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Ischemia-modified albumin levels in carbon monoxide poisoning
American Journal of Emergency Medicine (2011) 29, 675–681
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Brief Report
Ischemia-modified albumin levels in carbon monoxide poisoning☆ Suleyman Turedi MD a,⁎, Orhan Cinar MD b , Umit Kaldirim MD b , Ahmet Mentese BSc c , Ozgur Tatli MD a , Erdem Cevik MD b , Salim Kemal Tuncer MD b , Abdulkadir Gunduz MD a , Levent Yamanel MD d , Suleyman Caner Karahan MD c a
Department of Emergency Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey Department of Emergency Medicine, Gülhane Military Medical Academy, Ankara, Turkey c Department of Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey d Department of Internal Medicine, Gülhane Military Medical Academy, Ankara, Turkey b
Received 1 December 2009; revised 12 January 2010; accepted 3 February 2010
Abstract Objectives: Ischemia-modified albumin (IMA) is an emerging diagnostic biomarker for many ischemic conditions. This study was conducted to investigate whether there is a change in IMA levels in carbon monoxide (CO) poisoning and, if so, the clinical relevance of IMA levels. Methods: This cohort study, performed between November 2008 and April 2009, compared the serum IMA levels of 33 CO-poisoned patients taken at the time of presentation at the emergency department and after 3 hours of treatment and 49 healthy controls. In addition, IMA and carboxyhemoglobin levels were analyzed according to CO poisoning patients' poisoning severity scores. Results: Carbon monoxide patients' IMA levels were higher than those of the control group both at time of admission and at the third hour of the treatment, P b .0001. A significant fall was determined in carboxyhemoglobin (CO-Hb) levels at the end of the third hour of treatment, P b .0001. However, there was no significant difference between the IMA levels measured at admission and at the end of the third hour of treatment (P N .05). There was no significant correlation between IMA and CO-Hb levels in COpoisoned patients. Also, there was no difference in blood IMA levels in classification according to patients' poisoning severity score and CO-Hb levels. Conclusion: Results from this pioneering study established a high level of IMA in CO-poisoned patients, suggesting that IMA may also be sensitive to hypoxia. Considering the preliminary nature of this study, the clinical utility of IMA levels in CO poisoning should be further investigated with more comprehensive studies. © 2011 Elsevier Inc. All rights reserved.
1. Introduction ☆ We declare that we have no financial interest or conflict of interest with anybody or organizations in relation to the data presented in this study. ⁎ Corresponding author. Karadeniz Teknik Universitesi, Tip Fakultesi Acil Tip AD, 61080 Trabzon, Turkey. Tel.: +90 04623775819; fax: +90 04623250518. E-mail address: [email protected] (S. Turedi).
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1.1. Background Carbon monoxide (CO) poisoning is a common condition, leading to more than 40 000 estimated emergency department (ED) visits annually in the United States alone
676 [1]. Carbon monoxide is the main cause of poisoning-related death and morbidity in developed countries and may be responsible for more than half of the fatal poisonings reported in many countries [2]. Carbon monoxide is an odorless, colorless, poisonous gas that arises from incomplete combustion of carbon. When CO poisoning is suspected, carboxyhemoglobin (CO-Hb) is usually measured. A high CO-Hb level indicates exposure to exogenous CO and supports the diagnosis [3]. Given that the signs and symptoms of CO poisoning are nonspecific, it is probable that many more cases go unsuspected or are attributed to other etiologies and are therefore either undiagnosed or else misdiagnosed [4]. The mechanism of toxicity of CO poisoning is not fully understood. Carbon monoxide binds hemoglobin with an affinity some 200 times greater than that of oxygen, thus impairing the delivery of oxygen to tissue. Carbon monoxide also binds to myoglobin, aggravating the hypoxia in the cardiac muscle, and to mitochondrial cytochrome oxidase, thus impairing the production of adenosine triphosphatase. Carbon monoxide poisoning leads to free radical formation and lipid peroxidation in the brain and other tissues [5]. Exposure to elevated levels of CO may result in severe intoxication and death. Most CO intoxication patients die due to the ventricular dysrhythmia caused by tissue hypoxia [6].
1.2. Importance Ischemia-modified albumin (IMA) is a new and sensitive biomarker of myocardial ischemia [7]. However, high IMA concentrations do not seem to depend purely on myocardial involvement, and other organs seem to be responsible for the increase in IMA levels. Studies have demonstrated that many conditions may elevate IMA levels, such as pulmonary embolism, mesenteric ischemia, peripheral arterial occlusion, deep venous thrombosis, stroke, and acute cardiac arrest, and that IMA may be a diagnostic biomarker for these conditions [8-14]. According to available databases, there have been no studies evaluating IMA levels, which are extremely sensitive to ischemia, in CO-poisoned patients.
1.3. Goals of this investigation This study, planned in the light of the hypoxic condition existing in CO poisoning patients, was intended to investigate the hypothesis that IMA levels may rise significantly clinically, whether there is a change in IMA levels in CO poisoning and, if so, the clinical significance of such a change.
2. Materials and methods 2.1. Study design and setting This prospective, multicenter, cohort study was performed in the EDs of the Karadeniz Technical University and
S. Turedi et al. Gulhane Military Medical Academy hospitals, Turkey. The protocol for the study was approved by the institutional review board, and it was performed in accordance with the Helsinki Declaration.
