Repeated blood lactate measurements during clinical care of children with cerebral malaria

doi:10.21203/rs.3.rs-3123403/v1

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Repeated blood lactate measurements during clinical care of children with cerebral malaria

https://doi.org/10.21203/rs.3.rs-3123403/v1

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published 19 Jan, 2024

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Background

Admission blood lactate has previously guided therapy and is a valid estimator of prognosis in children with cerebral malaria (CM). Since bolus intravenous fluid administration to children with febrile coma and signs of hypovolemia (including high blood lactate) may be harmful, the use of blood lactate to guide therapy has waned. Its utility as a prognostic biomarker, either at admission or during hospitalization, remains unclear.

Methods

We performed a retrospective cohort study of 1674 Malawian children with CM hospitalized from 2000–2018 who had blood lactate measurements every 6 hours for the first 24 hours. We evaluated the strength of association between admission lactate or values measured at any time point in the first 24 hours post-admission, and outcomes (death or neurologic disability in survivors). We assessed the optimal duration of lactate monitoring of children with CM.

Results

When lactate is analyzed as a continuous variable, children with CM who have higher values at admission have a 1.05-fold higher odds (95% CI: 0.99–1.11) of death compared to those with lower lactate values. Children with higher blood lactate at 6 hours have 1.16-fold higher odds (95% CI: 1.09–1.23) of death, compared to those with lower values. If lactate levels are dichotomized into hyperlactatemic (lactate > 5.0 mmol/L) or not, the strength of association between admission lactate and death increases (OR = 2.49, 95% CI: 1.47–4.22). Neither blood lactate levels obtained after 18 hours post-admission nor trends in lactate concentrations during the first 24 hours of admission are associated with outcomes. Blood lactate during hospitalization is not associated with adverse neurologic outcomes in CM survivors.

Conclusions

In children with CM, blood lactate is associated with death but not neurologic morbidity in survivors. To comprehensively estimate prognosis, blood lactate in children with CM should be assessed at admission and for 18 hours afterwards.

Malaria

Lactate

Paediatric

Africa

Malawi

Despite decades of progress in decreasing disease incidence, malaria continues to have a significant public health impact, with an estimated 241 million cases and 627,000 deaths annually (1). Children under 5 years old account for two-thirds of these deaths (1). Clinical disease is classified as either uncomplicated or severe (2). Cerebral malaria (CM) is the severe malaria syndrome with the highest mortality risk (3). CM is clinically defined as an otherwise unexplained coma in someone with asexual Plasmodium parasitemia.(3) Universally fatal if untreated, with optimal clinical care the mortality risk in CM is 15–20 percent (3, 4). Among CM survivors, ten to thirty percent have cognitive, neurologic, and/or behavioral sequelae (5, 6).

In the WHO’s malaria treatment guidelines, routine measurement of blood lactate in severe malaria, including CM, is not discussed. Other published clinical care guidelines for children with CM recommend routine measurement of blood lactate to aid in patient care (7, 8). As higher blood lactate levels are known to be associated with poor outcomes (9–13), prior standard clinical practice often included bolus administration of intravenous fluids to children with CM who had elevations in blood lactate. The therapeutic goal was to decrease blood lactate and, logically, decrease mortality risk. However, the publication of the results of the Fluid Expansion as Supportive Therapy (FEAST) clinical trial in 2011 revealed increased mortality in hypovolemic African children who received bolus intravenous fluids (14). Children with malaria who received crystalloid boluses had a 1.59-fold higher odds of death (95% CI: 1.10–2.31) compared to those who did not (14). Consequently, administering bolus intravenous fluids to African children with febrile coma (including CM) who have signs or symptoms of hypovolemia, including hyperlactatemia, has largely ceased. Blood lactate results are unlikely to provide actionable information to guide clinical care.

While the use of blood lactate to target fluid resuscitation in African children with CM has waned, it is possible that lactate may be a valid prognostic biomarker whose measurement should not be abandoned. A blood lactate greater than 5.0 mmol/L as a risk factor of adverse outcomes (15). Though the WHO recognizes blood lactate as a valid prognostic biomarker in CM, it does not provide recommendations for the optimal duration of lactate measurement in children with CM or other severe malaria syndromes.

