Hidden acidosis: an explanation of acid base and lactate changes occurring in umbilical cord blood after delayed sampling

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1 DOI: / General obstetrics Hidden acidosis: an explanation of acid base and lactate changes occurring in umbilical cord blood after delayed sampling P Mokarami, a N Wiberg, b P Olofsson a a Institution of Clinical Sciences, Department of Obstetrics and Gynaecology, Skane University Hospital, Lund University, Malm o, Sweden b Institution of Clinical Sciences, Department of Obstetrics and Gynaecology, Skane University Hospital, Lund University, Lund, Sweden Correspondence: Dr P Mokarami, Department of Neurology, Skane University Hospital, S Malm o, Sweden. parisa.mokarami@med.lu.se Accepted 25 December Published Online 10 April Objective To explore the hidden acidosis phenomenon, in which there is a washout of acid metabolites from peripheral tissues in both vaginal and abdominal deliveries, by investigating temporal umbilical cord blood acid base and lactate changes after delayed blood sampling. Design Prospective comparative study. Setting University hospital. Sample Umbilical cord blood from 124 newborns. Methods Arterial and venous cord blood was sampled immediately after birth (T 0 ), and at 45 seconds (T 45 ), from unclamped cords with intact pulsations taken from 66 neonates born vaginally and 58 neonates born via planned caesarean section at weeks of gestation. Non-parametric tests were used for statistical comparisons, with P < 0.05 considered significant. Main outcome measures Temporal changes (T 0 T 45 )in umbilical cord blood ph, the partial pressure of CO 2 (P CO2 ) and O 2 (P O2 ), and in the concentrations of lactate, haematocrit (Hct), and haemoglobin (Hb). Results In both groups all arterial parameters, except for P CO2 in the group delivered by caesarean section, changed significantly (ph decreased and the other variables increased). There were corresponding changes in venous acid base parameters. When temporal arterial changes were compared between the two groups, the decrease in ph and increase in P CO2 were more pronounced in the group delivered vaginally. Neonates born vaginally had significantly lower ph and higher lactate, Hct, and Hb concentrations at T 0 and T 45 in both the artery and the vein. At T 45, arterial P CO2 and P O2 levels in the group delivered vaginally were also significantly higher. Conclusions Delayed umbilical cord sampling affected the acid base balance and haematological parameters after both vaginal and caesarean deliveries, although the effect was more marked in the group delivered vaginally. The hidden acidosis phenomenon explains this change towards acidaemia and lactaemia. Arterial haemoconcentration was not the explanation of the acid base drift. Keywords Blood gases, delayed sampling, hidden acidosis, lactate, ph, umbilical cord blood. Please cite this paper as: Mokarami P, Wiberg N, Olofsson P. Hidden acidosis: an explanation of acid base and lactate changes occurring in umbilical cord blood after delayed sampling. BJOG 2013;120: Introduction Delayed umbilical cord clamping at vaginal delivery results in a decrease in ph and base excess (BE), and an increase in the partial pressure of O 2 (P O2 ), the partial pressure of CO 2 (P CO2 ), and lactate concentration in the umbilical artery. 1 3 These changes towards acidaemia and lactaemia can be explained by the hidden acidosis phenomenon. During uterine contractions, the fetal circulation is centralised at the expense of perfusion of low-priority organs and peripheral tissues, 4 with a build-up of acid metabolites peripherally. When the newborn starts to breathe sufficiently the peripheral perfusion is restored and the trapped metabolites surge into the central circulation and, after some seconds, can be detected in umbilical cord blood. 3 The phenomenon has also been demonstrated in animal studies at the restoration of the peripheral circulation after provoked hypovolaemic shock. 5,6 Soon after volume expansion has started, a rapid drop in ph and increase in lactate concentration are seen. In animal limb tourniquet ischaemia reperfusion experiments, a similar phenomenon is seen during reperfusion. 7,8 996 ª 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2013 RCOG

