- Email: [email protected]
Neonatal metabolic acidosis at birth: In search of a reliable marker
Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
Available online at
ScienceDirect www.sciencedirect.com
Clinical expert series
Neonatal metabolic acidosis at birth: In search of a reliable marker§ Acidose me´tabolique ne´onatale a` la naissance : a` la recherche d’un marqueur pertinent C. Racinet a,b,*, P. Ouellet c,d, F. Charles e, T. Daboval f,g a
UGA Grenoble, Domaine Universitaire, 621, avenue Centrale, 38400 Saint-Martin-d’He`res, France Childhood Disabilities and Perinatal Data Register (RHEOP), 23, avenue Albert-1er-de-Belgique, 38000 Grenoble, France c Department of Surgery, Sherbrooke University, Sherbrooke, Quebec, Canada d Vitality Health Care Network, zone 4, Edmundston, New Brunswick, Canada e Regional Hospital Center of Toulon-La Seyne/Mer, Toulon, France f University of Ottawa, Ottawa, Canada g Department of Pediatrics, Children’s Hospital of East Ontario, Ottawa, Canada b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 March 2016 Accepted 11 April 2016 Available online 20 May 2016
Objective. – A newborn may present acidemia on the umbilical artery blood which can result from respiratory acidosis or metabolic acidosis or be of mixed origin. Currently, in the absence of a satisfactory definition, the challenge is to determine the most accurate marker for metabolic acidosis, which can be deleterious for the neonate. Methods. – We reviewed the methodological and physiological aspects of the perinatal literature to search for the best marker of NMA. Results. – Base deficit and pH have been criticized as the standard criteria to predict outcome. The proposed threshold of pathogenicity is not based on convincing studies. The algorithms of various blood gas analyzers differ and do not take into account the specific neonatal acid–base profile. Conclusion. – Birth-related neonatal eucapnic pH is described as the most pertinent marker of NMA at birth. The various means of calculating this value and the level below which it seems to play a possible pathogenic role are presented. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Neonate Respiratory acidosis Metabolic acidosis Birth-related eucapnic neonatal pH
R E´ S U M E´
Mots cle´s : Nouveau-ne´ Acidose respiratoire Acidose me´tabolique PH eucapnique ne´onatal a` la naissance
Objectif. – Un nouveau-ne´ peut pre´senter une acide´mie dans le sang cordonal, re´sultant d’une acidose respiratoire ou d’une acidose me´tabolique (ANM) ou bien d’une acidose mixte. Devant l’utilisation persistante de de´finitions non satisfaisantes, il paraıˆt ne´cessaire de de´terminer quel est le meilleur marqueur d’une ANM, car celle-ci peut se re´ve´ler pathoge`ne pour le nouveau-ne´. Me´thode. – Nous avons revu les aspects me´thodologiques et les bases physiologiques de la litte´rature pe´rinatale pour construire un marqueur fiable de l’ANM. Re´sultats. – Le de´ficit de base et le pH ne sont pas des marqueurs fiables du pronostic ne´onatal. Le seuil propose´ pour les valeurs pathoge`nes ne repose pas sur des e´tudes convaincantes. Les algorithmes utilise´s par les divers analyseurs de gaz du sang diffe`rent et ne prennent pas en compte le profil spe´cifique acidobasique du nouveau-ne´. Conclusion. – Le pH eucapnique ne´onatal a` la naissance est de´crit comme le marqueur le plus pertinent de l’AMN. Les diverses me´thodes de calcul et le niveau au-dessous duquel il paraıˆt pouvoir jouer un roˆle pathoge`ne sont pre´sente´s. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
DOI of original article: http://dx.doi.org/10.1016/j.gyobfe.2016.04.011 Voir, dans ce meˆme nume´ro de Gyne´cologie Obste´rique & Fertilite´, l’avant-propos signe´ par E. Simon : Interpre´tation du pH au cordon a` la naissance : le pie`ge de l’hypercapnie [Interpretation of umbilical cord pH at birth: the trap of hypercapnia]. Gynecol Obstet Fertil 2016;44. http://dx.doi.org/10.1016/j.gyobfe.2016.04.011. * Corresponding author. UGA Grenoble, Domaine Universitaire, 621, avenue Centrale, 38400 Saint-Martin-d’He`res, France. E-mail address: [email protected] (C. Racinet). §
http://dx.doi.org/10.1016/j.gyobfe.2016.04.005 1297-9589/ß 2016 Elsevier Masson SAS. All rights reserved.
358
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
1. Introduction The pathophysiology of fetal asphyxia ultimately leads to neonatal metabolic acidosis (NMA), measured in umbilical artery blood in the neonate, who may have survived the stress of acute or even chronic asphyxia in utero. NMA is considered to be an indirect measurement of fetal hypoxia [1]. The presence of NMA at birth is the necessary but not the only biochemical criterion to support an increasing probability that a peripartum hypoxic-ischemic event may be a causal pathway of neonatal encephalopathy preceding cerebral palsy (CP) [2,3]. Conversely, the presence or absence of NMA takes on a broader medical-legal dimension because of the significant compensation allowed for CP [4]. NMA could also be an argument for initiating cerebral hypothermia as a preventive measure [5].
2. Methodology Among the diagnostic criteria for NMA, pH and mainly base deficit (BD) should be challenged because various nomenclatures are used to express BD and it is calculated with different algorithms. We analyzed the most relevant publications on NMA that included pH and gazometry, in order to choose a reliable marker for clinical purposes at the bedside.
3. Results 3.1. Acid–base criteria of NMA diagnosis According to the consensus of the Task Force on Cerebral Palsy [2] and the 2003 consensus of the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics (ACOG-AAP) revised in 2014 [3], umbilical artery blood acid–base criteria are defined by: pH < 7.0; or BD 12 mmol/L (or > 16 mmol/L for therapeutic hypothermia [5]); or both.
3.1.2. The ‘‘base deficit’’ criterion should be more precise: in vitro vs. in vivo BD BD is usually used as an indicator of metabolic acidosis, especially if it is high and ventilation is normal, as is the case in the older child. However, in the newborn it is particularly important to know whether acidemia has a metabolic, hypercapnic, or mixed origin. BD is calculated from measurements of pH, PCO2, and bicarbonate ion, the latter being calculated with the HendersonHasselbalch (HH) equation as follows: pH ¼ 6:1 þ log ðHCO3 =0:03PCO2 Þ In fact, two forms of BD are known: in vitro and in vivo. Failure to specify which form of BD is used can misguide the interpretation. None of the two consensus statements [2,3] specifies which BD is used in the diagnostic criteria of NMA. The algorithms used to calculate blood gas parameters stem from the recommendations devised by the Clinical Laboratory Standards Institute (CLSI) [7]. Accordingly, the two forms of BD are calculated based on the following reasoning. In vitro BD (whole blood) is calculated from pH, HCO3, and total hemoglobin. It evaluates the quantity of base needed to titrate 1 L of blood to a pH of 7.40, without mentioning simultaneous titration to a referent PCO2. In vivo BD (extracellular fluid) is calculated from pH and PCO2. Modeling extracellular fluid using a mixture containing one part blood and two parts plasma is considered a good approximation of the composition of the whole body internal environment. This in vivo BD evaluates the quantity of base needed to titrate the extracellular fluid to a pH of 7.40, at a PCO2 of 40 mmHg. In vivo BD is meant to reflect only the metabolic component, but with reference to normal adult values. According to the CLSI, the in vivo BD is calculated by applying the following sequences: Invivo BD ¼ 24:8 HCO3 ð16:2 ðpH 7:40ÞÞ
Given that respiratory acidosis related to hypercapnia can explain a low pH and significant BD, the latter criterion, which is intended to measure the severity of NMA, appears imprecise and poorly adapted to the objective targeted in this high-risk period for asphyxia. It also appears that the defined threshold of pathogenicity is based on a methodology that calls for review.