If measured, blood lactate in children with CM is typically assessed only at admission. Though associations between admission laboratory factors and outcomes are important, it is possible that trends in prognostic biomarkers through time may be more informative than a single measurement collected at the time of hospital presentation. In children with non-malarial illnesses (e.g. pneumonia and sepsis) and hyperlactatemia, a higher rate of post-admission lactate clearance is associated with decreased mortality risk (16–21). Whether elevated post-admission lactate or trends in this laboratory value through time are also associated with outcomes in pediatric CM is unknown. To evaluate the optimal duration of measurements of blood lactate in children with CM, we assessed the strength of association of outcomes with lactate trends through time for the first 24 hours after hospitalization.

We performed a retrospective cohort study of children aged 6 months to 14 years old admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi with clinical CM, defined as a Blantyre Coma Scale (BCS) ≤ 2, asexual forms of Plasmodium falciparum on peripheral blood smear, and no other known etiology of coma. Children were admitted to a long-standing observational study of CM pathogenesis between September 2000 and June 2018. Participants were hospitalized on the Paediatric Research Ward, an inpatient unit specialized in the evaluation and clinical care of children with febrile coma, including CM. Guardians of all study participants consented to enrollment in the parent study, which was approved by the Institutional Review Boards of Michigan State University (USA) and the University of Malawi College of Medicine (Malawi). At the time of enrollment, guardians consented to the future use of deidentified data in secondary analyses, such as those used here. Ethical approval for this secondary analysis was provided by Children’s National Research Institute (Washington, DC, USA).

On admission, children were clinically stabilized, begun on intravenous fluids at maintenance rates, and administered intravenous antimalarials, quinine through 2013, and artesunate thereafter. Children treated with quinine received a loading dose of 20 mg/kg infused over 4 hours followed by three doses of 10 mg/kg every 12 hours. In 2014 and thereafter, antimalarial treatment was initiated with artesunate given as three doses per Malawi Ministry of Health dosing guidelines. After 24 hours of intravenous antimalarials, therapy was transitioned to a three-day course of enteral lumefantrine–artemether, either orally or via nasogastric tube for patients who remained unconscious. Those who received lumefantrine–artemether by nasogastric tube were transitioned to oral medications when clinically appropriate.

Supportive care included anticonvulsants for clinical or non-convulsive seizures (as determined by admission 30-minute electroencephalogram), blood transfusions at 10 ml/kg of packed red blood cells for those with a hematocrit less than 15%, and enteric feeds via nasogastric tube, typically begun 24 hours after admission. Mechanical ventilation was not available during the study period.

Before publication of the FEAST clinical trial in 2011 (14) most patients with signs of hypovolemia (e.g. decreased skin turgor, capillary refill more than 3 seconds, tachycardia, and/or gallop rhythm on cardiac auscultation) were administered normal saline 10–20 ml/kg intravenously over 1 hour. After 2011, bolus fluid administration for those with signs of hypovolemia was no longer standard practice.

Patient demographics, history, and physical examination findings were collected on admission. Baseline laboratory studies included a thick and thin smear for malaria parasites, full blood count (used for the calculation of circulating parasitemia), blood culture, lumbar puncture, and point of care testing for glucose and lactate using Accuchek (Roche, Indianapolis, Indiana, USA) and LactatePro (Arkray, Mumbai, India), respectively. After admission, blood was obtained every 6 hours until two consecutive thick and thin smears were negative for malaria parasites. Point of care testing for lactate and glucose were obtained every 6 hours for the first 24 to 48 hours after admission.

At the time of hospital discharge, survivors were assessed for the presence of neurologic sequelae by trained clinicians. Children with neurologic sequelae were classified as Survived with Neurologic Sequelae based on a standardized neurologic examination and/or family report of new abnormalities in hearing, vision, cognition, movement, tone, or development.

Statistical analysis.

We defined hyperlactatemia as a blood lactate greater than 5 mmol/L (13, 14, 22). We calculated summary statistics for patient demographics and baseline laboratory values as means and standard deviations for continuous variables, and counts and frequencies for categorical variables. We compared characteristics between children who died to those who survived. In a separate analysis, we compared these characteristics in those who survived and returned to their baseline to those who survived with neurologic sequelae. Comparisons were made using the Wilcoxon rank test for continuous characteristics, or χ2 tests for categorical variables. We logarithmically transformed peripheral parasite densities before comparison.

