigation 1983;71:467-75.

Cowett 1987

Cowett RM. Requested annotation to Ostertag SG et al: Insulin pump therapy in very low birth weight infants. In: Klaus M, Fanaroff A, editor(s). Yearbook of Perinatal Neonatal Medicine. Yearbook Medical Publishers, 1987:186-7.

Cowett 1997

Cowett AA, Farrag HM, Gelardi NL, Cowett RM. Hyperglycemia in the micropremie: evaluation of the metabolic disequilibrium during the neonatal period. Prenatal and Neonatal Medicine 1997;2:360-5.

Efron 2003

Efron D, South M, Volpe JJ, Inder T. Cerebral injury in association with profound iatrogenic hyperglycemia in a neonate. European Journal of Paediatric Neurology 2003;7:167-71.

Ertl 2006

Ertl T, Gyarmati J, Gaal V, Szabo I. Relationship between hyperglycemia and retinopathy of prematurity in very low birth weight infants. Biology of the Neonate 2006;89:56-9.

Falcão 1998

Falcão MC, Ramos JLA. Hyperglycemia and glucosuria in preterm infants receiving parenteral glucose: influence of birth weight, gestational age and infusion rate. Jornal de Pediatria 1998;74:389-96.

Finberg 1967

Finberg L. Dangers to infants caused by changes in osmolal concentration. The Journal of Pediatrics 1967;40:1031-4.

Fuloria 1998

Fuloria M, Friedberg MA, DuRant RH, Aschner JL. Effect of flow rate and insulin priming on the recovery of insulin from microbore infusion tubing. Pediatrics 1998;102:1401-6.

Garg 2003

Garg R, Agthe AG, Donohue PK, Lehmann CU. Hyperglycemia and retinopathy of prematurity in very low birth weight infants. Journal of Perinatology 2003;23:186-94.

Haynes 2005

Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SD, for the Hedges Team. Optimal search strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey. BMJ 2005;330:1179.

Hays 2006

Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth weight infants. Pediatrics 2006;118:1811-8.

Heimann 2007

Heimann K, Peschgens T, Kwiecien R, Stanzel S, Hoernchen H, Merz U. Are recurrent hyperglycaemic episodes and median blood glucose level a prognostic factor for increased morbidity and mortality in premature infants less than/or equal to 1500g ? Journal of Perinatal Medicine 2007;35:245-8.

Heird 1992

Heird WC. Parenteral Feeding. Chapter 8. In: JC Sinclair, MB Bracken, editor(s). Effective Care of the Newborn Infant. New York: Oxford University Press, 1992:141-60.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Jobe 2001

Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American Journal of Respiratory and Critical Care Medicine 2001;163:1723-9.

Kairamkonda 2006

Kairamkonda V. Does continuous insulin infusion improve glycaemic control and nutrition in hyperglycaemic very low birth weight infants? Archives of Disease in Childhood 2006;91:76-9.

Kairamkonda 2008

Kairamkonda V, Khashu M. Controversies in the management of hyperglycemia in the ELBW infant. Indian Pediatrics 2008;45:29-38.

Kao 2006

Kao LS, Morris BH, Lally KP, Stewart CD, Huseby V, Kennedy KA. Hyperglycemia and morbidity in extremely low birth weight infants. Journal of Perinatology 2006;26:730-6.

Louik 1985

Louik C, Mitchell AA, Epstein MF, Shapiro S. Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion. American Journal of Diseases of Children 1985;139:783-6.

Manzoni 2006

Manzoni P, Castagnola E, Mostert M, Sala U, Galletto P, Gomirato G. Hyperglycaemia as a possible marker of invasive fungal infection in preterm neonates. Acta Paediatrica 2006;95:486-93.

Mitanchez-Mokhtari 2004

Mitanchez-Mokhtari D, Lahlou N, Kieffer F, Magny J-F, Roger M, Voyer M. Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants. Pediatrics 2004;113:537-41.

Ostertag 1986

Ostertag SG, Jovanovic L, Lewis B, Auld PA. Insulin pump therapy in the very low birth weight infant. Pediatrics 1986;78:625-30.

Raney 2008

Raney M, Donze A, Smith JR. Insulin infusion for the treatment of hyperglycemia in low birth weight infants: examining the evidence. Neonatal Network 2008;27:127-40.

Rowen 1995

Rowen JL, Atkins JT, Levy ML, Baer SC, Baker CJ. Invasive fungal dermatitis in the less than/or equal to 1000-gram neonate. Pediatrics 1995;95:682-7.

Sinclair 2009

Sinclair JC, Bottino M, Cowett RM. Interventions for prevention of neonatal hyperglycemia in very low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007615. DOI: 10.1002/14651858.CD007615.

Sunehag 1993

Sunehag A, Ewald U, Larsson A, Gustafsson J. Glucose production rate in extremely immature neonates (< 28 weeks) studied by use of deuterated glucose. Pediatric Research 1993;33:97-100.

