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The use of acid-base measurements in the clinical evaluation and treatment of the sick neonate
FETAL
AND
MEDICINE
NEONATAL RichardE. Behrman, Editor
The use of acid-base measurements in the clinical evaluation and treatment of the sick neonate Richard E. Behrman, M.D. CHICAGO, ILL.
A s P i~ Y x i A T I O N at birth and the respiratory distress syndrome in the first day or two of life are the 2 major clinical problems that require an evaluation of the acid-base status of the infant during the neonatal period. In this commentary an attempt will be made to provide some practical guidelines for the clinical use of acid-base measurements in deciding upon specific diagnosis and treatment of the acid base disorders which occur during these disturbances. It will focus on those factors which should be taken into account in deciding what the possible relationships are between the numerical values obtained within the laboratory and the clinically estimated pathophysiologic status of the fetus or newborn infant. Pitfalls in the use of these determinations will be indicated. No attempt will be made to evaluate critically the results of treatment of acidbase abnormalities associated with particular diseases in the newborn infant. Some of the commentaries which wilI appear subsequently in this section will deal specifically with: the monitoring of the fetus by acidbase analysis of blood obtained from the From the University of lllinois at the Medical Center. Vol. 74, No. 4, pp. 632-637
scalp during labor; the treatment of asphyxia immediately after birth with sodium bicarbonate or T H A M , and the management of the idiopathic respiratory distress syndrome and other clinical disorders in which a critical understanding of the use of acid-base determinations is important. In recent years technological advances in laboratory medicine have made it possible to rapidly obtain information about the concentration of hydrogen and bicarbonate ions and the partial pressure of carbon dioxide in small samples of whole blood taken from acutely ill pediatric patients. Such acid-base determinations are now frequently available in both community and university hospitals. Paradoxically, in order to make appropriate use of this improved laboratory characterization of acid-base balance it has become more, rather than less, important for the clinician to make careful serial observations of the patient's respiratory and circulatory status and to interpret both laboratory and clinical findings in terms of basic physiologic conceps. In addition, the clinician must also know something about how these new tests are done in order to appreciate some of tgeir limitations. These considerations are particularly i,m-
Volume 74 Number 4
Acid-base measurements
portant for pediatricians and obstetricians in the making of therapeutic decisions concerning acutely ill newborn infants and fetuses, from whom blood is obtained by scalp vein sampling during labor. In dealing with these problems the margin of safety to avoid errors in the physician's judgment is small because of the patient's size and body composition and because of the precarious regulation of respiratory and circulatory systems during the period of transition from intrauterine to extrauterine life. Furthermore, clinical history and physical signs are often very limited; in the extreme they may consist only of the maternal obstetrical history and several determinations of the fetal heart rate. Frequently, the exact nature of the illness is unknown, and in general the efficacy of different modes of treatment is not established. THE MEASUREMENT
OF pH
The p H of blood is measured with a glass electrode at 38 ~ C. The pH, a reciprocal expression of hydrogen ion concentration, is closely related to the activity of the ion, and this activity varies directly with temperature. If the temperature of the patient is higher than 38 ~ C., the pH recorded will be higher (lower [H+]) than that of the blood in the patient. Conversely, as is more often the case in the acutely ill newborn infant, if the blood in the patient is at a temperature which is lower than 38 ~ C., the laboratory measurement of the p H will be lower (higher [H+]) than that of the blood within the patient. These temperature effects are further exaggerated by elevations or depressions in pCO2. It is possible to estimate roughly the necessary degree of correction for temperature between the in vivo and in vitro values by addlng or subtracting 0.0147 degree C. 1 Obviously, a decision cannot be made as to whether the temperature difference is large enough for the correction to be significant, nor can a correction be made in the laboratory or by the physician unless the temperature of the patient is known exactly at the time the blood sample is obtained. The site of the blood sampling and the patient's con-
633
dition should suggest whether the use of the skin or rectal temperature is most appropriate. Rectal temperature should be used when blood is obtained from an umbilical vein or artery catheter, but skin temperature may be more appropriate when capillary blood is obtained from a warmed extremity. Further, even assuming that the determinations are made with good equipment, by competent personnel, the method is very dependent upon the use of freshly opened, uncontaminated buffers, careful maintenance of both the glass and reference electrodes after each measurement, and scrupulous care in drawing blood into the system. When the p H meter is stationed in a nursery, as is often clinically desirable, outside the immediate supervision and responsibility of trained laboratory personnel for the use of house officers or inadequately trained technicians, unreliable values are more likely to be obtained. The fact that the pH meter indicates a given p H does not necessarily mean that the value is the correct one. THE MEASUREMENT