Significant terms with a p < 0.10 from univariate comparisons were then used in their respective multivariate logistic regression models with death or neurologic sequelae in survivors as the outcomes of interest. In these models, lactate values in longitudinal (post-admission) time points were included in addition to the admission status. Due to missing data after 24 hours post-admission, we included only lactate measurements in the first 24 hours in multivariate models. In multivariate models, we confined our analyses to children who had lactate measurements recorded at admission and at least one time point afterwards. We created one multivariate model using lactate as a continuous variable and a second multivariate model where we dichotomized lactate values into hyperlactatemia (blood lactate > 5.0 mmol/L) or no hyperlactatemia. In models where blood lactate values were dichotomized, we created a covariate for “ever hyperlactatemic” defined as a child with hyperlactatemia at any time point in the 6–24 hours post- admission greater than 5 mmol/L. Additionally, we evaluated the slope of the lactate clearance line as well as a dichotomized trend of serum lactate in the first 24 hours after admission (lactate at 24 hours greater than, equal to, or less than the admission value). In multivariate models, we estimated odds ratios and 95% CI for the addition of these longitudinal lactate measurements. In all models, we controlled for the antimalarial administered, quinine or artesunate.

We assessed mortality and morbidity risk in children who were newly hyperlactatemic at any time point in the first 24 hours of admission. To assess whether the administration of a fluid bolus is associated with a decrease in serum lactate, a two-sample t-test/Wilcoxon Rank Sum test was performed. The effect of fluid bolus on survival status was analyzed by chi-squared test to assess whether bolus given was independent of the outcome and then added to a multivariate logistic regression model. Analyses were performed using SAS version 9.4 (Cary, North Carolina, USA) with 2-sided tests.

A total of 1674 children with CM and at least one lactate measurement were admitted to the Paediatric Research Ward between September 2000 and June 2018. Of these, 272 (16.2%) died. Among the 1402 survivors, 152 (10.8%) had neurologic sequelae.

On univariate analysis, multiple admission demographic, clinical, and laboratory factors were associated with adverse outcomes (Table 1). Children with a lower BCS, higher peripheral parasite count, higher admission white blood cell count, and higher blood lactate all had an increased likelihood of death, compared to children who did not have these abnormalities. In survivors, children who were younger (with age measured as a continuous variable in months), had a lower admission BCS, longer coma duration, and higher admission white blood cell count all had higher rates of adverse neurologic outcomes, compared to those without these characteristics. Children who received a crystalloid fluid bolus were more likely to die compared to those who did not.

Table 1. Admission demographic, clinical information, and outcomes of children with cerebral malaria

Demographic or laboratory measure	Survived without neurologic sequelae (N=1250)	Survived with neurologic sequalae (N=152)	Died (N=272)	P value for difference (Died vs. survived)	P value for difference (in survivors, normal vs. neurologic sequelae)
Age, months, mean (SD)	47.2 (29.8)	42.0 (26.5)	44.7 (27.3)	0.463	0.037
Sex, N (%)
Male	605 (48%)	75 (49.3%)	120 (44.4%)	0.218	0.833
Female	644 (52%)	77 (50.7%)	150 (55.6%)
Blantyre Coma Scale at admission, N (%)
0	124 (9.9%)	25 (16.5%)	69 (25.3%)	<0.001	<0.001
1	480 (38.4%)	77 (50.7%)	122 (44.9%)
2	646 (51.7%)	50 (32.9%)	81 (29.8%)
Coma duration (hours), mean (SD)	12.3 (15.8)	13.9 (16.1)	11.0 (11.9)	0.990	0.008
Parasite count, mean (SD), log (10)	4.5 (1.2)	4.5 (1.1)	4.7 (1.1)	0.003	0.925
Hematocrit %, mean (SD)	22.4 (7.2)	23.7 (8.6)	22.6 (8.4)	0.858	0.165
White blood cell count, mean (SD)	11.0 (8.0)	12.5 (6.7)	15.0 (11.3)	<0.001	<0.001
Lactate (mmol/L), mean (SD)	6.3 (4.4)	6.6 (4.6)	9.2 (4.9)	<0.001	0.534
Hyperlactatemia, N (%)	496 (49%)	61 (52%)	162 (78%)	<0.001	0.555
Glucose (mmol/L), mean (SD)	6.6 (3.4)	6.7 (4.3)	6.7 (4.9)	0.179	0.483
Received blood transfusion, N (%)	445 (36%)	55 (36%)	92 (34%)	0.561	0.887
Received >1 blood transfusion	25 (2%)	5 (3%)	18 (7%)	<0.001	0.300
Received crystalloid bolus, N (%)	153 (12%)	25 (16%)	81 (30%)	<0.001	0.141
Received >1 bolus	25 (2.0%)	5 (3.3%)	18 (6.6%)	<0.001	0.300