where: pH = actual pH. HCO3 is calculated from PCO2 and pH as follows: log (HCO3) = pH + log (PCO2) 7.608. Under acid–base balance conditions (pH = 7.40 for adults), the values of these two forms of BD are very close, but they grow farther apart with increasing acidemia, a condition that is relatively frequent at birth. Accordingly, in vivo BD may demonstrate a value below the accepted threshold of pathogenicity of 12 mmol/L, whereas in vitro BD may be higher than in vivo BD. The choice of one or the other of the BDs adds to the uncertainty of clinical interpretation.
3.1.1. What is the pH threshold value for severe acidosis? According to the ACOG-AAP, the threshold for severe umbilical artery acidemia has evolved from pHua 7.00 in 2003 to pHua < 7.0 in 2014 (pHua, pH in umbilical artery). This second value appears to be more restrictive than the first one because it does not take into account values at 7.0. Moreover, for the ACOG-AAP, the threshold of severe acidemia changes from its original status as an ‘‘essential criterion’’ (supporting the notion that acute intrapartum asphyxia may have been sufficient to create CP) to a secondary criterion where it only increases the likelihood that neonatal encephalopathy has an intrapartum hypoxic component. However, in 2015, McLennan considered that the ACOG-AAP 2014’s report chose to focus on neonatal encephalopathy rather than discuss CP causation specifically and addressed the ramifications of litigation following a diagnosis of CP. For this purpose, he recommended keeping the 2003 essential criteria, which had disappeared in 2014 [6].
3.1.3. Elimination of the respiratory component in calculating in vivo BD The CLSI recommends calculating in vivo BD with a PCO2 to a classic value of 40 mmHg obtained after regular ventilation [7]. In fact, it seems implicit that the actual pH value should also be replaced by a pH value free of the influence of hypercapnia, which is referred to as standard or eucapnic pH. On several analyzers we have noted that this recommendation is not always applied, thus inducing different results for the same sample. We have taken the well-founded position of introducing eucapnic pH into this algorithm, instead conserving the measured value of pH. With reference to Saling’s experimental demonstration [1] and keeping in mind the theoretical objective of the CLSI, the in vivo BD, which we suggest calling birth-related neonatal eucapnic BD (to clearly specify that it measures acidity at normal newborn PCO2, as demonstrated in the next section), is always lower than the BD initially calculated from the measured data.
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
3.1.4. Calculation of in vivo BD should be adapted to the neonatal constants The nomograms, diagrams, and algorithms used to calculate in vivo BD refer to the average values of a well-ventilated child. These values differ from those of a healthy neonate at birth. In fact, neonates routinely present moderate acidemia and hypercapnia, pronounced hypoxemia, and moderate hyperlactatemia. Normal acid–base values for the umbilical artery are the following [8,9]1: pH: 7.282; PCO2: 53–54 mmHg (53.82); HCO3: 24–25 mmol/L (24.52); PO2: 15 mmHg; Lactate: 3.5 mmol/L. From these normal newborn data, a diagram can be constructed on the model presented by Grogono in Schistig et al. [10] and modified by Racinet et al. [8]. Grogono’s model was originally adapted to adult values of PCO2 and pH. Combined with Davenport diagrams [11], a new Charles-Racinet diagram was constructed with GNU Emacs software based on the [H+] ion concentration scale, taking newborn normal values into account. 3.2. Calculating birth-related neonatal eucapnic pHua Birth-related neonatal eucapnic pHua (bn-eucapnic pHua) is a calculated value that represents the residual acidity related solely to the metabolic component. Elimination of the hypercapnic component is warranted because it disappears after birth with a few effective ventilations, and classically there is no brain pathogenicity [2]. Eucapnic pH was first described in perinatal medicine in 1966 by Saling, who demonstrated that lowering PCO2 to its normal value simultaneously increases the so-called eucapnic pH when hypercapnia is present [1]. The calculation of eucapnic pH was incorporated by the American Heart Association (AHA) [12], then by Eisenberg et al. for adults [13] and Blickstein and Green [14] for newborns. The HH equation is another way to obtain eucapnic pH. A new method for calculating newborn eucapnic pH, based on the HH equation, is proposed herein: the Charles-Racinet diagram. 3.2.1. Eisenberg, Blickstein, and the American Heart Association For each 10-mmHg increase in PCO2, the pH simultaneously decreases by 0.08 in situations of acute asphyxia, limited to 0.03 for chronic asphyxia. The pH decrease may vary between these two conditions depending on the intensity of hypercapnia and its duration. However, we have observed that for rising levels of PCO2, this reduction in 0.08 decreases gradually when the resulting pH is < 7.15. No correction of this distortion has been proposed by the promoters of this calculation technique, which might result in overestimating bn-eucapnic pHua for high values of PCO2. In view of this observation, this method does not appear accurate and in particular does not take into account the effect of hypercapnia on HCO3. For these reasons, we no longer use it. 3.2.2. The Henderson-Hasselbalch equation and the Boston rule According to the HH equation [15] and knowing the average values of pH (7.28) and PCO2 (53.8 mmHg) at birth, we can deduce that the average value of HCO3 is equal to 24.5 mmol/L [9]. Brackett et al. showed that through a hydrolysis effect, every 10-mmHg rise in PCO2 also results in a simultaneous 1-mmol/L rise in HCO3 (the
1 Racinet C, Peresse JF, Richalet G, Ouellet P. Le pH arte´riel eucapnique a` la naissance : un nouveau marqueur de la composante me´tabolique de l’acide´mie ne´onatale [submitted for publication]. 2 Mean values extracted from [8].