OF pCO~
Blood pCO2 (ram. H g ) , which is the only adequate measure of the respiratory component of acid-base equilibrium for clinical purposes, can be assayed directly with a different electrode; however, in the past it has commonly been calculated arithmetically or graphically from the Henderson-Hasselbach equation after independent measurements of the total CO2 concentration and the pH. Now it is more frequently obtained with the Astrup-Radiometer equilibration system by measuring the p H of 2 aliquot parts of a sample of the patient's blood after each has been equilibrated with one of two gases of different known carbon dioxide concentrations (high and low). In vitro blood pCO2 and p H are lineally related. Therefore, having established the pCO2 and p H of the blood at 2 points, the pCO2 Of an aliquot part of the patient's nonequilibrated blood can then be obtained by interpolation from the straight line drawn between the two equilibration pCO2 points at known pH's and an independent p H measurement of the
634
Behrman
patient's nonequilibrated blood. The pCO2 reported is thus a function of the precision with which the concentrations of the equilibration gases are determined, the care with which equilibration is carried out, the accuracy with which the 3 p H measurements are performed, and the precision with which the data are graphed. I n addition, all of the factors relevant to the evaluation of the p H apply to that of the pCO2 which is derived from p H in the equilibration system. These considerations explain why a decision to undertake assisted ventilation should not be based primarily on the laboratory measurement of pCO2. Rather, serially increasing pCO2 values that are quantitatively compatible with the degree of fall in p H should be considered as necessary supportive evidence in those cases in which there is uncertainty about the existence of clinical signs of progressive respiratory failure. In most instances, the decision should be based upon the progressive development of increasing periods of apnea, cyanosis, bradycardia, and decreasing air exchange associated with either severe retractions or weakening respiratory efforts. BASE EXCESS AND BICARBONATE
Once having determined the p H and pCO2 as just indicated, or the p H and total CO2, base excess or bicarbonate concentration can be calculated from these data and several physical chemical constants of blood. There is, however, considerable disagreement about the best way to characterize the metabolic components of acid-base equilibrium for clinical purposes. O n e approach is to focus on the change in the sum of the concentrations of the buffer anions of whole blood (buffer base): blood bicarbonate, plasma proteins, and hemoglobin in red blood cells. T h e change from the "normal" buffer base is commonly referred to as a positive or negative base excess. The alternative is to stress the usefulness of the concentration of the bicarbonate ions defined physiologically to include carbamino compounds and carbonate as well as bicarbonate. Base
The Journal of Pediatrics April 1969
excess is the predominant term used in neonatal pediatrics today. Both base excess and plasma bicarbonate are dependent in part on the pCO2 of the patient in vivo; they are interconvertible if the hemoglobin concentration and the oxygen saturation of the blood are known. But m o s t important, a physiologic assessment of the patient is absolutely essential for the proper interpretation of either the base excess or the bicarbonate concentration. Because the level of pCO2 affects the base excess and the bicarbonate concentration, it is necessary to interpret the effect of marked elevations in pCO2 which increase the negative base excess (base deficit) and the bicarbonate concentration in infants suffering from idiopathic respiratory distress syndrome, asphyxia, pneumonia, or pulmonary atelectasis. An increase in negative base excess (base deficit) or a decrease in bicarbonate m a y not necessarily indicate the presence or the degree of metabolic acidosis that may be present. For example, an eleva, tion in pCO2 causes the generation of bicarbonate as well as carbonic acid in the circulating blood. T h e bicarbonate redistributes itself throughout both the interstitial space and the vascular space. The interstitial fluid which has little or no non-bicarbonate buffer may then act as a reservoir for bicarbonate which, produced in the blood or in cells, has shifted into the interstitial compartment. In contrast with the blood-generated bicarbonate, the other major sources o f blood buffer anions are contributed by hemoglobin and plasma proteins. The immediate result of hypercapnia is a fall in the concentration of blood buffer anions contributed by hemoglobin and plasma proteins as they are consumed in buffering the additional H2COa added to the blood by the elevation of pCO2. This effect is then coupled with a smaller than expected rise in blood bicarbonate concentration as the newly generated bicarbonate diffuses into the interstitial space. T h e total buffer base in the blood falls and base excess, which is the change in buffer base, decreases ( > -B.E. or greater base deficit) without the production or addition of
Volume 74 Number 4
Acid-base measurements
