A.S.P.E.N. Clinical Guidelines
2011; Wiley; Volume: 36; Issue: 1 Linguagem: Catalão
10.1177/0148607111418980
ISSN1941-2444
AutoresDanielle Arsenault, Megan Brenn, Sendia Kim, Kathleen M. Gura, Charlene Compher, Edwin Simpser, Mark Puder,
Tópico(s)Metabolism and Genetic Disorders
ResumoJournal of Parenteral and Enteral NutritionVolume 36, Issue 1 p. 81-95 Clinical GuidelineFree Access A.S.P.E.N. Clinical Guidelines Hyperglycemia and Hypoglycemia in the Neonate Receiving Parenteral Nutrition Danielle Arsenault RN, MSN, Danielle Arsenault RN, MSNSearch for more papers by this authorMegan Brenn RD, Megan Brenn RDSearch for more papers by this authorSendia Kim MD, Sendia Kim MDSearch for more papers by this authorKathleen Gura PharmD, Kathleen Gura PharmDSearch for more papers by this authorCharlene Compher PhD, RD, CNSC, LDN, FADA, Corresponding Author Charlene Compher PhD, RD, CNSC, LDN, FADA compherc@nursing.upenn.edu Charlene Compher, PhD, RD, CNSC, LDN, FADA, University of Pennsylvania School of Nursing, Claire M. Fagin Hall, 418 Curie Boulevard, Philadelphia, PA 19104-4217; e-mail: compherc@nursing.upenn.edu.Search for more papers by this authorEdwin Simpser MD, Edwin Simpser MDSearch for more papers by this authorMark Puder MD, PhD, Mark Puder MD, PhDSearch for more papers by this authorAmerican Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors, American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of DirectorsSearch for more papers by this author Danielle Arsenault RN, MSN, Danielle Arsenault RN, MSNSearch for more papers by this authorMegan Brenn RD, Megan Brenn RDSearch for more papers by this authorSendia Kim MD, Sendia Kim MDSearch for more papers by this authorKathleen Gura PharmD, Kathleen Gura PharmDSearch for more papers by this authorCharlene Compher PhD, RD, CNSC, LDN, FADA, Corresponding Author Charlene Compher PhD, RD, CNSC, LDN, FADA compherc@nursing.upenn.edu Charlene Compher, PhD, RD, CNSC, LDN, FADA, University of Pennsylvania School of Nursing, Claire M. Fagin Hall, 418 Curie Boulevard, Philadelphia, PA 19104-4217; e-mail: compherc@nursing.upenn.edu.Search for more papers by this authorEdwin Simpser MD, Edwin Simpser MDSearch for more papers by this authorMark Puder MD, PhD, Mark Puder MD, PhDSearch for more papers by this authorAmerican Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors, American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of DirectorsSearch for more papers by this author First published: 16 December 2011 https://doi.org/10.1177/0148607111418980Citations: 28AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Background This Clinical Guideline has been developed to guide clinical practice based on the authors' assessment of current published evidence on glycemic control in the neonate (within the first month of life) receiving parenteral nutrition (PN). The neonate receiving PN is worthy of special consideration with respect to glucose control, as this population carries an elevated risk of hyper- and hypoglycemia and may be more susceptible to deleterious effects associated with these conditions. Untreated hyper- or hypoglycemia may lead to undesirable clinical outcomes. Prolonged or symptomatic hypoglycemia may result in neurodevelopmental impairment.1-6 Severe hyperglycemia can lead to osmotic diuresis resulting in dehydration and electrolyte imbalance. Furthermore there is some evidence to suggest that hyperglycemia in premature infants (particularly those that are very low birth weight (VLBW <1500 g) or extremely low birth weight (ELBW 2 (< 0.5) based on consistent evidence from two or more observational studies, with no plausible confounders (+1) Moderate Consistency Low OBS Low Important inconsistency (−1) Directness Very strong evidence of association—significant relative risk of > 5 (< 0.2) based on direct evidence with no major threats to validity (+2) Very Low Some (−1) or major (−2) uncertainty about directness Precision Dose-response gradient Imprecise or sparse data (−1) Evidence of a dose response gradient (+1) Publication bias Unmeasured Confounders High probability of reporting bias (−1) All plausible confounders would have reduced the effect (+1) Expert Opinion Very Low Very Low Adapted from: Grade Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004, 328 (7454): 1490-1494. OBS=observational study; RCT=randomized controlled trial The GRADE system combines all the references obtained for a given question into a table that is organized by clinical outcome. The criteria to be used in evaluating the quality of