359
Boston rule of ‘‘1 for 10’’), which partly compensates for the pH decrease [16]. 3.2.3. The Charles-Racinet diagram The Charles-Racinet diagram is based on both the HH equation and the Boston rule (Fig. 1). From this diagram, the bn-eucapnic pHua expresses a residual acidity of metabolic origin. It is our opinion that the calculation proposed herein proves to be a reflection that is more consistent with the physicochemical reality of the newborn. Fig. 2 illustrates how this diagram works through a case study. This diagram brings together all the desired information in the same document and provides graphic traceability recommended for each case where pH < 7.0. As a supplement, an Excel form from the Charles-Racinet diagram is provided in Fig. 3. 3.2.4. Clinical application of birth-related neonatal eucapnic pHua We conducted a study based on a cohort of 5104 neonates1 and observed that hypercapnia was constant (mean, 91.7 mmHg) in the subgroup with pH 7.00, which justifies routinely calculating bn-eucapnic pHua. In this subgroup of 32 cases, the mean actual pH was 6.95 and the mean bn-eucapnic pHua was 7.114. Four of the five infants transferred to the neonatal unit had a bn-eucapnic pHua 7.11, but did not develop neonatal complications such as encephalopathy. This preliminary evaluation of the predictive value of bn-eucapnic pHua is underpowered and needs confirmation on larger cohorts. 3.3. Technology for acid–base status Blood gas analyzers are relatively complex. Basically, pH and PCO2 are measured. HCO3 and BD are calculated through various algorithms. PO2, hemoglobin, and oxygen saturation are measured and various oxygenation parameters are also calculated using algorithms. Eucapnic pH can also be obtained in this manner. The major pitfall is that it is based on adult reference values. Furthermore, for the same pH and PCO2 parameter values, the algorithms of the CLSI and the three analyzers tested by the institutions in Lund and Malmo¨ provide fairly scattered results [17] and are therefore deemed inappropriate for newborns for the calculation of BD in vivo. In fact, the prevalence of BD 12 mmol/L ranges from 0.73% to 5.18% (differing from one- to sevenfold) and the prevalence of the association of pH 7.00 and BD 12 mmol/L ranges from 0.30% to 0.66% (a twofold difference). Because of this, it would seem important for the results presented in various publications to specify not only the type of BD employed, but also the name and model of the analyzer used, which in practice is never done and therefore makes for dubious comparison of these results. 3.4. NMA threshold of cerebral pathogenicity According to the ACOG-AAP’s definition, severe NMA increases the probability that any neonatal encephalopathy includes a component of acute intrapartum fetal asphyxia. However, ACOGAAP has defined neither the type of BD nor the algorithm used to calculate it, and has not explained how to take into account any potential hypercapnic acidosis that might coexist with the metabolic portion. Low et al. base this definition primarily on their 1997 publication [18], which estimated that the threshold of cerebral pathogenicity was defined as BD 12 mmol/L, which they found in 2% of live neonates (more than double the incidence of severe acidemia). However, we disagree with the conclusions drawn from this study, which have already been criticized elsewhere [19–23]:
360 C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362 Fig. 1. Charles-Racinet diagram. X-axis: PCO2 in mmHg. Y-axis: HCO3 in mmol/L. Red line: the buffer line, which, in the case of acute respiratory acidosis, indicates an increase in HCO3 at a rate of 1 mmol/L for every 10-mmHg increase in PCO2. The iso-pH lines are plotted diagonally and converge near the origin of the coordinates. The corresponding concentrations of [H+] expressed in nmol/L are in parentheses beside the value of each iso-pH line. The bold vertical line at PCO2: 53.8 mmHg is the newborn reference value for PCO2. The bold horizontal line at HCO3 = 24.5 mmol/L is the newborn reference value for HCO3. The convergence of PCO2: 53.8, HCO3: 24.5, iso-pH: 7.28, and the buffer line is the newborn eucapnic reference point.
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
361
Fig. 2. Calculation of birth-related eucapnic pH with the Charles-Racinet diagram. Umbilical artery blood gas: pH: 6.92; PCO2: 100 mmHg. pH (N) indicates the newborn’s optimal pH, which is 7.28; pH (A) indicates the measured pH value in the case under study: 6.92; pH (R) indicates the pH level reached by compensation of hypercapnia; pH (B), or bn-eucapnic pHua, indicates the residual level related to the metabolic portion. The two pH (R) and pH (B) values should not be confused. They are equal if the hypercapnic and metabolic portions are equal. Otherwise, they are more or less different depending on the distribution of these parts. Instructions for using the diagram: 1. Plot the values of pH: 6,92 and PCO2: 100 mmHg (point A). 2. Estimate the corresponding pH value (point R) at the junction of the buffer line with the vertical line passing through the measured PCO2 of 100. 3. Estimate the value of the pH (B) or bn-eucapnic pHua, by applying the relation: pH euc (n) = pH (A) + pH (N) pH (R) = 6.92 + 7.28 7.08; pH euc(n) = 7,12 (Birth-related neonatal eucapnic pH). 4. Locate pH: 7.12 at PCO2: 53,8 mmHg (point B). 5. On the horizontal line passing through point B, eucapnic HCO3 is estimated at 16.8 mmol/L at the interception with the y-axis. 6. Estimate the value of Eucapnic Base Deficit (bn-eucapnic BD) by applying the relation: bn-eucapnic BD = (Normal HCO3 at birth) – (Eucapnic HCO3) where: Normal HCO3 at birth = 24,5; Eucapnic HCO3 at birth (point B) = 16,8 = 24,5–16,8; bn-eucapnic BD = 7,7 mmol/L (Eucapnic Base Deficit).
Birth-related neonatal eucapnic pH Normal baseline values at birth pH 7.28 PCO2 53.8 mmHg HCO3 24.5 mmol/L A case of a newborn umbilical artery blood gas Actual values to be entered (Excel spreadsheet) pH 6.92 PCO2 (mmHg) 100 Results as per described equations Expected HCO3 (According to actual PCO2) 29.1 mmol/L Actual HCO3 (According to HH equation) 20.0 mmol/L Calculated Eucapnic neonatal HCO3 16.8 mmol/L Calculated Eucapnic neonatal Base Deficit 7.7 mmol/L Calculated Birth-related neonatal pH 7.12 HH (Henderson-Hasselbalch) Fig. 3. Calculation of birth-related neonatal eucapnic pH with Excel. Instructions for using the Excel calculations: 1. Enter actual pH, PCO2 from the umbilical artery in the respective white boxes. 2. Press enter. 3. Read the calculated values in the Section 3.
