Published online October 2, 2006
PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1654-1659 (doi:10.1542/peds.2005-2463)
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ARTICLE

Cumulative Index of Exposure to Hypocarbia and Hyperoxia as Risk Factors for Periventricular Leukomalacia in Low Birth Weight Infants

Seetha Shankaran, MDa, John C. Langer, MSb, S. Nadya Kazzi, MD, MPHa, Abbot R. Laptook, MDc, Michele Walsh, MD, MS Epid for the National Institute of Child Health and Human Development Neonatal Research Network

a Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan
b Department of Biostatistics, Research Triangle Institute, Research Triangle Park, North Carolina
c Department of Pediatrics, Brown Medical School, Providence, Rhode Island
d Department of Pediatrics, Case Western University, Cleveland, Ohio


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. Hypocarbia and hyperoxia are risk factors for periventricular leukomalacia in low birth weight infants. The association of a cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia has not been evaluated.

OBJECTIVE. Our goal was to examine the relationship between cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia during the first 7 days of life in low birth weight infants.

METHODS. Blood gas results were recorded in 6-hour intervals among low birth weight infants in a prospective data registry. Cumulative index of exposure to hypocarbia was calculated as the difference between arterial carbon dioxide level and 35 mmHg multiplied by the time interval in hours for each 6-hour block in a 24-hour day for the first 7 days of life. Cumulative index of exposure to hyperoxia was calculated in the same manner for arterial oxygen level >80 mm Hg. The relationship between exposure to hypocarbia, hyperoxia, and periventricular leukomalacia was examined in 778 infants with blood gas and cranial sonography data.

RESULTS. Twenty-one infants had periventricular leukomalacia. Hypocarbia occurred in 489 infants and hyperoxia in 502 infants. Infants with periventricular leukomalacia were more likely to have a lower gestational age and to require delivery room resuscitation than those without periventricular leukomalacia. More infants in the highest quartile of exposure to hypocarbia had periventricular leukomalacia compared to those with no hypocarbia. Risk of periventricular leukomalacia was increased in infants with the highest quartile of exposure to hypocarbia after adjusting for maternal and neonatal variables, none to be associated with periventricular leukomalacia. Cumulative index exposure to hyperoxia was not related to periventricular leukomalacia.

CONCLUSIONS. Cumulative exposure to hypocarbia and not hyperoxia was independently related to risk of periventricular leukomalacia in low birth weight infants.

Key Words: hyperoxia • periventricular leukomalacia • low birth weight

Abbreviations: PVL—periventricular leukomalacia • PaCO2—partial pressure of arterial carbon dioxide • PaO2—partial pressure of oxygen • CIE—cumulative index of exposure • OR—odds ratio • CI—confidence interval

Periventricular leukomalacia (PVL) occurs in 3% to 6% of very low birth weight infants and is an important cause of neurodevelopmental impairment in these infants.1,2 Episodes of hypocarbia have been implicated as a risk factor for PVL, possibly mediated through reduction in cerebral blood flow.3–8 Hyperoxia may be a risk factor for PVL through the exacerbation of oxidative injury.9 In a recent study, Collins et al10 examined the relationship between cumulative hypocarbia and hyperoxia and risk for cerebral palsy. In their study, for each infant with blood gas samples during the first 8 days of life in which the partial pressure of arterial carbon dioxide (PaCO2) was <35 mmHg, the difference (35 – PaCO2) was multiplied by the time interval in hours for which that measurement was extrapolated to apply. The sum of such products for each infant constituted cumulative exposure to hypocarbia. A similar calculation was performed for partial pressure of oxygen (PaO2), multiplying (PaO2 – 60) by length of each time interval inclusive of a value >60 mmHg. The authors found that hypocarbia (PaCO2 <35 mmHg) and hyperoxia (PaO2 >60 mmHg) and prolonged duration of ventilation independently contributed to a twofold to threefold increased risk of cerebral palsy.10

