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Abstract

Pneumonia is a major cause of morbidity and mortality in children globally. Lactate, a product of anaerobic cellular metabolism, has been used as an indicator of poor tissue oxygenation and cellular hypoxia. Our objective was to determine whether serum lactate concentration at hospital admission predicted mortality in children aged 2 months to 5 years with pneumonia. Two hundred and eighty-one pediatric patients admitted to the Department of Pediatrics of a provincial hospital with WHO-defined pneumonia and severe pneumonia were included; of whom, 8 died during hospital stay. The median serum lactate concentration was 4.8 mmol/l (IQR 2.6-6.9) among children who died and 3.6 mmol/l (IQR 2.8-4.3) among children who survived (P > .05); 4.1 mmol/l (IQR 2.7-4.7) among children with severe pneumonia and 3.5 mmol/l (IQR 2.8-4.3) among children with pneumonia (P > .05). Serum lactate concentration had a low value in predicting pneumonia-related mortality (AUC 0.68, 95% CI 0.62-0.73); and the concentration cut-off of >4.06 mmol/l had the best sensitivity and specificity (75% and 68.9%, respectively) with a 2.4-fold risk of death (LR+ 2.4; 95% CI 1.6-3.7). Although hyperlactatemia was associated with severity and mortality in children 2 months to 5 years of age with pneumonia, its benefit was unclear.

Keywords

pediatrics serum lactate mortality pneumonia developing country

Introduction

Pneumonia is globally the main cause of disease and death among children. Pneumonia (15%), along with diarrhea (8%), and malaria (5%) remain among the leading causes of death globally among children under age 5—accounting for almost a third of global under 5 deaths.¹ In 2016, pneumonia accounted for an estimated 650 000 deaths in infants and young children (<5 years) globally, the vast majority occurred in developing countries.² In Vietnam, pneumonia is the leading cause of pediatric hospital admission and places a huge burden on the health care system.³

Biomarkers signifying pneumonia severity and suggesting appropriate treatment may help reduce mortality; of these, lactate is a product of anaerobic cellular metabolism. It is used as an indicator of poor tissue oxygen delivery, and cell hypoxia to monitor critically ill children, including those with sepsis,⁴ trauma,⁵ acute respiratory distress syndrome,⁶ and those with primary respiratory disease requiring extracorporeal membrane oxygenation (ECMO).⁷ In developing countries, elevated serum lactate has been shown to appear in children with severe malaria,⁸ kwashiorkor malnutrition,⁹ severe anemia,¹⁰ and pneumonia^11,12 as well.

This study aimed to determine whether serum lactate concentration measured at the time of hospital admission was a good predictor of mortality in children aged 2 months to 5 years with pneumonia.

Materials and Methods

We conducted a prospective cohort study of children aged 2 months to 5 years admitted to the Department of Pediatrics, Binh Dinh General Hospital, Quy Nhon City, Vietnam with WHO-defined pneumonia and severe pneumonia¹³ between April 2019 and March 2020. Data recorded included age, gender, fever, respiratory physical signs, severity of pneumonia according to WHO criteria, treatment outcomes, arterial oxygen saturation measured by pulse oximetry (S_pO₂, %), white blood cell (WBC) count (×10⁹/l), serum C-reactive protein (CRP) level (mg/l), and serum lactate concentration (mmol/l).

S_pO₂ was measured with a Mekics hand-held pulse oximeter model MP111 (Mekics Co., Ltd., Korea) on room air at admission. WBC count (10⁹/l), including differential count, were routinely analyzed on enrollment with Sysmex XN-1000™ Hematology Analyzer (Japan). WBC count was presented as an absolute count and age-adjusted ratio, and neutrophils were presented as the percentage of the total WBC count. CRP was measured in serum samples by an automated turbidimetric assay and serum lactate concentration was analyzed using the AU480 Clinical Chemistry System (Beckman Coulter, Inc., USA). We defined hypoxemia as an arterial oxygen saturation measured by pulse oximetry of less than 90% when breathing air.¹³ Hyperlactatemia was defined as serum lactate >2.0 mmol/l,¹¹ and was analyzed with the thresholds of >2.0 and >4.0 mmol/l. Serum CRP levels were evaluated with cut-off points of >10, >20, and >40 mg/l.

Univariate logistic regression was used to determine risk factors to mortality. The area under the receiver operating characteristics (ROC) curve was calculated for S_pO₂, WBC count, serum CRP level, and serum lactate concentration in prediction of mortality according to logistic regression. The association between lactate concentration and other clinical features was investigated using univariate logistic regression. All statistical analyses were performed using SPSS (Statistical Package for the Social Sciences) 20.0.