the BD values were determined based only on a small cohort of 174 newborns and were grouped into three categories (8–12, 12–16, and > 16 mmol/L), with a loss of power in the search for a pertinent threshold value, which could have been set more specifically by the ROC curve created from continuous variables; the type of BD and the manufacturer and model of the blood gas analyzer were not indicated, which introduces uncertainty because of the variability of the results related to these parameters; in particular, it would have been necessary to take into account only cases with pH 7.00; this information is absent from the Low’s article, which studied only data on BD. The prevalence of combined pH 7.00 and BD 12 mmol/L is 4–15 times less frequent than the prevalence of BD 12 mmol/L alone, which suggests that the threshold value proposed by Low et al. is an overvalued marker of true NMA because of mediocre specificity; similarly, the absence of data on PCO2, with no specific information on how BD was calculated, eliminates consideration of any hypercapnic component, which is nearly always present and contributes to the high value of BD at birth. In addition, the criticisms mentioned above question whether BD is a pertinent marker of NMA and accord it no additional value over and above knowledge of the actual pH [18–20], much less the birth-related neonatal eucapnic pH [8].1 4. Discussion and conclusion It appears from the data that diagnosis of NMA is currently based on imprecise criteria, and that the results also vary depending on the analyzer used. We have emphasized this lack of consistency: the choice of one BD or the other as well as the choice of the analyzer used add to the potential lack of accuracy in clinical interpretation. Older [19] and more recent studies [20–23] discount any value of in vivo BD over and above knowledge of the pH, which they consider as the best marker of fetal status at birth, but their conclusions on pH value at birth address ‘‘total’’ acidity, because
362
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
they do not take into account the hypercapnic portion that contributes substantially to acidemia (information on PCO2 values is lacking in the majority of articles). Our goal is to obtain a reliable method of diagnosing NMA that would be a true instantaneous picture at time zero (T0) of the metabolic part of newborn acid–base status, to measure fetal response to labor, and to identify any potential abnormalities that may result from labor, because this knowledge may help identify term infants at risk of morbidity, or later may have a recognized medical-legal importance in case of CP [4]. It is important to underline that the infant is born in an acid– base state close to respiratory decompensation [8],1 which is normal and indicative of an unavoidable birth-related biochemical stress that most newborns can tolerate with no subsequent harm. This biochemical snapshot is indispensable for correctly interpreting the antepartum history of any neonatal distress. Newborn biochemical conditions are not taken into account in any of the available algorithms: they all refer to adult standards. This results in overestimation of BD, which—despite uncertainty related to the absence of consensus between manufacturers on the algorithms used—assigns a threshold of pathogenicity that was not calculated with reference to neonatal conditions. We believe that this fully warrants our reviewing the situation and our recommendations. We have considered the primary methods used to diagnose and quantify NMA that might affect the child in the future, and none of them appears to be satisfactory. Starting from the basic premise that pH is the universally acknowledged marker of acidemia, but is not specific because by it cannot specify whether it originates from a respiratory or metabolic cause, but still seems to be the best predictor of neonatal outcomes, we believe that the concept of birth-related neonatal eucapnic pHua best fulfills this need for specificity in a simple, objective, and precise way, resulting in BD estimation no longer being of practical interest. Based on our clinical experience, we confirm that birth-related neonatal eucapnic BD adds nothing of value over and above knowledge of the birth-related neonatal eucapnic pH because their correlation is nearly linear (r = 0.98).1 It can be calculated using two possible methods, at the user’s discretion: direct use of the Charles-Racinet diagram; or the Excel form to calculate the newborn’s eucapnic pH. This recommendation calls for all researchers in obstetrics and perinatal medicine to converge towards a redefinition of the pathogenic threshold of NMA. Pending results of additional studies, we estimate that a birthrelated neonatal eucapnic pH of umbilical artery blood < 7.11 is more specific than a pH < 7.0 to define severe NMA. Its presence is necessary to strongly support a position that fetal intrapartum hypoxia might be the root of neonatal encephalopathy and eventually cerebral palsy. Conversely, this level of acidemia is not sufficient to confirm the diagnosis of perinatal asphyxia, which must be based on accumulated evidence from clinical practice, laboratory tests, and brain imaging.
Disclosure of interest The authors declare that they have no competing interest.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.gyobfe.2016.04. 005.
References [1] Saling E. Das Kind im Bereich der Geburtshilfe. Stuttgart: Georg Thieme Verlag; 1966. [2] MacLennan A, for the International Task Force on Cerebral Palsy. A template for defining a causal relationship between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054–9. [3] The American College of Obstetricians and Gynecologists. Neonatal encephalopathy and neurologic outcome, second edition, executive summary. Obstet Gynecol 2014;123(4):896–901. [4] Racinet C, Hoffmann P. Perinatal asphyxia and cerebral palsy: medico-legal implications. Bull Acad Natl Med 2010;194(6):891–901. [5] Papille LA, Committee on fetus and newborn. Hypothermia and neonatal encephalopathy. Pediatrics 2014;133(6):1146–9. [6] MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: causes, pathways, and the role of genetic variants. Am J Obstet Gynecol 2015. http://dx.doi.org/10. 1016/j.ajog.2015.05.034. [7] CLSI. Blood gas and pH analysis and related measurements; approved guidelines, Second edition. CLSI document C46-A2, Wayne, PA: Clinical and Laboratory Standards Institute; 2009. [8] Racinet C, Richalet G, Corne C, et al. Diagnosis of neonatal metabolic acidosis by eucapnic pH determination. Gynecol Obstet Fertil 2013;43:485–92. [9] Ramin SM. Umbilical cord blood acid-base analysis at delivery; 2015, http:// www.update.com. [10] Schistig R, Grogono AW, Severinghaus JW. Human pCO2 and standard base excess compensation for acid-base imbalance. Crit Care Med 1998;26(7): 1173–9. [11] Davenport HW. ABC de l’e´quilibre biochimique acido-basique. Masson; 1973. [12] McIntyre KM, Lewis AJ. Textbook of advanced cardiac life support. In: Carveth SW, editor. American Heart Association. Dallas; 1983. [13] Eisenberg MS, Cummins RO, Ho MT. Code blue: cardiac arrest and resuscitation. Philadelphia: Saunders; 1987. [14] Blickstein I, Green T. Umbilical cord blood gases. Clin Perinatol 2007;3(3):451–9. [15] Henderson LJ. Concerning the relationship between the strength of acids and their capacity to preserve neutrality. Am J Physiol 1908;21:173–9. [16] Brackett NC, Cohen JJ, Schwartz WB. Carbon dioxide titration curve of normal man. Effect of increasing degrees of acute hypercapnia on acid-base equilibrium. N Engl J Med 1965;272(1):6–12. [17] Mokarami P, Wiberg N, Olofsson P. An overlooked aspect on metabolic acidosis at birth: blood gas analysers calculate base deficit differently. Acta Obstet Gynecol Scandin 2012;91:574–9. [18] Low JA, Lindsay BG, Derrick EJ. Threshold of metabolic acidosis associated with newborn complications. Am J Obstet Gynecol 1997;177(6):1391–4. [19] Schwartz WB, Relmann AS. A critique of the parameters used in the evaluation of acid-base disorders: whole blood buffer base and standard bicarbonate compared with blood pH and plasma bicarbonate concentration. N Engl J Med 1963;268–325:1382–8. [20] Knutzen L, Svirko E, Impey L. The significance of base deficit in acidemic term neonates. Am J Obstet Gynecol 2015. http://dx.doi.org/10.1016/j.ajog.2015. 03.051. [21] Georgieva A, Moulden M, Redman C. Umbilical cord gases in relation to the neonatal condition: the EveREst plot. Eur J Obstet Gynecol Reprod Biol 2013; 168:155–60. [22] Olofsson P. Determination of base excess in umbilical cord blood at birth: accessory or J excess? Am J Obstet Gynecol 2015;213:259–61. [23] Cahill AG. Umbilical artery pH and base deficit in obstetrics. Am J Obstet Gynecol 2015;213(3):257–8.