2 Acid base changes after delayed umbilical cord sampling Our hypothesis was that hidden acidosis occurs in the newborn (Figure 1). As newborns after planned caesarean delivery (caesarean section) seldom show acrocyanosis, we hypothesized that hidden acidosis would be most pronounced after vaginal delivery. The opening of peripheral vascular beds might result in changes in haemoconcentration in the cord blood, and therefore we investigated temporal changes not only in blood gases and lactate concentration, but also in haematocrit (Hct) and total haemoglobin (cthb) concentration. Methods Arterial and venous umbilical cord blood were sampled from 124 newborn singletons immediately after birth (T 0 ), and again at 45 seconds (T 45 ), from unclamped umbilical cords with intact pulsations. The women s length of gestation was determined at an early second trimester ultrasound, and all were found to be at weeks of gestation. Of the 124 neonates, 66 were born vaginally in cephalic presentation and 58 were delivered by planned caesarean section. The newborns included in the study were expected to have no need of immediate rescue procedures that would interfere with the delayed cord clamping. The women who delivered vaginally were included in a previously published study. 3 Women in the group delivering vaginally were recruited to the study at admission to the labour and delivery ward, and women in the group delivering by caesarean section were asked to participate a few hours before the operation. Lactate ph Labour Birth First few minutes after birth Postpartum Figure 1. Schematic illustration of the hidden acidosis phenomenon. The grey box represents the first few minutes after birth, when a steep decrease in ph and an increase in lactate concentration are first seen, according to the hypothesis. All caesarean sections were planned and the indications were breech presentation or maternal request. Women undergoing spinal anaesthesia were placed in supine position, tilted 15º to the left, and received prehydration. Bupivacaine and fentanyl were used for spinal anaesthesia. Simultaneously, an intravenous infusion of ephedrine (50 mg in 500 ml of sodium chloride solution) was started and adjusted with the aim to maintain a mean arterial pressure within 25% of its initial value. Women undergoing general anaesthesia also received prehydration. Drugs administered at general anaesthesia were thiopental, suxamethonium, and sevoflorane. After cord clamping, all women received oxytocin. During cord blood sampling, babies delivered vaginally were placed on the abdomen of the mother, whereas babies born by caesarean section were placed between the mother s legs and kept warm under a towel. The procedure was meticulously prepared, and the samples were taken and analysed by one of the authors (N.W.), who was not involved in the obstetric care of the women. Blood was drawn first from the cord artery and then, within a few seconds, and at the same location on the cord, from the vein. The next pair of samples were taken 45 seconds later, and the needle punctures were made a few millimetres closer to the placenta. A 0.6- or 0.9-mm needle was used, and the samples were collected in 2 ml pre-heparinised plastic syringes. A minimum of 0.5 ml of blood from each vessel was used for analysis in the blood gas analyser (ABL735; Radiometer A/S, Copenhagen, Denmark). All samples were analysed within 15 min, in chronological order. The radiometer analyser works by measuring ph and P CO2 by potentiometry, P O2 and lactate by amperometry, and cthb by spectrophotometry. cthb includes deoxy-, oxy-, carboxy-, and methemoglobin. Hct is available as a derived parameter, calculated according to the formula: Hct = cthb The analyser was operated in an accredited laboratory (Laboratory Medicine Skane, Clinical Chemistry, Lund and Malm o). All women in labour were monitored with cardiotocography during the second stage of labour. Small for gestational age (SGA) was defined as a birthweight below 2 SD from the gestational age-adjusted mean value, appropriate for gestational age (AGA) was defined as a birthweight within the mean 2 SD range, and large for gestational age (LGA) was defined as a birthweight above the mean + 2 SD. 9 Statistical analyses The Mann Whitney U test was used for comparison of continuous parameters between groups, and the Wilcoxon signed-ranks matched-pairs test was used for longitudinal comparisons. Values are reported as median and range or mean with 95% confidence interval (95% CI), as appropri- ª 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2013 RCOG 997