organic acids or the loss of fixed base from the body. The magnitude of these changes would be expected to increase with greater concentrations of hemoglobin a n d / o r increased blood and interstitial volumes. Thus, the effect of elevation of pCO2 on the measured base excess in blood may be exaggerated in the newborn infant and particularly in the premature infant or fetus. At present the magnitude of these effects in infants of various gestational ages and body composition with various disorders is unknown, but a reasonable estimate suggests that an acute rise in pCO2 to 100 mm. Hg could produce a b~se excess of -9 mEq. per liter without any addition of metabolic acids to the extraeellular fluid or a loss of fixed base from the body. 2 Equating changes in base excess with metabolic abnormalities in acid-base balance, in particular a negative base excess with metabolic acidosis, could then lead to errors in diagnosis. For example, if a respiratory illness causing an increase in pCO2 and a base deficit improved spontaneously or secondarily t o artificial ventilation, treatment of the acidosis with sodium bicarbonate could result in a superimposed metabolic alkalosis with the attendant risks of tetany, respiratory depression, hypernatremia, and the like. It seems very likely that physiologic qualifications of the clinical interpretation of base excess and bicarbonate concentration in the newborn infant will increase as more is learned about the adjustments of the respiratory and circulatory systems and the changes in renal function, body composition, and the buffering capacity of proteins during acute and chronic illness during this period of life. HANDLING
THE BLOOD
SAMPLE
A delay in time between obtaining the blood sample and carrying out the acid-base determinations will result in a lower pH, a higher pCO2, and a greater negative base excess, owing to the continuous metabolism of the red blood cells. If the blood is kept uniformly cold in iced water immediately after being obtained, this effect will generally
635
be minimal for a short period of time. The pCO2 and p H of this blood should be determined within 5 minutes of sampling for optimal accuracy. However, routinely it may be kept at 25 ~ C. for as long as 20 minutes with minimal error (-0.01 p H ) . Care must also be taken to use a small amount of heparin anticoagulant (fewer than 100 units per milliliter of blood), as several commercially available heparin compounds will contaminate the blood with acid if used in excess, and other commonly used anticoagulants have a significant acidotic effect on blood pH. Lastly, when capillary tubes, syringes, or vacuum tubes are used to collect the blood, they should be airtight and filled completely and anaerobically. They should contain some inert material for mixing in addition to heparin for anticoagulation, since the blood must be mixed thoroughly after filling the tube and just prior to making measurements. Exposure to room air 02 tensions and loss of CO2 to the atmosphere of adequately anticoagulated and promptly assayed blood could result in a higher p H and lower pCOz than exists in the patient. THE PATIENT
In order to correctly interpret acid-base determinations for subsequent therapeutic decisions, it is particularly critical for the clinician to be aware of the general condition of the patient at the time the blood sample is obtained for laboratory analysis and the local conditions at the site from which the blood sample was removed. It is generally agreed that arterial blood is desirable blood for assay, since it supplies 02 and nutrients to the vital organs and reflects the efficiency of the hmgs, kidneys, and body compartments in regulating the over-all acid-base equilibrium. Although there is a reliable relationship between arterial and arterialized capillary blood in normal adults and infants, there is no established correlation between arterial and arterialized capillary blood or venous blood in acutely ill infants. For example, the low p H in blood obtained by an adequate free flow from the capillaries in a warmed foot (or from a peripheral vein) of an infant
63 6
Behrman
who has moderately severe respiratory distress or who is recovering from asphyxia may be associated with high pCO2 a n d / o r increased negative base excess (base deficit) as a result of local circulatory stasis, tissue hypoxia, and the accumulation of lactic acid. Such capillary blood does not necessarily reflect the degree of systemic hypercapnea or metabolic acidemia. T h e vasomotor instability of such infants coupled with transient cooling and the decreased ambient 02 concentration which may occur during even minimal manipulation of the foot while obtaining the blood sample will exaggerate the differences between arterialized capillary and systemic artery blood. If the capillary sample is difficult to obtain, the difference between it and the systemic blood sample will be even greater. On the other hand, a blood sample obtained from the umbilical or temporal artery in an infant who is hypothermic with poor peripheral tissue profusion may be relatively normal due to a decreased hydrogen ion activity, increased solubility of CO2, and" increased buffering capacity of blood proteins, but as the circulation improves and the infant becomes normothermic, there may be a sudden acidemia with cardiac irregularity secondary to rapid uptake by the improved circulation of lactic acid that has been accumulating in peripheral tissues. Conclusions about the acid-base balance of a patient, based on laboratory analysis of blood obtained at some prior time, must also be reinterpreted in light of subsequent changes in the patient's condition and management. Artificial or spontaneous changes in ventilation have immediate and profound effect~ on p H a n d pCO2 and may with time have increasingly marked effects on base ex-tess due to changes in hemoglobin concentration, the volumes of intravascular and interstitial fluid compartments, and variations in the permeability of biologic membranes to critical ions. The effects of renal function on acid-base homeostasis must also be taken into account. I f the circulatory status is stable in a small premature infant, even under mild stress a significant, amount of a therapeutic load of sodium bicarbonate