The roles of cumulative exposure to hypocarbia and hyperoxia as risk factors for PVL have not been examined to date. The objective of our study was to examine the relationship between cumulative exposure to hypocarbia or hyperoxia during the first 7 days of life and PVL in low birth weight infants.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
In the National Institute of Child Health and Human Development Multicenter Neonatal Research Network, results of blood gas analyses were recorded in 6-hour intervals during the first 7 days of age among all <1250-g inborn low birth weight infants. The blood gas results closest to 6 AM, 12 noon, 6 PM, and 12 midnight were recorded on flow sheets. These data were collected as part of a prospective study evaluating the role of benchmarking practices on bronchopulmonary dysplasia conducted between October 2000 and November 2001. Hypocarbia was defined as PaCO2 <35 mmHg, and cumulative index of exposure (CIE) to hypocarbia was calculated as (35 – PaCO2) multiplied by time interval in hours for each 6-hour block in a 24-hour day. For example, on day 1 of life, if the PaCO2 was recorded as 33, 38, 33, and 45 mmHg in the 4 blocks of 6 index durations, respectively, CIE for the first day of life was expressed as (35 – 33) x 12 = 24 mmHg · hour. The CIE to hypocarbia for the first 7 days of age was defined as the sum of such products for each infant reported as millimeters of mercury · hour over the first 7 days of age. Hyperoxia was defined as arterial PaO2 >80 mmHg, and the hours of exposure to hyperoxia were calculated as (arterial PaO2 – 80 mmHg) multiplied by the time interval in hours for each 6-hour block in a 24-hour day. The CIE to hyperoxia was the sum of such products for each child reported as millimeters of mercury · hour over the first 7 days of life. The quartiles of CIE to hypocarbia and hyperoxia were calculated separately for each infant. The total duration of hypocarbia and hyperoxia for each infant was expressed as 5 levels of exposure (none, lowest, second, third, and highest quartile).

Infants had serial cranial sonograms performed as per each centers' practice, and sonograms were read by sonographers at each participating center. The diagnosis of PVL was based on the most severe diagnosis on the cranial sonogram at either the study closest to 28 days or 36 weeks' postmenstrual age. The diagnosis of PVL was based on lucencies in the periventricular region. Increased echogenicity in the periventricular region or ventriculomegaly was not diagnosed as PVL. Infants who died or were transferred at <14 days of life were not included in the analysis.

The relationship between CIE to hypocarbia and PVL, modeled as both a continuous and 5-level variable, was examined by multiple linear and logistic regression analysis, adjusting for variables selected a priori as having an association with PVL. These included maternal hypertension, maternal steroid and antibiotic use, mode of delivery, and infants gestational age, race, gender, 5-minute Apgar score, intubation at birth, ventilator days, and late-onset sepsis. Maternal steroids were documented as either dexamethasone or betamethasone, and antibiotics noted when given within 72 index of delivery. The same models were applied to examining the relationship between CIE and hyperoxia and PVL.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
PVL
Among the 16 National Institute of Child Health and Human Development Neonatal Research Network Centers, serial blood gas measurements recorded during the first 7 days were available for 925 inborn infants with birth weight ranging from 501 to 1249 g. Of these 925 infants, data on PaCO2 (venous, capillary, or arterial) were available on 884 infants. Data on arterial PaO2 were available on 783 infants. Twenty infants died within 12 hours of age. Of the remaining 905 infants surviving beyond 12 hours of age, cranial sonography data at >14 days of age documenting the presence or absence of PVL by sonographers at the each site were available on 778 infants. A diagnosis of PVL was noted in 21 infants; 12 infants had PVL on the 28-week sonogram, whereas 17 infants had findings of PVL noted on the 36-week study, and 8 infants had PVL on both the 28- and 36-week study. The frequency of PVL between the clinical centers ranged from 0% to 10% among <1250-g infants.

The clinical characteristics of infants with and without PVL are noted in Table 1. Infants with PVL were more likely to have a lower gestational age and to require delivery room resuscitation than infants without PVL. The frequency of late-onset sepsis and overall mortality rate was higher among infants with PVL as compared with infants without PVL.


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  		TABLE 1 Characteristics of Infants With and Without PVL

 
Hypocarbia (PaCO2 <35 mmHg)
Infants in the study received ventilatory support for 16.8 ± 22.9 days (mean ± SD) with a range between centers of 9.5 to 26.2 days. Hypocarbia was noted in the first 7 days of age in 489 (63%) of 778 infants. The range of cumulative index of hypocarbia was 6 to 504 mmHg · hour with a median of 48 mmHg · hour and the 25th to 75th interquartile range of 24 to 96 mmHg · hour. The range of CIE to hypocarbia between centers was 12.5 to 108.1 mmHg · hour.

The average number of blood gas measurements over the first 7 days of age among infants when hypocarbia was examined were as follows: no hypocarbia (n = 11.7) blood gas measurements, and 14.3, 13.9, 14.3, and 15.9 in the lowest, second, third, and highest quartiles, respectively. The number of blood gas measurements obtained between infants with no hypocarbia was lower than those obtained from infants with hypocarbia (none versus all other quartiles, P < .05). The clinical characteristics of infants with and without hypocarbia are noted in Table 2. Fewer infants with hypocarbia were born to women who received antenatal steroids or had hypertension or preeclampsia. Infants with hypocarbia were more likely to have a lower birth weight and gestational age, require delivery room resuscitation, and have more days on ventilatory support.