the evidence are summarized in Table 2. Consistency, directness, precision and risk of publication bias are important to include in the assessment of evidence quality.17 Inconsistency of randomized controlled trial (RCT) findings means that the effect size represented by the intervention has a wide confidence interval, that the effects are conditional (one effect at baseline with a different effect at a later time point), or that some studies report a positive and others a negative finding for reasons that cannot be explained by research quality. Indirect evidence might include use of a surrogate outcome (adequate energy intake rather than measured growth in children) or data tangential for the question at hand (interpolated from evidence in another age group or compared to oral diet rather than to parenteral nutrition). Imprecision risk is high when there is no power statement to justify the sample size. The risk of publication bias is high when most of the published research reports were funded by an industry that might benefit from positive outcomes reported. Meta-analyses and systematic reviews may be used to combine the results of studies to further clarify the overall outcome of these studies but will not be considered in the grading of the Guideline to avoid considering primary research reports multiple times. RCT evidence begins with a high rating and observational evidence with a low quality rating. The quality rating may be downgraded due to limitations in study design or project implementation, to wide confidence intervals, to variable results across studies, indirect evidence or suspected publication bias. The quality rating may be upgraded if the effect size is very large, a dose-response gradient is shown, or if all plausible, unreported biases or unmeasured confounders would strengthen the reported treatment effect even further (Table 2). When expert opinion is included, the evidence base is assigned a grade of very low and may not be changed. If the evidence grade is high, it is unlikely that further research will change our confidence in the estimate of effect. With moderate grade evidence, further research is likely to modify the confidence in the effect estimate and may change the estimate. With low grade evidence, further research is very likely to change the estimate, and with very low evidence grades, an estimate of the effect is very uncertain. A clinical recommendation is then developed by consensus of the Clinical Guidelines authors, based on the best available evidence. The risks and benefits to the patient are weighed in light of the available evidence. Conditional language is used for weak recommendations (Table 3). The summary of clinical guidelines for glucose control in neonates receiving parenteral nutrition is in Table 4. Table 3. Developing and Grading the Clinical Guideline Recommendation Quality of Evidence Weighing Risks vs. Benefits GRADE Recommendation Clinical Guideline Statement High to very low Net benefits outweigh harms Strong We recommend High to very low Tradeoffs for patient are important Weak We suggest High to very low Uncertain tradeoffs Further research needed We cannot make a recommendation at this time Adapted from: Grade Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004, 328 (7454): 1490-1494 Table 4. Nutrition Support Clinical Guideline Recommendations for Glucose Control in Neonates receiving Parenteral Nutrition Question 1: How should blood glucose concentration be determined in neonates? We suggest that blood glucose screening be conducted by laboratory serum glucose or glucose electrode measurements rather than point of care reagent test strips. Weak Question 2: What blood glucose concentration is associated with reduced clinical complications in neonates receiving PN We suggest keeping the blood glucose concentration < 150 mg dL Weak We cannot make a recommendation to determine whether serum glucose should be maintained > 40 mg/dL Recommend Further Research We recommend treating symptomatic hypoglycemia. Strong Question 3: What strategies may be used to maintain optimal blood glucose concentration in neonates receiving PN? We suggest that excess energy and dextrose delivery be avoided. Weak We suggest that fat emulsion be added to PN infusion. Weak We recommend against the use of early insulin therapy to prevent hyperglycemia. Strong We cannot make a recommendation to evaluate the impact of treating hyper- or hypoglycemia on clinical outcomes. Recommend Further Research Question 1 How should blood glucose concentration be