2.2. Selection of participants All patients with CO poisoning admitted to the 2 EDs between November 2008 and April 2009 were eligible for this prospective study. A total of 49 age- and sex-matched healthy volunteers served as controls. Exclusion criteria were (i) acute ischemia disease including acute coronary syndrome, acute ischemic cerebrovascular disease, acute peripheral arterial occlusion, or acute mesenteric ischemia; (ii) a history of advanced liver or heart failure; (iii) patients with CO-Hb levels lower than 2%, regardless of normobaric oxygen therapy during transportation to our Institutes with emergency transport system, and those referred after initial CO poisoning therapy in different hospitals and those referred for hyperbaric oxygen (HBO) or intensive care; (iv) arrest stage at arrival to the ED; or (v) refusal to participate in the study. The control group was selected from nonsmoking individuals not employed in activities involving chronic CO exposure, such as chefs cooking “doner kebab” and barbecue grill, who met none of the exclusion criteria used in the selection of the patient group and who were comparable in terms of age and sex.
2.3. Data collection and processing Medical details (such as symptoms, cause of CO exposure, and CO exposure duration) were recorded for all patients using a questionnaire. All patients' vital signs (heart rate, systolic and diastolic blood pressure, respiration rate, temperature) at admission and Glasgow Coma Scale scores were evaluated. Electrocardiography (ECG) was administered to all patients at admission, and ECG variations were recorded. In addition, CO-Hb levels were determined by measuring arterial blood gas from all patients at admission. Poisoning severity score (PSS) was applied to the most severe symptomatology as described in the literature [15] (grade 0, none: no symptoms or signs related to poisoning; grade 1, minor-mild: transient and spontaneously resolving symptoms; grade 2, moderate: pronounced or prolonged symptoms; grade 3, severe: severe or life-threatening symptoms; grade 4, fatal: death). All patients were administered 100% normobaric oxygen as initial treatment. In the event of special circumstances such as prolonged confusion, neurologic findings, cardiovascular dysfunction, severe acidosis, and a CO-Hb level greater than 25% or pregnancy, patients were treated with hyperbaric oxygen treatment.
IMA levels in CO poisoning
677
Table 1 Baseline demographic and clinical characteristics of the study population Variables
Control group CO poisoning (n = 49) group (n = 33)
Age, mean ± SD (y) 36 ± 11 Sex (M/F) 23/26 Hemodynamic characteristics SbP, mean ± SD (mm Hg) 119 ± 12 DbP, mean ± SD (mm Hg) 74 ± 10 Heart rate, mean ± SD 73 ± 11 (beats/min) Respiratory rate, 15 ± 2 mean ± SD (breaths/min) Symptoms, n (%) Dizziness Headache Vomiting Syncope Nausea Dyspnea Blurred vision Chest pain Palpitations Ataxia Confusion Loss of consciousness Flu-like symptoms Month of exposure to CO poisoning, n (%) December January February March April Cause of exposure to CO poisoning, n (%) Coal-fired stove Gas-fired stove Hot water boiler Gas boiler Wood-burning stove Length of exposure to CO, mean ± SD (h) Length of follow-up at the ED, mean ± SD (h) Glasgow Coma Score at admission, n (%) 11 14 15 Poisoning score at admission, n (%) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 ECG findings at admission, n (%) Normal Sinusal tachycardia T wave variation Branch block
34 ± 13 15/18 120 ± 20 75 ± 12 90 ± 16 18 ± 6
16 (47.6) 29 (87.8) 9 (27.2) 4 (12.1) 19 (57.6) 7 (21.3) 7 (21.3) 5 (15.2) 10 (30.3) 1 (3) 5 (15.2) 3 (9.1) 4 (12.1) 7 (21.2) 10 (30.3) 5 (15.1) 7 (21.2) 4 (12.1) 12 (36.4) 9 (27.3) 7 (21.2) 4 (12.1) 1 (3) 3.2 ± 1.9 5.2 ± 2.2
1 (3) 3 (9.1) 29 (87.9)
22 (66.7) 10 (30.3) 1 (3)
Table 1 (continued) Variables
Control group CO poisoning (n = 49) group (n = 33)
ECG findings at admission, n (%) ST depression QT extension Gas analysis at admission PO2, mean ± SD (mm Hg) PCO2, mean ± SD (mm Hg) sO2, mean ± SD (%) pH, mean ± SD Treatment applied, n (%) Normobaric oxygen treatment Hyperbaric oxygen treatment
1 (3) 1 (3) 93.1 ± 33.3 33.9 ± 6.4 96.2 ± 3.5 7.43 ± 0.06 29 (87.9) 4 (12.1)
SbP, systolic blood pressure; Dbp, diastolic blood pressure.
2.4. Methods of measurement 2.4.1. IMA measurements Five-milliliter blood samples were taken from the brachial vein of CO-poisoned patients at the time of admission to the ED and at the end of 3 hours of treatment. These were immediately placed in ice and centrifuged at 3000 rpm for 15 minutes and then pipetted into Eppendorf tubes in the ED and stored at −80°C until analysis (maximum of 5 months). Blood samples were taken only once from the healthy individual comprising the control group, for IMA measurement. Reduced cobalt to albumin binding capacity (IMA levels) was analyzed by a blinded biochemist using the rapid and colorimetric method developed by Bar-Or et al [16]. 2.4.2. Primary data analysis Statistical analysis was performed using SPSS for Windows 11.0 (SPSS, Chicago, Ill) and MedCalc statistical software. Results are expressed as mean ± SD. The normality of data was tested using Kolmogorov-Smirnov test. Student t test was used to compare the mean IMA and CO-Hb levels of the control and CO poisoning groups at admission, paired t test was used to compare mean IMA levels of the CO poisoning group at the admission and third hour of the therapy. One-way analysis of variance was used for IMA and CO-Hb level comparisons of groups categorized according to the PSS. Correlations between the IMA and CO-Hb levels were assessed using Pearson correlation test. Statistical significance was assumed at a level of P b .05.