Available online at
ScienceDirect www.sciencedirect.com
Clinical expert series
Neonatal metabolic acidosis at birth: In search of a reliable marker§ Acidose me´tabolique ne´onatale a` la naissance : a` la recherche d’un marqueur pertinent C. Racinet a,b,*, P. Ouellet c,d, F. Charles e, T. Daboval f,g a
UGA Grenoble, Domaine Universitaire, 621, avenue Centrale, 38400 Saint-Martin-d’He`res, France Childhood Disabilities and Perinatal Data Register (RHEOP), 23, avenue Albert-1er-de-Belgique, 38000 Grenoble, France c Department of Surgery, Sherbrooke University, Sherbrooke, Quebec, Canada d Vitality Health Care Network, zone 4, Edmundston, New Brunswick, Canada e Regional Hospital Center of Toulon-La Seyne/Mer, Toulon, France f University of Ottawa, Ottawa, Canada g Department of Pediatrics, Children’s Hospital of East Ontario, Ottawa, Canada b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 March 2016 Accepted 11 April 2016 Available online 20 May 2016
Objective. – A newborn may present acidemia on the umbilical artery blood which can result from respiratory acidosis or metabolic acidosis or be of mixed origin. Currently, in the absence of a satisfactory definition, the challenge is to determine the most accurate marker for metabolic acidosis, which can be deleterious for the neonate. Methods. – We reviewed the methodological and physiological aspects of the perinatal literature to search for the best marker of NMA. Results. – Base deficit and pH have been criticized as the standard criteria to predict outcome. The proposed threshold of pathogenicity is not based on convincing studies. The algorithms of various blood gas analyzers differ and do not take into account the specific neonatal acid–base profile. Conclusion. – Birth-related neonatal eucapnic pH is described as the most pertinent marker of NMA at birth. The various means of calculating this value and the level below which it seems to play a possible pathogenic role are presented. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Neonate Respiratory acidosis Metabolic acidosis Birth-related eucapnic neonatal pH
R E´ S U M E´
Mots cle´s : Nouveau-ne´ Acidose respiratoire Acidose me´tabolique PH eucapnique ne´onatal a` la naissance
Objectif. – Un nouveau-ne´ peut pre´senter une acide´mie dans le sang cordonal, re´sultant d’une acidose respiratoire ou d’une acidose me´tabolique (ANM) ou bien d’une acidose mixte. Devant l’utilisation persistante de de´finitions non satisfaisantes, il paraıˆt ne´cessaire de de´terminer quel est le meilleur marqueur d’une ANM, car celle-ci peut se re´ve´ler pathoge`ne pour le nouveau-ne´. Me´thode. – Nous avons revu les aspects me´thodologiques et les bases physiologiques de la litte´rature pe´rinatale pour construire un marqueur fiable de l’ANM. Re´sultats. – Le de´ficit de base et le pH ne sont pas des marqueurs fiables du pronostic ne´onatal. Le seuil propose´ pour les valeurs pathoge`nes ne repose pas sur des e´tudes convaincantes. Les algorithmes utilise´s par les divers analyseurs de gaz du sang diffe`rent et ne prennent pas en compte le profil spe´cifique acidobasique du nouveau-ne´. Conclusion. – Le pH eucapnique ne´onatal a` la naissance est de´crit comme le marqueur le plus pertinent de l’AMN. Les diverses me´thodes de calcul et le niveau au-dessous duquel il paraıˆt pouvoir jouer un roˆle pathoge`ne sont pre´sente´s. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
DOI of original article: http://dx.doi.org/10.1016/j.gyobfe.2016.04.011 Voir, dans ce meˆme nume´ro de Gyne´cologie Obste´rique & Fertilite´, l’avant-propos signe´ par E. Simon : Interpre´tation du pH au cordon a` la naissance : le pie`ge de l’hypercapnie [Interpretation of umbilical cord pH at birth: the trap of hypercapnia]. Gynecol Obstet Fertil 2016;44. http://dx.doi.org/10.1016/j.gyobfe.2016.04.011. * Corresponding author. UGA Grenoble, Domaine Universitaire, 621, avenue Centrale, 38400 Saint-Martin-d’He`res, France. E-mail address: [email protected] (C. Racinet). §
http://dx.doi.org/10.1016/j.gyobfe.2016.04.005 1297-9589/ß 2016 Elsevier Masson SAS. All rights reserved.
358
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
1. Introduction The pathophysiology of fetal asphyxia ultimately leads to neonatal metabolic acidosis (NMA), measured in umbilical artery blood in the neonate, who may have survived the stress of acute or even chronic asphyxia in utero. NMA is considered to be an indirect measurement of fetal hypoxia [1]. The presence of NMA at birth is the necessary but not the only biochemical criterion to support an increasing probability that a peripartum hypoxic-ischemic event may be a causal pathway of neonatal encephalopathy preceding cerebral palsy (CP) [2,3]. Conversely, the presence or absence of NMA takes on a broader medical-legal dimension because of the significant compensation allowed for CP [4]. NMA could also be an argument for initiating cerebral hypothermia as a preventive measure [5].
2. Methodology Among the diagnostic criteria for NMA, pH and mainly base deficit (BD) should be challenged because various nomenclatures are used to express BD and it is calculated with different algorithms. We analyzed the most relevant publications on NMA that included pH and gazometry, in order to choose a reliable marker for clinical purposes at the bedside.
3. Results 3.1. Acid–base criteria of NMA diagnosis According to the consensus of the Task Force on Cerebral Palsy [2] and the 2003 consensus of the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics (ACOG-AAP) revised in 2014 [3], umbilical artery blood acid–base criteria are defined by: pH < 7.0; or BD 12 mmol/L (or > 16 mmol/L for therapeutic hypothermia [5]); or both.
3.1.2. The ‘‘base deficit’’ criterion should be more precise: in vitro vs. in vivo BD BD is usually used as an indicator of metabolic acidosis, especially if it is high and ventilation is normal, as is the case in the older child. However, in the newborn it is particularly important to know whether acidemia has a metabolic, hypercapnic, or mixed origin. BD is calculated from measurements of pH, PCO2, and bicarbonate ion, the latter being calculated with the HendersonHasselbalch (HH) equation as follows: pH ¼ 6:1 þ log ðHCO3 =0:03PCO2 Þ In fact, two forms of BD are known: in vitro and in vivo. Failure to specify which form of BD is used can misguide the interpretation. None of the two consensus statements [2,3] specifies which BD is used in the diagnostic criteria of NMA. The algorithms used to calculate blood gas parameters stem from the recommendations devised by the Clinical Laboratory Standards Institute (CLSI) [7]. Accordingly, the two forms of BD are calculated based on the following reasoning. In vitro BD (whole blood) is calculated from pH, HCO3, and total hemoglobin. It evaluates the quantity of base needed to titrate 1 L of blood to a pH of 7.40, without mentioning simultaneous titration to a referent PCO2. In vivo BD (extracellular fluid) is calculated from pH and PCO2. Modeling extracellular fluid using a mixture containing one part blood and two parts plasma is considered a good approximation of the composition of the whole body internal environment. This in vivo BD evaluates the quantity of base needed to titrate the extracellular fluid to a pH of 7.40, at a PCO2 of 40 mmHg. In vivo BD is meant to reflect only the metabolic component, but with reference to normal adult values. According to the CLSI, the in vivo BD is calculated by applying the following sequences: Invivo BD ¼ 24:8 HCO3 ð16:2 ðpH 7:40ÞÞ
Given that respiratory acidosis related to hypercapnia can explain a low pH and significant BD, the latter criterion, which is intended to measure the severity of NMA, appears imprecise and poorly adapted to the objective targeted in this high-risk period for asphyxia. It also appears that the defined threshold of pathogenicity is based on a methodology that calls for review.