determined in neonates? (Tables 5, 6) We suggest that blood glucose screening be conducted by laboratory serum glucose or glucose electrode measurements rather than point of care reagent test strips when possible (weak). Table 5. Evidence Table Question 1: How should blood glucose concentration be determined in neonates? Author, Year (ref #) Study Design, Quality Population, Setting, N Study Objective Results Comments Hussain, 2000 19 OBS Infants admitted to NICU over 1 y(N=180) Compare capillary and venous glucose by test strip to laboratory-measured plasma glucose values Mean difference Between capillary test strips and plasma glucose, -0.058 mmol/L (SD= 1.39)Between venous test strip and plasma glucose, 0.138 mmol/L (SD= 0.96) Confirms inaccuracy of whole blood glucose test strips compared to plasma glucose values Reynolds, 1993 20 OBS Infants admitted to NICU over 80 d (N=82) Compare reagent test strips to laboratory-measured values Reagent test strips have 82-83% sensitivity, 69-70% specificity for detection of hypoglycemia CI = confidence interval, d = days, NICU = neonatal intensive care unit, OBS= observational study, Ref # = reference number, SD = standard deviation, y = years Table 6. GRADE Table Question 1: How should blood glucose concentration be determined in neonates? Comparison Outcome Quantity, Type Evidence Findings Evidence GRADE for Outcome Overall Recommendation GRADE, Rationale Test strip vs. measured plasma glucose SD or CI 2 OBS Test strip greater error Low Low CI=confidence interval, OBS=observational study, SD=standard deviation Rationale Blood glucose measurements taken with point of care reagent strips may be susceptible to error due to possible contamination of the blood sample with alcohol which has been shown to increase the blood glucose reading,18 while an elevated hematocrit may falsely lower the result.19 Additionally glucose measurements obtained using reagent test strips measure glucose concentrations of whole blood and thus have been found to be as much as 15% lower when compared with laboratory plasma glucose values.19-20 Plasma glucose measurements have a lower standard deviation between repeated values and are considered the gold standard for monitoring of hypoglycemia.19 When it is not possible to utilize plasma glucose measurement, the clinician should be aware of these potential sources of error associated with point of care reagent test strips. Question 2 What blood glucose concentration is associated with reduced clinical complications in neonates receiving PN? (Tables 7, 8) We suggest keeping the serum glucose concentration < 150 mg/dL (weak). We cannot make a recommendation to determine whether serum glucose should be maintained > 40 mg/dL (recommend further research). We recommend treating symptomatic hypoglycemia (strong). Table 7. Evidence Table for Question 2: What blood glucose concentration is associated with reduced clinical complications in neonates receiving PN? Author, Year (ref #) Study Design, Quality Population, Setting, N Study Objective Results Comments Hyperglycemia Studies Heimann, 2007 11 OBSLarge sample sizeRetrospective record review Premature VLBW infants 27.4 (24-35) weeks GA with persistently elevated plasma glucose (N=252) Evaluate mortality related to moderate hyperglycemia defined as 1-3 glucose measures > 150 mg/dL (n=125), severe hyperglycemia defined as ≥ 4 glucose measures > 150 mg/dL (n=45) relative to normoglycemic with no serum glucose measure > 150 mg/dL (n=82) Mortality:Normoglycemia,13.4%Moderate hyperglycemia, 7.2%Severe hyperglycemia, 22.2%Nonsurvivors had lower (< 27 weeks) GA than survivors, P<0.001Sepsis primary cause of deathHyperglycemia vs. mortality:Blood glucose levels and frequency hyperglycemia higher in nonsurvivors than survivors (both P 120 mg/dL vs. normoglycemic as maximal serum glucose ≤ 120 mg/dLNonsurvivors (n=6)Survivors (n=31)Hyperglycemic survivors (n=20)Normoglycemic survivors (n=11) Maximum serum glucose:Nonsurvivors 241± 46Survivors 141± 47 mg/dL, (P 150 mg/dL (n=149) vs. normoglycemia as plasma glucose ≤ 150 mg/dL (n=20) Prevalence hyperglycemia, 88%.Hyperglycemia risk:Odds of hyperglycemia lower with GA ≥ 26 wk (OR 0.11, 95% CI 0.01-0.89) relative to more premature infantsHyperglycemia vs. ROP risk:Odds of ROP, adjusted for GA, BW and postnatal steroid exposure increased in hyperglycemia vs. normoglycemia (OR 4.6, 95% CI 1.12-18.9) Hays 20069 OBSSmall sampleRetrospective record review ELBW infants 25.4± 1.9 week GA in 1st wk life (N=82) Evaluate incidence hyperglycemia as blood glucose 