3. Results 17 (51.5) 8 (24.2) 4 (12.1) 2 (6.1)
3.1. Characteristics of study subjects Thirty-seven patients (29 admitted to the Gulhane Military Academy ED Hospital and 8 admitted to the Karadeniz Technical University Hospital ED), all suffering
S. Turedi et al.
1 (3) 2 (6.1) 1 (3)
1 (3) 2 (6.1) 1 (3) 1 (3) 1 (3)
1 (3)
1 (3) 2 (6.1) 3 (9.1) 4 (12.1) 1 (3)
Table 3 Measured IMA levels of the patients and control groups at admission and third hour of treatment Time dependent IMA levels (ABSU)
Groups Control group CO poisoning P (n = 49) group (n = 33)
Admission 0.17 ± 0.07 Third hour of treatment P
0.29 ± 0.04 0.31 ± 0.06 .40
.0001 .0001
from CO poisoning, together with 49 healthy control subjects were enrolled. Four patients were excluded for being transferred to our hospitals from the intensive care units of other hospitals. None of the patients enrolled died, and all were discharged in a healthy condition with no aftereffects. The baseline demographic and clinical characteristics of subjects are presented in Table 1. Numbers of patients' major symptoms and signs of and their classification in CO-Hb levels are shown in Table 2.
3.2. Main results Measured IMA levels of the patients and control groups at admission and third hour of the treatment are shown in Table 3 and Fig. 1. Mean IMA levels were statistically significant higher in the patient group than in the control group. A significant fall was determined in CO-Hb levels at the end of the third hour of treatment, P b .0001 (23.9% ± 11.1% at admission versus 7.5% ± 4.3% at the third hour of the treatment). However, there was no significant change in IMA levels measures at admission or at the end of the third hour of treatment, P = .9 (0.31 ± 0.06 absorbance unit [ABSU] and 0.29 ± 0.04 ABSU, respectively).
(6.1%) (18.2) (24.2) (6.1) (3) 2 6 8 2 1 b10% 10%-20% 20%-30% 30%-40% N40%
3 10 12 3 1
(9.1) (30.3) (36.4) (9.1) (3)
1 3 3 2 1
(3) (9.1) (9.1) (6.1) (3)
1 (3) 1 (3) 1 (3)
1 (3) 6 (18.2) 10 (30.3) 2 (6.1)
2 (6.1) 4 (12.1) 1 (3)
1 (3) 4 (12.1) 1 (3) 1 (3)
1 (3) 3 (9.1)
Ataxia Palpitation Chest pain Blurred vision Dyspnea Nausea Syncope Vomiting Headache Dizziness CO-Hb levels
Table 2
Numbers of major symptoms and signs in patients and their classification according to CO-Hb levels, n (%)
Confusion
Loss of consciousness
Flu-like symptoms
678
Fig. 1 Measured IMA levels and 95% confidence interval for median of the patients and control groups at the admission and at the third hour of the treatment.
IMA levels in CO poisoning
679
Table 4 Mean CO-Hb and IMA levels among the study groups classified according to PSS PSS Grade Grade Grade Grade Grade
0 (n 1 (n 2 (n 3 (n 4 (n
= 0) = 22) = 10) = 1) = 0)
CO-Hb, mean ± SD (%)
IMA, mean ± SD (ABSU)
22.4 ± 8.9a 22.8 ± 10.5b 51.6a,b
0.29 ± 0.05 0.26 ± 0.03 0.31
Different letters in the same row indicate statistical difference (a: grade 1 versus grade 3, P b .005; b: grade 2 versus grade 3, P b .03).
In addition, there was no significant correlation between IMA and CO-Hb levels in CO-poisoned patients (correlation coefficient −0.197' P = .273; 95% confidence interval, −0.157 to 0.505). Ischemia-modified albumin and CO-Hb levels were investigated in terms of CO patients classified according to PSS, the results being shown in Table 4. Carboxyhemoglobin levels were significantly high in patients with high PSS results, taken as an indicator of degree of poisoning, whereas no difference in IMA levels between the groups was determined. Also, there was no difference in blood IMA levels in classification according to CO-Hb levels (Table 5).
4. Limitations The patients comprising the study group were made up of PSS grades 1 and 2. The number of patients exposed to more severe levels of poisoning was very small, and this prevented our obtaining reliable findings regarding serious poisoning. In addition, the intensive care planned as an indicator of clinical course was not possible because the patients applying during the study period were exposed to a relatively less severe level of poisoning, and we could not therefore obtain such prognostic findings as neurologic sequels at discharge and mortality. We could not exclude the possible impact of normobaric oxygen therapy on CO-Hb and IMA levels; this is despite the fact that we considered only patients with CO-Hb levels lower than 2% regardless of consideration of normobaric Table 5 Mean IMA levels among the study groups classified according to CO-Hb levels CO-Hb groups
n
IMA mean ± SD (ABSU)
≤10% 10%-20% 20%-30% 30%-40% ≥40
4 10 13 4 2
0.31 ± 0.03 0.25 ± 0.05 0.30 ± 0.04 0.31 ± 0.05 0.32 ± 0.01
P N .05, for comparison of the all groups.
oxygen treatment during transport. Normobaric oxygen therapy is a routine application in emergency transport system, but the interval of poisoning to admission varies also due to distance of location of incidents. However, considering the lack of reduction in increased IMA levels after the controlled normobaric oxygen therapy in our setting for 3 hours, this is not so critical for the IMA, bearing in mind that it definitely has an impact on CO-Hb levels.
