Blood Gas Values During Hypothermia in Asphyxiated Term Neonates

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COMMENTARY

Blood Gas Values During Hypothermia in

Asphyxiated Term Neonates

Floris Groenendaal, MD, PhDa_{, Karen M. K. De Vooght, PharmD, PhD}b_{, Frank van Bel, MD, PhD}a

a_{Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, Netherlands;}b_{Department of Clinical Chemistry and Hematology,}

University Medical Center, Utrecht, Netherlands

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

H

YPOTHERMIA HAS BECOMEan important novel neu-roprotective strategy for asphyxiated term neo-nates.1 _{Most of these neonates will receive mechanical} ventilation. Hypothermia affects blood gas parameters such as pH and PCO2. At lower temperatures pH increases

and PCO2 decreases. This is relevant, because PaCO2 is

known to affect vascular tone and, hence, cerebral per-fusion.2_{In addition, cerebral blood flow decreases during} hypothermia, which increases the risk of insufficient blood flow during hypocapnia.3

Most blood gas instruments, whether a central labo-ratory or point-of-care device, contain a temperature-controlled sample chamber specified to be 37°C. It is at that temperature that all measurements of pH and par-tial pressure of gases are performed. In the␣-stat strat-egy, uncorrected values are used to keep the pH and PCO2close to the 37°C reference value.4However, most

instruments can calculate and present temperature-cor-rected pH and PCO2 values. In the so-called pH-stat

method, the measured pH is corrected to the actual body temperature of the patient. Ventilator settings can be adjusted to keep the actual pH as close to 7.4 as possible.4 At present, it is unclear whether the ␣-stat or pH-stat theory should be used in the neuroprotective strategy for asphyxiated term neonates.

In the 2 large randomized, controlled trials on thera-peutic hypothermia in term neonates with perinatal as-phyxia, attending physicians were advised to correct blood gases and pH for rectal temperature.5,6 _{Here we} will summarize the relevance of blood gas values in and the effects on cellular function during hypothermia.

HYPOTHERMIA, PCO2, AND pH

Physical laws determine that the solubility of a gas within a liquid decreases when lowering the tempera-ture. During hypothermia, arterial PCO2 decreases and

pH increases compared with 37°C when measurements are made at the actual body temperature (Fig 1). In healthy subjects with a body temperature of 37°C, pH and PaCO2should approach 7.4 and 5.3 kPa (40 mm Hg),

respectively. During hypothermia (33°C), pH will rise to 7.5 and PCO2will decrease to 4.5 kPa (34 mm Hg).

PaCO2AND CEREBRAL BLOOD FLOW

Under normal conditions, term neonates autoregulate their cerebral blood flow in response to changes in sys-temic arterial pressure, but this mechanism can be im-paired during neonatal distress.7_{In particular, changes in} PaCO2 have a well-recognized effect on cerebral blood

flow. Hypocapnia induces cerebral vasoconstriction and may decrease cerebral tissue high-energy phosphates.8,9 This effect has been extensively investigated in experi-ments in neonatal animals.9–11_{In preterm neonates,} pro-found hypocapnia below values of 4 kPa (30 mm Hg) was related to periventricular leukomalacia.12 _{There is} little reason to assume that hypocapnia could not dam-age the brain in the sick term neonate.13_{Klinger et al}14 reported that in asphyxiated term neonates early hypo-capnia was independently associated with adverse out-come. Others have reported an association between neurodevelopmental sequelae and profound hypocapnia in infants who were referred for extracorporeal mem-brane oxygenation because of severe cardiopulmonary failure.15_{Substantial hypercapnia and, in particular,} hy-pocapnia must therefore be considered to be potentially dangerous for the sick asphyxiated term infant.

pH AND CELLULAR ENZYMATIC PROCESSES

There is some evidence that intracellular pH changes with temperature such that the intracellular pH remains at or close to the pH of neutrality (the state when [H⫹_]_⫽

