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Carbon Dioxide and Glucose Affect Electrocortical Background in Extremely Preterm Infants

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Background in Extremely Preterm Infants

WHAT’S KNOWN ON THIS SUBJECT: Both high and low PaCO2and

plasma glucose levels, respectively, are associated with brain damage in preterm infants. Little is known about carbon dioxide and glucose effects on electrocortical activity in extremely preterm infants.

WHAT THIS STUDY ADDS: Moderate changes in PaCO2and

plasma glucose levels influenced electroencephalogram

continuity and power in extremely preterm infants. The long-term effects on brain function from variations in PaCO2and glucose

levels need to be explored.

abstract

OBJECTIVES:To investigate if PaCO2and plasma glucose levels affect

electrocortical activity.

METHODS:Ours was an observational study of 32 infants with a gesta-tional age of 22 to 27 weeks. We performed simultaneous single-channel electroencephalogram (EEG) and repeated blood gas/plasma glucose analyses during the first 3 days (n⫽247 blood samples with corresponding EEG). Interburst intervals (IBIs) and EEG power were averaged at the time of each blood sample.

RESULTS:There was a linear relationship between PaCO2and IBI;

in-creasing PaCO2was associated with longer IBIs. One day after birth, a

1-kPa increase in PaCO2was associated with a 16% increase in IBI in

infants who survived the first week without severe brain injury. EEG power was highest at a PaCO2value of 5.1 kPa and was attenuated both

at higher and lower PaCO2values. Corrected for carbon dioxide effects,

plasma glucose was also associated with IBI. Lowest IBI appeared at a plasma glucose level of 4.0 mmol/L, and there was a U-shaped relation-ship between plasma glucose level and EEG with increasing disconti-nuity at glucose concentrations above and below 4.0 mmol/L.

CONCLUSIONS:Both carbon dioxide and plasma glucose level influ-enced EEG activity in extremely preterm infants, and values considered to be within normal physiologic ranges were associated with the best EEG background. Increasing EEG discontinuity occurred at carbon di-oxide levels frequently applied in lung-protection strategies; in addi-tion, moderate hyperglycemia was associated with measurable EEG changes. The long-term effects of changes in carbon dioxide and glu-cose on brain function are not known. Pediatrics 2011;127: e1028–e1034

AUTHORS:Sverre Wikström, MD,a,bFredrik Lundin, PhD,b

David Ley, MD, PhD,cIngrid Hansen Pupp, MD, PhD,c

Vineta Fellman, MD, PhD,c,dIngmar Rosén, MD, PhD,eand

Lena Hellström-Westas, MD, PhDa

aDepartment of Women’s and Children’s Health, Uppsala

University, Uppsala, Sweden;bCenter for Clinical Research,

County Council of Värmland, Karlstad, Sweden; Departments of

cPediatrics andeClinical Neurophysiology, Lund University

Hospital, Lund, Sweden;dDepartment of Pediatrics, University of

Helsinki, Helsinki, Finland

KEY WORDS

hypercapnia, hypoglycemia, hyperglycemia, electrocortical activity

ABBREVIATIONS

EEG—electroencephalogram IBI—interburst interval

IVH—intraventricular hemorrhage ln—natural logarithm

IQR—interquartile range CI—confidence interval CBF—cerebral blood flow aEEG—amplitude-integrated EEG

Dr Wikström was primarily responsible for the EEG data-analysis strategy, EEG data analysis, and writing of the manuscript; Dr Lundin was primarily responsible for statistical analysis and contributed to interpretation of the data and the writing of the manuscript; Dr Ley initiated the study together with Drs Hellström-Westas and Fellman and contributed to the collection of data and the writing of the manuscript; Dr Pupp participated in developing the study protocol, was responsible for the cranial ultrasound examinations, and contributed to interpretation of results and the writing of the manuscript; Dr Fellman initiated the study together with Drs Hellström-Westas and Ley and contributed to interpretation of results and writing of the manuscript; Dr Rosén had senior responsibility for EEG analysis protocol and interpretation of EEG results and contributed to the writing of the manuscript; and Dr Hellström-Westas initiated the study together with Drs Ley and Fellman, had senior

responsibility for the overall analysis of data and interpretation of results, and contributed to the writing of the manuscript. www.pediatrics.org/cgi/doi/10.1542/peds.2010-2755 doi:10.1542/peds.2010-2755