5. Discussion Our study is the first in which IMA levels were higher in CO-poisoned patients than in healthy individuals, in which this was determined to continue at the end of the third hour of treatment and in which this biochemical parameter was evaluated as a clinical course indicator in CO-poisoned patients. The pathophysiologic mechanism of CO poisoning consists of a tissue hypoxia caused by CO-mediated circulatory failure [17]. After being inhaled, CO is easily absorbed from the lungs into the bloodstream and then forms a tight but slowly reversible complex with hemoglobin, known as CO-Hb. A high CO-Hb level usually indicates exogenous exposure to CO, but CO is also produced endogenously in states of rapid hemoglobin turnover such as severe hemolytic anemia. Intravascular hemolysis with associated endogenous CO production as a byproduct of heme metabolism results in the elevation of the CO-Hb levels to as high as 9.7% [18]. Carboxyhemoglobin being present in the bloodstream restricts erythrocyte oxygen transport and also lowers tissue oxygen availability, resulting in tissue hypoxia. Carbon monoxide raises cytosolic heme levels, leading to oxidative stress. It binds to platelet heme protein and cytochrome C oxidase, thus interrupting cellular respiration and leading to the production of reactive oxygen species, which in turn leads to neuronal necrosis and apoptosis. Cellular respiration impairment leads to a stress response, including hypoxiainducible factor 1α activation, which results in neurologic and cardiac protection or injury, depending on the level of CO involved, by means of gene regulation. Carbon monoxide exposure also causes inflammation through multiple pathways that are independent of those involved in hypoxia, leading to neurologic and cardiac injury [19]. Carbon monoxide poisoning symptoms may be the result of exposure either to low levels of CO for extended periods of time or, alternatively, to higher levels for a shorter period. Carbon monoxide poisoning may result in a wide variety of signs and symptoms. Because these are frequently nonspecific, CO poisoning may be overlooked [20]. Carbon monoxide poisoning symptoms, signs, and prognosis have a poor correlation with the CO-Hb level determined on arrival at hospital [21]. Numerous tables of symptom-associated CO-Hb levels are available; however,
680 most physicians recognize the poor correlation between COHb levels and the clinical presentation of patients with CO poisoning [22]. The reason is that there are wide variations in CO-Hb levels in CO-poisoned patients. This may be related to the time elapsing between exposure to CO ceasing and taking blood samples for measuring CO-Hb. Alternatively, variations in clinical presentation may be related to the duration of exposure to CO, its concentration, the basic health of the person concerned and their susceptibility to CO, or the amount and duration of supplemental oxygen administered before blood samples are taken [22]. As the related evidence ample, the risk factors for squeal from CO poisoning (including CO-Hb levels, loss of consciousness, etc) are now better documented, and a relation between the severity of CO-related illness and risk of squeal is categorized and guides the management of this cases [20,23]. However, relatively instability of the conventional marker during a long period, CO-Hb, necessitates discovery of a longer stable and sensitive markers such as IMA according to findings from this preliminary study. During acute ischemic conditions, the metal binding capacity of albumin is modified and reduces transition metal binding, generating a metabolic variant of protein. This change is quantifiable and commonly known as IMA [24]. Recently, IMA measurement has been proposed as a sensitive marker for the diagnosis of myocardial ischemia presenting with typical acute chest pain and licensed by the US Food and Drug Administration for diagnostic use in suspected myocardial ischemia [24]. However, high IMA concentrations do not seem to depend purely on myocardial involvement, and other organs seem to be responsible for the increase in IMA levels. Ischemia-modified albumin levels may rise during ischemia-reperfusion, affecting any organ, and cannot be considered together with oxidative stress [24]. According to available databases, this study is the first to examine IMA as a biochemical parameter of CO poisoning. Serum IMA levels were significantly higher in CO-poisoned patients compared with healthy individuals at both time of admission and at the third hour of treatment. That elevation was thought to be in all likelihood related to the hypoxic condition already present in CO-poisoned patients and to increased oxidative stress. The impact on the patient's clinical status of the level of CO in the tissue may be equal or greater than that of CO in the blood [22]. Elevated levels of CO-Hb can produce sufficient tissue hypoxia for CO to bind to cytochrome C oxidase in a noncompetitive manner. Cytochrome C oxidase represents the terminal enzyme within the mitochondrial electrontransport chain. Carbon monoxide noncompetitive binding in local tissue hypoxia has also been observed in vivo in a heart preparation. The reduction in high-energy stores and intracellular acidosis during the course of CO-induced hypoxia can even be aggravated after CO exposure, even though CO-Hb has been eradicated. The worsening in energy metabolism during reoxygenation may be ascribed to CO uptake by cytochrome C oxidase. Human lymphocytic
S. Turedi et al. mitochondrial cytochrome C oxidase inhibition persisting for several days has been observed in the wake of acute CO poisoning, with CO-Hb levels varying from 11.6% to 22.3% [20]. The results of our study show that blood CO-Hb levels declined significantly with normobaric oxygen treatment. The CO-Hb half-life in patients with CO poisoning who are treated with 100% oxygen at atmospheric pressure is approximately 75 minutes [25]. Because this relatively short half-life of CO-Hb and CO-Hb levels of CO-poisoned patients should also be obtained as soon as possible. However, there was no significant reduction in IMA levels, regarded as a sensitive marker for ischemia; indeed, and even slightly higher IMA levels were determined than those at time of admission. This is in accordance with the information that IMA levels increases rapidly within minutes after ischemia and remains elevated 6 to 12 hours [26]. We did not expect significant decline on the IMA levels before clinical decision on discharge of our cases. Our findings have importance with regard to 2 points. One is significant to establish that the sensitive ischemia marker, IMA, is also elevated under hypoxia, although the contribution of associated oxidative stress should also be considered. Second, the longer turnover time of IMA may represent advantage compared with COHb, and this may have critical importance in the screening and management of CO poisoning. Although it would not be correct, in the light of these findings, to definitively conclude that IMA levels can be used as a clinical marker in CO poisoning, Ischemia-modified albumin may be a parameter that can be used clinically together with CO-Hb levels in terms of reflecting tissue hypoxia and oxidative burden to which tissues are exposed. This study also evaluated the severity of clinical status of CO-poisoned patients in the light of their PSS. Poisoning severity score as a grading of acute poisoning was described in the late 1990s and used in some toxicologic reports [27]. Cevik et al [27] determined significantly higher CO-Hb levels in PSS grade 3 patients that in patients with lower degrees. Similarly to the study of Cevik et al, we determined a significant correlation between CO-Hb levels and PSS at the time of admission. Also, CO-Hb levels in our PSS grade 3 patients were significantly higher than those in patients with lower grades. Serum IMA levels examined at admission exhibited no such correlation. However, because there was only 1 PSS grade 3 patient, it is not possible to say that these findings are completely clarificatory.
