Introduction: Blood lactate levels in neonates with hypoxic-ischemic encephalopathy (HIE) vary, and their impact on neurodevelopmental outcome is unclear. We assessed blood lactate course over time in neonates with HIE during therapeutic hypothermia (TH) and investigated if blood lactate values were associated with neurodevelopmental outcome at 2 years of age. Methods: This is a retrospective cohort study of neonates with HIE born between 2013 and 2019, treated at the University Children’s Hospital Zurich. We recorded blood lactate values over time and calculated time until lactate was ≤2 mmol/L. Neurodevelopmental outcome was assessed at 18–24 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and categorized as favorable or unfavorable. We investigated associations between blood lactate values and outcome using logistic regression and adjusted for Sarnat stage. Results: 33/45 neonates (69%) had a favorable and 14 (31%) an unfavorable neurodevelopmental outcome. Mean initial lactate values were lower in the favorable (13.9 mmol/L, standard deviation [SD]: 2.9) versus unfavorable group (17.1 mmol/L, SD 3.2; p = 0.002). Higher initial and maximal blood lactate levels were associated with unfavorable outcome, also when adjusted for Sarnat stage (adjusted odds ratio [aOR]: 1.37, 95% CI: 1.01–1.88, p = 0.046, and aOR: 1.35, 95% CI: 1.01–1.81, p = 0.041, respectively). Conclusion: In neonates with HIE receiving TH, initial and maximal blood lactate levels were associated with neurodevelopmental outcome at 18–24 months of age, also when adjusted for Sarnat stage. Further investigations to analyze blood lactate as a biomarker for prognostic value are needed.

Hypoxic-ischemic encephalopathy (HIE) is a common cause for admission to neonatal intensive care units (NICUs) among term or near-term neonates after birth, affecting 1–8/1,000 live births in high-income countries [1, 2]. HIE is responsible for most of perinatally acquired brain damage, including death, cerebral palsy, motor and cognitive developmental deficits, epilepsy, visual and hearing impairments, and limitations in social interaction [1‒4]. Therapeutic hypothermia (TH) is the only proven effective neuroprotective therapy for moderate and severe HIE [5, 6]. However, there remains a non-negligible risk of permanent neurological impairment or death due to HIE [5]. Predicting neurodevelopmental outcome in neonates with HIE remains a major challenge.

Currently, the risk of neurological damage is assessed based on clinical course and on results of neuromonitoring and neuroimaging tools [7]. In research, the prognostic value of body-fluid biomarkers (neuron-specific enolase, ubiquitin carboxyterminal hydrolase L1, brain-derived neurotrophic factor, Tau protein, inflammatory cytokines/chemokines) has been investigated in the context of HIE, and an association with the severity of neurological damage was reported [6, 8]. However, the determination of these parameters is not yet commonly used to predict outcomes. Larger studies are necessary to proof feasibility and clinical benefit. In contrast, blood lactate is a biomarker usually available bedside in NICUs, easy and quick to measure. Lactate is produced during anaerobic glycolysis under hypoxic conditions, also formed in brain tissue and can be transported across the blood-brain barrier [9, 10].

In this context, analysis of different umbilical cord biomarkers in asphyxiated neonates revealed that increased blood lactate contributes more to the prediction of HIE development than other biomarkers, and slow blood lactate clearance has been associated with an increased incidence of cerebral seizures and more severe encephalopathy during TH [11, 12]. Thus, blood lactate may help assess the extent of cerebral hypoxia and cerebral damage. However, the studies mentioned above only assessed short-term outcome (first 24–72 h of life and at discharge). We aimed to assess blood lactate course over time and to investigate the association between blood lactate levels during the first days of life and neurodevelopmental outcome at 18–24 months of age in neonates with moderate and severe HIE receiving TH.

Study Design, Setting, and Population

This is a single-center retrospective cohort study of prospectively collected data of term and near-term neonates (≥35 0/7 weeks of gestational age) with HIE from the Swiss National Asphyxia and Cooling Register treated at the University Children’s Hospital Zurich, Switzerland, between 2013–2019 [13]. TH (target core temperature: 33–34°C) was initiated according to Azzopardi et al. [4] within the first 6 h of life and maintained for 72 h. Neonates had to fulfill the following criteria for TH:

  • Apgar score ≤5 at 10 min or need for resuscitation within 60 min after birth, acidosis (defined as umbilical cord, arterial, or capillary pH of <7.00 or base deficit of ≥16 mmol/L or lactate ≥12 mmol/L)

  • additionally seizures or moderate to severe encephalopathy (according to Sarnat stage 2 or 3) [14]

Rewarming with 0.2–0.5°C/h was performed until a core temperature of 36.5°C. Sarnat staging was performed by a senior neonatal consultant on admission and at 24, 48, 72, and 96 h of life [14].