Accepted for publication Dec 22, 2010

Address correspondence to Sverre Wikström, MD, Center for Clinical Research, Karlstad Central Hospital, Rosenborgsgatan 2, SE-65185 Karlstad, Sweden. E-mail: sverre.wikstrom@liv.se PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2011 by the American Academy of Pediatrics

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Preterm electroencephalogram (EEG) recordings have a basically dichoto-mous (“discontinuous”) nature in which periods of very low-voltage activity (called interburst intervals [IBIs]) alter-nate with high-voltage activity bursts of mixed frequency content.1 The electro-cortical activity, including the degree of (dis-)continuity, in preterm infants is af-fected by a number of factors during the first days after birth. Development of in-traventricular hemorrhage (IVH) and periventricular leukomalacia is associ-ated with EEG depression.2–6In addition, the administration of sedative medica-tions and opioids is associated with transient EEG depression.7,8

Three previous studies indicate that high PaCO2 levels in preterm infants

may be associated with EEG back-ground depression and changes in brainstem auditory responses.9–11The mechanisms for these reactions are not known, although it is well known that carbon dioxide has a depressant effect on central nervous system activ-ity and EEG activactiv-ity in adult subjects and in animal studies.12,13

Neonatal hypoglycemia and hypergly-cemia are associated with adverse neurodevelopmental outcomes.14–17 Both conditions are common during the first postnatal days in very preterm infants. However, in newborn infants, only a few studies have addressed neu-rophysiologic effects from hypoglyce-mia,18,19and no previous studies have, to our knowledge, investigated possi-ble EEG changes during neonatal hyperglycemia.

The aim of this study was to investigate if PaCO2and plasma glucose levels are associated with EEG continuity and frequency content during the first days after birth in extremely preterm infants.

METHODS

Thirty-two inborn infants with a gesta-tional age of⬍28 weeks were

prospec-tively recruited to this observational study after informed parental consent was provided. The infants were treated at the NICU at Lund University Hospital (Lund, Sweden) between July 2005 and May 2007. Included infants had a least 3 paired samples of good quality EEG with simultaneous blood gas/glucose analyzed (see below). They constitute a subgroup of a larger cohort of pre-term infants in whom mechanisms for brain injury are investigated. During the study period (ie, the first 72 hours), infants were cared for according to clinical routines, with additional re-cording of a single-channel EEG and blood sampling for analysis of cyto-kines and growth factors (not included in the present study). Cranial ultra-sound examinations were performed on days 1, 3, and 7, at 3 and 6 weeks, and at term (Acuson Sequoia, Siemens Healthcare, Erlangen, Germany). The regional ethical review board (Lund University, Lund, Sweden) approved the protocol.

Twenty-seven of the 32 infants needed mechanical ventilation, and 5 were supported by continuous positive air-way pressure. All infants had umbilical or peripheral arterial catheters in-serted on clinical indication. Moderate permissive hypercapnea (PaCO2: 5–7

kPa) was practiced during mechanical ventilation. Peripheral oxygen satura-tion was kept between 88% and 92%, and mean arterial blood pressure at or above a level corresponding to the infant’s gestational age in weeks. Arte-rial blood gases and plasma glucose values were checked repeatedly, as clinically indicated, and analyzed in the NICU within a few minutes after sam-pling (ABL 700, Radiometer Medical, Brønshøj, Denmark).

Most infants received oral feedings with donor breast milk from the first hours after birth and were supported with intravenous 10% glucose infu-sion, with additional amino acid and

lipid infusion after the first 24 hours.20 An overall aim was to keep plasma glu-cose concentrations between 3.0 and 6.0 mmol/L. Bolus doses of morphine (0.05– 0.10 mg/kg), and sometimes continuous morphine infusion, were administered as indicated by validated pain scores to mechanically ventilated infants. Clinical data are presented in Table 1.

Single-channel EEG (Nervus/Nicol-etOne 1.3 EEG System, Taugagreining HF, Reykjavik, Iceland) was applied as soon as possible after initial stabiliza-tion at the NICU (ie, usually within the first 8 hours of age). Hydrogel elec-trodes (Ambu Neuroline, Ambu A/S, Ballerup, Denmark) were applied at the P3 and P4 positions according to the international 10 –20 system; a fron-tal reference electrode was also applied.