6. Conclusions Results from this pioneering study established high levels of IMA in CO-poisoned patients. Considering the rather preliminary nature of this current study, further studies targeting the significance of this biomarker in relation to brain or cardiac injury, immediate or late outcome, as well as its possible correlation with established biomarkers such as
IMA levels in CO poisoning troponin and SB-100 for the heart and brain, respectively, are warranted.
References [1] Hampson NB, Weaver LK. Carbon monoxide poisoning: a new incidence for an old disease. Undersea Hyperb Med 2007;34:163-8. [2] Buckley NA, Isbister GK, Stokes B, Juurlink DN. Hyperbaric oxygen for carbon monoxide poisoning: a systematic review and critical analysis of the evidence. Toxicol Rev 2005;24:75-92. [3] Hampson NB, Scott KL, Zmaeff JL. Carboxyhemoglobin measurement by hospitals: implications for the diagnosis of carbon monoxide poisoning. J Emerg Med 2006;31:13-6. [4] Hampson NB, Hauff NM. Carboxyhemoglobin levels in carbon monoxide poisoning: do they correlate with the clinical picture? Am J Emerg Med 2008;26:665-9. [5] Wolf SJ, Lavonas EJ, Sloan EP, Jagoda AS, American College of Emergency Physicians. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. Ann Emerg Med 2008;51: 138-52. [6] Davutoglu V, Gunay N, Kocoglu H, Gunay NE, Yildirim C, Cavdar M, et al. Serum levels of NT-ProBNP as an early cardiac marker of carbon monoxide poisoning. Inhal Toxicol 2006;18:155-8. [7] Sinha MK, Roy D, Gaze DC, Collinson PO, Kaski JC. Role of “Ischemia modified albumin,” a new biochemical marker of myocardial ischaemia, in the early diagnosis of acute coronary syndromes. Emerg Med J 2004;21:29-34. [8] Turedi S, Gunduz A, Mentese A, Karahan SC, Yilmaz SE, Eroglu O, et al. Value of ischemia-modified albumin in the diagnosis of pulmonary embolism. Am J Emerg Med 2007;25:770-3. [9] Turedi S, Gunduz A, Mentese A, Topbas M, Karahan SC, Yeniocak S, et al. The value of ischemia-modified albumin compared with D-dimer in the diagnosis of pulmonary embolism. Respir Res 2008;9:49. [10] Gunduz A, Turedi S, Mentese A, Karahan SC, Hos G, Tatli O, et al. Ischemia-modified albumin in the diagnosis of acute mesenteric ischemia: a preliminary study. Am J Emerg Med 2008;26:202-5. [11] Gunduz A, Turkmen S, Turedi S, Mentese A, Yulug E, Ulusoy H, et al. Time-dependent variations in ischemia-modified albumin levels in mesenteric ischemia. Acad Emerg Med 2009;16:539-43. [12] Mentese A, Mentese U, Turedi S, Gunduz A, Karahan SC, Topbas M, et al. Effect of deep vein thrombosis on ischaemia-modified albumin levels. Emerg Med J 2008;25:811-4.
681 [13] Gunduz A, Mentese A, Turedi S, Karahan SC, Mentese U, Eroglu O, et al. Serum ischaemia-modified albumin increases in critical lower limb ischaemia. Emerg Med J 2008;25:351-3. [14] Gunduz A, Turedi S, Mentese A, Altunayoglu V, Turan I, Karahan SC, et al. Ischemia-modified albumin levels in cerebrovascular accidents. Am J Emerg Med 2008;26:874-8. [15] Persson HE, Sjöberg GK, Haines JA, Pronczuk de Garbino J. Poisoning severity score. Grading of acute poisoning. J Toxicol Clin Toxicol 1998;36:205-13. [16] Bar-Or D, Lau E, Winkler JV. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia—a preliminary report. J Emerg Med 2000;19:311-5. [17] Atalay H, Aybek H, Koseoglu M, Demir S, Erbay H, Bolaman AZ, et al. The effects of amifostine and dexamethasone on brain tissue lipid peroxidation during oxygen treatment of carbon monoxide-poisoned rats. Adv Ther 2006;23:332-41. [18] Hampson NB. Carboxyhemoglobin elevation due to hemolytic anemia. J Emerg Med 2007;33:17-9. [19] Weaver LK. Clinical practice. Carbon monoxide poisoning. N Engl J Med 2009;360:1217-25. [20] Weaver LK. Carbon monoxide poisoning. Crit Care Clin 1999;15: 297-317. [21] Thom SR, Taber RL, Mendiguren II, Clark JM, Hardy KR, Fisher AB. Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995;25:474-80. [22] Raub JA, Mathieu-Nolf M, Hampson NB, Thom SR. Carbon monoxide poisoning—a public health perspective. Toxicology 2000; 145:1-14. [23] Weaver LK, Valentine KJ, Hopkins RO. Carbon monoxide poisoning: risk factors for cognitive sequelae and the role of hyperbaric oxygen. Am J Respir Crit Care Med 2007;176:491-7. [24] Turedi S, Gunduz A, Mentese A, Dasdibi B, Karahan SC, Sahin A, et al. Investigation of the possibility of using ischemia-modified albumin as a novel and early prognostic marker in cardiac arrest patients after cardiopulmonary resuscitation. Resuscitation 2009;80:994-9. [25] Weaver LK, Howe S, Hopkins R, Chan KJ. Carboxyhemoglobin halflife in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure. Chest 2000;117:801-8. [26] Lippi G, Montagnana M, Salvagno GL, Guidi GC. Potential value for new diagnostic markers in the early recognition of acute coronary syndromes. CJEM 2006;8:27-31. [27] Cevik AA, Unluoglu I, Yanturali S, Kalkan S, Sahin A. Interrelation between the Poisoning Severity Score, carboxyhaemoglobin levels and in-hospital clinical course of carbon monoxide poisoning. Int J Clin Pract 2006;60:1558-64.