The Journal o[ Pediatrics April 1969
may be excreted in the urine to maintain normal serum sodium levels. However, when peripheral perfusion is inadequate or when the circulatory stability is precarious from one hour to the next, the ability of the kidneys to excrete a bicarbonate load or eliminate organic acids is often unpredictable even when sufficient time has elapsed to expect that some renal compensation should have taken place. Finally, interim changes in skin or rectal temperature may need to be taken into consideration. Little is known about the effects of temperature on acidbase balance in vivo when they are superimposed on infants with circulatory instability. From the foregoing comments the following clinical guidelines can be formulated. 1. In planning the treatment of acidosis associated with fetal and neonatal asphyxia or respiratory distress syndrome, clinical evaluation of the patient is essential to the interpretation of laboratory results. The patient's condition must be assessed both at the time blood is obtained for laboratory analysis and later when the results of the analysis are available. These assessments should include an appreciation of the patient's respiratory and circulatory status, body temperature, and site of blood sampling. Otherwise there can be significant under- or overestimation of the degree of acidosis. 2. After the blood is obtained, delay in carrying out the analysis and variations in amounts of anticoagulation used and in mixing may result in exaggeration of apparent acidosis. Exposure of blood to air may cause an error in the opposite direction. 3. The techniques for determinations of pH, pCO2, bicarbonate, and base excess, though easy to perform, are subject to a number of technical errors that can significantly distort the results. The direction of the distortion of the values reported by the laboratory cannot be predicted and the values obtained may not in themselves alert the clinician to the existence of an error. In this latter regard it is useful to have independent microdeterminations of sodium, potassium, chloride, and CO2 concentrations. If
Volume 74 Number 4
the sum of the cations (sodium, potassium) is approximately 25 mEq. per liter more than the sum of the anions (CI, CO2) and the concentrations of each electrolyte are in the normal range, a metabolic abnormality in acid-base balance is unlikely. 4. When equipment is placed within the nursery and is operated by house staff or by technicians not thoroughly skilled, regular and frequent checks should be made to insure that the equipment is in a functional state and that it is being used appropriately. 5. It is rarely necessary or advisable to correct p H values of 7.25 and above, and it is often uncessary to correct those between 7.20 and 7.25. Except in the management of assisted ventilation, pH's in this range should not be used as the principal determinant of whether the infant's illness requires respiratory or metabolic correction; clinical evaluation per se is the critical factor. 6. T h e measurement of blood pCOa is the best laboratory indicator of the respiratory component of acid-base balance. In current practice it is derived from the p H value. Because of the potential errors in this determination, the reported pCO2 value should also be used cautiously as a basis for therapeutic decisions. It should be interpreted in terms of clinical respiratory signs, and the value should be consistent with the p H measurement. PCO2 values between 35 and 50 mm. H g usually do not require iatrogenic manipulation. 7. A laboratory report of a negative base excess (base deficit) should not be equated with metabolic acidosis in the presence of a high pCO2 value, owing to the effects of pCO2 on buffer base and bicarbonate in vlvo. Because of this feature and the limitations in accurately measuring and evaluating p H and pCO2 in vivo, it is usually advisable to limit the initial intravenous treatment of
Acid-base measurements
637
acidosis to ~ to ~ of the estimated requirements for total correction and then to reevaluate the effects clinically and chemically within 1 hour. Any remaining deficit can then be corrected during the ensuing 2 to 4 hours. In general, the total dose of bicarbonate should not exceed 10 to 12 mEq. per kilogram per 24 hr. If severe acidosis persists requiring further alkali therapy, T H A M (Tris) should be used to avoid or minimize hypernatremia. I n order to minimize some of the complications of hypoglycemia, respiratory depression, and local irritation associated with T H A M , only ~ of the calculated initial dose in 5 per cent glucose should be slowly injected intravenously over a 10 minute period. The remainder may be given intravenously within 2 to 4 hours. When base excess (B. E.) is used to calculate the total base deficit, the following equation is a useful rule of thumb : mEq. base needed ~----B.E. (mEq./liter) 'x wt. (kg.) x 0.3 In summary, it can be stated unequivocally that an adequate laboratory description of acid-base balance is an important adjunct to the management of acid-base disorders in the newborn infant. However, as in the management of fluid and electrolyte disturbances in older infants, laboratory measurements cannot be substituted for sound clinical judgments about initial and continuing pathophysiology and the changing condition of the patient in response to therapy. REFERENCES
1. Adamsons, K., Jr., Daniel, S. S., Gandy, G. M., and James, C. S.: The influence of temperature on blood pH of the human adult and newborn, J. Appl. Physiol. 19:897, 1964. 2. Dell, R. B., Engel, K., and Winters, R. W.: Relevance to acid-base changes in the respiratory distress syndrome, J. PEVIAT. 69: 909, 1966.