Written informed consent was obtained from the patient’s parent(s) or guardian(s). The study protocol was approved by the Ethics Committee at Hue University of Medicine and Pharmacy (H2019/279).

Results

Population

We enrolled 281 children aged 2 months to 5 years admitted with WHO-defined clinical pneumonia and severe pneumonia from April 2019 and March 2020. The proportion of pneumonia in children under 12 months of age was similar to that in children aged 12 months to 5 years (48.4% vs 51.6%, respectively); of which 26% of pneumonia occurred quite early before the age of 6 months. Pneumonia was more common in boys than in girls (60.1% vs 39.9%, respectively). Of these children, 43 (15.3%) were diagnosed as severe pneumonia. Among the 281 children, 8 died during their stay in hospital (case-death 2.8%), in which 7 deaths were children with severe pneumonia, and the other child with pneumonia. Mortality rates were not different between age groups; but different by gender, 6 (75%) deaths were in boys. Table 1 describes the patient clinical and laboratory characteristics in relation to treatment outcomes.

Table 1.

Clinical and Laboratory Features in Relation to Treatment Outcomes.

Characteristic	Entire cohort (n = 281)	Survivors (n = 273)	Non-survivors (n = 8)	P	OR
Age group (months)
2-5	73 (26.0)	70 (25.6)	3 (37.5)	>.05
6-11	63 (22.4)	61 (22.3)	2 (25.0)
12-60	145 (51.6)	142 (52.0)	3 (37.5)
Gender
Boy	169 (60.1)	163 (59.7)	6 (75.0)	>.05^a
Girl	112 (39.9)	110 (40.3)	2 (25.0)	>.05^a
Clinical examination
Decreased conscious level/coma	9 (3.2)	5 (1.8)	4 (50.0)	<.05^a	53.6 (10.4-277.5)
S_pO₂ < 90%	32 (11.4)	25 (9.2)	7 (87.5)	<.05^a	69.4 (8.2-587.4)
Grunting	6 (2.1)	4 (1.5)	2 (25.0)	<.05^a	22.4 (3.4-147.0)
Severe chest indrawing	8 (2.8)	6 (2.2)	2 (25.0)	<.05^a	14.8 (2.5-89.1)
Diminished breath sounds	19 (6.8)	14 (5.1)	5 (62.5)	<.05^a	30.8 (6.7-142.3)
Peripheral leukocyte count
Leukocytosis	183 (65.1)	179 (65.6)	4 (50.0)	>.05^a
Neutrophilic leukocytosis	113 (40.2)	109 (39.9)	4 (50.0)	>.05^a
Serum CRP level (mg/l)
>20	65 (23.1)	60 (22.0)	5 (62.5)	<.05^a	5.9 (1.4-25.5)
>40	32 (11.4)	28 (10.3)	4 (50.0)	<.05^a	8.8 (2.1-36.9)
Serum lactate concentration (mmol/l)
>2	266 (94.7)	258 (94.5)	8 (100)
>4	95 (33.8)	89 (32.6)	6 (75.0)	<.05^a	6.2 (1.2-31.3)
Pneumonia severity
Pneumonia	238 (84.7)	237 (86.8)	1 (12.5)	<.05	46.1 (5.5-385.6)
Severe pneumonia	43 (15.3)	36 (13.2)	7 (87.5)	<.05	46.1 (5.5-385.6)

Abbreviations: CRP, C-reactive protein; S_pO₂, arterial oxygen saturation measured by pulse oximetry.

Fisher’s exact test.

Many signs discriminated significantly between survivors and non-survivors in our study. The proportion of S_pO₂ < 90% was 87.5% among children who died and 9.2% among children who survived (OR = 69.4; 95% CI 8.2-587.4). Decreased conscious level/coma was observed in 50% of died children compared to in 1.8% of survived children (OR = 53.6), while a higher proportion of pneumonia children with diminished breath sounds died compared to pneumonia children without this sign on auscultation (62.5% vs 5.1%, respectively, OR = 30.8). The rates of other signs such as grunting and severe chest indrawing were also significantly higher in pneumonia children who died than in survivors (25.0% vs 1.5%, OR = 22.4; and 25.0% vs 2.2%, OR = 14.8%, respectively).

The proportions of peripheral leukocytosis and neutrophilic leukocytosis were not statistically different in pneumonia children who died, compared with those who survived (65.6% vs 50.0% and 39.9% vs 50.0%, respectively, P > .05 for all comparisons).