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Brief Report
Ischemia-modified albumin levels in carbon monoxide poisoning☆ Suleyman Turedi MD a,⁎, Orhan Cinar MD b , Umit Kaldirim MD b , Ahmet Mentese BSc c , Ozgur Tatli MD a , Erdem Cevik MD b , Salim Kemal Tuncer MD b , Abdulkadir Gunduz MD a , Levent Yamanel MD d , Suleyman Caner Karahan MD c a
Department of Emergency Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey Department of Emergency Medicine, Gülhane Military Medical Academy, Ankara, Turkey c Department of Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey d Department of Internal Medicine, Gülhane Military Medical Academy, Ankara, Turkey b
Received 1 December 2009; revised 12 January 2010; accepted 3 February 2010
Abstract Objectives: Ischemia-modified albumin (IMA) is an emerging diagnostic biomarker for many ischemic conditions. This study was conducted to investigate whether there is a change in IMA levels in carbon monoxide (CO) poisoning and, if so, the clinical relevance of IMA levels. Methods: This cohort study, performed between November 2008 and April 2009, compared the serum IMA levels of 33 CO-poisoned patients taken at the time of presentation at the emergency department and after 3 hours of treatment and 49 healthy controls. In addition, IMA and carboxyhemoglobin levels were analyzed according to CO poisoning patients' poisoning severity scores. Results: Carbon monoxide patients' IMA levels were higher than those of the control group both at time of admission and at the third hour of the treatment, P b .0001. A significant fall was determined in carboxyhemoglobin (CO-Hb) levels at the end of the third hour of treatment, P b .0001. However, there was no significant difference between the IMA levels measured at admission and at the end of the third hour of treatment (P N .05). There was no significant correlation between IMA and CO-Hb levels in COpoisoned patients. Also, there was no difference in blood IMA levels in classification according to patients' poisoning severity score and CO-Hb levels. Conclusion: Results from this pioneering study established a high level of IMA in CO-poisoned patients, suggesting that IMA may also be sensitive to hypoxia. Considering the preliminary nature of this study, the clinical utility of IMA levels in CO poisoning should be further investigated with more comprehensive studies. © 2011 Elsevier Inc. All rights reserved.
1. Introduction ☆ We declare that we have no financial interest or conflict of interest with anybody or organizations in relation to the data presented in this study. ⁎ Corresponding author. Karadeniz Teknik Universitesi, Tip Fakultesi Acil Tip AD, 61080 Trabzon, Turkey. Tel.: +90 04623775819; fax: +90 04623250518. E-mail address: [email protected] (S. Turedi).
0735-6757/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2010.02.006
1.1. Background Carbon monoxide (CO) poisoning is a common condition, leading to more than 40 000 estimated emergency department (ED) visits annually in the United States alone
676 [1]. Carbon monoxide is the main cause of poisoning-related death and morbidity in developed countries and may be responsible for more than half of the fatal poisonings reported in many countries [2]. Carbon monoxide is an odorless, colorless, poisonous gas that arises from incomplete combustion of carbon. When CO poisoning is suspected, carboxyhemoglobin (CO-Hb) is usually measured. A high CO-Hb level indicates exposure to exogenous CO and supports the diagnosis [3]. Given that the signs and symptoms of CO poisoning are nonspecific, it is probable that many more cases go unsuspected or are attributed to other etiologies and are therefore either undiagnosed or else misdiagnosed [4]. The mechanism of toxicity of CO poisoning is not fully understood. Carbon monoxide binds hemoglobin with an affinity some 200 times greater than that of oxygen, thus impairing the delivery of oxygen to tissue. Carbon monoxide also binds to myoglobin, aggravating the hypoxia in the cardiac muscle, and to mitochondrial cytochrome oxidase, thus impairing the production of adenosine triphosphatase. Carbon monoxide poisoning leads to free radical formation and lipid peroxidation in the brain and other tissues [5]. Exposure to elevated levels of CO may result in severe intoxication and death. Most CO intoxication patients die due to the ventricular dysrhythmia caused by tissue hypoxia [6].
1.2. Importance Ischemia-modified albumin (IMA) is a new and sensitive biomarker of myocardial ischemia [7]. However, high IMA concentrations do not seem to depend purely on myocardial involvement, and other organs seem to be responsible for the increase in IMA levels. Studies have demonstrated that many conditions may elevate IMA levels, such as pulmonary embolism, mesenteric ischemia, peripheral arterial occlusion, deep venous thrombosis, stroke, and acute cardiac arrest, and that IMA may be a diagnostic biomarker for these conditions [8-14]. According to available databases, there have been no studies evaluating IMA levels, which are extremely sensitive to ischemia, in CO-poisoned patients.
1.3. Goals of this investigation This study, planned in the light of the hypoxic condition existing in CO poisoning patients, was intended to investigate the hypothesis that IMA levels may rise significantly clinically, whether there is a change in IMA levels in CO poisoning and, if so, the clinical significance of such a change.
2. Materials and methods 2.1. Study design and setting This prospective, multicenter, cohort study was performed in the EDs of the Karadeniz Technical University and
S. Turedi et al. Gulhane Military Medical Academy hospitals, Turkey. The protocol for the study was approved by the institutional review board, and it was performed in accordance with the Helsinki Declaration.