[OH⫺]). Experimental work has shown that protein

buffering, largely because of the imidazole group of his-tidine, is responsible for maintaining this tempera-ture-pH relationship (aided by phosphate and bicarbon-ate buffering). The idea that the degree of dissociation (known as ␣) of imidazole remains constant despite changes in temperature is known as the “␣-stat hypoth-esis.”4 _{The net charge on all proteins is kept constant} despite changes in temperature. It is hypothesized that as a result, all proteins can function optimally despite temperature changes.4_The␣_{-stat strategy is often used} for pediatric and adult cardiac surgery, although there are no good data to support this practice. In contrast, in the pH-stat strategy, pH and PaCO2 are maintained at

constant values during cooling such that in vivo hypo-thermic blood is at a pH of 7.40 and the PaCO2is 5.3 kPa

(40 mm Hg), whereas the blood measured at 37°C is hypercapnic and acidotic. Studies of hypothermic

circu-Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.

www.pediatrics.org/cgi/doi/10.1542/peds.2008-1955 doi:10.1542/peds.2008-1955

Accepted for publication Oct 9, 2008

Address correspondence to Floris Groenendaal, MD, PhD, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Department of Neonatology, Room KE 04.123.1, Lundlaan 6, 3584 EA Utrecht, Netherlands. E-mail: f.groenendaal@umcutrecht.nl

170 GROENENDAAL et al

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latory arrest in pigs have shown that pH-stat manage-ment could confer neurologic protection against isch-emia.16–20

STUDIES COMPARING THE␣-STAT AND pH-STAT METHODS There has hardly been any literature indicating whether to use the␣-stat or pH-stat method as part of the neu-roprotective strategy for asphyxiated term neonates. It was shown in infants undergoing deep hypothermic car-diopulmonary bypass that the use of the pH-stat method resulted in less postoperative morbidity.21 _However, these findings could not be confirmed in a subsequent study in which developmental outcome at 1 and 2 to 4 years of age in the same children was studied.22_{In adults} who were undergoing continuous moderately hypother-mic cardiopulmonary bypass, 3 randomized prospective studies indicated that postoperative neurologic or neu-ropsychological outcome is slightly, but consistently, better with␣-stat management.23–25 _{This is probably} be-cause of the lower cerebral blood flow of␣-stat manage-ment resulting in fewer cerebral emboli during cardio-pulmonary bypass. In contrast, several studies in pig and piglet models of deep hypothermic arrest found im-proved cerebral physiologic recovery with pH-stat man-agement.16–20_{It is not clear if the outcome of these} stud-ies performed in hypothermic pigs in circulatory arrest can be translated to the clinical condition of mild

hypo-thermia in asphyxiated term neonates. Li et al26 sug-gested that in mild hypothermia, brain tissue oxygen saturation in␣-stat management was greater than that in pH-stat management. Thus, the superiority of␣-stat versus pH-stat management in asphyxiated term neo-nates still remains to be established.

SUMMARY

Hypothermia affects blood gas parameters such as pH

and PCO2. At present, it is unknown which method

should be used for asphyxiated term neonates with moderate hypothermia; therefore, additional studies are justified. Secondary analysis of the effect of tempera-ture-adjusted PaCO2on outcome in trials of therapeutic

hypothermia is of interest.

We strongly advise colleagues to include information on the method of blood gas analysis in articles that deal with neonatal hypothermia.

REFERENCES

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3. Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia is not neuroprotective when started

af-FIGURE 1

Relation between temperature and PCO2(upper) and pH (lower),

given according to the physical properties of the solution (␣-stat method). Lines represent PaCO2or pH values of a single sample

measured at different temperatures. When measured in a blood gas analyzer at 37°C, PaCO2is 6.35 kPa and pH is 7.34; the in vivo

PaCO2is 5.33 kPa and pH is 7.40 at a patient temperature of 33°C.

PEDIATRICS Volume 123, Number 1, January 2009 171

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DOI: 10.1542/peds.2008-1955

2009;123;170

Pediatrics

Floris Groenendaal, Karen M. K. De Vooght and Frank van Bel

Blood Gas Values During Hypothermia in Asphyxiated Term Neonates

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DOI: 10.1542/peds.2008-1955

2009;123;170

Pediatrics

Floris Groenendaal, Karen M. K. De Vooght and Frank van Bel

Blood Gas Values During Hypothermia in Asphyxiated Term Neonates

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