Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2015

Open Access 01-12-2015 | Research

The role of previously unmeasured organic acids in the pathogenesis of severe malaria

Authors: M. Trent Herdman, Natthida Sriboonvorakul, Stije J. Leopold, Sam Douthwaite, Sanjib Mohanty, M. Mahtab Uddin Hassan, Richard J. Maude, Hugh WF Kingston, Katherine Plewes, Prakaykaew Charunwatthana, Kamolrat Silamut, Charles J. Woodrow, Kesinee Chotinavich, Md. Amir Hossain, M. Abul Faiz, Saroj Mishra, Natchanun Leepipatpiboon, Nicholas J. White, Nicholas PJ Day, Joel Tarning, Arjen M. Dondorp

Published in: Critical Care | Issue 1/2015

Login to get access

Abstract

Introduction

Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria.

Methods

In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death.

Results

Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean±SD) was elevated in severe malaria (8.2 mEq/L±4.5) and severe sepsis (8.6 mEq/L±7.7) compared with uncomplicated malaria (6.0 mEq/L±5.1) and encephalopathy (6.6 mEq/L±4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6–7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5–7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).

Conclusions

Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.
Appendix
Available only for authorised users
Literature
1.
Dondorp AM, Lee SJ, Faiz MA, Mishra S, Price R, Tjitra E, et al. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin Infect Dis. 2008;47:151–7.PubMed
2.
World Health Organisation, Communicable Diseases Cluster. Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94:S1–90.
3.
Bruneel F, Tubach F, Corne P, Megarbane B, Mira JP, Peytel E, et al. Severe imported falciparum malaria: a cohort study in 400 critically ill adults. PLoS One. 2010;5:e13236.PubMedPubMedCentral
4.
Day NP, Phu NH, Mai NT, Chau TT, Loc PP, Chuong LV, et al. The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med. 2000;28:1833–40.PubMed
5.
Warrell DA, White NJ, Veall N, Looareesuwan S, Chanthavanich P, Phillips RE, et al. Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria. Lancet. 1988;2:534–8. A published erratum appears in Lancet 1988;2:698.PubMed
6.
Hanson J, Lam SW, Mahanta KC, Pattnaik R, Alam S, Mohanty S, et al. Relative contributions of macrovascular and microvascular dysfunction to disease severity in falciparum malaria. J Infect Dis. 2012;206:571–9.PubMed
7.
Planche T, Onanga M, Schwenk A, Dzeing A, Borrmann S, Faucher JF, et al. Assessment of volume depletion in children with malaria. PLoS Med. 2004;1:e18.PubMedPubMedCentral
8.
Dondorp AM, Ince C, Charunwatthana P, Hanson J, van Kuijen A, Faiz MA, et al. Direct in vivo assessment of microcirculatory dysfunction in severe falciparum malaria. J Infect Dis. 2008;197:79–84.PubMed
9.
Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, et al. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2. PLoS Med. 2005;2:e204. A published erratum appears in PLoS Med. 2005;2:390.PubMedPubMedCentral
10.
Maude RJ, Beare NA, Abu Sayeed A, Chang CC, Charunwatthana P, Faiz MA, et al. The spectrum of retinopathy in adults with Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg. 2009;103:665–71.PubMed
11.
Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, et al. Impaired nitric oxide bioavailability and l-arginine–reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med. 2007;204:2693–704.PubMedPubMedCentral
12.
Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A. 2008;105:17097–102.PubMedPubMedCentral
13.
Pukrittayakamee S, White NJ, Davis TM, Looareesuwan S, Supanaranond W, Desakorn V, et al. Hepatic blood flow and metabolism in severe falciparum malaria: clearance of intravenously administered galactose. Clin Sci (Lond). 1992;82:63–70.
14.