150-250 mg/dL and severe hyperglycemia as mean blood glucose ≥ 250 mg/dL and associated mortality, IVH On DOL 2-7,Incidence hyperglycemia 57%Incidence severe hyperglycemia 32%Hyperglycemia predicts early death or IVH with 91% sensitivity, 25% specificityWith FiO2>40%, risk of death or IVH:Normoglycemia, 33%Hyperglycemia, 57%, P=0.052.LOS:Normoglycemia, 119 dHyperglycemia, 182 d, P 8, risk of death or IVH:Normoglycemia, 20%Hyperglycemia, 43%, P<0.05 Hyperglycemia predicts death, LOS Kao, 200610 OBSLarge sampleRetrospective analysis of a prospective cohort study ELBW infants 26.2±1.9 weeks GA in 1st wk life (N=201) Evaluate prevalence of normoglycemia as serum glucose < 120 mg/dL,mild hyperglycemia as serum glucose 120-179 mg/dL, severe hyperglycemia as serum glucose ≥180 mg/dL vs. mortality and infection Prevalence hyperglycemia:Normoglycemia 65%,Mild hyperglycemia 28%,Severe hyperglycemia 7%Mild-moderate hyperglycemia vs. death or infection:Mild-moderate hyperglycemia not significantly associated with death or infection, adjusted for age, P=0.09Hyperglycemia vs. mortality or infection:Relative to normoglycemia, severe hyperglycemia in DOL 1-3 increased risk of mortality or infection, (adjusted OR 5.07, 95% CI 1.06-24.3, P=0.04)Hyperglycemia vs. mortality:Relative to normoglycemia, severe hyperglycemia in DOL 1-3and 1st 7 DOL (adjusted for age) associated with increased risk for mortality (OR 15.7, 95% CI 3.74-65.9, P 145 mg/dL) and incidence of IVH and mortality in stressed (n=18) and control (n=12) infants with constant dextrose infusion Incidence Hyperglycemia:Stressed 72.2%Control 8.3%Outcomes vs. Stress:Mortality:Stressed 83.3%Control 16.7%, P<0.001IVH:Stressed 55.6%Control 8.3%, P<0.05Hyperglycemia vs. Outcomes:Mortality:Hyperglycemic Stressed 84.6%Hyperglycemic Control 0%Normoglycemic Stressed 80%Normoglycemic Control 9%IVH:Hyperglycemic Stressed 69.2%Hyperglycemic Control 0%Euglycemic Stressed 20%Euglycemic Control 9% Stress associated with greater mortality and IVH, but not significantly increased with hyperglycemia Zarif, 19767 OBSSmall sample Premature VLBW infants (N=75) Evaluate risk of mortality due to hyperglycemia.Normoglycemia as blood glucose < 125 mg/dL (n=43)Hyperglycemia as blood glucose > 125 mg/dL (n=32) Mortality:Hyperglycemia 59%,Normoglycemia 12%, X2 = 19.1 (P<0.001) Hypoglycemia Studies Burns, 20094 OBSCase control Term neonates, n=69Neonates with symptomatic hypoglycemia, n=35Term neonate controls, n=229 Evaluate neurodevelopmental outcomes at age 18 months and MRI abnormalities at <6 weeks in term neonates with symptomatic hypoglycemia (<1 week of age) MRI findings:WM abnormalities in 94% (43% of these severe)BGT lesion in 40%Cortical abnormalities in 51%WM hemorrhage in 30%PLIC abnormality in 11%Neurodevelopmental impairment:None, 8/34Mild, 15/34 Moderate,8/34 Severe, 3/34 Symptomatic hypoglycemia associated with early brain abnormalities and developmental impairment at 18 mo Filan, 20065 OBSCase seriesNo controlNo standard neuro- developmental measuresSmall sample Term neonates with symptomatic hypoglycemia (N=4) Evaluate brain abnormalities by MRI DOL 4-7, 11-50 after hypoglycemia and neurodevelopmental outcomes at 9-12 mo MRI Findings:Abnormalities observed in allNeurodevelopment impairment:Microcephaly, gross motor delay, visual impairment in 25% Symptomatic hypoglycemia associated with abnormal MRI and abnormal neurodevelopment in 25% Sexson, 198429 OBSInaccurate glucose test measureNo clinical outcomes All infants born during 4 mo at single institution (N=232)Screened for hypoglycemia if preterm, LGA, SGA, erythroblastosis, CNS abnormality, respiratory distress, temperature instability, asphyxia, meconium staining, polycythemia or perinatal stress (n=168) Evaluate incidence of hypoglycemia as blood glucose < 40 mg/dL by test strip Incidence Hypoglycemia:Overall, 20.6%At risk infants, 28.6%Mean age at hypoglycemia 3.4 h (range 0.5-12 h)Mean laboratory blood glucose after hypoglycemia by test strip screen 27.6 (range 0-38) mg/dL. BGT= basal ganglia or thalamic; BPD= bronchopulmonary dysplasia; BW = birth weight; CI=95% confidence interval; CNS= central nervous system; d = days; DOL= day of life; ELBW= extremely low birth weight (<1000 g); GA = gestational age; GIR= glucose infusion rate; IVH= intraventricular hemorrhage; LGA= large for gestational age; LOS= length of hospital stay; mo = months; MRI=magnetic resonance imaging; OBS = observational study; OR=odds ratio; PLIC= posterior limb of the internal capsule; PN=parenteral nutrition; ROP=retinopathy of