Inclusion criteria were registered neonatal and TH data of neonates with moderate or severe HIE according to Sarnat staging (with informed parental consent) and available results of the neurodevelopmental follow-up (NDFU) assessment at 18–24 months of age, if alive. Demographic, perinatal, and clinical characteristics were collected prospectively in the register [13]. Data on blood lactate values and NDFU were collected retrospectively by review of medical charts.

Blood Lactate Values

Blood samples were taken routinely according to the national guidelines of the register during the first 96 h of life. ABL825 FLEX (Radiometer, Thalwil, Switzerland) was used for blood gas, lactate, and glucose analyses, all done at 37°C.

Initial blood lactate was defined as the first value within 60 min of life taken from the umbilical artery, umbilical vein, or capillary. Maximal lactate levels were defined as the highest blood lactate value within 72 h of life or until death. Hyperlactatemia was defined as a lactate value >2 mmol/L, according to the reference values given by the ABL825 FLEX, Radiometer. Time to the normal lactate level was defined as time in hours until the lactate level was ≤2 mmol/L.

NDFU Assessment

At the age of 18–24 months, NDFU was performed by experienced developmental pediatricians. Bayley Scales of Infant and Toddler Development, Third Edition III (BSID-III), was used to assess the neurodevelopmental status of survivors [15]. It provides three main composite scores: cognitive (CCS), language (LCS), and motor composite score (MCS) with a mean score of 100 and a standard deviation (SD) of ±15 [15]. Additionally, a full neurological examination, hearing and visual assessment was performed. Cerebral palsy was graded according to the Gross Motor Function Classification System (GMFCS) of Palisano et al. for children aged ≤2 years [16, 17].

The neurodevelopmental outcome was categorized as favorable or unfavorable based on previously published randomized controlled trials, investigating the neurodevelopmental outcome at 18–24 months [4, 5, 18]. Death was categorized as an unfavorable outcome, as indicated below.

Unfavorable outcome was defined as follows:

  • 1.

    death before 2 years of age

  • 2.

    severe disability, which was defined as any of the following: a CCS or LCS (BSID-III) more than 2 SD below the mean score (i.e., < 70), a GMFCS grade of level 3–5, hearing impairment (inability to follow commands despite amplification) or blindness

  • 3.

    moderate disability, defined as a CCS or LCS of 1–2 SDs below the mean score (i.e., 70–84) in addition to one or more of the following: GMFCS grade of level 2, hearing impairment (hearing deficit with the ability to follow commands after amplification), or persistent seizure disorder

Favorable neurodevelopmental outcome was defined as follows:

  • 1.

    mild disability, defined as CCS or LCS of 70–84 alone or CCS or LCS ≥85 and a GMFCS level 1 or 2, seizure disorder (without anti-epileptic medication), or hearing deficit with ability to follow commands with amplification

  • 2.

    the absence of any of the above

Reasons for death during the neonatal period were categorized as follows:

  • 1.

    death despite full range of intensive care support (e.g., maximal catecholamine therapy, maximal invasive ventilation)

  • 2.

    anticipated poor neurological outcome according to clinical findings (no protective reflexes, no neurological improvement), electroencephalography with burst suppression or flat trace ≥48 h after birth, or therapy-refractory seizure equivalents and/or MRI findings with severe hypoxic-ischemic damage. Lactate or blood gas results did not influence clinical decision for redirection of care.

Statistical Analysis

To describe population characteristics, we summarized categorical variables as percentages and continuous variables as mean (SD) if normally distributed and median (interquartile range) if non-normally distributed. We compared differences between groups (Sarnat stages 2 and 3; favorable and unfavorable outcome), using the χ2 test for categorical variables, t test for continuous normally distributed variables, and Wilcoxon for continuous non-normally distributed variables. To study the association of initial blood lactate levels and maximal blood lactate levels with unfavorable versus favorable outcome, we used logistic regression and adjusted for Sarnat stage 3 versus 2 as proxy for severity. We did not impute missing values and excluded participants with missing values.

Data were analyzed with Stata 17 (StataCorp), and graphs were done using Stata 17 and Microsoft Excel (2016 MSO Version 2208). We followed STROBE reporting guidelines [19].

Study Participants

Out of 63 neonates who received TH at the University Children’s Hospital Zurich, 45 (71%) were included (Fig. 1). Among these, 25 (56%) were female and 27 (60%) had an initial Sarnat stage 2. Demographic characteristics of the study population are shown in Table 1. Characteristics of neonates excluded from the study are presented in the online supplementary Table S1 (for all online suppl. material, see https://doi.org/10.1159/000538879).

Fig. 1.