Electroencephalographic Analysis

IBIs were measured by using an auto-mated algorithm and averaged from 10-minute artifact-free epochs of EEG recordings, 15 to 5 minutes before each blood sample. The time window was chosen to obtain a representative measure of electrocortical continuity even for prolonged IBIs, and before blood sampling and handling of infants would produce EEG artifacts. The IBI

TABLE 1 Characteristics of Infants in the Study Group

Characteristic Study Group (N⫽32) Gestational age, wk 25 (22–27) Birth weight, g 738 (460–1092) 5-min Apgar score 7 (3–10) Male infants,n 17 Mechanical ventilation,n 27 CPAP,n 5 IVH grade 3–4,n 5 cPVL,n 0 Survived the first week,n 29 PaCO2, kPa 6.2 (3.0–12.5)

pH 7.29 (7.05–7.51) Glucose, mmol/L 6.1 (1.1–26.0)

Values are median (range). CPAP indicates continuous positive airway pressure; cPVL, cystic periventricular leu-komalacia.

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System. The nonlinear energy operator reflects both amplitude and frequency content of the EEG and has been de-scribed previously.21–23 The quality of all EEG epochs was visually assessed without knowledge of the blood gas re-sults. Epochs showing artifacts that could affect the quantitative EEG mea-sures were excluded, as were epochs within 2 hours after administration of morphine bolus doses.

EEG spectral power was analyzed from artifact-free 5-minute epochs, ob-tained between 10 and 5 minutes be-fore blood gas analyses. The shorter 5-minute epoch was chosen, as power spectral analysis, according to our ex-perience, is more sensitive to artifacts than IBI analysis. Power spectral anal-ysis was performed using fast Fourier transformation– based tools in the Nervus/NicoletOne EEG System with a time base of 10 seconds. For every 5-minute epoch, total and relative (%) band power was calculated within the following frequency bands: ␦ (0.5– 4 Hz), ␪(4 – 8 Hz), ␣(8 –13 Hz), and ␤ (13–30 Hz).

Statistical Analysis

Data were analyzed as cross-sectional time series (panel data) together with multivariate regression splines24to al-low for more general dependencies than in standard linear regression. Re-gression splines are functions that do not require a particular model as-sumption (linear, quadratic, or cubic) for the dependent variable. Instead, a set of functions (spline bases) are cho-sen during estimation from a general, larger set of functions. This procedure results in estimated functions suitable for regression analyses. IBI and EEG power variables were used as out-come variables in regression analyses using population-averaged,

general-proximately normal distributions. PaCO2, blood glucose, postnatal age,

and gestational age were entered as independent variables in a backward stepwise procedure.

For comparison with the study by Vic-tor et al,11 we analyzed a restricted data set comprising EEG measure-ments from one moment per infant; namely, the first collected sample af-ter 24 hours postnatal age. These sam-ples were obtained at a median of 24.5 hours of age (interquartile range [IQR]: 24.2–28.6 hours). This data set of independent observations was ana-lyzed using linear regression with mul-tivariate regression splines.

Because major brain injury is associ-ated with EEG depression, data were dichotomized in terms of short-term outcome: “poor outcome” was defined as death during the first postnatal week, or surviving with major brain

first post natal week without major brain damage.

For complementary analysis, plasma glucose concentrations were divided into 4 categories representing strate-gies of the clinical care:⬍3.0 mmol/L (hypoglycemia), 3.0 to 5.9 mmol/L (in-tended range), 6.0 to 9.9 mmol/L (mod-erate hyperglycemia, for which the first step was to reduce the glucose infusion), andⱖ10.0 mmol/L (severe hyperglycemia; insulin was started in case of a repeated plasma glucose level of⬎10.0 mmol/L). To test for dif-ferences in EEG variables between glucose categories, panel data regres-sion with dichotomized glucose cate-gories was used as a single predictor variable.

Plasma glucose levels of⬎150 mg/dL (8.3 mmol/L) have been identified as a risk factor for death and brain damage in very preterm infants.14–16 To

com-FIGURE 1

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pare EEG data for glucose values below and above this threshold, we also di-chotomized glucose concentrations at 8.3 mmol/L and used the same method as described here for tests between glucose categories.