Sunehag 1994

Sunehag A, Gustaffson J, Ewald U. Very immature infants (less than/or equal to 30 Wk) respond to glucose infusion with incomplete suppression of glucose production. Pediatric Research 1994;36:550-5.

Sunehag 1999

Sunehag AL, Haymond MW, Schanler RJ, Reeds PJ, Bier DJ. Gluconeogenesis in very low birth weight infants receiving total parenteral nutrition. Diabetes 1999;48:791-800.

Thabet 2003

Thabet F, Bourgeois J, Guy B, Putet G. Continuous insulin infusion in hyperglycaemic very-low-birth-weight infants receiving parenteral nutrition. Clinical Nutrition 2003;22:545-7.

Thureen 1999

Thureen PJ. Early aggressive nutrition in the neonate. Pediatrics in Review 1999;20:e45-55.

Vaucher 1982

Vaucher YE, Walson PD, Morrow G 3rd. Continuous insulin infusion in hyperglycemic, very low birth weight infants. Journal of Pediatric Gastroenterology and Nutrition 1982;1:211-7.

Zlotkin 1981

Zlotkin SH, Bryan MH, Anderson GH. Intravenous nitrogen and energy intakes required to duplicate in utero nitrogen accretion in prematurely born human infants. The Journal of Pediatrics 1981;99:115-20.

Other published versions of this review

Bottino 2009

Bottino M, Cowett RG, Sinclair JC. Interventions for the treatment of neonatal hyperglycemia in very low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD007453. DOI: 10.1002/14651858.CD007453.pub2.

Classification pending references

  • None noted.

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Data and analyses

1 Glucose reduction versus No glucose reduction (no eligible trials)

Comparison 1: Reduction of the rate of parenteral glucose infusion compared with no reduction of the rate of parenteral glucose infusion

No eligible trials that tested this comparison were detected.

2 Insulin infusion versus No glucose reduction

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 All-cause mortality 1 23 Risk Ratio (M-H, Fixed, 95% CI) 1.64 [0.33, 8.03]
2.1.1 Death before discharge 1 23 Risk Ratio (M-H, Fixed, 95% CI) 1.64 [0.33, 8.03]
2.2 Bacterial sepsis, one or more episodes 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.29, 1.25]
2.3 Caloric intake, kcal/kg/day 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2.3.1 Non-protein energy intake (kcal/kg/day) 1 23 Mean Difference (IV, Fixed, 95% CI) 38.70 [27.53, 49.87]
2.3.2 Glucose infusion rate (mg/kg/min) 1 23 Mean Difference (IV, Fixed, 95% CI) 6.90 [4.56, 9.24]
2.4 Weight gain (g/kg/day) 1 23 Mean Difference (IV, Fixed, 95% CI) 12.30 [4.59, 20.01]
2.5 Mechanical ventilation (days) 1 23 Mean Difference (IV, Fixed, 95% CI) 4.00 [-10.42, 18.42]

3 Insulin infusion versus Glucose reduction

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 All-cause mortality 1 23 Risk Ratio (M-H, Fixed, 95% CI) 2.77 [0.12, 61.65]
3.1.1 Death, to latest follow-up 1 23 Risk Ratio (M-H, Fixed, 95% CI) 2.77 [0.12, 61.65]
3.2 Severe IVH (grade 3 or 4) 1 23 Risk Ratio (M-H, Fixed, 95% CI) 2.71 [0.33, 22.51]
3.2.1 BW 500-749g 1 10 Risk Ratio (M-H, Fixed, 95% CI) 2.14 [0.11, 42.52]
3.2.2 BW 750-999g 1 13 Risk Ratio (M-H, Fixed, 95% CI) 3.43 [0.16, 71.36]
3.3 ROP any stage 1 23 Risk Ratio (M-H, Fixed, 95% CI) 1.49 [0.95, 2.33]
3.3.1 BW 500-749g 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.72, 2.44]
3.3.2 BW 750-999g 1 13 Risk Ratio (M-H, Fixed, 95% CI) 1.65 [0.87, 3.15]
3.4 ROP requiring treatment 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.16, 2.21]
3.4.1 BW 500-749g 1 10 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.03, 1.45]
3.4.2 BW 750-999g 1 13 Risk Ratio (M-H, Fixed, 95% CI) 3.43 [0.16, 71.36]
3.5 Bacterial sepsis 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.10, 2.03]
3.6 Fungal sepsis 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.18 [0.01, 3.47]
3.7 Prolonged hyperglycemia (> 24 hours) 1 23 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
3.8 Treatment failure (need for alternative treatment) 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.18 [0.01, 3.47]
3.9 Hypoglycemia (one or more episodes) 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.06, 12.95]
3.10 Energy intake (days to reach 60 kcal/kg/day) 1 23 Mean Difference (IV, Fixed, 95% CI) -3.10 [-5.91, -0.29]
3.11 NEC 1 23 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.01, 6.85]

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Figures

  • None noted.

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Sources of support

Internal sources

  • No sources of support provided.

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 10, 2011 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.