Flowchart of the study population of neonates with HIE who received TH. Definitions: TH according to guidelines of Azzopardi et al. [4]. HIE, hypoxic-ischemic encephalopathy; TH, therapeutic hypothermia; NDFU, neurodevelopmental follow-up; ECMO, extracorporeal membrane oxygenation.

Fig. 1.

Flowchart of the study population of neonates with HIE who received TH. Definitions: TH according to guidelines of Azzopardi et al. [4]. HIE, hypoxic-ischemic encephalopathy; TH, therapeutic hypothermia; NDFU, neurodevelopmental follow-up; ECMO, extracorporeal membrane oxygenation.

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Table 1.

Characteristics of neonates with HIE by Sarnat stage and neurodevelopmental outcome (N = 45)

Total (N = 45)Sarnat 2 (N = 27)Sarnat 3 (N = 18)p valueFavorable outcome (N = 31)Unfavorable outcome (N = 14)p value
Sociodemographic characteristics 
Sex, n (%) 
 Female 25 (56) 16 (59) 9 (50) 0.54 19 (61) 6 (43) 0.25 
 Male 20 (44) 11 (41) 9 (50)  12 (39) 8 (57)  
Gestational age, median (IQR), days 280 (274, 288) 285 (274, 290) 280 (277, 285) 0.72 280 (271, 290) 281 (280, 288) 0.57 
SES, median (IQR) 3.5 (2.0, 5.5) 3.0 (2.0, 4.0) 4.5 (3.5, 6.0) 0.088 3.0 (2.0, 5.0) 6.0 (6.0, 6.0) 0.24 
Maternal age, mean (SD), years 33.1 (5.1) 33.6 (3.8) 32.3 (6.7) 0.41 32.9 (4.7) 33.4 (6.3) 0.76 
Outborn, n (%) 45 (100) 27 (100) 18 (100)  31 (100) 14 (100)  
Clinical characteristics 
Cesarean section 22 (49) 14 (52) 8 (44) 0.63 13 (42) 9 (64) 0.16 
Birth weight, mean (SD), g 3,264 (471) 3,294 (520) 3,219 (396) 0.61 3,226 (505) 3,347 (389) 0.43 
Head circumference, mean (SD), cm 35.4 (1.7) 35.4 (1.7) 35.5 (1.8) 0.81 35.4 (1.7) 35.5 (2.0) 0.87 
Apgar 
 1 min, median (IQR) 1 (0, 3) 1 (0, 3) 0 (0, 2) 0.12 1 (0, 4) 0 (0, 1) 0.003 
 5 min, median (IQR) 3 (1, 5) 4 (2, 5) 2 (1, 4) 0.11 4 (2, 5) 1 (0, 4) 0.016 
 10 min, median (IQR) 3 (2, 6) 4 (2, 6) 3 (2, 4) 0.066 4 (2, 6) 2 (1, 4) 0.036 
Prolonged resuscitation (>10 min), n (%) 29 (64) 14 (52) 15 (83) 0.031 18 (58) 11 (79) 0.18 
Arterial cord pH, median (IQR) 7.0 (6.8, 7.1) 7.0 (6.9, 7.1) 6.9 (6.8, 7.1) 0.24 7.0 (6.9, 7.1) 6.8 (6.5, 7.0) 0.033 
Lowest pH, mean (SD) 6.8 (0.2) 6.9 (0.1) 6.7 (0.1) 0.007 6.9 (0.1) 6.7 (0.1) 0.002 
Lowest base excess, median (IQR), mmol/L 19.3 (16.0, 24.4) 19.0 (14.0, 22.0) 24.0 (19.0, 28.5) 0.006 19.0 (15.0, 22.0) 25.0 (19.3, 28.5) <0.001 
Lowest bicarbonate, mean (SD), mmol/L 12.7 (4.8) 14.3 (3.9) 10.3 (5.0) 0.005 14.1 (3.8) 9.7 (5.4) 0.003 
Lowest pCO2 values, median (IQR), kPa 4.1 (3.9, 4.3) 4.1 (3.9, 4.2) 4.0 (3.8, 4.4) 0.91 4.1 (3.9, 4.3) 4.0 (3.7, 4.2) 0.31 
Highest pO2 values, median (IQR), kPa 20.2 (14.8, 32.7) 17.9 (12.9, 28.3) 22.0 (15.8, 36.8) 0.18 19.6 (15.2, 31.4) 21.2 (13.7, 40.8) 0.83 
pO2 values at admission, median (IQR), kPa 7.3 (5.7, 9.9) 7.1 (5.4, 10.1) 7.8 (5.7, 9.9) 0.26 6.8 (5.4, 9.6) 8.0 (6.9, 10.1) 0.095 