where: pH = actual pH. HCO3 is calculated from PCO2 and pH as follows: log (HCO3) = pH + log (PCO2) 7.608. Under acid–base balance conditions (pH = 7.40 for adults), the values of these two forms of BD are very close, but they grow farther apart with increasing acidemia, a condition that is relatively frequent at birth. Accordingly, in vivo BD may demonstrate a value below the accepted threshold of pathogenicity of 12 mmol/L, whereas in vitro BD may be higher than in vivo BD. The choice of one or the other of the BDs adds to the uncertainty of clinical interpretation.
3.1.1. What is the pH threshold value for severe acidosis? According to the ACOG-AAP, the threshold for severe umbilical artery acidemia has evolved from pHua 7.00 in 2003 to pHua < 7.0 in 2014 (pHua, pH in umbilical artery). This second value appears to be more restrictive than the first one because it does not take into account values at 7.0. Moreover, for the ACOG-AAP, the threshold of severe acidemia changes from its original status as an ‘‘essential criterion’’ (supporting the notion that acute intrapartum asphyxia may have been sufficient to create CP) to a secondary criterion where it only increases the likelihood that neonatal encephalopathy has an intrapartum hypoxic component. However, in 2015, McLennan considered that the ACOG-AAP 2014’s report chose to focus on neonatal encephalopathy rather than discuss CP causation specifically and addressed the ramifications of litigation following a diagnosis of CP. For this purpose, he recommended keeping the 2003 essential criteria, which had disappeared in 2014 [6].
3.1.3. Elimination of the respiratory component in calculating in vivo BD The CLSI recommends calculating in vivo BD with a PCO2 to a classic value of 40 mmHg obtained after regular ventilation [7]. In fact, it seems implicit that the actual pH value should also be replaced by a pH value free of the influence of hypercapnia, which is referred to as standard or eucapnic pH. On several analyzers we have noted that this recommendation is not always applied, thus inducing different results for the same sample. We have taken the well-founded position of introducing eucapnic pH into this algorithm, instead conserving the measured value of pH. With reference to Saling’s experimental demonstration [1] and keeping in mind the theoretical objective of the CLSI, the in vivo BD, which we suggest calling birth-related neonatal eucapnic BD (to clearly specify that it measures acidity at normal newborn PCO2, as demonstrated in the next section), is always lower than the BD initially calculated from the measured data.
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
3.1.4. Calculation of in vivo BD should be adapted to the neonatal constants The nomograms, diagrams, and algorithms used to calculate in vivo BD refer to the average values of a well-ventilated child. These values differ from those of a healthy neonate at birth. In fact, neonates routinely present moderate acidemia and hypercapnia, pronounced hypoxemia, and moderate hyperlactatemia. Normal acid–base values for the umbilical artery are the following [8,9]1: pH: 7.282; PCO2: 53–54 mmHg (53.82); HCO3: 24–25 mmol/L (24.52); PO2: 15 mmHg; Lactate: 3.5 mmol/L. From these normal newborn data, a diagram can be constructed on the model presented by Grogono in Schistig et al. [10] and modified by Racinet et al. [8]. Grogono’s model was originally adapted to adult values of PCO2 and pH. Combined with Davenport diagrams [11], a new Charles-Racinet diagram was constructed with GNU Emacs software based on the [H+] ion concentration scale, taking newborn normal values into account. 3.2. Calculating birth-related neonatal eucapnic pHua Birth-related neonatal eucapnic pHua (bn-eucapnic pHua) is a calculated value that represents the residual acidity related solely to the metabolic component. Elimination of the hypercapnic component is warranted because it disappears after birth with a few effective ventilations, and classically there is no brain pathogenicity [2]. Eucapnic pH was first described in perinatal medicine in 1966 by Saling, who demonstrated that lowering PCO2 to its normal value simultaneously increases the so-called eucapnic pH when hypercapnia is present [1]. The calculation of eucapnic pH was incorporated by the American Heart Association (AHA) [12], then by Eisenberg et al. for adults [13] and Blickstein and Green [14] for newborns. The HH equation is another way to obtain eucapnic pH. A new method for calculating newborn eucapnic pH, based on the HH equation, is proposed herein: the Charles-Racinet diagram. 3.2.1. Eisenberg, Blickstein, and the American Heart Association For each 10-mmHg increase in PCO2, the pH simultaneously decreases by 0.08 in situations of acute asphyxia, limited to 0.03 for chronic asphyxia. The pH decrease may vary between these two conditions depending on the intensity of hypercapnia and its duration. However, we have observed that for rising levels of PCO2, this reduction in 0.08 decreases gradually when the resulting pH is < 7.15. No correction of this distortion has been proposed by the promoters of this calculation technique, which might result in overestimating bn-eucapnic pHua for high values of PCO2. In view of this observation, this method does not appear accurate and in particular does not take into account the effect of hypercapnia on HCO3. For these reasons, we no longer use it. 3.2.2. The Henderson-Hasselbalch equation and the Boston rule According to the HH equation [15] and knowing the average values of pH (7.28) and PCO2 (53.8 mmHg) at birth, we can deduce that the average value of HCO3 is equal to 24.5 mmol/L [9]. Brackett et al. showed that through a hydrolysis effect, every 10-mmHg rise in PCO2 also results in a simultaneous 1-mmol/L rise in HCO3 (the
1 Racinet C, Peresse JF, Richalet G, Ouellet P. Le pH arte´riel eucapnique a` la naissance : un nouveau marqueur de la composante me´tabolique de l’acide´mie ne´onatale [submitted for publication]. 2 Mean values extracted from [8].