3 Mokarami et al. ate. A two-tailed P < 0.05 was considered to be statistically significant. Statistical analyses were performed with the aid of STATVIEW â (SAS Institute, Cary, NC, USA). As umbilical cord blood gas and lactate values are dependent on gestational age, comparisons between groups delivered vaginally and by caesarean section were also performed using cord arterial ph adjusted to a gestational age of 280 days, according to the regression coefficient per day of gestational age. 10 Results The characteristics of the study population are shown in Table 1. Gestational age at delivery was significantly lower, and Apgar score (AS) at 1 minute was significantly higher, Table 1. Characteristics of the study population (n = 124) Vaginal delivery (n = 66) Caesarean delivery (n = 58) Maternal characteristics Duration of second 41 (5 234) stage of labour (min) Duration of 24 (4 90) pushing (min) Induction of labour 5 (7.6%) Instrumental birth 9 (13.6%) Drugs administered Pethidin 6 (9.1%) Oxytocin 31 (47.0%) Nitrous oxide 50 (75.8%) Anaesthesia Epidural 15 (22.7%) Spinal 52 (90.0%) General 6 (10.0%) Newborn characteristics Gestational age 40+0 ( ) 38+4 ( ) (weeks)* Birthweight (g) 3595 ( ) 3535 ( ) SGA 3 (4.5%) 0 AGA 62 (93.9%) 47 (81.0%) LGA 1 (1.5%) 11 (19.0%) Apgar score 1 minute* 9 (4 10) 9 (8 10) 5 minute 10 (8 10) 10 (7 10) 10 minute 10 (9 10) 10 (9 10) Cardiotocography Intermediate 13 (19.7%) Pathological 3 (4.5%) *The difference in gestational age and Apgar score at 1 minute was statistically significant (Mann Whitney U test; P 0.03) between the two groups. Values are median (range) or number of cases (%). in the group delivered by caesarean section. One newborn had an AS of 4 at 1 minute, but otherwise all scores at 1 minute were 8 and at 5 and 10 minutes were 9. Serial blood samples were taken in all 124 cases, but four analyses at T 0 (one vaginal delivery and three caesarean sections) and ten analyses at T 45 (six vaginal deliveries and four caesarean sections) failed because of instrument failure or blood clotting. For each parameter, only cases with valid measurements obtained at both T 0 and T 45 were included in the statistical analyses. Data for arterial and venous acid base and haematological measurements are shown in Tables 2 and 3. Longitudinal changes between T 0 and T 45 Longitudinal changes in arterial blood gases, and in lactate, Hct, and cthb concentrations are illustrated in Figure 2. With the exception of P CO2 in the group delivered by caesarean section (P = 0.4), all blood gas and lactate parameters changed significantly. Acid base changes in venous blood were in the same directions as in arterial blood, although in the group delivered vaginally only the increase in lactate was significant (P = 0.001), and in the group delivered by caesarean section only the decrease in ph (P = 0.03) and increase in lactate (P < ) were significant (not shown in Figure 2). Hct and cthb increased significantly in the artery in both groups, whereas venous values decreased significantly in the group delivered vaginally (P 0.04), and remained unchanged in the group delivered by caesarean section (P 0.2). Vaginal versus caesarean delivery When longitudinal arterial ph, lactate, and P CO2 changes were compared between groups, the decrease in ph and increase in P CO2 were found to be significantly greater in the group delivered vaginally (P 0.04), but there was no statistically significant difference between the groups regarding the increase in lactate concentration from T 0 to T 45 (P = 0.9). Adjusting ph for the difference in gestational age between the groups did not change the results. Neonates born by vaginal delivery had significantly lower ph values and higher lactate, Hct, and cthb concentrations at T 0 and T 45, in both the artery and the vein, compared with neonates delivered by caesarean section (Tables 1 and 2). At T 45, P CO2 and P O2 in the artery in the group delivered vaginally were also significantly higher. Spinal versus general anaesthesia Neonates in the group delivered by caesarean section with spinal anaesthesia (n = 52) had lower ph values, and higher P CO2 and lactate concentration at T 0, compared with neonates in the general anaesthesia group (n = 6), but only the difference in lactate concentration was statistically significant (P = 0.03). 998 ª 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2013 RCOG

4 Acid base changes after delayed umbilical cord sampling Table 2. Arterial blood gas, lactate, haematocrit (Hct), and total haemoglobin (cthb) concentration median (range) values obtained immediately after birth (time T 0 ), and again 45 seconds later (T 45 ), in unclamped umbilical cords with intact pulsations after vaginal delivery and caesarean delivery Vaginal Caesarean T 0 T 45 Vaginal versus caesarean Vaginal Caesarean Vaginal Caesarean Significance of difference (P) n n Median (range) Median (range) Median (range) Median (range) T 0 T 45 ph ( ) ( ) ( ) ( ) < < P CO2 (kpa) ( ) 7.30 ( ) 7.87 ( ) 7.57 ( ) P O2 (kpa) ( ) 1.99 ( ) 2.66 ( ) 2.28 ( ) Lactate ( ) 1.8 ( ) 5.5 ( ) 2.2 ( ) < < (mmol/l) Hct ( ) ( ) ( ) ( ) < < cthb (g/l) ( ) 148 ( ) 168 ( ) 151 ( ) < < The Mann Whitney U test was used for group comparisons. Table 3. Venous blood gas, lactate, haematocrit (Hct), and total haemoglobin (cthb) concentration median (range) values obtained immediately after birth (time T 0 ), and again 45 seconds later (T 45 ), in unclamped umbilical cords with intact pulsations after vaginal delivery and caesarean delivery Vaginal Caesarean T 0 T 45 Vaginal versus caesarean Vaginal Caesarean Vaginal Caesarean Significance of difference (P) n n Median (range) Median (range) Median (range) Median (range) T 0 T 45 ph ( ) ( ) ( ) ( ) < < P CO2 (kpa) ( ) 5.78 ( ) 5.42 ( ) 5.77 ( ) P O2 (kpa) ( ) 3.46 ( ) 3.68 ( ) 3.46 ( ) Lactate ( ) 1.5 ( ) 4.7 ( ) 1.6 ( ) < < (mmol/l) Hct ( ) ( ) ( ) ( ) < < cthb (g/l) ( ) 148 ( ) 168 ( ) 149 ( ) < < The Mann Whitney U test was used for group comparisons. Discussion This study showed significant changes in acid base and haematological parameters in umbilical cord blood when sampling was delayed by 45 seconds, with these changes being more marked for ph and P CO2 in the group delivered vaginally. The similar increases in lactate concentration in the two groups indicate that considerable hidden acidosis was also present in the group delivered by caesarean section. The lack of change in venous P CO2 indicates that placental perfusion and gas exchange were maintained during the first 45 seconds, after both vaginal and abdominal deliveries. Thus, the temporal increase in arterial P CO2 must be a result of CO 2 inflow from the newborn, and not from the placenta, or of an accumulation of CO 2 in the blood circuit. Moreover, the significant increase in P O2 indicates the rapid establishment of functional pulmonary ventilation, which would result in the escape of CO 2 and in a lowering of P CO2 unless there was a considerable continuing fetal ª 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2013 RCOG 999

5 Mokarami et al. Vaginal delivery Caesarean delivery 7,32 7,30 * 8,6 8,4 *** ph 7,28 7,26 7,24 7,22 P CO2 (kpa) 8,2 8,0 7,8 7,6 7,4 NS 7,20 7,2 7,18 7,0 Hct (%) P O2 (kpa) 2,9 2,8 2,7 2,6 2,5 2,4 2,3 2,2 2,1 2,0 1, *** 6,5 6,0 5,5 * 5,0 4,5 4,0 3,5 3,0 2,5 2,0 1, * T 0 T 45 T 0 T 45 cthb (g/l) Lactate (mmol/l) ** Figure 2. Measurements of arterial umbilical cord blood gases, and concentrations of lactate, haematocrit (Hct), and total haemoglobin (cthb) obtained immediately after birth (T 0 ), and then again 45 seconds later (T 45 ), in unclamped umbilical cords with intact pulsations after vaginal and caesarean deliveries. The figure shows mean values and 95% confidence intervals. The Wilcoxon signed-ranks test was used to compare values at T 0 and T 45 : *P < 0.05; **P < 0.01; ***P < 0.001; P < ; NS, not significant. contribution. As it is unlikely that the CO 2 contribution was a result of a sudden rise in neonatal metabolism, a washout of CO 2 from peripheral tissues is the most plausible explanation for this finding. After 45 seconds, arterial blood showed a small but significant haemoconcentration and venous blood showed a haemodilution in the group delivered vaginally. A relevant question is, then, whether these concentration changes could have influenced the temporal acid base and lactate changes. According to Stewart s physicochemical concept, a change towards alkalosis should occur during haemoconcentration, as dehydration results in a higher [OH ]. 13 In the present study, the changes in haemoconcentration paralleled changes towards acidosis in the artery, indicating that the temporal acetous change was not a result of the haemoconcentration. The study was performed in cases in which minimal neonatal assistance was expected to be required, and only two newborns in the group delivered vaginally and none in the group delivered by caesarean section had an umbilical artery ph <7.10 in the first samples. Both these newborns had a pathological cardiotocogram. One newborn was vigorous immediately, with 1-, 5-, and 10-minute AS scores of 8, 9, and 10, respectively, whereas the other was initially moderately depressed, and had corresponding AS scores of 4, 8, and 10. Interestingly, in the newborn with a1-minute AS score of 8, the blood gas and lactate values deteriorated further by 45 seconds of age: ph changed 1000 ª 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2013 RCOG

