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Is Asymmetric Dimethylarginine a Useful Biomarker in Children With Carbon
Monoxide Poisoning?
Article in Pediatric Emergency Care · February 2019
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Is Asymmetric Dimethylarginine a Useful Biomarker in
Children With Carbon Monoxide Poisoning?
Abdullah Yazar, MD,* Fatih Ak
ın, MD,* Ahmet Sert, MD,† Esra Türe, MD,* Cemile Topcu, MD,‡
Alaaddin Yorulmaz, MD,§ and Fatih Ercan, MD||
Objective:Carbon monoxide poisoning (COP) is the leading cause of
mortality and morbidity due to poisoning worldwide. Because children are affected more quick and severely from COP, they may require a longer treat-ment period, even if carboxyhemoglobin (CO-Hb) and/or lactate levels return to normal. Therefore, a new marker that predicts the duration of treatment and the final outcomes of COP is needed.
Methods: This case control study was conducted on 32 carbon
monoxide–poisoned patients younger than 18 years who had been admitted to pediatric emergency department. The control group included age- and sex-matched 30 healthy children. Blood samples were obtained for analysis of arterial blood gases, CO-Hb percent, methemoglobine, lactate, and asym-metric dimethylarginine (ADMA).
Results:Asymmetric dimethylarginine levels were significantly increased
(P < 0.05) in patients with COP on admission and after the treatment when compared with controls (1.36 [0.89–6.94], 1.69 [0.76–7.81], 1.21 [0.73–3.18] nmol/L, respectively). There was no positive correlation between CO-Hb and ADMA levels on admission and at 6 hours (P = 0.903, r = 0.218, P = 0.231, r = 0.022, respectively). Positive correlation was found between lactate and CO-Hb levels on admission (P = 0.018, r = 0.423).
Conclusions:This study showed that ADMA levels were still high after
6 hours of 100% oxygen therapy in children with COP, even CO-Hb and/or lactate levels return to normal range. On the basis of these results, we con-sider that ADMA may be a useful biomarker in patient with COP. Key Words: ADMA, biomarker, carbon monoxide
(Pediatr Emer Care 2019;35: 226–230)
C
arbon monoxide poisoning (COP) is the leading cause ofmortality and morbidity due to poisoning worldwide.1The
annual prevalance and mortality rates of COP cases in Turkey have been reported to be 0.0137% (approximately 14 in every
100,000) and 5 in every 10 million people, respectively.2Carbon
monoxide (CO) releases into the environment by incomplete com-bustion of carbon containing materials. It is nonirritating, taste-less, odortaste-less, and colorless; thus, exposured patients usually
become unconscious before they realize that they are poisoned.3
After inhalation of CO via the lungs, it easily diffuses from lungs into the bloodstream and then forms carboxyhemoglobin (CO-Hb) with hemoglobin (Hb), which is a tight but slowly re-versible complex. The affinity of CO to Hb is 210 times greater than oxygen, and when binded, it decreases the oxygen-carrying
and oxygen-delivery capacity of Hb.4,5When CO-Hb levels rise,
the cerebral blood vessels become dilated, and coronary blood flow and capillary density increased. Continued exposure results with central respiratory depression due to cerebral hypoxia. Especially, ventricular
arrhythmias develop with cardiac involvement.3,4In addition to CO
in-duced hypoxia, other mechanisms including inhibited mitochondrial respiration, lipid peroxidation, oxidative stress due to impaired antioxi-dant balance, and direct toxic effects also have been reported to
contrib-ute to organ damage in patients with COP.6,7
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (eNOS). It is synthe-sized by protein arginine methyltransferases (PRMTs) from argi-nine and degraded by dimethylargiargi-nine dimethylaminohydrolase
(DDAH).8,9Asymmetric dimethylarginine levels increase in the
course of oxidative stress, owing to increased activity of PRMTs
and inhibition of DDAH.10Asymmetric dimethylarginine suppresses
the activity of eNOS by competing withL-arginine, and this results
with low expression of nitric oxide (NO).8Nitric oxide has protective
effects on vascular structure and function. These effects include pre-vention of smooth muscle proliferation, leukocyte adhesion, and platelet aggregation. In the absence of NO, vascular smooth muscles proliferate and the elasticity of vessel wall decreases owing to loss of vasodilatation. Asymmetric dimethylarginine causes a decrease in
NO levels leading to endothelial dysfunction.11
In this respect, increased levels of ADMA may indicate en-dothelial dysfunction in patients exposed to CO gas. In literature, there is only 1 study on this topic, which was conducted on adults, and ADMA levels were found to be increased on admission with a
turn to normal levels after treatment.12The aim of this study was
to determine the changes of ADMA levels, as an oxidative stress marker, in patients with COP on admission and after treatment. To the best of our knowledge, our study is the first to analyze ADMA levels in children with COP.