In multivariate modeling using death as the outcome of interest and blood lactate as a continuous variable, similar clinical and demographic variables were independently associated with death. For each 1 mmol/L increase in blood lactate, the odds of death increased by 1.05 (95% confidence interval [CI]: 0.99-1.11). At six hours after admission, the strength of association between blood lactate and death was higher with 1.16-fold higher odds of death (95% CI: 1.09-1.23) for each 1 mmol/L blood lactate increase (Table 2). Addition of other post-admission lactate values (slope of lactate values through 24 hours, dichotomized comparisons of admission and 24-hour lactate, lactate values after 6 hours) were not retained in multivariate model selection. We did not perform multivariate modelling with adverse neurologic sequelae in survivors as the outcome of interest because lactate was not associated with this outcome on univariate analysis.

Table 2: Independent association of demographic, clinical, and laboratory values with death in children with CM using blood lactate as a continuous independent variable

	Univariate		Backwards selection (P-stay < 0.1)
	Univariate		Backwards selection (P-stay < 0.1)
	OR	95% CI	OR	95% CI
Age, months, mean (SD)	0.99	(0.99-1.00)
Sex, N (%)
Male	1	(Ref)	1	(Ref)
Female	1.37	(0.94-2.01)	1.72	(1.12-2.66)
Blantyre Coma Scale at admission, N (%)
0	1	(Ref)	1	(Ref)
1	0.53	(0.31-0.91)	0.71	(0.39-1.32)
2	0.30	(0.17-0.53)	0.45	(0.24-0.84)
Parasite count, mean (SD), log (10)	1.28	(1.07-1.53)
Admission hematocrit %, mean (SD)	1.03	(1.00-1.05)	1.06	(1.03-1.05)
Admission white blood cell count, mean (SD)	1.04	(1.02-1.06)	1.02	(1.00-1.05)
Admission Lactate (mmol/L), mean (SD)	1.12	(1.07-1.16)	1.05	(0.99-1.11)
6 Hour Lactate (mmol/L), mean (SD)	1.20	(1.14-1.26)	1.16	(1.09-1.23)
Glucose (mmol/L), mean (SD)	1.01	(0.96-1.07)
Received blood transfusion, N (%)	1.18	(0.81-1.72)
Received >1 blood transfusion	3.38	(1.62-7.05)
Received crystalloid bolus, N (%)	3.29	(2.22-4.87)	1.80	(1.07-3.03)
Received >1 bolus	3.38	(1.62-7.05)

When blood lactate values were dichotomized into hyperlactatemia and no hyperlactatemia (using 5 mmol/L as a cutoff), the results of multivariate modeling changed (Table 3). Those who had hyperlactatemia on admission had a 2.49-fold higher odds of death (95% CI: 1.47-4.22) compared to those who did not. If hyperlactatemia was present at 6 hours after admission, the odds of death were 2.20-fold higher (95% CI: 0.91-5.32) compared to those without hyperlactatemia at this time point. Children who receive crystalloid boluses had a higher risk of death compared to those who did not (Table 3). Children administered blood had no change in mortality risk.

Table 3: Independent association of demographic, clinical, and laboratory values with death in children with CM when blood lactate values are dichotomized.