All statistical analyses were conducted by using Stata/IC 10 (Stata Corp LP, Col-lege Station, TX).

RESULTS

A total of 606 blood samples were ob-tained for clinical purposes in the 32 infants during the study period (range: 9 –30 samples per infant). Of these, 359 were excluded because of missing or unreadable EEG data at the time of blood sampling or because of previous administration of morphine. In total, 247 sets of samples were included in the analysis, each sample consisting of a measure of PaCO2, blood glucose, IBI,

and EEG power (n⫽185 for EEG power samples). The median number of

in-cluded samples per infant was 8 (range: 3–17).

Gestational age was not associated with either IBI or EEG spectral power. However, postnatal age in hours showed a weak positive association to ln EEG power (regression coefficient for ln EEG power: 0.01 [95% confidence interval (CI): 0.004 – 0.017]) and was in-versely related to ln IBI (regression co-efficient⫽ ⫺0.004 [95% CI:⫺0.007 to

⫺0.001]). Consequently, the analyses of EEG in relation to PaCO2and plasma

glucose (below) were all adjusted for postnatal age.

Carbon Dioxide Effects on Electroencephalogram

Interburst Interval

Figure 1 shows all unadjusted IBI and PaCO2values. There was a positive

as-sociation between ln IBI and PaCO2;

higher PaCO2was associated with

lon-ger IBI (regression coefficient for ln IBI⫽0.08 [95% CI: 0.04 – 0.12]) (Fig 2). However, this association only oc-curred in the 206 samples from the 26 infants with good outcome in whom the regression coefficient for PaCO2

versus ln IBI was 0.09 (95% CI: 0.05– 0.14), indicating that a 1-kPa increase in PaCO2was associated with a 9%

in-crease in IBI. The association between PaCO2 and ln IBI was stronger in the

subset of data restricted to the first sample collected 24 hours after birth (regression coefficient for ln IBI⫽0.15 [95% CI: 0.04 – 0.27]); a 1-kPa increase in PaCO2was associated with a 16%

in-crease in IBI.

Power Spectral Measures

There were significant nonlinear asso-ciations between PaCO2 and ln EEG

power in all frequency bands but only in the 157 samples from infants with a good outcome. The association was

0 25 50 IBI (s)

PaCO2:9.7 kPa PaCO2:5.5 kPa

150 µV

-150 µV

150 µV

-150 µV

PaCO2:9.7 kPa

PaCO2:5.5 kPa

FIGURE 2

Upper, IBI trend during 5 hours in an infant born at 24 gestational weeks. Lower, Two EEG tracings (duration: 64 seconds). The upper trace shows the prolonged IBI when the infant had a PaCO2value of 9.7 kPa, and the lower trace shows the IBI at a PaCO2of 5.5 kPa.

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resided (coefficients for regression splines,r⫽ ⫺0.23 [95% CI:⫺0.35 to

⫺0.11], 0.13 [95% CI: 0.01– 0.24], and 0.12, [95% CI: 0.02– 0.23], respectively) when analyzed with third-grade polyno-mial multivariate regression). Total EEG power reached a maximum at a PaCO2

value of 5.1 kPa and was attenuated both at higher and lower PaCO2values. There

were no associations between PaCO2and

relative band power.

Glucose Effects on Electroencephalogram

Corrected for carbon dioxide effects, plasma glucose level had a nonlinear association with ln IBI (coefficients for regression splines,r ⫽0.06 [95% CI:

⫺0.02 to 0.13], 0.1 [95% CI: 0.04 – 0.16],

⫺0.03 [95% CI:⫺0.09 to 0.3], and 0.06 [95% CI: 0.01– 0.12]) in infants with good outcome when analyzed with third-grade polynomial regression. Figure 3 shows the independent multi-plicative effects of PaCO2 and plasma

glucose level on IBI at different carbon dioxide and glucose levels, respec-tively. The lowest IBI appeared at a plasma glucose level of 4.0 mmol/L. There were no correlations between plasma glucose level and total or rela-tive EEG band power, respecrela-tively.