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  		TABLE 2 Characteristics of Infants With and Without Hypocarbia

 
The association between CIE and hypocarbia and frequency of PVL is seen in Fig 1. Among infants with no hypocarbia (n = 289), the rate of PVL was 1.4%; those in the lowest quartile (n = 145) had a rate of 1.4%, and among the second (n = 104), third (n = 118), and highest quartile (n = 122), the rate was 2.9%, 2.5%, and 7.4%, respectively. CIE to hypocarbia as a continuous variable was significantly related to PVL (P < .01), and the highest quartile of hypocarbia had a significant association with PVL (P < .03) in the model where hypocarbia was measured in 5 levels.


Figure 1
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  		FIGURE 1 Relationship between quartiles of CIE to hypocarbia (PaCO2 <35 mmHg) and frequency of PVL. CIE and % PVL. a P < .005, highest quartile versus no hypocarbia.

 
Hyperoxia (PaO2 >80 mmHg)
Arterial hyperoxia was noted during the first 7 days of age in 502 (73%) of 686 infants. The average number of blood gas measurements among the infants when hyperoxia was examined was as follows: no hyperoxia (n = 8.2) measurements, and 11.6, 11.2, 12.7, and 16.3 in the lowest, second, third, and highest quartile, respectively. The number of blood gas measurements obtained between infants with no hyperoxia was lower than those obtained from infants with hyperoxia (none versus all other quartiles, P < .05). The range of CIE of hyperoxia was 6 to 9600 mmHg · hour with a median of 321 mmHg · hour. The interquartile range was 108 (25th) to 684 mmHg · hour (75th). The association between CIE to hyperoxia and PVL is seen in Fig 2. Among infants with no hyperoxia (n = 184), the rate of PVL was 3.8%; those with the lowest quartile of CIE to hyperoxia (n = 126) had a rate of 3.2%, and among the second (n = 125), third (n = 126), and highest quartiles (n = 125), the rate was 1.6%, 3.2%, and 2.4%, respectively.


Figure 2
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  		FIGURE 2 Relationship between quartiles of CIE to hyperoxia (PaO2 >80 mmHg) and frequency of PVL. CIE to hyperoxia and % PVL.

 
Risk Factors for PVL
When the relationship between CIE to hypocarbia and PVL was examined by logistic regression analysis adjusting for maternal hypertension, maternal antibiotics, antenatal corticosteroid use, mode of delivery, and neonatal gestational age, gender, 5-minute Apgar score, intubation at birth, ventilator days, and late onset sepsis, only late-onset sepsis, odds ratio ([OR]) 4.7 (95% confidence interval [CI]: 1.7–13.5) and >96 mmHg · hour index of exposure to hypocarbia (OR: 5.9; 95% CI: 1.6–21.2) were independently related to risk for PVL (Fig 3). Because hypotension is a risk factor for PVL,9 the mean blood pressures between days 1 and 7 for infants with and without PVL are shown in Fig 4. No significant differences were noted on each of the 7 days of life.


Figure 3
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  		FIGURE 3 OR and 95% CI demonstrating risk for PVL.

 

Figure 4
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  		FIGURE 4 Mean ± SEM blood pressure during the first 7 days of life between infants with ({blacktriangleup}) and without ({blacksquare}) PVL. Mean blood pressure (mmHg) days 1 to 7 for subjects with and without PVL.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
PVL is a multifactorial disease caused by ischemia, oxidant injury, and inflammation.9 Risk factors for PVL in low birth weight infants include perinatal factors, such as maternal antepartum hemorrhage,11 chorioamnionitis,12 antenatal corticosteroids (especially dexamethasone),13 and disturbances in placental circulation.9,14 Neonatal risk factors include systemic hypotension,9 "mature" premature infants with advanced gestational age,15 and hypocarbia.2–8,16 These factors may be associated with decrease in cerebral blood flow to the periventricular white matter region. Hyperoxia may be a risk factor for PVL mediated through exacerbation of oxidant injury to the maturation-dependent precursor cells during ischemia-reperfusion.9