AND
MEDICINE
NEONATAL RichardE. Behrman, Editor
The use of acid-base measurements in the clinical evaluation and treatment of the sick neonate Richard E. Behrman, M.D. CHICAGO, ILL.
A s P i~ Y x i A T I O N at birth and the respiratory distress syndrome in the first day or two of life are the 2 major clinical problems that require an evaluation of the acid-base status of the infant during the neonatal period. In this commentary an attempt will be made to provide some practical guidelines for the clinical use of acid-base measurements in deciding upon specific diagnosis and treatment of the acid base disorders which occur during these disturbances. It will focus on those factors which should be taken into account in deciding what the possible relationships are between the numerical values obtained within the laboratory and the clinically estimated pathophysiologic status of the fetus or newborn infant. Pitfalls in the use of these determinations will be indicated. No attempt will be made to evaluate critically the results of treatment of acidbase abnormalities associated with particular diseases in the newborn infant. Some of the commentaries which wilI appear subsequently in this section will deal specifically with: the monitoring of the fetus by acidbase analysis of blood obtained from the From the University of lllinois at the Medical Center. Vol. 74, No. 4, pp. 632-637
scalp during labor; the treatment of asphyxia immediately after birth with sodium bicarbonate or T H A M , and the management of the idiopathic respiratory distress syndrome and other clinical disorders in which a critical understanding of the use of acid-base determinations is important. In recent years technological advances in laboratory medicine have made it possible to rapidly obtain information about the concentration of hydrogen and bicarbonate ions and the partial pressure of carbon dioxide in small samples of whole blood taken from acutely ill pediatric patients. Such acid-base determinations are now frequently available in both community and university hospitals. Paradoxically, in order to make appropriate use of this improved laboratory characterization of acid-base balance it has become more, rather than less, important for the clinician to make careful serial observations of the patient's respiratory and circulatory status and to interpret both laboratory and clinical findings in terms of basic physiologic conceps. In addition, the clinician must also know something about how these new tests are done in order to appreciate some of tgeir limitations. These considerations are particularly i,m-
Volume 74 Number 4
Acid-base measurements
portant for pediatricians and obstetricians in the making of therapeutic decisions concerning acutely ill newborn infants and fetuses, from whom blood is obtained by scalp vein sampling during labor. In dealing with these problems the margin of safety to avoid errors in the physician's judgment is small because of the patient's size and body composition and because of the precarious regulation of respiratory and circulatory systems during the period of transition from intrauterine to extrauterine life. Furthermore, clinical history and physical signs are often very limited; in the extreme they may consist only of the maternal obstetrical history and several determinations of the fetal heart rate. Frequently, the exact nature of the illness is unknown, and in general the efficacy of different modes of treatment is not established. THE MEASUREMENT
OF pH
The p H of blood is measured with a glass electrode at 38 ~ C. The pH, a reciprocal expression of hydrogen ion concentration, is closely related to the activity of the ion, and this activity varies directly with temperature. If the temperature of the patient is higher than 38 ~ C., the pH recorded will be higher (lower [H+]) than that of the blood in the patient. Conversely, as is more often the case in the acutely ill newborn infant, if the blood in the patient is at a temperature which is lower than 38 ~ C., the laboratory measurement of the p H will be lower (higher [H+]) than that of the blood within the patient. These temperature effects are further exaggerated by elevations or depressions in pCO2. It is possible to estimate roughly the necessary degree of correction for temperature between the in vivo and in vitro values by addlng or subtracting 0.0147 degree C. 1 Obviously, a decision cannot be made as to whether the temperature difference is large enough for the correction to be significant, nor can a correction be made in the laboratory or by the physician unless the temperature of the patient is known exactly at the time the blood sample is obtained. The site of the blood sampling and the patient's con-
633
dition should suggest whether the use of the skin or rectal temperature is most appropriate. Rectal temperature should be used when blood is obtained from an umbilical vein or artery catheter, but skin temperature may be more appropriate when capillary blood is obtained from a warmed extremity. Further, even assuming that the determinations are made with good equipment, by competent personnel, the method is very dependent upon the use of freshly opened, uncontaminated buffers, careful maintenance of both the glass and reference electrodes after each measurement, and scrupulous care in drawing blood into the system. When the p H meter is stationed in a nursery, as is often clinically desirable, outside the immediate supervision and responsibility of trained laboratory personnel for the use of house officers or inadequately trained technicians, unreliable values are more likely to be obtained. The fact that the pH meter indicates a given p H does not necessarily mean that the value is the correct one. THE MEASUREMENT