METHODS
This case control study was conducted on CO-poisoned pa-tients younger than 18 years who had been admitted to pediatric emergency department of Necmettin Erbakan University Meram Medical Faculty, between October 2016 and May 2017. The diagnosis of COP was based on history, clinical examination, and CO-Hb percent (CO-Hb%) greater than 3% at the time of admission. Pa-tients with liver disease, pulmonary disease, congenital heart or metabolic diseases, and hemolytic disorder were excluded from the study. The sources of poisoning of all the patients were gas from coal or wood burnt in stoves. Patients were divided into 2 groups as symptomatic and asymptomatic on admission. All
pa-tients received high-flow (12–15 L/min) 100% oxygen therapy
with nonrebreathing mask with an oxygen reservoir bag for at least 6 hours. The control group included age- and sex-matched 30 healthy children who did not have any chronic illness or sign of infection and undergoing blood analyses for any reason (ie, anemia, check-up, abdominal pain, constipation, loss of appetite). Informed consent was obtained from their parents. The study was approved by the ethics committee of our institution (approval number, 14567952-050/2016/758).
From the *Department of Pediatric Emergency, Meram Medical Faculty, Necmettin Erbakan University;†Department of Pediatric Cardiology, Medical Faculty, Selcuk University;‡Department of Medical Biochemistry, Meram Medical Faculty, Necmettin Erbakan University; §Department of Pediatrics, Medical Faculty, Selcuk University; and ||Department of Pediatrics, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
Disclosure: The authors declare no conflict of interest.
Reprints: Abdullah Yazar, MD, Necmettin Erbakan University, Meram Medical Faculty, Department of Pediatric Emergency, 42080, Meram-Konya, Turkey (e‐mail: drabdullahyazar@hotmail.com).
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0749-5161
Blood samples were obtained for analysis of arterial blood gases, CO-Hb%, methemoglobine percent (MetHb%), lactate, and ADMA on admission and after 6 hours of treatment. Serum creatine kinase (CK), CK-myocardial band isoenzyme (CK-MB), lactate dehydrogenase (LDH), cardiac troponin I, aspartate amino-transferase (AST) and alanine aminoamino-transferase (ALT), urea, creat-inine, and complete blood count were measured only at admission.
Samples were separated by centrifugation and stored at−80°C until
the day of analysis as suggested in the literature.13,14Samples were
analyzed at the Biochemistry Laboratory of Necmettin Erbakan University Meram Medical Faculty.