	Univariate		Backwards selection (P-stay < 0.1)
	Univariate		Backwards selection (P-stay < 0.1)
	OR	95% CI	OR	95% CI
Age, months, mean (SD)	0.99	(0.99-1.00)
Sex, N (%)
Male	1	(Ref)	1	(Ref)
Female	1.37	(0.94-2.01)	1.63	(1.07-2.48)
Blantyre Coma Scale at admission, N (%)
0	1	(Ref)	1	(Ref)
1	0.53	(0.31-0.91)	0.67	(0.37-1.21)
2	0.30	(0.17-0.53)	0.42	(0.23-0.77)
Parasite count, mean (SD), log (10)	1.28	(1.07-1.53)
Admission hematocrit %, mean (SD)	1.03	(1.00-1.05)	1.04	(1.01-1.07)
Admission white blood cell count, mean (SD)	1.04	(1.02-1.06)	1.03	(1.01-1.05)
Admission hyperlactatemia	2.95	(1.94-4.50)	2.49	(1.47-4.22)
6 Hour hyperlactatemia	0.99	(0.46-2.12)	2.20	(0.91-5.32)
Glucose (mmol/L), mean (SD)	1.01	(0.96-1.07)
Received blood transfusion, N (%)	1.18	(0.81-1.72)
Received >1 blood transfusion	3.38	(1.62-7.05)
Received crystalloid bolus, N (%)	3.29	(2.22-4.87)	2.40	(1.52-3.79)
Received >1 bolus	3.38	(1.62-7.05)

Results of longitudinal measurements of blood lactate reveal that new episodes of hyperlactatemia were detected throughout the first 24 hours after hospital admission (Table 4). Mortality and morbidity rates in those with hyperlactatemia detected at admission and at 6, 12, and 18 hours post-admission were higher than those without hyperlactatemia. At 24 hours post-admission, those with newly detected hyperlactatemia had a similar risk of adverse outcomes compared to those with normal lactate.

Table 4: Incidence of hyperlactatemia in the first 24 hours of hospital admission children with cerebral malaria

Time (hours)	N at beginning of time interval¹	Deaths before next time point	Hyperlactatemia (n)	Number of those with hyperlactatemia without previous episodes of hyperlactatemia	Mortality rate of those with hyperlactatemia	Mortality rate of those without hyperlactatemia	p-value	Morbidity rate of those with hyperlactatemia
0 (admit)	1336	61	717	NA	22%	8%	<0.001	49%
6	1043	28	286	67	22%	9%	<0.001	25%
12	977	17	142	21	22%	8%	<0.001	13%
18	929	23	119	24	22%	6%	<0..01	10%
24	864	25	112	30	12%	6%	0.022	10%

Lactate is the primary measurable result of anaerobic metabolism. In severe illness, when blood oxygen levels fail to meet tissue oxygen demands, anaerobic metabolism begins, and lactate is produced. In CM and other severe malaria syndromes, the etiology of elevated blood lactate is likely multifactorial. Proposed mechanisms include parasite production, decreased host perfusion secondary to parasite sequestration (and secondary anaerobic metabolism), and anemia resulting in lower oxygen carrying capacity (23, 24). In both malarial and non-malarial severe illness, addressing this oxygenation deficit through resuscitation is a therapeutic goal. The persistence of hyperlactatemia after presentation to the hospital and initial resuscitation efforts likely speaks to the failure of initial interventions, thus explaining the association noted in our study and others of blood lactate of 6, 12, and 18 hours post-admission being associated with mortality. Congruent with our results, in Indian children with sepsis, blood lactate levels at 6 hours after admission are more strongly associated with mortality than levels at admission (21).

In both univariate and multivariate analyses, admission lactate and values of lactate during the first 24 hours after admission are not associated with adverse neurologic outcomes in CM survivors. Our findings are similar to those in previously published studies evaluating associations between exposures and neurologic sequelae in CM survivors.(4–6, 8) The association of elevated lactate with mortality but not with neurologic morbidity supports the hypothesis that the pathophysiological pathway between infection and death may be different than that between infection and neurologic morbidity. When evaluating the efficacy of interventions in CM, death and neurologic morbidity may not be ordinal outcomes, but have separate pathophysiological pathways.