OF pCO~
Blood pCO2 (ram. H g ) , which is the only adequate measure of the respiratory component of acid-base equilibrium for clinical purposes, can be assayed directly with a different electrode; however, in the past it has commonly been calculated arithmetically or graphically from the Henderson-Hasselbach equation after independent measurements of the total CO2 concentration and the pH. Now it is more frequently obtained with the Astrup-Radiometer equilibration system by measuring the p H of 2 aliquot parts of a sample of the patient's blood after each has been equilibrated with one of two gases of different known carbon dioxide concentrations (high and low). In vitro blood pCO2 and p H are lineally related. Therefore, having established the pCO2 and p H of the blood at 2 points, the pCO2 Of an aliquot part of the patient's nonequilibrated blood can then be obtained by interpolation from the straight line drawn between the two equilibration pCO2 points at known pH's and an independent p H measurement of the
634
Behrman
patient's nonequilibrated blood. The pCO2 reported is thus a function of the precision with which the concentrations of the equilibration gases are determined, the care with which equilibration is carried out, the accuracy with which the 3 p H measurements are performed, and the precision with which the data are graphed. I n addition, all of the factors relevant to the evaluation of the p H apply to that of the pCO2 which is derived from p H in the equilibration system. These considerations explain why a decision to undertake assisted ventilation should not be based primarily on the laboratory measurement of pCO2. Rather, serially increasing pCO2 values that are quantitatively compatible with the degree of fall in p H should be considered as necessary supportive evidence in those cases in which there is uncertainty about the existence of clinical signs of progressive respiratory failure. In most instances, the decision should be based upon the progressive development of increasing periods of apnea, cyanosis, bradycardia, and decreasing air exchange associated with either severe retractions or weakening respiratory efforts. BASE EXCESS AND BICARBONATE
Once having determined the p H and pCO2 as just indicated, or the p H and total CO2, base excess or bicarbonate concentration can be calculated from these data and several physical chemical constants of blood. There is, however, considerable disagreement about the best way to characterize the metabolic components of acid-base equilibrium for clinical purposes. O n e approach is to focus on the change in the sum of the concentrations of the buffer anions of whole blood (buffer base): blood bicarbonate, plasma proteins, and hemoglobin in red blood cells. T h e change from the "normal" buffer base is commonly referred to as a positive or negative base excess. The alternative is to stress the usefulness of the concentration of the bicarbonate ions defined physiologically to include carbamino compounds and carbonate as well as bicarbonate. Base
The Journal of Pediatrics April 1969
excess is the predominant term used in neonatal pediatrics today. Both base excess and plasma bicarbonate are dependent in part on the pCO2 of the patient in vivo; they are interconvertible if the hemoglobin concentration and the oxygen saturation of the blood are known. But m o s t important, a physiologic assessment of the patient is absolutely essential for the proper interpretation of either the base excess or the bicarbonate concentration. Because the level of pCO2 affects the base excess and the bicarbonate concentration, it is necessary to interpret the effect of marked elevations in pCO2 which increase the negative base excess (base deficit) and the bicarbonate concentration in infants suffering from idiopathic respiratory distress syndrome, asphyxia, pneumonia, or pulmonary atelectasis. An increase in negative base excess (base deficit) or a decrease in bicarbonate m a y not necessarily indicate the presence or the degree of metabolic acidosis that may be present. For example, an eleva, tion in pCO2 causes the generation of bicarbonate as well as carbonic acid in the circulating blood. T h e bicarbonate redistributes itself throughout both the interstitial space and the vascular space. The interstitial fluid which has little or no non-bicarbonate buffer may then act as a reservoir for bicarbonate which, produced in the blood or in cells, has shifted into the interstitial compartment. In contrast with the blood-generated bicarbonate, the other major sources o f blood buffer anions are contributed by hemoglobin and plasma proteins. The immediate result of hypercapnia is a fall in the concentration of blood buffer anions contributed by hemoglobin and plasma proteins as they are consumed in buffering the additional H2COa added to the blood by the elevation of pCO2. This effect is then coupled with a smaller than expected rise in blood bicarbonate concentration as the newly generated bicarbonate diffuses into the interstitial space. T h e total buffer base in the blood falls and base excess, which is the change in buffer base, decreases ( > -B.E. or greater base deficit) without the production or addition of
Volume 74 Number 4
Acid-base measurements