Serum levels of ADMA were measured by enzyme-linked immunosorbent assay (ELISA) technique with ELISA device (BioTek, Instruments; ELISA kit catalog number, 201-12-1888, Sunredbio). Arterial blood gases and lactate, metHb%, and CO-Hb% measurements were performed by using blood gas ana-lyzer (Radiometer, Copenhagen BL 700 Series). The CK-MB values were assayed by the ADVIA Centaur System (Siemens), using 2-site sandwich direct chemiluminometric immunoassay technology. Troponin I levels were measured with a 3-site sandwich immunoassay using direct chemiluminometric technology (The ADVIA Centaur CP TnI-Ultra assay). Levels of urea, creatinine, AST, ALT, CK, and LDH tests were measured by using a fully au-tomatic biochemical analyzer (Architect c Systems, Abbott Labora-tories). Complete blood count analyses were performed by using Coulter analyzer Sysmex XN-1000, Sysmex Corporation, Kobe, Japan. The evaluation of 12-lead electrocardiogram (ECG) was
recorded with a paper speed of 25 mm/s for every patient before and after 6 hours of treatment.
Statistical Analysis
The collected data were computerized and statistically ana-lyzed using Statistical Package for the Social Sciences (SPSS for Windows, version 15.0). Quantitative data were summarized as mean ± SD. If not normally distributed, parameters were presented as median (range). The Kolmogorov-Smirnov test was applied to check distribution of parameters. Data that did not normally distrib-uted (ADMA levels) were log-transformed for analysis. Differences in the means of variables were evaluated using both parametric and nonparametric tests depending on the distribution of the variables. Independent t test or Mann-Whitney U test was used to compare groups, and the associations between parameters were assessed using the Pearson or Spearman correlation test. Paired samples t test or Wilcoxon-signed rank test was used to compare pretreatment and posttreatment values of the study group. Results were considered
significant if P≤ 0.05.
RESULTS
Thirty-eight patients had admitted to pediatric emergency de-partment during this period with CO poisoning. Whereas 6 of them were excluded owing to exclusion criteria, the study group was consisted of 32 patients. The groups were similar with respect to age (P > 0.05). Table 1 shows the demographic and laboratory
TABLE 1. Demographic and Laboratory Characteristics of Patients With COP and the Controls
Healthy Controls Patients With COP on Admission
Patients With COP
After Treatment P Age, y 7.94 ± 5.06 8.68 ± 4.84 8.68 ± 4.84 Male/female 11/19 12/20 12/20 WBC, /mm3 11.468.75 ± 4545.62 9847.81 ± 3250 ± 0.2 <0.01 ANC, /mm3 6746.56 ± 3176.47 5499.69 ± 2034.15 <0.01 ALC, /mm3 3839.81 ± 3954.41 3335.31 ± 2236.58 >0.05 Hb, g/dL 12.73 ± 1.41 12.69 ± 1.35 >0.05 MCV, fL 78.17 ± 6.64 77.98 ± 6.43 >0.05 Platelets,103/mm3 321.38 ± 117.27 314.75 ± 85.81 >0.05 MPV, fL 7.98 ± 1.58 8.16 ± 1.78 >0.05 Urea, mg/dL 25.66 ± 6.47 26.76 ± 7.76 >0.05 Crea, mg/dL* 0.48 (0.19–0.83) 0.52 (0.21-0.89) >0.05 ALT, U/L 20.09 ± 10.10 19.69 ± 8.61 >0.05 AST, U/L 25.47 ± 9.47 23.28 ± 8.64 >0.05 CK, U/L 98.23 ± 39.19 82.47 ± 38.40 <0.05 CK-MB, ng/mL 2.03 ± 1.64 1.61 ± 1.43 <0.05 Troponin, ng/mL* 0.01 (0.01-0.27) 0.01 (0.01-0.25) >0.05 LDH, U/L 276.78 ± 49.48 227.25 ± 52.26 <0.001 CO-Hb% 13.51 ± 7.54 1.18 ± 0.60 <0.001 Ph 7.36 ± 0.067 7.39 ± 0.03 <0.05 PCO2, mm/Hg 37.63 ± 5.40 39.42 ± 4.81 >0.05 PO2, mm/Hg 76.4 ± 9.80 90.5 ± 7.48 <0.001 HCO3, mmol/L 22.3 ± 3.21 23.30 ± 3.21 >0.05 MetHb% 1.50 ± 0.41 1.20 ± 0.37 <0.001 Lactate, mmol/L 2.14 ± 0.73 1.46 ± 0.41 <0.001
Data were presented as mean ± SD.