This study reports the association of CIE during the first week of life and occurrence of PVL. Investigators have examined the relationship of single or multiple episodes of hypocarbia and PVL and have found an association.2–8,16 Giannakopoulou et al3 evaluated 52 mechanically ventilated infants with a gestational age <34 weeks with hypocarbia defined as lowest carbon dioxide tension <25 mmHg compared with a matched group not exhibiting hypocarbia in the first 3 days of life and found that the rate of PVL was 19.2% in the hypocarbia group compared with 3.8% in the control group. Erickson et al4 examined the relationship between PaCO2 levels during the first 92 hours and intraventricular hemorrhage, PVL, and bronchopulmonary dysplasia. Infants whose PaCO2 fell below 30 mmHg at any time in the first 48 hours had an increased risk of severe IVH or PVL (OR: 2.4; 95% CI: 1.3–4.5). Okumura et al5 explored the relationship of hypocarbia in the first 72 hours and occurrence of PVL. The time-averaged PaCO2 levels were lower in the infants with PVL (n = 26) as compared with those (n = 26) with normal neurodevelopment. In a large group of infants (n = 799), Dammann et al6 found an association between hypocarbia (defined as the lowest PaCO2 on the first day of life) and white matter echolucency in univariable analysis; however, the association diminished after adjusting for potential confounders. Wiswell et al7 have demonstrated that hypocarbia below a threshold level of 25 mmHg produced by treatment with high-frequency jet ventilation during the first 3 days of life is associated with PVL. In our study, we have attempted to calculate the cumulative exposure to a PaCO2 level <35 mmHg during the first 7 days of age and to examine the impact on PVL. We did find that infants with hypocarbia had a higher number of blood gas measurements obtained during the first 7 days of life compared with those without any hypocarbia, probably reflecting more illness severity in infants with hypocarbia.

Not all studies have found an association between hypocarbia and PVL. Salokorpi et al17 assessed the outcome of 215 infants with birth weight <1000 g and found no association between hypocarbia defined as ≥2 episodes of PaCO2 <3 kPa and either PVL or cerebral palsy.

The mechanism by which hypocarbia results in PVL is unclear. In experimental models, decreases in systemic PCO2 levels are associated with decreased cerebral blood flow, which, in turn, has been suggested as a risk factor for brain abnormalities.18 Another possible mechanism for the development of PVL was reported by Fritz et al,19 who demonstrated that moderate hypocapnia (PaCO2 <20 mmHg) of 1-hour duration results in decreased oxidative metabolism that is associated with DNA fragmentation in the cerebral cortex of newborn piglets. The authors speculate that hypocapnia-induced hypoxia results in increased intranuclear calcium flux, which causes protease and endonuclease activation, DNA fragmentation, and PVL in newborn infants. It should be noted, however, that hypocarbia can be a result or sequence of PVL.20

The relationship of hypocarbia and cerebral palsy in low birth weight infants has also been reported.10,16 Collins et al10 examined a population-based cohort of 657 infants with blood gases in the neonatal period and neurodevelopmental outcome data at ≥2 years of age. Disabling cerebral palsy was diagnosed in 2.3% of unventilated infants, 9.4% of infants without hypocarbia, and 27.5% of infants with hypocarbia (PaCO2 <35 mmHg). In the study by Graziani et al, prenatal and neonatal factors including the need for mechanical ventilation on the first day of life and marked hypocarbia during the first 3 postnatal days were associated with increased risk for damage to the periventricular white matter, severe intracranial hemorrhage, and cerebral palsy.16 However, the authors caution that a causal relationship between hypocarbia and brain damage in preterm infants remains unproven.16

The relationship of hyperoxia and PVL is less understood. It has been demonstrated that PVL involves free radical injury to the developing oligodendrocytes, resulting from ischemia/reperfusion, particularly between 24 and 32 weeks' gestation. Folkerth et al21 have demonstrated that during the period of greatest PVL risk, expression of superoxide dismutase lagged behind that of catalase and glutathione peroxidase in the white matter of the human fetus. Haynes et al22 examined autopsy brain tissue from PVL and non-PVL controls and noted that PVL involves injury to the premyelinating oligodendrocytes, potentially through activation of microglia and release of reactive oxygen and nitrogen species. These data demonstrate that oxidative stress may play a role in the development of PVL.

The strengths of this study are that a large number of infants was evaluated, the data were collected prospectively from a recent cohort, and the serial blood gas measurements were recorded in a consistent matter allowing measurement of CIE to hypocarbia and hyperoxia in the first 7 days of life. The limitations of the study are that the blood gas measurements were intermittent measurements (every 6 hours). Other limitations include the lack of a central reader to evaluate all of the sonograms. Information on chorioamnionitis was not available. Maternal antibiotic therapy initiated on suspicion of clinical chorioamnionitis may be used as a surrogate for chorioamnionitis. Clinical chorioamnionitis, however, underestimates the presence of histologic chorioamnionitis.23


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
In this study, we have demonstrated an association between CIE to hypocarbia (>102 mmHg · hour) in the first week and development of PVL, which is a marker of neurodevelopmental impairment in high-risk low birth weight infants.


   ACKNOWLEDGMENTS
 
This research was supported by National Institute of Child Health and Human Development grants U10HD21385, U01HD36790, U10HD40689, and U10HD40461.


   FOOTNOTES
 
Accepted May 23, 2006.

Address correspondence to Seetha Shankaran, MD, Children's Hospital of Michigan, Division of Neonatology, 3901 Beaubien, Room 4H46, Detroit, MI 48201. E-mail: sshankar{at}med.wayne.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2008; 93(2): F153 - F161.
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