359
Boston rule of ‘‘1 for 10’’), which partly compensates for the pH decrease [16]. 3.2.3. The Charles-Racinet diagram The Charles-Racinet diagram is based on both the HH equation and the Boston rule (Fig. 1). From this diagram, the bn-eucapnic pHua expresses a residual acidity of metabolic origin. It is our opinion that the calculation proposed herein proves to be a reflection that is more consistent with the physicochemical reality of the newborn. Fig. 2 illustrates how this diagram works through a case study. This diagram brings together all the desired information in the same document and provides graphic traceability recommended for each case where pH < 7.0. As a supplement, an Excel form from the Charles-Racinet diagram is provided in Fig. 3. 3.2.4. Clinical application of birth-related neonatal eucapnic pHua We conducted a study based on a cohort of 5104 neonates1 and observed that hypercapnia was constant (mean, 91.7 mmHg) in the subgroup with pH 7.00, which justifies routinely calculating bn-eucapnic pHua. In this subgroup of 32 cases, the mean actual pH was 6.95 and the mean bn-eucapnic pHua was 7.114. Four of the five infants transferred to the neonatal unit had a bn-eucapnic pHua 7.11, but did not develop neonatal complications such as encephalopathy. This preliminary evaluation of the predictive value of bn-eucapnic pHua is underpowered and needs confirmation on larger cohorts. 3.3. Technology for acid–base status Blood gas analyzers are relatively complex. Basically, pH and PCO2 are measured. HCO3 and BD are calculated through various algorithms. PO2, hemoglobin, and oxygen saturation are measured and various oxygenation parameters are also calculated using algorithms. Eucapnic pH can also be obtained in this manner. The major pitfall is that it is based on adult reference values. Furthermore, for the same pH and PCO2 parameter values, the algorithms of the CLSI and the three analyzers tested by the institutions in Lund and Malmo¨ provide fairly scattered results [17] and are therefore deemed inappropriate for newborns for the calculation of BD in vivo. In fact, the prevalence of BD 12 mmol/L ranges from 0.73% to 5.18% (differing from one- to sevenfold) and the prevalence of the association of pH 7.00 and BD 12 mmol/L ranges from 0.30% to 0.66% (a twofold difference). Because of this, it would seem important for the results presented in various publications to specify not only the type of BD employed, but also the name and model of the analyzer used, which in practice is never done and therefore makes for dubious comparison of these results. 3.4. NMA threshold of cerebral pathogenicity According to the ACOG-AAP’s definition, severe NMA increases the probability that any neonatal encephalopathy includes a component of acute intrapartum fetal asphyxia. However, ACOGAAP has defined neither the type of BD nor the algorithm used to calculate it, and has not explained how to take into account any potential hypercapnic acidosis that might coexist with the metabolic portion. Low et al. base this definition primarily on their 1997 publication [18], which estimated that the threshold of cerebral pathogenicity was defined as BD 12 mmol/L, which they found in 2% of live neonates (more than double the incidence of severe acidemia). However, we disagree with the conclusions drawn from this study, which have already been criticized elsewhere [19–23]:
360 C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362 Fig. 1. Charles-Racinet diagram. X-axis: PCO2 in mmHg. Y-axis: HCO3 in mmol/L. Red line: the buffer line, which, in the case of acute respiratory acidosis, indicates an increase in HCO3 at a rate of 1 mmol/L for every 10-mmHg increase in PCO2. The iso-pH lines are plotted diagonally and converge near the origin of the coordinates. The corresponding concentrations of [H+] expressed in nmol/L are in parentheses beside the value of each iso-pH line. The bold vertical line at PCO2: 53.8 mmHg is the newborn reference value for PCO2. The bold horizontal line at HCO3 = 24.5 mmol/L is the newborn reference value for HCO3. The convergence of PCO2: 53.8, HCO3: 24.5, iso-pH: 7.28, and the buffer line is the newborn eucapnic reference point.
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
361
Fig. 2. Calculation of birth-related eucapnic pH with the Charles-Racinet diagram. Umbilical artery blood gas: pH: 6.92; PCO2: 100 mmHg. pH (N) indicates the newborn’s optimal pH, which is 7.28; pH (A) indicates the measured pH value in the case under study: 6.92; pH (R) indicates the pH level reached by compensation of hypercapnia; pH (B), or bn-eucapnic pHua, indicates the residual level related to the metabolic portion. The two pH (R) and pH (B) values should not be confused. They are equal if the hypercapnic and metabolic portions are equal. Otherwise, they are more or less different depending on the distribution of these parts. Instructions for using the diagram: 1. Plot the values of pH: 6,92 and PCO2: 100 mmHg (point A). 2. Estimate the corresponding pH value (point R) at the junction of the buffer line with the vertical line passing through the measured PCO2 of 100. 3. Estimate the value of the pH (B) or bn-eucapnic pHua, by applying the relation: pH euc (n) = pH (A) + pH (N) pH (R) = 6.92 + 7.28 7.08; pH euc(n) = 7,12 (Birth-related neonatal eucapnic pH). 4. Locate pH: 7.12 at PCO2: 53,8 mmHg (point B). 5. On the horizontal line passing through point B, eucapnic HCO3 is estimated at 16.8 mmol/L at the interception with the y-axis. 6. Estimate the value of Eucapnic Base Deficit (bn-eucapnic BD) by applying the relation: bn-eucapnic BD = (Normal HCO3 at birth) – (Eucapnic HCO3) where: Normal HCO3 at birth = 24,5; Eucapnic HCO3 at birth (point B) = 16,8 = 24,5–16,8; bn-eucapnic BD = 7,7 mmol/L (Eucapnic Base Deficit).
Birth-related neonatal eucapnic pH Normal baseline values at birth pH 7.28 PCO2 53.8 mmHg HCO3 24.5 mmol/L A case of a newborn umbilical artery blood gas Actual values to be entered (Excel spreadsheet) pH 6.92 PCO2 (mmHg) 100 Results as per described equations Expected HCO3 (According to actual PCO2) 29.1 mmol/L Actual HCO3 (According to HH equation) 20.0 mmol/L Calculated Eucapnic neonatal HCO3 16.8 mmol/L Calculated Eucapnic neonatal Base Deficit 7.7 mmol/L Calculated Birth-related neonatal pH 7.12 HH (Henderson-Hasselbalch) Fig. 3. Calculation of birth-related neonatal eucapnic pH with Excel. Instructions for using the Excel calculations: 1. Enter actual pH, PCO2 from the umbilical artery in the respective white boxes. 2. Press enter. 3. Read the calculated values in the Section 3.