*If not normally distributed, values were presented as median (minimum-maximum).
ALC indicates absolute lymphocyte count; MCV, mean corpuscular volume; MPV, mean platelet volume; Urea, blood urea nitrogen; Crea, creatinine; MetHb%, methemoglobin percent; P, P value of comparison between patients with COP on admission and after treatment.
Pediatric Emergency Care • Volume 35, Number 3, March 2019 ADMA, a Useful Biomarker in CO-Poisoned Children?
characteristics of patients and the controls. Although loss of con-sciousness was not present in any patient, 12 of the patients had no complaints on admission, 7 had headache, and 13 had vomiting and vertigo. Cardiovascular and respiratory system examinations of all patients were normal.
Serum ADMA levels of the patients and controls are given in Table 2. Comparison of ADMA and logADMA levels of patients with COP on admission and control group is given in Figures 1A and B, respectively. Asymmetric dimethylarginine levels were sig-nificantly increased in patients with COP on admission and after the treatment when compared with controls (P < 0.05). Asymmet-ric dimethylarginine levels did not significantly differ in patients with COP after the treatment when compared with baseline (P > 0.05). Serum ADMA values were not correlated with other parameters before and after treatment. After log transformation, serum ADMA values were not correlated with other parameters before and after treatment. There was no positive correlation be-tween CO-Hb and ADMA levels on admission and at 6 hours (P = 0.903, r = 0.218, P = 0.231, r = 0.022, respectively). Positive correlation was found between lactate and CO-Hb levels on ad-mission (P = 0.018, r = 0.423) (Fig. 2). There was no statistically difference between symptomatic and asymptomatic patients in terms of both ADMA and CO-Hb levels (P > 0.05).
When the admission ECGs of the patients were examined, si-nus tachycardia was found in 9 patients, t-negativity in precordial derivations in 5, early repolarization in 2, and incomplete right branching block in 1. All patients had normal ECGs after treatment. Asymmetric dimethylarginine levels did not significantly differ in patients with abnormal ECGs when compared with normal ECGs
on admission (P > 0.05). Serum CK, CK-MB, LDH, lactate, CO-Hb%, and metHb% values were significantly decreased in pa-tients with COP after the treatment when compared with the baseline (Table 1).
DISCUSSION
Although the pathophysiology of COP is complex and in-completely understood, oxidative stress plays an important role. Recent studies focused on tissue damage due to CO-induced oxi-dative stress. Here we showed that levels of ADMA, which is an oxidative stress biomarker, were elevated in patients with COP.
In the literature, COP patients without consciousness loss were classified as minor and moderate according to the patients'
complaints.15,16In our study, more than one third of our patients
had no complaints at the time of admission and they were accom-panying other affected family members. Remaining patients had complaints of headache, nausea and vomiting, and all of them were conscious. This was owing to the fact that severe COP cases in our region were taken to another center where a hyperbaric ox-ygen therapy was available.
Abnormal ECG findings including sinus tachycardia, ST segment or T-waves changes, and prolonged Q-T interval in patients
with COP have also been reported in various studies.12,17In our
study, sinus tachycardia was detected in 9 patients, t-negativity in precordial derivations in 5, early repolarization in 2, and incomplete right bundle branch block in 1 at the time of admission, all of which returned to normal after treatment.