2.2. Selection of participants All patients with CO poisoning admitted to the 2 EDs between November 2008 and April 2009 were eligible for this prospective study. A total of 49 age- and sex-matched healthy volunteers served as controls. Exclusion criteria were (i) acute ischemia disease including acute coronary syndrome, acute ischemic cerebrovascular disease, acute peripheral arterial occlusion, or acute mesenteric ischemia; (ii) a history of advanced liver or heart failure; (iii) patients with CO-Hb levels lower than 2%, regardless of normobaric oxygen therapy during transportation to our Institutes with emergency transport system, and those referred after initial CO poisoning therapy in different hospitals and those referred for hyperbaric oxygen (HBO) or intensive care; (iv) arrest stage at arrival to the ED; or (v) refusal to participate in the study. The control group was selected from nonsmoking individuals not employed in activities involving chronic CO exposure, such as chefs cooking “doner kebab” and barbecue grill, who met none of the exclusion criteria used in the selection of the patient group and who were comparable in terms of age and sex.
2.3. Data collection and processing Medical details (such as symptoms, cause of CO exposure, and CO exposure duration) were recorded for all patients using a questionnaire. All patients' vital signs (heart rate, systolic and diastolic blood pressure, respiration rate, temperature) at admission and Glasgow Coma Scale scores were evaluated. Electrocardiography (ECG) was administered to all patients at admission, and ECG variations were recorded. In addition, CO-Hb levels were determined by measuring arterial blood gas from all patients at admission. Poisoning severity score (PSS) was applied to the most severe symptomatology as described in the literature [15] (grade 0, none: no symptoms or signs related to poisoning; grade 1, minor-mild: transient and spontaneously resolving symptoms; grade 2, moderate: pronounced or prolonged symptoms; grade 3, severe: severe or life-threatening symptoms; grade 4, fatal: death). All patients were administered 100% normobaric oxygen as initial treatment. In the event of special circumstances such as prolonged confusion, neurologic findings, cardiovascular dysfunction, severe acidosis, and a CO-Hb level greater than 25% or pregnancy, patients were treated with hyperbaric oxygen treatment.
IMA levels in CO poisoning
677
Table 1 Baseline demographic and clinical characteristics of the study population Variables
Control group CO poisoning (n = 49) group (n = 33)
Age, mean ± SD (y) 36 ± 11 Sex (M/F) 23/26 Hemodynamic characteristics SbP, mean ± SD (mm Hg) 119 ± 12 DbP, mean ± SD (mm Hg) 74 ± 10 Heart rate, mean ± SD 73 ± 11 (beats/min) Respiratory rate, 15 ± 2 mean ± SD (breaths/min) Symptoms, n (%) Dizziness Headache Vomiting Syncope Nausea Dyspnea Blurred vision Chest pain Palpitations Ataxia Confusion Loss of consciousness Flu-like symptoms Month of exposure to CO poisoning, n (%) December January February March April Cause of exposure to CO poisoning, n (%) Coal-fired stove Gas-fired stove Hot water boiler Gas boiler Wood-burning stove Length of exposure to CO, mean ± SD (h) Length of follow-up at the ED, mean ± SD (h) Glasgow Coma Score at admission, n (%) 11 14 15 Poisoning score at admission, n (%) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 ECG findings at admission, n (%) Normal Sinusal tachycardia T wave variation Branch block
34 ± 13 15/18 120 ± 20 75 ± 12 90 ± 16 18 ± 6
16 (47.6) 29 (87.8) 9 (27.2) 4 (12.1) 19 (57.6) 7 (21.3) 7 (21.3) 5 (15.2) 10 (30.3) 1 (3) 5 (15.2) 3 (9.1) 4 (12.1) 7 (21.2) 10 (30.3) 5 (15.1) 7 (21.2) 4 (12.1) 12 (36.4) 9 (27.3) 7 (21.2) 4 (12.1) 1 (3) 3.2 ± 1.9 5.2 ± 2.2
1 (3) 3 (9.1) 29 (87.9)
22 (66.7) 10 (30.3) 1 (3)
Table 1 (continued) Variables
Control group CO poisoning (n = 49) group (n = 33)
ECG findings at admission, n (%) ST depression QT extension Gas analysis at admission PO2, mean ± SD (mm Hg) PCO2, mean ± SD (mm Hg) sO2, mean ± SD (%) pH, mean ± SD Treatment applied, n (%) Normobaric oxygen treatment Hyperbaric oxygen treatment
1 (3) 1 (3) 93.1 ± 33.3 33.9 ± 6.4 96.2 ± 3.5 7.43 ± 0.06 29 (87.9) 4 (12.1)
SbP, systolic blood pressure; Dbp, diastolic blood pressure.
2.4. Methods of measurement 2.4.1. IMA measurements Five-milliliter blood samples were taken from the brachial vein of CO-poisoned patients at the time of admission to the ED and at the end of 3 hours of treatment. These were immediately placed in ice and centrifuged at 3000 rpm for 15 minutes and then pipetted into Eppendorf tubes in the ED and stored at −80°C until analysis (maximum of 5 months). Blood samples were taken only once from the healthy individual comprising the control group, for IMA measurement. Reduced cobalt to albumin binding capacity (IMA levels) was analyzed by a blinded biochemist using the rapid and colorimetric method developed by Bar-Or et al [16]. 2.4.2. Primary data analysis Statistical analysis was performed using SPSS for Windows 11.0 (SPSS, Chicago, Ill) and MedCalc statistical software. Results are expressed as mean ± SD. The normality of data was tested using Kolmogorov-Smirnov test. Student t test was used to compare the mean IMA and CO-Hb levels of the control and CO poisoning groups at admission, paired t test was used to compare mean IMA levels of the CO poisoning group at the admission and third hour of the therapy. One-way analysis of variance was used for IMA and CO-Hb level comparisons of groups categorized according to the PSS. Correlations between the IMA and CO-Hb levels were assessed using Pearson correlation test. Statistical significance was assumed at a level of P b .05.