organic acids or the loss of fixed base from the body. The magnitude of these changes would be expected to increase with greater concentrations of hemoglobin a n d / o r increased blood and interstitial volumes. Thus, the effect of elevation of pCO2 on the measured base excess in blood may be exaggerated in the newborn infant and particularly in the premature infant or fetus. At present the magnitude of these effects in infants of various gestational ages and body composition with various disorders is unknown, but a reasonable estimate suggests that an acute rise in pCO2 to 100 mm. Hg could produce a b~se excess of -9 mEq. per liter without any addition of metabolic acids to the extraeellular fluid or a loss of fixed base from the body. 2 Equating changes in base excess with metabolic abnormalities in acid-base balance, in particular a negative base excess with metabolic acidosis, could then lead to errors in diagnosis. For example, if a respiratory illness causing an increase in pCO2 and a base deficit improved spontaneously or secondarily t o artificial ventilation, treatment of the acidosis with sodium bicarbonate could result in a superimposed metabolic alkalosis with the attendant risks of tetany, respiratory depression, hypernatremia, and the like. It seems very likely that physiologic qualifications of the clinical interpretation of base excess and bicarbonate concentration in the newborn infant will increase as more is learned about the adjustments of the respiratory and circulatory systems and the changes in renal function, body composition, and the buffering capacity of proteins during acute and chronic illness during this period of life. HANDLING
THE BLOOD
SAMPLE
A delay in time between obtaining the blood sample and carrying out the acid-base determinations will result in a lower pH, a higher pCO2, and a greater negative base excess, owing to the continuous metabolism of the red blood cells. If the blood is kept uniformly cold in iced water immediately after being obtained, this effect will generally
635
be minimal for a short period of time. The pCO2 and p H of this blood should be determined within 5 minutes of sampling for optimal accuracy. However, routinely it may be kept at 25 ~ C. for as long as 20 minutes with minimal error (-0.01 p H ) . Care must also be taken to use a small amount of heparin anticoagulant (fewer than 100 units per milliliter of blood), as several commercially available heparin compounds will contaminate the blood with acid if used in excess, and other commonly used anticoagulants have a significant acidotic effect on blood pH. Lastly, when capillary tubes, syringes, or vacuum tubes are used to collect the blood, they should be airtight and filled completely and anaerobically. They should contain some inert material for mixing in addition to heparin for anticoagulation, since the blood must be mixed thoroughly after filling the tube and just prior to making measurements. Exposure to room air 02 tensions and loss of CO2 to the atmosphere of adequately anticoagulated and promptly assayed blood could result in a higher p H and lower pCOz than exists in the patient. THE PATIENT
In order to correctly interpret acid-base determinations for subsequent therapeutic decisions, it is particularly critical for the clinician to be aware of the general condition of the patient at the time the blood sample is obtained for laboratory analysis and the local conditions at the site from which the blood sample was removed. It is generally agreed that arterial blood is desirable blood for assay, since it supplies 02 and nutrients to the vital organs and reflects the efficiency of the hmgs, kidneys, and body compartments in regulating the over-all acid-base equilibrium. Although there is a reliable relationship between arterial and arterialized capillary blood in normal adults and infants, there is no established correlation between arterial and arterialized capillary blood or venous blood in acutely ill infants. For example, the low p H in blood obtained by an adequate free flow from the capillaries in a warmed foot (or from a peripheral vein) of an infant
63 6
Behrman
who has moderately severe respiratory distress or who is recovering from asphyxia may be associated with high pCO2 a n d / o r increased negative base excess (base deficit) as a result of local circulatory stasis, tissue hypoxia, and the accumulation of lactic acid. Such capillary blood does not necessarily reflect the degree of systemic hypercapnea or metabolic acidemia. T h e vasomotor instability of such infants coupled with transient cooling and the decreased ambient 02 concentration which may occur during even minimal manipulation of the foot while obtaining the blood sample will exaggerate the differences between arterialized capillary and systemic artery blood. If the capillary sample is difficult to obtain, the difference between it and the systemic blood sample will be even greater. On the other hand, a blood sample obtained from the umbilical or temporal artery in an infant who is hypothermic with poor peripheral tissue profusion may be relatively normal due to a decreased hydrogen ion activity, increased solubility of CO2, and" increased buffering capacity of blood proteins, but as the circulation improves and the infant becomes normothermic, there may be a sudden acidemia with cardiac irregularity secondary to rapid uptake by the improved circulation of lactic acid that has been accumulating in peripheral tissues. Conclusions about the acid-base balance of a patient, based on laboratory analysis of blood obtained at some prior time, must also be reinterpreted in light of subsequent changes in the patient's condition and management. Artificial or spontaneous changes in ventilation have immediate and profound effect~ on p H a n d pCO2 and may with time have increasingly marked effects on base ex-tess due to changes in hemoglobin concentration, the volumes of intravascular and interstitial fluid compartments, and variations in the permeability of biologic membranes to critical ions. The effects of renal function on acid-base homeostasis must also be taken into account. I f the circulatory status is stable in a small premature infant, even under mild stress a significant, amount of a therapeutic load of sodium bicarbonate