the BD values were determined based only on a small cohort of 174 newborns and were grouped into three categories (8–12, 12–16, and > 16 mmol/L), with a loss of power in the search for a pertinent threshold value, which could have been set more specifically by the ROC curve created from continuous variables; the type of BD and the manufacturer and model of the blood gas analyzer were not indicated, which introduces uncertainty because of the variability of the results related to these parameters; in particular, it would have been necessary to take into account only cases with pH 7.00; this information is absent from the Low’s article, which studied only data on BD. The prevalence of combined pH 7.00 and BD 12 mmol/L is 4–15 times less frequent than the prevalence of BD 12 mmol/L alone, which suggests that the threshold value proposed by Low et al. is an overvalued marker of true NMA because of mediocre specificity; similarly, the absence of data on PCO2, with no specific information on how BD was calculated, eliminates consideration of any hypercapnic component, which is nearly always present and contributes to the high value of BD at birth. In addition, the criticisms mentioned above question whether BD is a pertinent marker of NMA and accord it no additional value over and above knowledge of the actual pH [18–20], much less the birth-related neonatal eucapnic pH [8].1 4. Discussion and conclusion It appears from the data that diagnosis of NMA is currently based on imprecise criteria, and that the results also vary depending on the analyzer used. We have emphasized this lack of consistency: the choice of one BD or the other as well as the choice of the analyzer used add to the potential lack of accuracy in clinical interpretation. Older [19] and more recent studies [20–23] discount any value of in vivo BD over and above knowledge of the pH, which they consider as the best marker of fetal status at birth, but their conclusions on pH value at birth address ‘‘total’’ acidity, because
362
C. Racinet et al. / Gyne´cologie Obste´trique & Fertilite´ 44 (2016) 357–362
they do not take into account the hypercapnic portion that contributes substantially to acidemia (information on PCO2 values is lacking in the majority of articles). Our goal is to obtain a reliable method of diagnosing NMA that would be a true instantaneous picture at time zero (T0) of the metabolic part of newborn acid–base status, to measure fetal response to labor, and to identify any potential abnormalities that may result from labor, because this knowledge may help identify term infants at risk of morbidity, or later may have a recognized medical-legal importance in case of CP [4]. It is important to underline that the infant is born in an acid– base state close to respiratory decompensation [8],1 which is normal and indicative of an unavoidable birth-related biochemical stress that most newborns can tolerate with no subsequent harm. This biochemical snapshot is indispensable for correctly interpreting the antepartum history of any neonatal distress. Newborn biochemical conditions are not taken into account in any of the available algorithms: they all refer to adult standards. This results in overestimation of BD, which—despite uncertainty related to the absence of consensus between manufacturers on the algorithms used—assigns a threshold of pathogenicity that was not calculated with reference to neonatal conditions. We believe that this fully warrants our reviewing the situation and our recommendations. We have considered the primary methods used to diagnose and quantify NMA that might affect the child in the future, and none of them appears to be satisfactory. Starting from the basic premise that pH is the universally acknowledged marker of acidemia, but is not specific because by it cannot specify whether it originates from a respiratory or metabolic cause, but still seems to be the best predictor of neonatal outcomes, we believe that the concept of birth-related neonatal eucapnic pHua best fulfills this need for specificity in a simple, objective, and precise way, resulting in BD estimation no longer being of practical interest. Based on our clinical experience, we confirm that birth-related neonatal eucapnic BD adds nothing of value over and above knowledge of the birth-related neonatal eucapnic pH because their correlation is nearly linear (r = 0.98).1 It can be calculated using two possible methods, at the user’s discretion: direct use of the Charles-Racinet diagram; or the Excel form to calculate the newborn’s eucapnic pH. This recommendation calls for all researchers in obstetrics and perinatal medicine to converge towards a redefinition of the pathogenic threshold of NMA. Pending results of additional studies, we estimate that a birthrelated neonatal eucapnic pH of umbilical artery blood < 7.11 is more specific than a pH < 7.0 to define severe NMA. Its presence is necessary to strongly support a position that fetal intrapartum hypoxia might be the root of neonatal encephalopathy and eventually cerebral palsy. Conversely, this level of acidemia is not sufficient to confirm the diagnosis of perinatal asphyxia, which must be based on accumulated evidence from clinical practice, laboratory tests, and brain imaging.
Disclosure of interest The authors declare that they have no competing interest.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.gyobfe.2016.04. 005.
References [1] Saling E. Das Kind im Bereich der Geburtshilfe. Stuttgart: Georg Thieme Verlag; 1966. [2] MacLennan A, for the International Task Force on Cerebral Palsy. A template for defining a causal relationship between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054–9. [3] The American College of Obstetricians and Gynecologists. Neonatal encephalopathy and neurologic outcome, second edition, executive summary. Obstet Gynecol 2014;123(4):896–901. [4] Racinet C, Hoffmann P. Perinatal asphyxia and cerebral palsy: medico-legal implications. Bull Acad Natl Med 2010;194(6):891–901. [5] Papille LA, Committee on fetus and newborn. Hypothermia and neonatal encephalopathy. Pediatrics 2014;133(6):1146–9. [6] MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: causes, pathways, and the role of genetic variants. Am J Obstet Gynecol 2015. http://dx.doi.org/10. 1016/j.ajog.2015.05.034. [7] CLSI. Blood gas and pH analysis and related measurements; approved guidelines, Second edition. CLSI document C46-A2, Wayne, PA: Clinical and Laboratory Standards Institute; 2009. [8] Racinet C, Richalet G, Corne C, et al. Diagnosis of neonatal metabolic acidosis by eucapnic pH determination. Gynecol Obstet Fertil 2013;43:485–92. [9] Ramin SM. Umbilical cord blood acid-base analysis at delivery; 2015, http:// www.update.com. [10] Schistig R, Grogono AW, Severinghaus JW. Human pCO2 and standard base excess compensation for acid-base imbalance. Crit Care Med 1998;26(7): 1173–9. [11] Davenport HW. ABC de l’e´quilibre biochimique acido-basique. Masson; 1973. [12] McIntyre KM, Lewis AJ. Textbook of advanced cardiac life support. In: Carveth SW, editor. American Heart Association. Dallas; 1983. [13] Eisenberg MS, Cummins RO, Ho MT. Code blue: cardiac arrest and resuscitation. Philadelphia: Saunders; 1987. [14] Blickstein I, Green T. Umbilical cord blood gases. Clin Perinatol 2007;3(3):451–9. [15] Henderson LJ. Concerning the relationship between the strength of acids and their capacity to preserve neutrality. Am J Physiol 1908;21:173–9. [16] Brackett NC, Cohen JJ, Schwartz WB. Carbon dioxide titration curve of normal man. Effect of increasing degrees of acute hypercapnia on acid-base equilibrium. N Engl J Med 1965;272(1):6–12. [17] Mokarami P, Wiberg N, Olofsson P. An overlooked aspect on metabolic acidosis at birth: blood gas analysers calculate base deficit differently. Acta Obstet Gynecol Scandin 2012;91:574–9. [18] Low JA, Lindsay BG, Derrick EJ. Threshold of metabolic acidosis associated with newborn complications. Am J Obstet Gynecol 1997;177(6):1391–4. [19] Schwartz WB, Relmann AS. A critique of the parameters used in the evaluation of acid-base disorders: whole blood buffer base and standard bicarbonate compared with blood pH and plasma bicarbonate concentration. N Engl J Med 1963;268–325:1382–8. [20] Knutzen L, Svirko E, Impey L. The significance of base deficit in acidemic term neonates. Am J Obstet Gynecol 2015. http://dx.doi.org/10.1016/j.ajog.2015. 03.051. [21] Georgieva A, Moulden M, Redman C. Umbilical cord gases in relation to the neonatal condition: the EveREst plot. Eur J Obstet Gynecol Reprod Biol 2013; 168:155–60. [22] Olofsson P. Determination of base excess in umbilical cord blood at birth: accessory or J excess? Am J Obstet Gynecol 2015;213:259–61. [23] Cahill AG. Umbilical artery pH and base deficit in obstetrics. Am J Obstet Gynecol 2015;213(3):257–8.