Hyperoxia (pO2 >13.3 kPa) at admission, n (%) 8 (18) 4 (15) 4 (22) 0.52 5 (16) 3 (21) 0.67 
Initial Sarnat score, n (%) 
 2 27 (60)    23 (74) 4 (29) 0.004 
 3 18 (40)    8 (26) 10 (71)  
Hypoglycemia, n (%) 6 (13) 3 (11) 3 (17) 0.59 3 (10) 3 (21) 0.28 
Seizures, n (%) 16 (36) 6 (22) 10 (56) 0.022 5 (16) 11 (7%) <0.001 
Death before discharge, n (%) 13 (29) 3 (11) 10 (56) 0.001 0 (0) 13 (93) <0.001 
Total (N = 45)Sarnat 2 (N = 27)Sarnat 3 (N = 18)p valueFavorable outcome (N = 31)Unfavorable outcome (N = 14)p value
Sociodemographic characteristics 
Sex, n (%) 
 Female 25 (56) 16 (59) 9 (50) 0.54 19 (61) 6 (43) 0.25 
 Male 20 (44) 11 (41) 9 (50)  12 (39) 8 (57)  
Gestational age, median (IQR), days 280 (274, 288) 285 (274, 290) 280 (277, 285) 0.72 280 (271, 290) 281 (280, 288) 0.57 
SES, median (IQR) 3.5 (2.0, 5.5) 3.0 (2.0, 4.0) 4.5 (3.5, 6.0) 0.088 3.0 (2.0, 5.0) 6.0 (6.0, 6.0) 0.24 
Maternal age, mean (SD), years 33.1 (5.1) 33.6 (3.8) 32.3 (6.7) 0.41 32.9 (4.7) 33.4 (6.3) 0.76 
Outborn, n (%) 45 (100) 27 (100) 18 (100)  31 (100) 14 (100)  
Clinical characteristics 
Cesarean section 22 (49) 14 (52) 8 (44) 0.63 13 (42) 9 (64) 0.16 
Birth weight, mean (SD), g 3,264 (471) 3,294 (520) 3,219 (396) 0.61 3,226 (505) 3,347 (389) 0.43 
Head circumference, mean (SD), cm 35.4 (1.7) 35.4 (1.7) 35.5 (1.8) 0.81 35.4 (1.7) 35.5 (2.0) 0.87 
Apgar 
 1 min, median (IQR) 1 (0, 3) 1 (0, 3) 0 (0, 2) 0.12 1 (0, 4) 0 (0, 1) 0.003 
 5 min, median (IQR) 3 (1, 5) 4 (2, 5) 2 (1, 4) 0.11 4 (2, 5) 1 (0, 4) 0.016 
 10 min, median (IQR) 3 (2, 6) 4 (2, 6) 3 (2, 4) 0.066 4 (2, 6) 2 (1, 4) 0.036 
Prolonged resuscitation (>10 min), n (%) 29 (64) 14 (52) 15 (83) 0.031 18 (58) 11 (79) 0.18 
Arterial cord pH, median (IQR) 7.0 (6.8, 7.1) 7.0 (6.9, 7.1) 6.9 (6.8, 7.1) 0.24 7.0 (6.9, 7.1) 6.8 (6.5, 7.0) 0.033 
Lowest pH, mean (SD) 6.8 (0.2) 6.9 (0.1) 6.7 (0.1) 0.007 6.9 (0.1) 6.7 (0.1) 0.002 
Lowest base excess, median (IQR), mmol/L 19.3 (16.0, 24.4) 19.0 (14.0, 22.0) 24.0 (19.0, 28.5) 0.006 19.0 (15.0, 22.0) 25.0 (19.3, 28.5) <0.001 
Lowest bicarbonate, mean (SD), mmol/L 12.7 (4.8) 14.3 (3.9) 10.3 (5.0) 0.005 14.1 (3.8) 9.7 (5.4) 0.003 
Lowest pCO2 values, median (IQR), kPa 4.1 (3.9, 4.3) 4.1 (3.9, 4.2) 4.0 (3.8, 4.4) 0.91 4.1 (3.9, 4.3) 4.0 (3.7, 4.2) 0.31 
Highest pO2 values, median (IQR), kPa 20.2 (14.8, 32.7) 17.9 (12.9, 28.3) 22.0 (15.8, 36.8) 0.18 19.6 (15.2, 31.4) 21.2 (13.7, 40.8) 0.83 
pO2 values at admission, median (IQR), kPa 7.3 (5.7, 9.9) 7.1 (5.4, 10.1) 7.8 (5.7, 9.9) 0.26 6.8 (5.4, 9.6) 8.0 (6.9, 10.1) 0.095 
Hyperoxia (pO2 >13.3 kPa) at admission, n (%) 8 (18) 4 (15) 4 (22) 0.52 5 (16) 3 (21) 0.67 
Initial Sarnat score, n (%) 
 2 27 (60)    23 (74) 4 (29) 0.004 
 3 18 (40)    8 (26) 10 (71)  
Hypoglycemia, n (%) 6 (13) 3 (11) 3 (17) 0.59 3 (10) 3 (21) 0.28 
Seizures, n (%) 16 (36) 6 (22) 10 (56) 0.022 5 (16) 11 (7%) <0.001 
Death before discharge, n (%) 13 (29) 3 (11) 10 (56) 0.001 0 (0) 13 (93) <0.001 