About 23.1% of children had a CRP concentration >20 mg/l, and 11.4% of children had a CRP concentration >40 mg/l. About 62.5% of children who died has a CRP concentration >20 mg/l (compared with 22.0% of those who survived), and 50% of died children has a CRP concentration >40 mg/l (compared with 10.3% of survivors). Serum CRP levels >20 and >40 mg/l increased the risk of death by 5.9 times (OR = 5.9; 95% CI 1.4-25.5) and by 8.8 times (OR = 8.8; 95% CI 2.1-36.9), respectively. About 94.7% of pneumonia children had a serum lactate concentration >2 mmol/l, while 33.8% of pneumonia children had a serum lactate concentration >4 mmol/l. All 8 deaths (100%) had a serum lactate concentration >2 mmol/l; and there were 6 deaths (75%) had a serum lactate concentration >4 mmol/l; and serum lactate concentrations >4 mmol/l increased the risk of death by 6.2 times (OR = 6.2; 95% CI 1.2-31.3).

Factors Associated With Serum Lactate

Table 2 indicates the serum lactate concentrations in relation to age groups, gender, clinical characteristics and treatment outcomes. The median serum lactate concentration for entire pneumonia children in this study was 3.6 mmol/l (IQR 2.8-4.3); 3.6 mmol/l (IQR 2.9-4.4) in boys; and 3.4 mmol/l (IQR 2.7-4.1) in girls (P < .05). The median lactate concentrations were not significantly different between age groups. The median lactate concentration was 4.8 mmol/l (IQR 2.6-6.9) among children who died and 3.6 mmol/l (IQR 2.8-4.3) among children who survived (P > .05); 4.1 mmol/l (IQR 2.7-4.7) among children with severe pneumonia and 3.5 mmol/l (IQR 2.8-4.3) among children with pneumonia (P > .05).

Table 2.

Population, Clinical Features and Treatment Outcomes Associated With Serum Lactate.

Characteristic	Entire cohort (n = 281)	Serum lactate concentration (mmol/l) median (25th-75th)	P
Entire population	281	3.6 (2.8-4.3)
Age group (months)
2-5	73	3.6 (2.9-4.3)	>.05
6-11	63	3.5 (3.1-4.2)
12-60	145	3.6 (2.6-4.5)
Gender
Boy	169	3.6 (2.9-4.4)	<.05
Girl	112	3.4 (2.7-4.1)	<.05
Clinical features
Convulsions
Yes	6	4.7 (2.0-9.4)	>.05
No	275	3.6 (2.8-4.3)	>.05
Unable to feed/drink
Yes	7	6.5 (3.9-9.4)	<.05
No	274	3.6 (2.8-4.3)	<.05
Decreased conscious level/coma
Yes	9	4.6 (4.1-8.2)	<.05
No	272	3.5 (2.8-4.3)	<.05
Fever
Yes	196	3.6 (2.7-4.4)	>.05
No	85	3.6 (3.0-4.3)	>.05
Grunting
Yes	6	4.3 (2.6-5.1)	>.05
No	275	3.6 (2.8-4.3)	>.05
Severe chest indrawing
Yes	8	3.0 (2.5-6.7)	>.05
No	273	3.6 (2.8-4.3)	>.05
Diminished breath sounds
Yes	19	4.2 (3.6-6.9)	<.05
No	262	3.5 (2.8-5.0)	<.05
Crackles
Yes	276	3.6 (2.8-4.3)	>.05
No	5	3.1 (2.5-6.3)	>.05
S_pO₂ (%)
<90	32	4.1 (2.7-5.5)	<.05
≥90	249	3.5 (2.8-4.3)	<.05
Pneumonia severity
Pneumonia	238	3.5 (2.8-4.3)	>.05
Severe pneumonia	43	4.1 (2.7-4.7)	>.05
Treatment outcomes
Survivors	273	3.6 (2.8-4.3)	>.05
Non-survivors	8	4.8 (2.6-6.9)	>.05

Abbreviations: S_pO₂, arterial oxygen saturation measured by pulse oximetry.

Higher concentrations of lactate were also found in children with unable to feed/drink compared to children with normal feed/drink (median 6.5, IQR 3.9-9.4, compared to 3.6, IQR 2.8-4.3 mmol/l); in children with decreased conscious level compared to children with normal conscious state (median 4.6, IQR 4.1-8.2, compared to 3.5, IQR 2.8-4.3 mmol/l); and in those with diminished breath sounds compare to those with normal breath sounds (median 4.2, IQR 3.6-6.9, compared to 3.5, IQR 2.8-5.0 mmol/l, P < .05 for all comparisons).