The Journal o[ Pediatrics April 1969
may be excreted in the urine to maintain normal serum sodium levels. However, when peripheral perfusion is inadequate or when the circulatory stability is precarious from one hour to the next, the ability of the kidneys to excrete a bicarbonate load or eliminate organic acids is often unpredictable even when sufficient time has elapsed to expect that some renal compensation should have taken place. Finally, interim changes in skin or rectal temperature may need to be taken into consideration. Little is known about the effects of temperature on acidbase balance in vivo when they are superimposed on infants with circulatory instability. From the foregoing comments the following clinical guidelines can be formulated. 1. In planning the treatment of acidosis associated with fetal and neonatal asphyxia or respiratory distress syndrome, clinical evaluation of the patient is essential to the interpretation of laboratory results. The patient's condition must be assessed both at the time blood is obtained for laboratory analysis and later when the results of the analysis are available. These assessments should include an appreciation of the patient's respiratory and circulatory status, body temperature, and site of blood sampling. Otherwise there can be significant under- or overestimation of the degree of acidosis. 2. After the blood is obtained, delay in carrying out the analysis and variations in amounts of anticoagulation used and in mixing may result in exaggeration of apparent acidosis. Exposure of blood to air may cause an error in the opposite direction. 3. The techniques for determinations of pH, pCO2, bicarbonate, and base excess, though easy to perform, are subject to a number of technical errors that can significantly distort the results. The direction of the distortion of the values reported by the laboratory cannot be predicted and the values obtained may not in themselves alert the clinician to the existence of an error. In this latter regard it is useful to have independent microdeterminations of sodium, potassium, chloride, and CO2 concentrations. If
Volume 74 Number 4
the sum of the cations (sodium, potassium) is approximately 25 mEq. per liter more than the sum of the anions (CI, CO2) and the concentrations of each electrolyte are in the normal range, a metabolic abnormality in acid-base balance is unlikely. 4. When equipment is placed within the nursery and is operated by house staff or by technicians not thoroughly skilled, regular and frequent checks should be made to insure that the equipment is in a functional state and that it is being used appropriately. 5. It is rarely necessary or advisable to correct p H values of 7.25 and above, and it is often uncessary to correct those between 7.20 and 7.25. Except in the management of assisted ventilation, pH's in this range should not be used as the principal determinant of whether the infant's illness requires respiratory or metabolic correction; clinical evaluation per se is the critical factor. 6. T h e measurement of blood pCOa is the best laboratory indicator of the respiratory component of acid-base balance. In current practice it is derived from the p H value. Because of the potential errors in this determination, the reported pCO2 value should also be used cautiously as a basis for therapeutic decisions. It should be interpreted in terms of clinical respiratory signs, and the value should be consistent with the p H measurement. PCO2 values between 35 and 50 mm. H g usually do not require iatrogenic manipulation. 7. A laboratory report of a negative base excess (base deficit) should not be equated with metabolic acidosis in the presence of a high pCO2 value, owing to the effects of pCO2 on buffer base and bicarbonate in vlvo. Because of this feature and the limitations in accurately measuring and evaluating p H and pCO2 in vivo, it is usually advisable to limit the initial intravenous treatment of
Acid-base measurements
637
acidosis to ~ to ~ of the estimated requirements for total correction and then to reevaluate the effects clinically and chemically within 1 hour. Any remaining deficit can then be corrected during the ensuing 2 to 4 hours. In general, the total dose of bicarbonate should not exceed 10 to 12 mEq. per kilogram per 24 hr. If severe acidosis persists requiring further alkali therapy, T H A M (Tris) should be used to avoid or minimize hypernatremia. I n order to minimize some of the complications of hypoglycemia, respiratory depression, and local irritation associated with T H A M , only ~ of the calculated initial dose in 5 per cent glucose should be slowly injected intravenously over a 10 minute period. The remainder may be given intravenously within 2 to 4 hours. When base excess (B. E.) is used to calculate the total base deficit, the following equation is a useful rule of thumb : mEq. base needed ~----B.E. (mEq./liter) 'x wt. (kg.) x 0.3 In summary, it can be stated unequivocally that an adequate laboratory description of acid-base balance is an important adjunct to the management of acid-base disorders in the newborn infant. However, as in the management of fluid and electrolyte disturbances in older infants, laboratory measurements cannot be substituted for sound clinical judgments about initial and continuing pathophysiology and the changing condition of the patient in response to therapy. REFERENCES
1. Adamsons, K., Jr., Daniel, S. S., Gandy, G. M., and James, C. S.: The influence of temperature on blood pH of the human adult and newborn, J. Appl. Physiol. 19:897, 1964. 2. Dell, R. B., Engel, K., and Winters, R. W.: Relevance to acid-base changes in the respiratory distress syndrome, J. PEVIAT. 69: 909, 1966.