TABLE 2. Serum ADMA and logADMA Levels of Patients With COP and the Controls
Healthy Controls
Patients With COP on Admission
Patients With COP
After Treatment P1 P2 P3
No. patients 30 32 32
ADMA, nmol/mL 1.21 (0.73–3.18) 1.36 (0.89–6.94) 1.69 (0.76–7.81) <0.05 <0.05 >0.05 logADMA 0.0828 (−0.14–0.50) 0.1319 (−0.05–0.84) 0.2279 (−0.12–0.89) <0.05 <0.05 >0.05
Values were presented as median (minimum-maximum) for the ADMA levels were not normally distributed. Mann-Whitney U test was used to compare ADMA levels in healthy controls and patients groups on admission and after treatment. Wilcoxon-signed rank test was used to compare pretreatment and posttreatment values of the patient group.
P1indicates P value of comparison between controls and patients with COP on admission; P2, P value of comparison between controls and patients with COP after treatment; P3, P value of comparison between patients with COP on admission and after treatment.
FIGURE 1. A, Comparison of ADMA levels of patients with COP on admission and control group. B, Comparison of logADMA levels of patients with COP on admission and control group.
Carbon monoxide–induced myocardial dysfunction without ECG changes had been attributed to myocardial stunning by some authors. Thus, some biomarkers including CK, CK-MB, LDH,
and troponin I that show cardiac damage have been studied.18,19
Satran et al17reported that myocardial injury due to moderate to
severe COP is common. Elevated CK-MB or cardiac troponin I re-garding myocardial injury was seen in 35% of the patients in that
study.17 In another study, approximately 15% of patients with
COP had elevated CK and CK-MB levels, whereas troponin I
was slightly elevated in only 1 patient.20In our study, all the
pa-tients' troponin I levels were within normal limits. However, initial CK, CK-MB, and LDH levels were significantly higher compared with posttreatment levels. These biomarkers are not unique to cardiac tissue alone. They may also elevate in the ischemia of non-cardiac tissues. This elevation can last for days in major non-cardiac
is-chemias.21 Elevation of these enzymes accompanying ECG
abnormalities suggested cardiac involvement in our patients, and rapid recovery of these findings after oxygen therapy shows that these involvements were minor cardiac ischemias that had devel-oped secondary to hypoxia.
Elevated CO-Hb% levels are used to confirm the clinical
di-agnosis of COP.1Whereas half-life of CO-Hb in COP patients
treated with 100% oxygen at atmospheric pressure is approxi-mately 75 minutes, it is nearly 20 to 30 minutes in patients treated
with hyperbaric O2therapy. Hyperbaric O2therapy is usually
recom-mended for intermediate and severe poisonings.22,23In our study, as
expected, blood CO-Hb% was increased in the study group on ad-mission (maximum CO-Hb level was 27.1%). They were treated with 100% oxygen at atmospheric pressure for nearly 4 to 6 hours. After treatment, CO-Hb levels had returned to normal limits.
Studies showed that CO-Hb levels were reflecting the sever-ity of the poisoning, but there was poor correlation with clinical findings. Sufficient coherence was not observed between levels of CO-Hb and clinical symptoms. This brings the opinion that in-creased CO-Hb concentrations help to diagnose acute COP but do not conclude possible long-term neuropsychiatric or cardiac
con-sequences.24,25Elevated CO-Hb levels alone are not predictive for
symptoms or the final outcome. Therefore, a new and better marker that can predict the duration of treatment and outcome of COP is essential. Oxidative stress is an important factor in the
pathogenesis of acute COP.7Change of balance between
antioxi-dants and prooxiantioxi-dants has been reported.
Whereas ADMA is synthesized from arginine by PRMTs, it
is degraded by DDAH.9 Regulation of the activities of both
PRMTs and DDAH is in a redsensitive fashion. Although ox-idative stress increases the activity of PRMTs, it inhibits the
DDAH, which leads to increased levels of ADMA.10Increased
levels of ADMA inhibit eNOS leading to decreased NO levels
and subsequent endothelial dysfunction.8,26There are many
clin-ical studies related to ADMA levels in various diseases, whereas ADMA levels in COP have been studied for the first time by
Abass et al,8and no other study is currently available in the
liter-ature. In that study, in addition to ADMA levels, heart-type fatty acid-binding protein 3 and cardiac biomarkers were evaluated on admission and after treatment in patients with COP. They found that ADMA levels on the admission were significantly higher than the control group, similar to our results.