The results, as shown in Table 3, indicate that the serum lactate concentration had a moderate negative correlation with S_pO₂ (r_s: −0.30 [−0.46 to −0.09]), a moderate positive correlation with WBC count (r_s: 0.30 [0.14-0.45]) and a low positive correlation with serum CRP level (r_s: 0.28 [0.14-0.43]).

Table 3.

S_pO₂, WBC Count, and Serum CRP Level in Relation to Serum Lactate Concentration.

Characteristic	Serum lactate concentration (mmol/l)
Characteristic	r _s	P
S_pO₂	−0.30 (−0.46 to −0.09)	<.05
WBC count	0.30 (0.14 to 0.45)	<.05
Serum CRP level	0.28 (0.14 to 0.43)	<.05

Abbreviations: CRP, C-reactive protein; r_s, Spearman’s rank correlation coefficient; S_pO₂, arterial oxygen saturation measured by pulse oximetry; WBC, white blood cell.

Discriminative Power of S_pO₂, WBC Count, Serum CRP Level, and Serum Lactate Concentration as Predictors of Mortality

As Table 4 shows, the WBC count, serum CRP level, and serum lactate concentration were not specific in predicting pneumonia-related mortality (AUC 0.55, 95% CI 0.49-0.61; AUC 0.66, 95% CI 0.60-0.71; and AUC 0.68, 95% CI 0.62-0.73, respectively). Serum lactate concentration cut-off of >4.06 mmol/l had the best sensitivity and specificity (75% and 68.9%, respectively) with a 2.4-fold risk of death (LR+ 2.4; 95% CI 1.6-3.7). Among the predictors of mortality, S_pO₂, a noninvasive assessment, discriminated best between survivors and non-survivors in our study with AUC 0.96 and 95% CI 0.94 to 0.98. Oxygen saturation of ≤86% accurately predicted death with high sensitivity and specificity (87.5% and 95.2%, respectively); LR+ 18.4 (95% CI 10.2-33.2); and LR− 0.1 (95% CI 0.02-0.8).

Table 4.

Discriminative Power of S_pO₂, WBC, CRP, and Lactate as Predictors of Mortality.

Predictors	AUC (95% CI)	Cut-off	Sensitivity	Specificity	LR+	LR−
S_pO₂	0.96 (0.94-0.98)	≤86%	87.5	95.2	18.4 (10.2-33.2)	0.1 (0.02-0.8)
WBC count	0.55 (0.49-0.61)	≤10 130/mm³	62.5	60.8	1.6 (0.9-2.8)	0.6 (0.3-1.5)
Serum CRP level	0.66 (0.60-0.71)	>27.8 mg/l	62.5	86.5	4.6 (2.5-8.5)	0.4 (0.2-1.1)
Serum lactate concentration	0.68 (0.62-0.73)	>4.06 mmol/l	75.0	68.9	2.4 (1.6-3.7)	0.4 (0.1-1.2)

Abbreviations: AUC, area under ROC curve; CI, confidence interval; CRP, C-reactive protein; LR−, negative likelihood ratio; LR+, positive likelihood ratio; S_pO₂, arterial oxygen saturation measured by pulse oximetry; WBC, white blood cell.

Discussion

This study showed that serum lactate concentration was associated with many clinical signs, changes in peripheral white blood cell counts and serum CRP level, as well, in pneumonia in children aged 2 months to 5 years. Children with signs of serious illness such as grunting, severe chest indrawing; and especially those unable to feed/drink, those with decreased conscious level or coma, had significantly higher serum lactate concentration. These signs have also been shown by previous studies to be related to hypoxemia.¹⁴ Therefore, serum lactate concentration was higher in the severe pneumonia group than in the pneumonia group.

Some studies in adults have demonstrated that initial serum lactate level on admission was associated with mortality in patients with pneumonia.^15,16 Other studies in children have also demonstrated that hyperlactatemia can be used as an indicator of poor prognosis in critically ill children in the Pediatric Intensive Care Units (PICUs); therein, initial serum lactate levels >2 mmol/l were observed in the majority of patients admitted to the PICUs,^4,7,17-19 and lactate levels >5^17,18 or >5.55 mmol/l¹⁹ had high sensitivity and specificity in predicting mortality. Our study also recorded that 75% of children with pneumonia who died had serum lactate level >4 mmol/l and this lactate threshold increased the risk of mortality more than 6 times (OR = 6.2; 95% CI 1.2-31.3). However, based on ROC analysis, lactate level had only a low predictive value for mortality risk in children aged 2 months to 5 years with pneumonia (AUC = 0.68; 95% CI 0.62-0.73). This value was not similar to the results of other authors.¹¹ Serum lactate level >4.06 mmol/l was also noted the cut-off point with the best sensitivity and specificity (though not high) in predicting mortality (75.0% and 68.9%, respectively).