Figure 4 shows a box plot for IBI in re-lation to plasma glucose categories. The median (IQR) IBI and total EEG power values at plasma glucose levels of 3.0 to 5.9 vs 6.0 to 9.9 mmol/L were 6.2 (4.9 – 8.7) vs 8.5 (6.1–13.2) seconds (P⫽.001) and 672 (457–1080) vs 495 (328 –783)␮V2(P.061). There were no significant differences in EEG pa-rameters for glucose categories⬍3.0 vs 3.0 to 5.9 mmol/L or for the glucose categories 6.0 to 9.9 vsⱖ10.0 mmol/L (see Fig 4). There were no differences in IBI or EEG power measures for the dichotomized plasma glucose samples (up to 8.3 vs⬎8.3 mmol/L).

DISCUSSION

The present study shows that both PaCO2and plasma glucose levels

signif-icantly affect electrocortical activity in extremely preterm infants. Carbon di-oxide and plasma glucose levels con-sidered to be within “normal” physio-logic ranges (ie, PaCO2 ⬃5 kPa [38

mm Hg]) and plasma glucose levels of 4.0 mmol/L were associated with the best EEG background. However, the re-sults are limited by the low number of

very low or very high carbon dioxide and glucose values, respectively (Figs 1 and 4). This may also explain why the shape of the associations varied. The relationship between PaCO2and IBI was

linear: that is, increasing PaCO2was

as-sociated with prolonged IBIs, whereas the association between PaCO2and EEG

power was dome shaped, with the highest EEG power at PaCO25.1 kPa and

attenuated power both above and be-low this level. The association between

FIGURE 3

Interaction between, and multiplicative effects of, PaCO2and plasma glucose level, respectively, on IBIs.

Shown are multiplicative effects at different levels in relation to sample means (PaCO2: 6.3 kPa; glucose: 6.7 mmol/L) of the study group.

FIGURE 4

Box plot showing IBIs in relation to plasma glucose categories (without outliers).aP.001 according

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glucose and IBI was U shaped: that is, the shortest IBIs occurred at plasma glucose concentrations of⬃4 mmol/L, and both higher and lower concentra-tions of glucose were associated with higher IBIs, whereas there was no cor-relation between plasma glucose level and EEG power. The present data also demonstrate that increasing EEG dis-continuity occurs at carbon dioxide levels that are used in many NICUs for mechanical ventilation as part of lung-protection strategies.

The present data are supported by 2 earlier studies in preterm infants,9,11 and accordingly the association be-tween increasing carbon dioxide and EEG discontinuity in newborn infants can now be regarded as established. Also comparable to the study by Victor et al, the association between arterial carbon dioxide and EEG was strongest during the first postnatal day.11 How-ever, Victor et al only studied infants without large IVHs; we also included data from infants with severe ultra-sound abnormalities, but the associa-tion between carbon dioxide and elec-trocortical activity was only present in infants who survived the first week without major brain damage. These findings imply that the EEG response to carbon dioxide, in parallel with cere-bral blood flow (CBF) autoregulation, may be disrupted in infants with brain injury.25,26

Eaton et al also noted that both meta-bolic and respiratory acidosis was as-sociated with EEG changes.9In the pres-ent study, pH was to 80% determined by PaCO2 (data not shown), and there

were very few samples with metabolic acidosis. Consequently, we abstained from analyzing the effects of metabolic acidosis on EEG.

We also found an association between plasma glucose level and IBI, with the lowest IBI (best EEG) at plasma glucose concentrations of 4 mmol/L. Neuro-physiologic evidence demonstrating

that hypoglycemia adversely affects brain function in newborn infants is scarce. Abnormal sensory evoked po-tentials were present in 10 of 11 chil-dren (including 5 newborn infants) when blood glucose concentrations fell below 2.6 mmol/L.19The investiga-tors concluded that “the blood glucose concentration should be maintained above 2.6 mmol/L to ensure normal neural function in children irrespec-tive of the presence or absence of ab-normal clinical signs.” This conclusion was further supported in a cohort of 661 preterm infants showing that an increased number of days with blood glucose concentrations of ⬍2.6 mmol/L was associated with subopti-mal development at 18 months.17 Sten-ninger et al evaluated effects of hypo-glycemia on the amplitude-integrated EEG (aEEG) in 12 term infants of moth-ers with diabetes. Hypoglycemia was associated with a subtle reduction in maximum aEEG amplitude.18 In con-trast, hypoglycemia was not associ-ated with measurable changes in vari-ous EEG parameters (aEEG minimum amplitude and continuity, and spectral edge frequency) in newborn lambs having a more continuous EEG.27 Con-sequently, measures of EEG continuity (such as IBI) may be more sensitive for evaluating preterm infants than term infants. Furthermore, given the normal EEG discontinuity in preterm infants, measures of continuity may be more directly correlated to brain function than power measures. Skov and Pryds measured CBF in preterm infants who had low blood glucose and found a rapid decrease in CBF after intrave-nous infusion of glucose.28 They sug-gested the presence of a central glu-cose sensor, which increases CBF at low glucose concentrations to provide sufficient amounts of substrate for brain function. It is possible that such mechanisms also influence electro-cortical activity.