Socioeconomic status (SES) = Maternal SES plus paternal SES divided by two, if one was unknown, the other was doubled. SES was calculated according to the recommendations of Largo et al. [31]. SES was not available for 13/45 neonates. Hypoglycemia (infant) = Blood glucose <2.5 mmol/L (45 mg/dL). Seizures = Clinical or subclinical identified on a EEG. Favorable outcome = cognitive or language composite score BSID-III 70–84 alone or a cognitive or language composite score BSID-III ≥85 and GMFCS level 1 or 2, seizure disorder (without anti-epileptic medication), or hearing deficit with ability to follow commands with amplification, the absence of any of the above. Unfavorable outcome = Death before 2 years of age, cognitive or language composite score BSID-III <70, GMFCS grade of level 3–5, hearing impairment or blindness, cognitive or language composite score BSID-III 70–84 in addition to a GMFCS grade of level 2 and/or hearing impairment and/or a persistent seizure disorder.

BSID-III, Bayley Scales of Infant and Toddler Development – Third Edition; EEG, electroencephalography; g, gram; GMFCS, Gross Motor Function Classification System; HIE, hypoxic-ischemic encephalopathy; IQR, interquartile range; SD, standard deviation; SES, socioeconomic status; TH, therapeutic hypothermia.

Neurodevelopmental Outcome at 18–24 Months of Age

Of the 45 neonates included, 13 (29%) died during the neonatal period and 32 (71%) had an NDFU. Among those who died, 8 (62%) died during TH and 5 (38%) died after completion of TH. There were no deaths after NICU discharge. Reasons for death included anticipated poor neurological outcome (9; 69%) and death despite full range of intensive care (4; 31%). Among those with NDFU, 31 children (97%) were assessed with BSID-III at 18–24 months [15] and one child was assessed via video call due to COVID-19 restrictions.

Among the 45 included neonates, 31 (69%) had a favorable neurodevelopmental outcome, of whom 30 did not have any disability and one had mild disability. Among 14 (31%) with unfavorable outcome, one had severe disability at NDFU and 13 died. The individual BSID- III score distributions can be found in the online supplement (online suppl. Table S2).

Blood Lactate Course according to Sarnat Staging and Neurodevelopmental Outcome

Blood lactate decreased over time in both outcome groups (Fig. 2). Initial lactate was measured in arterial blood in most cases (42/45; 93%), with only few in umbilical venous blood (2/45) or capillary (1/45). Initial lactate levels were higher in neonates with Sarnat stage 3 (16.4 mmol/L, SD 3.6) than stage 2 (13.8 mmol/L, SD 2.6; p = 0.008) and in those with unfavorable (17.1 mmol/L, SD 3.2) than favorable (13.9 mmol/L, SD 2.9; p = 0.002) outcome (Fig. 3; 4). Higher initial blood lactate levels and maximal lactate levels were associated with unfavorable outcome, also when adjusted for Sarnat stage (adjusted odds ratio: 1.37, 95% CI: 1.01−1.88, p = 0.046, and adjusted odds ratio: 1.35, 95% CI: 1.01−1.81, p = 0.041, respectively; Table 2).

Fig. 2.

Evolution of lactate values over time (0–96 h of life) in neonates with HIE by neurodevelopmental outcome. a Mean for both groups (unfavorable and favorable outcome group), mean for the unfavorable outcome group, and mean for the favorable outcome group. b Mean ± SD for the favorable outcome group. c Mean ± SD for the unfavorable outcome group. Definitions: Favorable outcome = cognitive or language composite score BSID-III 70–84 alone or a cognitive or language composite score BSID-III ≥85 and GMFCS level 1 or 2, seizure disorder (without anti-epileptic medication), or hearing deficit with ability to follow commands with amplification, the absence of any of the above. Unfavorable outcome = Death before 2 years of age, cognitive or language composite score BSID-III <70, GMFCS grade of level 3–5, hearing impairment or blindness, cognitive or language composite score BSID-III 70–84 in addition to a GMFCS grade of level 2 and/or hearing impairment and/or a persistent seizure disorder. BSID-III, Bayley Scales of Infant and Toddler Development – Third Edition; GMFCS, Gross Motor Function Classification System; HIE, hypoxic-ischemic encephalopathy; SD, standard deviation; TH, therapeutic hypothermia.

Fig. 2.