Meanwhile, oxygen saturation had a very good predictive value of mortality (AUC = 0.96; 95% CI 0.94-0.98); and S_pO₂ threshold ≤86% had very high sensitivity and specificity (87.5% and 95.2% respectively) in predicting mortality. Among 8 deaths in our study, 87.5% (7/8 patients) had S_pO₂ < 90%; and this cut-off was defined as high risk of death with OR = 69.4; 95% CI 8.2 to 587.4. This was also mentioned by some previous studies; when hypoxemia was found to be a stronger predictor of mortality. A recent study in Malawi showed that S_pO₂ < 90% was an independent predictor of death from WHO danger signs with RR = 9.37; 95% CI 2.17 to 40.4.²⁰

Hypoxemia is common in pneumonia due to ventilation-perfusion mismatch that results in reducing oxygen exchange and creating pulmonary shunts. Additionally, there may be a decrease in minute hypoventilation in serious condition or in late stage. Hypoxemia represents the severity of pneumonia, so the prognostic value of this factor is very high. One question to be raised is whether serum lactate concentration can reflect blood oxygenation status. Historically, lactate concentration was considered a “waste product” of anaerobic metabolism. When oxygen supply to the tissues is insufficient to sustain aerobic metabolism, cells must rely on anaerobic metabolism, a form of energy-producing process that does not require oxygen, but produces lactic acid as a secondary product. The more severe the lactic acidosis suggests the more critical the condition; and is considered an important indicator of tissue hypoperfusion in shock and hypoxemia. This raised the issue of quantifying and monitoring lactate levels in critically ill patients in general as well as in patients with shock or pneumonia, in particular.²¹ However, more recent evidence has suggested other ways of understanding the mechanisms of lactate formation in the body; through which an increase in serum lactate level is complex and not necessarily related to hypoxemia.²² In addition to the lactate formation mechanism mentioned, it is also important to consider the mechanism of lactate production by well-oxygenated tissues. In muscle, bone, and some other tissues, aerobic glycolysis involves supplying ATP to the Na-K-ATPase pump, and its activity is stimulated by epinephrine. In traumatic patients, increased Na-K-ATPase activity may be observed; reflected by hypokalemia. The hyperlactatemia in these cases reflects increased aerobic glycolysis in muscle and bone secondary to epinephrine-stimulated Na-K-ATPase activity rather than hypoperfusion-induced anaerobic glycolysis.²³ Besides, this aerobic glycolysis process is also an important mechanism for the generation of more ATP under stress.²⁴ The result of our study also recognized this when serum lactate concentration had a weak correlation (r_s = −0.3) with pulse oximetry, a valuable indicator of blood oxygenation status.

Ramakrishna et al in a study in children with WHO-defined pneumonia in Malawi noted that 65 out of 87 children with hypoxemia by definition (S_pO₂ < 90%) had normal lactate concentrations. The authors concluded that elevated serum lactate concentration should be used in conjunction with known risk factors, young age, and hypoxemia in identifying the sickest patients.¹¹ Some other studies have suggested that hyperlactatemia may predict mortality if it persisted after 24 hours of treatment⁴; and serum lactate level in the first 24 hours of admission had the best sensitivity and specificity in predicting outcome.²⁵

Inflammatory markers such as CRP, IL-6, IL-8, and procalcitonin levels have also been shown to be potential to predict severe community-acquired pneumonia in pediatric populations.²⁶ However, in our study, serum CRP levels, similar to serum lactate levels, had a low value (AUC = 0.66; 95% CI 0.60-0.71) in predicting mortality in children with pneumonia. Therefore, we suggest that serum lactate level should be combined with clinical manifestations and non-invasive but high-value indicators such as S_pO₂ in approaching, assessing, and prognosing children with pneumonia.

Conclusion

Serum lactate has been widely evaluated in pediatric clinical practice. Although there was an association between hyperlactatemia and severity as well as mortality in children aged 2 months to 5 years with pneumonia but its benefit was unclear. Future studies are needed to investigate the role of serum lactate as a biomarker in pneumonia for better treatment and prognosis.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Son Bui-Binh-Bao

Nguyen Thi Kim Hoa

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Is Serum Lactate a Good Predictor of Mortality in Children Aged 2 Months to 5 Years With Pneumonia in Central Vietnam