6 Acid base changes after delayed umbilical cord sampling from 7.06 to 7.02; P CO2 changed from 10.0 to 10.5 kpa; BE changed from 12.7 to 15.3 mmol/l; and lactate changed from 12.2 to 12.9 mmol/l. In the depressed newborn, the values remained mainly unchanged: ph was 7.01 at both time points, P CO2 changed from 11.2 to 11.8 kpa, BE changed from 14.9 to 14.4 mmol/l, and lactate concentration was 13.3 mmol/l at both time points. These observations further support the hypothesis that hidden acidosis is a physiological phenomenon, occurring in newborns with a rapidly established circulation. It was not expected that the hidden acidosis phenomenon would occur so clearly in neonates born by caesarean section, as these neonates were not exposed to hypoxic stress by uterine labour contractions; however, it is well known that fetal/neonatal effects occur during regional anaesthesia for planned caesarean section. Despite precautions in terms of prehydration and vasopressor administration, spinal anaesthesia in particular is frequently associated with maternal hypotension and lower umbilical cord arterial ph Vasopressor substances can cross the placenta, 14,19 22 and the maternal supine wedged position during caesarean section frequently results in fetal heart rate changes as a result of occult aortocaval compression. 23 Doppler ultrasound has shown uteroplacental circulation to be affected after spinal blockade. 16,19,24,25 In concordance with these findings, the present study showed higher lactate values in the spinal anaesthesia group than in the general anaesthesia group. It seems that, even with the most modern techniques for spinal anaesthesia, this side effect is difficult to avoid. 26 An interesting finding was that at T 0, P O2 was similar in the groups delivered vaginally and by caesarean sections, but at T 45 it was significantly higher in the group delivered vaginally, as a result of a steeper increase. This demonstrates the protective role of vaginal delivery, with the more effective release of lung surfactant and alveolar expansion, absorption of pulmonary fluid, and rapid circulatory transition to extra-uterine life. At 45 seconds, alveolar clearance of fluid and alveolar expansion are the most important processes. 27 Strengths and weaknesses Repeated blood sampling performed by an experienced obstetrician and analyses within 15 minutes in chronological order minimised the sampling and measurement errors. The inclusion of only newborns presumed to be vigorous makes extrapolation to asphyxiated newborns problematic. Interpretation Even small blood gas changes can affect the interpretation of a newborn s status and lead to a false diagnosis of acidosis, as we have previously demonstrated. 3 Hypoxic neonates are expected to have a more pronounced circulatory centralisation and hidden acidosis, and, as they already have lower ph levels, an additional decrease is more likely to tip them below the lower limit of the reference interval. It would be difficult to create reliable normal reference intervals taking late cord blood sampling into account, because, as discussed above, vigorous newborns would show changes towards acidaemia, lactaemia, and hypercapnia, whereas depressed newborns would show small changes. Conclusion Delayed cord blood sampling with intact pulsations affected umbilical acid base values and haematological parameters following both vaginal and caesarean deliveries. A change towards acidaemia and lactaemia can be explained by the hidden acidosis phenomenon. A small degree of haemoconcentration occurred in arterial blood, and haemodilution occurred in venous blood, but these changes could not explain the change in acid base status. Disclosure of interests The authors state explicitly that there are no conflicts of interest in connection with this article. Contribution to authorship PM was involved in the conception and planning of the study, analysis of the data, and writing of the article; NW was involved in the conception, planning, and carrying out of the study, analysis of the data, and writing of the article. PO was involved in the conception and planning of the study, analysis of the data, and writing of the article. Details of ethics approval The study was approved on 24 February 2006 by the Central Ethical Review Board, Stockholm, Sweden (reference number O ), and all the women gave their informed oral and written consent to participate in the study. Funding This study was supported by grants from Region Skane and the Medical Faculty at Lund University (ALF). The funding sources had no role in the writing of the article or in the decision to submit it for publication. Acknowledgement None. & References 1 Lievaart M, de Jong PA. Acid-base equilibrium in umbilical cord blood and time of cord clamping. Obstet Gynecol 1984;63: Ullrich JR, Ackerman BD. Changes in umbilical artery blood gas values with the onset of respiration. Biol Neonate 1972;20: ª 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2013 RCOG 1001

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