Evolution of lactate values over time (0–96 h of life) in neonates with HIE by neurodevelopmental outcome. a Mean for both groups (unfavorable and favorable outcome group), mean for the unfavorable outcome group, and mean for the favorable outcome group. b Mean ± SD for the favorable outcome group. c Mean ± SD for the unfavorable outcome group. Definitions: Favorable outcome = cognitive or language composite score BSID-III 70–84 alone or a cognitive or language composite score BSID-III ≥85 and GMFCS level 1 or 2, seizure disorder (without anti-epileptic medication), or hearing deficit with ability to follow commands with amplification, the absence of any of the above. Unfavorable outcome = Death before 2 years of age, cognitive or language composite score BSID-III <70, GMFCS grade of level 3–5, hearing impairment or blindness, cognitive or language composite score BSID-III 70–84 in addition to a GMFCS grade of level 2 and/or hearing impairment and/or a persistent seizure disorder. BSID-III, Bayley Scales of Infant and Toddler Development – Third Edition; GMFCS, Gross Motor Function Classification System; HIE, hypoxic-ischemic encephalopathy; SD, standard deviation; TH, therapeutic hypothermia.

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Fig. 3.

a–c Distribution of initial blood lactate, maximal blood lactate, and time to normal blood lactate by Sarnat stage in neonates with HIE. Box plots: Upper horizontal line of the box = 75th percentile; middle horizontal line of the box = median; lower horizontal line of the box = 25th percentile; diamond inside the box = mean; upper whisker = 90th percentile; lower whisker = 10th percentile; circles outside the whiskers = outside values. Definitions: Initial lactate = first value measured within 60 min of life; maximal lactate = highest lactate value within 72 h of life or until death; hours to blood lactate ≤2 mmol/L = hours until first registered blood lactate ≤ 2mml/L; Sarnat staging according to the guidelines of Sarnat and Sarnat [14]. HIE, hypoxic-ischemic encephalopathy; IQR, interquartile range; SD, standard deviation; TH, therapeutic hypothermia; n, number.

Fig. 3.

a–c Distribution of initial blood lactate, maximal blood lactate, and time to normal blood lactate by Sarnat stage in neonates with HIE. Box plots: Upper horizontal line of the box = 75th percentile; middle horizontal line of the box = median; lower horizontal line of the box = 25th percentile; diamond inside the box = mean; upper whisker = 90th percentile; lower whisker = 10th percentile; circles outside the whiskers = outside values. Definitions: Initial lactate = first value measured within 60 min of life; maximal lactate = highest lactate value within 72 h of life or until death; hours to blood lactate ≤2 mmol/L = hours until first registered blood lactate ≤ 2mml/L; Sarnat staging according to the guidelines of Sarnat and Sarnat [14]. HIE, hypoxic-ischemic encephalopathy; IQR, interquartile range; SD, standard deviation; TH, therapeutic hypothermia; n, number.

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Fig. 4.

a–c Distribution of initial blood lactate, maximal blood lactate, and time to normal lactate by neurodevelopmental outcome in neonates with HIE. Box plots: upper horizontal line of the box = 75th percentile; middle horizontal line of the box = median; lower horizontal line of the box = 25th percentile; diamond inside the box = mean; upper whisker = 90th percentile; lower whisker = 10th percentile; circles outside the whiskers = outside values. Definitions: Initial lactate = first value measured within 60 min of life; maximal lactate = highest lactate value within 72 h of life or until death; hours to blood lactate ≤2 mmol/L = hours until first registered blood lactate ≤ 2mml/L; favorable outcome = cognitive or language composite score BSID III 70–84 alone or a cognitive or language composite score BSID III ≥85 and GMFCS level 1 or 2, seizure disorder (without anti-epileptic medication), or hearing deficit with ability to follow commands with amplification, the absence of any of the above. Unfavorable outcome = Death before 2 years of age, cognitive or language composite score BSID III <70, GMFCS grade of level 3–5, hearing impairment or blindness, cognitive or language composite score BSID III 70–84 in addition to a GMFCS grade of level 2 and/or hearing impairment and/or a persistent seizure disorder. BSID-III, Bayley Scales of Infant and Toddler Development – Third Edition; GMFC, Gross Motor Function Classification System; HIE, hypoxic-ischemic encephalopathy; IQR, interquartile range; SD, standard deviation; TH, therapeutic hypothermia.