Our study has many strengths, foremost its large sample size. To our knowledge, this is the largest study of lactate in pediatric CM to date. Additionally, the personnel caring for the children over the 18-year data collection period did not substantially vary through time, decreasing the likelihood of differential clinical care impacting the outcomes of children across years.

Our study has several limitations. Hospital laboratory confirmation of point of care testing of lactate values was unavailable at our institution. As the blood lactate levels reported were from finger stick samples as opposed to free-flowing venous samples, there may have been false elevations in blood lactate, especially in children who were hypovolemic. Additionally, blood lactate measurements, if any, that were taken prior to arrival on the Pediatric Research Ward were not included in our analyses. It is possible that children may have received intravenous fluid boluses before arrival at our referral hospital. As the administration of bolus fluids prior to hospital admission could not be confirmed, our analyses may not truly reflect the amount of intravenous fluid resuscitation given. Future prospective cohort studies evaluating high blood lactate as a prognostic biomarker in pediatric CM should consider enrolling children from the time they present for healthcare.

We evaluated demographic, clinical, and laboratory factors associated with neurologic sequelae at the time of hospital discharge. Since neurologic sequelae may either resolve (e.g., motor disorders) or newly appear (e.g., developmental delay, epilepsy) post-hospitalization, it is likely more meaningful to evaluate associations between exposures and long-term neurologic abnormalities. As post-discharge neurologic and developmental assessments were available for only a small proportion of the children in our cohort, we did not include them in our analyses. Our study’s results should be confirmed with prospective data collection.

In pediatric CM, high blood lactate at the time of admission or 6 hours after admission is independently associated with death but not with neurologic sequelae in CM survivors. Whether analyzed as a dichotomous variable, blood lactate is associated with death at the time of admission and up to 18 hours afterwards. Neither trends in blood lactate through time nor blood lactate levels obtained after 18 hours post-admission were associated with death. Neither blood lactate values in the first 24 hours after hospitalization nor the trends in lactate through time are not associated with adverse neurologic outcomes in CM survivors. To accurately assess prognosis in a child with CM, blood lactate should be measured at both admission and 6, 12, and 18 hours afterwards. Given blood lactate’s limited utility as a decision point for targeted intervention, measurements longer than 18 hours post-admission are unlikely to be of value.

BCS Blantyre Coma Scale

CI Confidence interval

CM Cerebral malaria

FEAST Fluid Expansion as Supportive Therapy

Ethics approval and consent to participate. Ethical approval for the parent study was obtained through the Institutional Review Boards of Michigan State University (USA) and the University of Malawi College of Medicine (Malawi). Consent to participate in the parent study was obtained from guardians of all study participants at time of enrollment. Ethical approval for secondary analysis presented here was provided by Children’s National Research Institute (Washington, DC, USA).

Consent for publication. Not applicable.

Availability of data and materials. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests. The authors declare that they have no competing interests.

Funding. This work was supported by internal funding from the Global Health Initiative at Children’s National Hospital (Washington, DC, USA) to RO and MGS. Internal funding from the Children’s National Research Institute was granted to KMC for this work. Additional funding for this work was provided by the W.T. Gill Fellowship of The George Washington University (Washington, DC, USA) to RI.

Authors’ contributions. RO, KBS, and DGP conceptualized the study. RO, MGS, AMM, RI, AML, and KMC were involved in acquisition and extraction of the data from paper records at Queen Elizabeth Central Hospital. JRB analyzed the data and interpreted the results. RO drafted the manuscript. RO, NFO, and DGP edited the manuscript. All authors read and approved the final manuscript.

Acknowledgements. We would like to thank the dedicated clinical team of the Pediatric Research Ward at the Queen Elizabeth Central Hospital in Blantyre, Malawi for their tireless work in caring for the children admitted to the ward. We would also like to thank the Children’s National Global Health Initiative, the Children’s National Research Institute, and the W.T. Gill Fellowship for the funding provided to members of our team for this work.

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No competing interests reported.

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Repeated blood lactate measurements during clinical care of children with cerebral malaria

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Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusions

BACKGROUND

METHODS

Statistical analysis.

RESULTS

DISCUSSION

CONCLUSIONS

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1