Corey HE, Vallo A, Rodríguez-Soriano J. An analysis of renal tubular acidosis by the Stewart method. Pediatr Nephrol. 2006;21:206–11.PubMed
15.
Figge J, Rossing TH, Fencl V. The role of serum proteins in acid–base equilibria. J Lab Clin Med. 1991;117:453–67.PubMed
16.
Dondorp AM, Chau TT, Phu NH, Mai NT, Loc PP, Chuong LV, et al. Unidentified acids of strong prognostic significance in severe malaria. Crit Care Med. 2004;32:1683–8.PubMed
17.
Forni LG, McKinnon W, Lord GA, Treacher DF, Peron JM, Hilton PJ. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care. 2005;9:R591–5.PubMedPubMedCentral
18.
Moviat M, Terpstra AM, Ruitenbeek W, Kluijtmans LA, Pickkers P, van der Hoeven JG. Contribution of various metabolites to the “unmeasured” anions in critically ill patients with metabolic acidosis. Crit Care Med. 2008;36:752–8.PubMed
19.
Balasubramanyan N, Havens PL, Hoffman GM. Unmeasured anions identified by the Fencl-Stewart method predict mortality better than base excess, anion gap, and lactate in patients in the pediatric intensive care unit. Crit Care Med. 1999;27:1577–81.PubMed
20.
Sriboonvorakul N, Leepipatpiboon N, Dondorp AM, Pouplin T, White NJ, Tarning J, et al. Liquid chromatographic-mass spectrometric method for simultaneous determination of small organic acids potentially contributing to acidosis in severe malaria. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;941:116–22.PubMedPubMedCentral
21.
Tran TH, Day NP, Nguyen HP, Nguyen TH, Tran TH, Pham PL, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med. 1996;335:76–83.PubMed
22.
Charunwatthana P, Abul Faiz M, Ruangveerayut R, Maude RJ, Rahman MR, Roberts 2nd LJ, et al. N-acetylcysteine as adjunctive treatment in severe malaria: a randomized, double-blinded placebo-controlled clinical trial. Crit Care Med. 2009;37:516–22.PubMedPubMedCentral
23.
Hanson J, Lee SJ, Mohanty S, Faiz MA, Anstey NM, Charunwatthana P, et al. A simple score to predict the outcome of severe malaria in adults. Clin Infect Dis. 2010;50:679–85.PubMed
24.
Kellum JA, Bellomo R, Kramer DJ, Pinsky MR. Hepatic anion flux during acute endotoxemia. J Appl Physiol. 1995;78:2212–7.PubMed
25.
Olszewski KL, Llinas M. Central carbon metabolism of Plasmodium parasites. Mol Biochem Parasitol. 2011;175:95–103.PubMed
26.
Assadian A, Assadian O, Senekowitsch C, Rotter R, Bahrami S, Fürst W, et al. Plasma d-lactate as a potential early marker for colon ischaemia after open aortic reconstruction. Eur J Vasc Endovasc Surg. 2006;31:470–4.PubMed
27.
Stolberg L, Rolfe R, Gitlin N, Merritt J, Mann Jr L, Linder J, et al. d-Lactic acidosis due to abnormal gut flora—diagnosis and treatment of two cases. N Engl J Med. 1982;306:1344–8.PubMed
28.
Halparin ML, Kamel KS. d-Lactic acidosis: turning sugar into acids in the gastrointestinal tract. Kidney Int. 1996;49:1–8.
29.
Uribarri J, Oh MS, Carroll HJ. d-Lactic acidosis: a review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine (Baltimore). 1998;77:73–82.
30.
Bender DA. The aromatic amino acids: phenylalanine, tyrosine and tryptophan. In: Amino acid metabolism. 3rd ed. Chichester, UK: John Wiley & Sons; 2012. p. 323–76.
31.
Hoffmann G, Aramaki S, Blum-Hoffmann E, Nyhan WL, Sweetman L. Quantitative analysis for organic acids in biological samples: batch isolation followed by gas chromatographic-mass spectrometric analysis. Clin Chem. 1989;35:587–95.PubMed
32.
Khodakova A, Beloboradova N. Microbial metabolites in the blood of patients with sepsis [abstract P5]. Crit Care. 2007;11:S3.
33.
Deutsch JC. Determination of p-hydroxyphenylpyruvate, p-hydroxyphenyllactate and tyrosine in normal human plasma by gas chromatography-mass spectrometry isotope-dilution assay. J Chromatogr B Biomed Sci Appl. 1997;690:1–6.PubMed
34.