Hyperglycemia is increasingly recog-nized as a risk factor for brain damage and death in very preterm infants.14–16In the present study, there were no dif-ferences in EEG activity above versus below plasma glucose concentrations of 8.3 mmol/L (corresponding to 150 mg/dL). With the U-shaped association between plasma glucose level and IBI in mind, this is an expected finding. However, a significant decrease in EEG continuity (ie, prolonged IBI) was dem-onstrated for plasma glucose values between 6.0 and 9.9 mmol/L compared with glucose concentrations between 3.0 and 5.9 mmol/L. The small numbers of glucose samples⬎10.0 mmol/L may ex-plain why there was no statistical differ-ence between IBI at plasma glucose con-centrations⬎10.0 vs⬍10.0 mmol/L.

Another limitation in the present study is that the data consist of time series but not with a natural course. Carbon dioxide and plasma glucose were mea-sured on clinical indications, and ac-tions were taken to correct values

to-ward the intended ranges. This

compresses the range of observations around values that have been re-garded as “optimal.” The data there-fore consist of relatively few very low or high values for both carbon dioxide and plasma glucose, and consequently should be interpreted with caution if they are outside the clinically intended ranges. The varying numbers of obser-vations for each infant also reduces the statistical power of the analysis. Further-more, the estimation of IBI in the present study should be regarded as a proxy for the “true” value, although the automated quantification of IBI was recently validated against visual estimation.23

CONCLUSIONS

Our data indicate that moderate changes in PaCO2, frequently applied in

lung-protection strategies, signifi-cantly influenced electrocortical activ-ity in extremely preterm infants and

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clinical and experimental studies, mainly in older subjects, have indi-cated that both carbon dioxide and glu-cose modulate neuronal activity.19,28,29 The importance and clinical relevance of these findings on the developing brain are not presently known. It has been suggested that spontaneous ac-tivity transients (SATs) (ie, acac-tivity cor-responding to bursts in the EEG) are

development and the response of SATs to changes in carbon dioxide or glu-cose are not known. More research is clearly needed on the neurophysio-logic effects of carbon dioxide and glu-cose on the immature brain.

ACKNOWLEDGMENTS

This study was supported by the Swed-ish Research Council (grants 0037,

ström was supported by grants from the County Council of Värmland (Värm-land, Sweden).

We thank the patients and their par-ents; we also thank Ann-Cathrine

Berg, RN, and Elisabeth Norman, MD, for help with data collection and Lars-Johan Ahnlide (Cephalon A/S, Norresundby, Denmark) for techni-cal support.

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DOI: 10.1542/peds.2010-2755 originally published online March 28, 2011;

2011;127;e1028

Pediatrics

Ingmar Rosén and Lena Hellström-Westas

Sverre Wikström, Fredrik Lundin, David Ley, Ingrid Hansen Pupp, Vineta Fellman,

Preterm Infants

Carbon Dioxide and Glucose Affect Electrocortical Background in Extremely

Services

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http://pediatrics.aappublications.org/content/127/4/e1028

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DOI: 10.1542/peds.2010-2755 originally published online March 28, 2011;

2011;127;e1028

Pediatrics

Ingmar Rosén and Lena Hellström-Westas

http://pediatrics.aappublications.org/content/127/4/e1028

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 1 Characteristics of Infants in theStudy Group
FIGURE 1
FIGURE 2Upper, IBI trend during 5 hours in an infant born at 24 gestational weeks. Lower, Two EEG tracings (duration: 64 seconds)
FIGURE 4

References

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