prematurity; SGA= small for gestational age; VLBW= very low birth weight ( 150 mg/dL LOS 1 OBS Increased Low Very low Low Ventilator days 1 OBS Increased Low Very low ROP 1 OBS Increased Low Low Mortality 4 OBS Increased Moderate to very low Low Hypoglycemia as blood glucose < 40 mg/dL Incidence hypoglycemia 1 OBS Increased Very low Very low Very low Symptomatic hypoglycemia should be treated White matter abnormalities on MRI 2 OBS Increased Low Low to very low Very Low Neurodevelopmental abnormalities age 9-12 mo 2 OBS Increased Low Low to very low LOS=length of stay; MRI=magnetic resonance imaging; OBS=observational study; ROP=retinopathy of prematurity Rationale Hyperglycemia may occur in the neonate receiving PN due to excessive glucose infusion rates, stress, or treatment with certain medications including steroids and methylxanthines.21 Less effective insulin response to elevated blood glucose levels, probable partial insulin resistance, and a lack of negative feedback on hepatic glucose production during PN dextrose infusion all make the preterm infant particularly susceptible.21-25 Historically, hyperglycemia has been defined as whole blood glucose concentration >125 mg/dL or serum glucose concentration > 150 mg/dL.21,26 Under this definition, the incidence of hyperglycemia in VLBW infants during the first week of life ranges from 40-80%.7,27 Multiple studies in neonates (particularly those that are low birth weight [LBW] and/or premature) have indicated that persistently elevated serum glucose concentrations of >150 mg/dL are correlated with adverse clinical outcomes and/or increased mortality.7-9,11,28 Other research identifies a link between increased morbidity and mortality and a serum glucose level >180 mg/dL.10 Research in this area draws correlations between hyperglycemia and morbidity and mortality, however clinical trials demonstrating causality are lacking. There is great variability in the definition of neonatal hypoglycemia,29-36 and a lack of research focusing on hypoglycemia in the neonate receiving PN. Hypoglycemia has been defined as a serum glucose < 40 mg/dL29, but no firm consensus on this level can be drawn based upon the current literature. As discussed in a review of current research on subsequent neurodevelopmental outcomes following episodes of hypoglycemia in the first week of life, there is a need for a well-designed, prospective study in this area in order to draw accurate conclusions and firmly establish a clinically-relevant definition for neonatal hypoglycemia.37 Populations of neonates with increased risk of hypoglycemia include premature, VLBW, ELBW, small for gestational age (SGA) ( 90th percentile for age) and severely stressed neonates.34 Infectious physiology and hyperinsulinemia can also contribute to hypoglycemia in these populations.34 Prevention of hypoglycemia in this population may therefore require higher thresholds of dextrose provision.34 Neonates receiving PN are at a relatively low risk of developing hypoglycemia due to PN dextrose infusion, however receipt of insufficient PN energy provision,36 loss of central venous access,40 and the use of cyclic PN may all render the neonate receiving PN susceptible to hypoglycemia. We recommend further research to fill the gaps in evidence regarding hypoglycemia in neonates receiving PN. Neonates who demonstrate signs or symptoms of hypoglycemia including cyanotic spells, apnea, somnolence, respiratory distress or convulsions36 should undergo clinical interventions for normalization of serum glucose concentration.34 Recurrent or symptomatic hypoglycemia may result in neurodevelopmental impairment,1,4 with the most common and severe sequelae of hypoglycemia including intractable epilepsy, cerebral palsy, mental motor retardation and visual disturbance.3 Because of the severity of clinical outcomes associated with hypoglycemia in neonates, we recommend treatment of symptomatic hypoglycemia. At this time high level data are not sufficient to provide specific approaches for the treatment of hyper- and hypoglycemia. Perhaps once the definitions of these conditions are more clearly established, randomized controlled trials can be conducted to determine the safest approaches for management. Question 3 What strategies may be used to maintain optimal blood glucose concentration in neonates receiving PN? (Tables 9, 10) We suggest that excess energy and dextrose delivery be avoided (weak) and fat emulsion be added to the PN infusion (weak). We recommend a
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