Beloboradova NV, Olenin AY, Khodakova AS. Phenylcarboxylic acids as potential markers for diagnosis of sepsis in cardiac surgery patients. In: Archiv Euromedica: advanced methods of diagnosis, treatment and prophylactics. 1 and 2nd ed. Hannover, Germany: Europäische Wissenschaftliche Gesellschaft; 2011. p. 20–6.
35.
Beloborodova N, Bairamov I, Olenin A, Shubina V, Teplova V, Fedotcheva N. Effect of phenolic acids of microbial origin on production of reactive oxygen species in mitochondria and neutrophils. J Biomed Sci. 2012;19:89.PubMedPubMedCentral
36.
Müting D, Wuzel H, Bucsis L, Flasshoff HJ. Urinary p-hydroxyphenyllactic acid as indicator of hepatic encephalopathy in patients with hepatic cirrhosis. Lancet. 1985;2:1365–6.PubMed
37.
Endo F, Kitano A, Uehara I, Nagata N, Matsuda I, Shinka T, et al. Four-hydroxyphenylpyruvic acid oxidase deficiency with normal fumarylacetoacetase: a new variant form of hereditary hypertyrosinemia. Pediatr Res. 1983;17:92–6.PubMed
38.
Enwonwu CO, Afolabi BM, Salako LA, Idigbe EO, al-Hassan H, Rabiu RA. Hyperphenylalaninaemia in children with falciparum malaria. QJM. 1999;92:495–503.PubMed
39.
Lopansri BK, Anstey NM, Stoddard GJ, Mwaikambo ED, Boutlis CS, Tjitra E, et al. Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications. Infect Immun. 2006;74:3355–9.PubMedPubMedCentral
40.
Seydel KB, Milner Jr DA, Kamiza SB, Molyneux ME, Taylor TE. The distribution and intensity of parasite sequestration in comatose Malawian children. J Infect Dis. 2006;194:208–5.PubMed
41.
Windus-Podehl G, Lyftogt C, Zieve L, Brunner G. Encephalopathic effect of phenol in rats. J Lab Clin Med. 1983;101:586–92.PubMed
42.
Hicks JM, Young DS, Wootton ID. The effect of uraemic blood constituents on certain cerebral enzymes. Clin Chim Acta. 1964;9:228–35.PubMed
43.
Krnjević K, Walz W. Acidosis and blockade of orthodromic responses caused by anoxia in rat hippocampal slices at different temperatures. J Physiol. 1990;422:127–44.PubMedPubMedCentral
44.
Sasi P, English M, Berkley J, Lowe B, Shebe M, Mwakesi R, et al. Characterisation of metabolic acidosis in Kenyan children admitted to hospital for acute non-surgical conditions. Trans R Soc Trop Med Hyg. 2006;100:401–9.PubMed
45.
Record CO, Iles RA, Cohen RD, Williams R. Acid–base and metabolic disturbances in fulminant hepatic failure. Gut. 1975;16:144–9.PubMedPubMedCentral
46.
Lord RS, Bralley JA. Clinical applications of urinary organic acids. Part I: Detoxification markers. Altern Med Rev. 2008;13:205–15.PubMed
47.
Pettersen JE, Landaas S, Eldjarn L. The occurrence of 2-hydroxybutyric acid in urine from patients with lactic acidosis. Clin Chim Acta. 1973;48:213–9.PubMed
Metadata
Title
The role of previously unmeasured organic acids in the pathogenesis of severe malaria
Authors
M. Trent Herdman
Natthida Sriboonvorakul
Stije J. Leopold
Sam Douthwaite
Sanjib Mohanty
M. Mahtab Uddin Hassan
Richard J. Maude
Hugh WF Kingston
Katherine Plewes
Prakaykaew Charunwatthana
Kamolrat Silamut
Charles J. Woodrow
Kesinee Chotinavich
Md. Amir Hossain
M. Abul Faiz
Saroj Mishra
Natchanun Leepipatpiboon
Nicholas J. White
Nicholas PJ Day
Joel Tarning
Arjen M. Dondorp
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-015-1023-5

Other articles of this Issue 1/2015

Critical Care 1/2015 Go to the issue

Research

Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study

Research

Neurological outcomes in children dead on hospital arrival

Review

Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock

Commentary

Shedding metabo‘light’ on the search for sepsis biomarkers

Research

Daily estimation of the severity of organ dysfunctions in critically ill children by using the PELOD-2 score

Research

Nurses’ worry or concern and early recognition of deteriorating patients on general wards in acute care hospitals: a systematic review