Fig. 4.

a–c Distribution of initial blood lactate, maximal blood lactate, and time to normal lactate by neurodevelopmental outcome in neonates with HIE. Box plots: upper horizontal line of the box = 75th percentile; middle horizontal line of the box = median; lower horizontal line of the box = 25th percentile; diamond inside the box = mean; upper whisker = 90th percentile; lower whisker = 10th percentile; circles outside the whiskers = outside values. Definitions: Initial lactate = first value measured within 60 min of life; maximal lactate = highest lactate value within 72 h of life or until death; hours to blood lactate ≤2 mmol/L = hours until first registered blood lactate ≤ 2mml/L; favorable outcome = cognitive or language composite score BSID III 70–84 alone or a cognitive or language composite score BSID III ≥85 and GMFCS level 1 or 2, seizure disorder (without anti-epileptic medication), or hearing deficit with ability to follow commands with amplification, the absence of any of the above. Unfavorable outcome = Death before 2 years of age, cognitive or language composite score BSID III <70, GMFCS grade of level 3–5, hearing impairment or blindness, cognitive or language composite score BSID III 70–84 in addition to a GMFCS grade of level 2 and/or hearing impairment and/or a persistent seizure disorder. BSID-III, Bayley Scales of Infant and Toddler Development – Third Edition; GMFC, Gross Motor Function Classification System; HIE, hypoxic-ischemic encephalopathy; IQR, interquartile range; SD, standard deviation; TH, therapeutic hypothermia.

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Table 2.

Association of initial blood lactate and maximal blood lactate with neurodevelopmental outcome (unfavorable vs. favorable) among neonates with HIE

nUnadjustednAdjusted by Sarnat stage
OR95% CIp valueaOR95% CIp value
Initial lactate value, per 1 mmol/L increase 42 1.49 1.10, 2.01 0.009 42 1.37 1.01, 1.88 0.046 
Maximum lactate value, per 1 mmol/L increase 45 1.47 1.12, 1.93 0.006 45 1.35 1.01, 1.81 0.041 
nUnadjustednAdjusted by Sarnat stage
OR95% CIp valueaOR95% CIp value
Initial lactate value, per 1 mmol/L increase 42 1.49 1.10, 2.01 0.009 42 1.37 1.01, 1.88 0.046 
Maximum lactate value, per 1 mmol/L increase 45 1.47 1.12, 1.93 0.006 45 1.35 1.01, 1.81 0.041 

Initial lactate = first value measured within 60 min of life. Maximal lactate = highest lactate value within 72 h of life or until death. Favorable outcome = cognitive or language composite score BSID III 70–84 alone or a cognitive or language composite score BSID III ≥85 and GMFCS level 1 or 2, seizure disorder (without anti-epileptic medication), or hearing deficit with ability to follow commands with amplification, the absence of any of the above. Unfavorable outcome = Death before 2 years of age, cognitive or language composite score BSID III <70, GMFCS grade of level 3–5, hearing impairment or blindness, cognitive or language composite score BSID III 70–84 in addition to a GMFCS grade of level 2 and/or hearing impairment and/or a persistent seizure disorder.

BSID-III, Bayley Scales of Infant and Toddler Development – Third Edition; GMFCS, Gross Motor Function Classification System; HIE, hypoxic-ischemic encephalopathy; TH, therapeutic hypothermia; OR, odds ratio; aOR, adjusted odds ratio.

Among 34 neonates where blood lactate decreased ≤2 mmol/L in the first 96 h of life, 30 (88%) had a favorable outcome and 4 (12%) had an unfavorable outcome, of whom 3 died and 1 survived but had severe disability at NDFU (online suppl. Fig. S1). Mean time to blood lactate ≤2 mmol/L was 38.3 h (SD 20.9, n = 30) in those with favorable and 52.0 h (SD 31.0; n = 4; p = 0.25) in those with unfavorable outcome. Among 11 neonates where lactate never decreased ≤2 mmol/L, 10 neonates died and the surviving one had a minimum lactate of 2.1 mmol/L at 74 h of life.

In this study, two-thirds of neonates with moderate or severe HIE had a favorable neurodevelopmental outcome at 18–24 months of age. These neonates showed lower initial and maximal blood lactate levels during TH than neonates with unfavorable outcome. Blood lactate decreased ≤2 mmol/L within the first 96 h of life in 34/45 neonates, and mean time to blood lactate ≤2 mmol/L was 38.3 h in those with favorable versus 52.0 h in those with unfavorable outcome.

Usually, there is a homeostasis between the daily lactate production and consumption in the human body [20, 21]. This homeostasis can be disturbed by various processes, resulting in hyperlactatemia, commonly caused by the impairment of mitochondrial oxidation in global or local tissue hypoxia [20, 22]. Hyperlactatemia as a marker of tissue hypoxia is generally associated with a less favorable outcome in intensive care unit patients [23‒26].

Wu et al. investigated the relationship between cerebral and serum lactate in neonates with HIE receiving TH, hypothesizing that cerebral lactate would be elevated in regions of cerebral injury [27]. Their results showed a strong correlation between serum lactate and cerebral lactate at the basal ganglia, thalamus, and gray matter region in neonates with moderate to severe brain damage [27]. Future studies are necessary to elucidate the direction of cerebral lactate flux by using carbon tagging in neonates with moderate or severe brain injury [27].