Asymmetric dimethylarginine levels in human serum can be measured by various methods (ie, high-performance liquid chro-matography, mass spectrometry, ELISA). All these technologies are equal in terms of their rapidity. However, the technology re-quired for ELISA is widely available, and the result can be
ob-tained in as short as 1 hour.27In our study, serum ADMA levels
were measured by ELISA technique and the incubation period of ADMA ELISA kit we used was 60 minutes. Although there are no data on the half-life of ADMA in pediatric subjects, it was measured to be approximately 20 to 30 minutes in healthy
adults.28Therefore, it is expected that the plasma level will decrease
rapidly when the tissue damage caused by oxidative stress is
over-came. Abass et al12observed significant reductions of ADMA
levels in their work after 6 hours of oxygen therapy. However, in our study, when admission levels of ADMA were compared, no decrease was observed after treatment. This result might suggest that increased oxidative stress and tissue damage in childhood COP still persist after 6 hours of treatment.
Lactate, which is an important marker of tissue hypoxia, oc-curs as a product of anerobic glycolysis. Lactate levels have been increasingly used in the course of critical patients as well as COP.29,30Recent studies also show that lactate levels are more
meaningful in determining prognosis, hospitalization, and the
choice of treatment.31,32In our study, we also found that lactate
levels were significantly higher in patients with COP on admission when compared with levels after treatment, and positive correla-tion was found between lactate and CO-Hb levels at the time of admission.
Methemoglobinemia is a rare but well known life-threatening condition that can be congenital or acquired. The togetherness of methemoglobinemia with high CO-Hb levels can be much more
fa-tal.33In our patients, MetHb levels at the time of admission were in
the normal range, with a statistically significant decrease after treat-ment. White blood cell (WBC) counts increase owing to physical and emotional stress as well as metabolic conditions including aci-dosis, azotemia, diabetic coma, hypoxia, acute gout, thyroid storm,
and burns.34 In our study, WBC and absolute neutrophil count
(ANC) values at the time of admission were significantly higher than those after treatment, as expected.
Our study had some limitations. The first and the most im-portant issue was that severe COP cases could not be included into the study because patients with unconsciousness had been directly referred to the hospital where hyperbaric oxygen therapy was available, and hence, no neurological sequelae was seen in any pa-tient. The second, it was not possible to select a control group that also received 6 hours of oxygen therapy to understand clearly whether high levels of ADMA after treatment were owing to hyperoxi or hypoxia. The third, lack of the knowledge of half-life, reference levels of ADMA, and what high levels of ADMA imply in children were other limitations.
FIGURE 2. Correlation of lactate and CO-Hb levels of patients with COP on admission.
Pediatric Emergency Care • Volume 35, Number 3, March 2019 ADMA, a Useful Biomarker in CO-Poisoned Children?
This study mainly focused on ADMA levels of children with
acute COP. Carbon monoxide exposure–induced oxidative stress
leads to an increase in ADMA levels. A subsequent decrease in NO levels results with endothelial dysfunction. In our study, we found that ADMA levels were significantly increased in patients with COP before and after treatment when compared with con-trols. Although high levels of WBC, ANC, CO-Hb, lactate, CK, and CK-MB levels returned to normal after treatment, ADMA levels continued to be high. This suggests that possible oxidative stress is continuing after 100% oxygen therapy, even if CO-Hb and/or lactate levels return to normal. In conclusion, on the basis of these results, we consider that ADMA may be a useful bio-marker in patients with COP, especially where CO-Hb and lactate level may be normal in delayed cases. However, this study has been conducted on a small sample size, so it is felt that further larger clinical trials should be conducted to clarify the role of ADMA in CO-induced endothelial dysfunction in children.
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