The published studies investigating the correlation of blood lactate levels and neurologic outcome of neonates with HIE show similar results, but most of them analyzed different endpoints [11, 12, 27‒30]. Studies with similar populations found that prolonged hyperlactatemia was associated with a higher incidence of electrographic seizures and correlated with the severity of encephalopathy (also shown in the pre-TH era) [11, 28]. Hence, blood lactate levels were higher in neonates with moderate to severe HIE compared to those with mild or no HIE [28]. Neonates with a rapid decrease of lactate levels within 24 h of TH showed a better neurological short-term outcome and MRI findings at the time of hospital discharge in a study by Heljić et al. [29]. Since neurodevelopmental outcome was not assessed in this study, it can only be assumed that the higher the initial serum lactate and the more persistent hyperlactatemia, the greater the neurological damage. The studies mentioned above investigated short-term outcome.

Polackova et al. [30] showed that blood lactate levels were significantly higher in neonates with moderate to severe HIE receiving TH with unfavorable neurodevelopmental outcome at 2 years of age. This study is similar to ours with regarding sample size (n = 51 vs. 45) and inclusion criteria for TH (Sarnat stages 2 and 3). In contrast to our study, lactate progression was only monitored for 36 h, and follow-up examination was limited to motor ability using GMFCS and did not include cognitive, language, and motor outcome using BSID-III. In their study, there were more survivors in the unfavorable outcome group than in ours (59% survivors with unfavorable outcome; in detail, survivors in the unfavorable outcome group 10/17 vs. 1/13). One possible reason for this discrepancy could be a different approach to initiating redirection of care. At the University Children’s Hospital Zurich, redirection of care was mostly initiated due to anticipated poor neurodevelopmental outcome and not in context of ongoing maximum intensive care.

All these previous mentioned studies showed that blood lactate as an easy and quick to measure biomarker possibly contributes to predict long-term neurodevelopmental outcome of this patients. A major strength of our study is that data were collected prospectively from a standardized national registry over a long time period. The same standardized HIE treatment protocol was applied, standardized NDFU (using BSID-III with detailed assessment of cognitive, language, and motor outcome) was performed, and our study stands with a high rate of follow-up. Our data should be generalizable to other HIE populations since we investigated a representative and homogenous population, despite a small sample size.

Due to the limited sample size, it was not possible to develop a prediction model, in consideration of extrinsic and intrinsic confounding factors on blood lactate levels. As limitations, performing NDFU could not be blinded to the patient’s history because this was part of routine follow-up care and assessment of long-term neurodevelopmental outcome at school age was not included. Only 4 patients in the unfavorable outcome group could be included in the blood lactate clearance analysis as the group with unfavorable outcome mainly consisted of non-survivors, most of whom did not show a decrease in blood lactate ≤2 mmol/L before death. Furthermore, we did not capture other factors influencing blood lactate progression (severe sepsis, liver failure, catecholamines, sedatives, hypothermia itself) or other biological markers which may be associated with poor outcome and merit further investigation. Few of the initial lactate measurements were taken from non-arterial samples. However, this is unlikely to have affected our results since most initial lactate values were taken from arterial samples, as well as all the following.

In our study on cooled neonates with moderate to severe HIE, higher initial and maximal blood lactate levels were associated with unfavorable outcome, also when adjusted for Sarnat stage. In contrast, most neonates whose blood lactate decreased ≤2 mmol/L in the first 96 h of life had a favorable neurodevelopmental outcome at 18–24 months of age. This suggests that blood lactate could play an important role in prediction models assessing long-term neurodevelopmental outcome after HIE and has the advantage of being a non-expensive parameter that is readily available at bedside and can be easily and frequently measured. This work may contribute to future research collaborations to develop comprehensive prediction models.

Data collection, evaluation, and publication for this study was approved by the Swiss Association of Research Ethics Committees and the Swiss Federal Commission for Privacy Protection in Medical Research (Cantonal Ethics Committee Zurich [KEK-ZH], decision reference No. KEK-ZH 2022-01261) and conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Parental written informed consent was obtained for each study participant.

The authors declare that they have no potential, perceived, or actual conflicts of interest.

The authors did not receive funding for this study.

All the authors have accepted responsibility for the entire content of this manuscript and approved its submission. W.B., B.B., and B.G. conceptualized the study. W.B. was responsible for acquisition of data and data analysis and search and review of the literature. R.M. performed all statistical analyses. R.L. was involved in outcome data acquisition and analysis. B.B., B.G., and B.F. supervised design of the study, data analysis, and search and review of the literature. All the authors interpreted the results and critically reviewed the manuscript.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants and due to not asking parents to public datasets. However, they are available from the corresponding author (B.B.).

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