3. Results 17 (51.5) 8 (24.2) 4 (12.1) 2 (6.1)
3.1. Characteristics of study subjects Thirty-seven patients (29 admitted to the Gulhane Military Academy ED Hospital and 8 admitted to the Karadeniz Technical University Hospital ED), all suffering
S. Turedi et al.
1 (3) 2 (6.1) 1 (3)
1 (3) 2 (6.1) 1 (3) 1 (3) 1 (3)
1 (3)
1 (3) 2 (6.1) 3 (9.1) 4 (12.1) 1 (3)
Table 3 Measured IMA levels of the patients and control groups at admission and third hour of treatment Time dependent IMA levels (ABSU)
Groups Control group CO poisoning P (n = 49) group (n = 33)
Admission 0.17 ± 0.07 Third hour of treatment P
0.29 ± 0.04 0.31 ± 0.06 .40
.0001 .0001
from CO poisoning, together with 49 healthy control subjects were enrolled. Four patients were excluded for being transferred to our hospitals from the intensive care units of other hospitals. None of the patients enrolled died, and all were discharged in a healthy condition with no aftereffects. The baseline demographic and clinical characteristics of subjects are presented in Table 1. Numbers of patients' major symptoms and signs of and their classification in CO-Hb levels are shown in Table 2.
3.2. Main results Measured IMA levels of the patients and control groups at admission and third hour of the treatment are shown in Table 3 and Fig. 1. Mean IMA levels were statistically significant higher in the patient group than in the control group. A significant fall was determined in CO-Hb levels at the end of the third hour of treatment, P b .0001 (23.9% ± 11.1% at admission versus 7.5% ± 4.3% at the third hour of the treatment). However, there was no significant change in IMA levels measures at admission or at the end of the third hour of treatment, P = .9 (0.31 ± 0.06 absorbance unit [ABSU] and 0.29 ± 0.04 ABSU, respectively).
(6.1%) (18.2) (24.2) (6.1) (3) 2 6 8 2 1 b10% 10%-20% 20%-30% 30%-40% N40%
3 10 12 3 1
(9.1) (30.3) (36.4) (9.1) (3)
1 3 3 2 1
(3) (9.1) (9.1) (6.1) (3)
1 (3) 1 (3) 1 (3)
1 (3) 6 (18.2) 10 (30.3) 2 (6.1)
2 (6.1) 4 (12.1) 1 (3)
1 (3) 4 (12.1) 1 (3) 1 (3)
1 (3) 3 (9.1)
Ataxia Palpitation Chest pain Blurred vision Dyspnea Nausea Syncope Vomiting Headache Dizziness CO-Hb levels
Table 2
Numbers of major symptoms and signs in patients and their classification according to CO-Hb levels, n (%)
Confusion
Loss of consciousness
Flu-like symptoms
678
Fig. 1 Measured IMA levels and 95% confidence interval for median of the patients and control groups at the admission and at the third hour of the treatment.
IMA levels in CO poisoning
679
Table 4 Mean CO-Hb and IMA levels among the study groups classified according to PSS PSS Grade Grade Grade Grade Grade
0 (n 1 (n 2 (n 3 (n 4 (n
= 0) = 22) = 10) = 1) = 0)
CO-Hb, mean ± SD (%)
IMA, mean ± SD (ABSU)
22.4 ± 8.9a 22.8 ± 10.5b 51.6a,b
0.29 ± 0.05 0.26 ± 0.03 0.31
Different letters in the same row indicate statistical difference (a: grade 1 versus grade 3, P b .005; b: grade 2 versus grade 3, P b .03).
In addition, there was no significant correlation between IMA and CO-Hb levels in CO-poisoned patients (correlation coefficient −0.197' P = .273; 95% confidence interval, −0.157 to 0.505). Ischemia-modified albumin and CO-Hb levels were investigated in terms of CO patients classified according to PSS, the results being shown in Table 4. Carboxyhemoglobin levels were significantly high in patients with high PSS results, taken as an indicator of degree of poisoning, whereas no difference in IMA levels between the groups was determined. Also, there was no difference in blood IMA levels in classification according to CO-Hb levels (Table 5).
4. Limitations The patients comprising the study group were made up of PSS grades 1 and 2. The number of patients exposed to more severe levels of poisoning was very small, and this prevented our obtaining reliable findings regarding serious poisoning. In addition, the intensive care planned as an indicator of clinical course was not possible because the patients applying during the study period were exposed to a relatively less severe level of poisoning, and we could not therefore obtain such prognostic findings as neurologic sequels at discharge and mortality. We could not exclude the possible impact of normobaric oxygen therapy on CO-Hb and IMA levels; this is despite the fact that we considered only patients with CO-Hb levels lower than 2% regardless of consideration of normobaric Table 5 Mean IMA levels among the study groups classified according to CO-Hb levels CO-Hb groups
n
IMA mean ± SD (ABSU)
≤10% 10%-20% 20%-30% 30%-40% ≥40
4 10 13 4 2
0.31 ± 0.03 0.25 ± 0.05 0.30 ± 0.04 0.31 ± 0.05 0.32 ± 0.01
P N .05, for comparison of the all groups.
oxygen treatment during transport. Normobaric oxygen therapy is a routine application in emergency transport system, but the interval of poisoning to admission varies also due to distance of location of incidents. However, considering the lack of reduction in increased IMA levels after the controlled normobaric oxygen therapy in our setting for 3 hours, this is not so critical for the IMA, bearing in mind that it definitely has an impact on CO-Hb levels.
5. Discussion Our study is the first in which IMA levels were higher in CO-poisoned patients than in healthy individuals, in which this was determined to continue at the end of the third hour of treatment and in which this biochemical parameter was evaluated as a clinical course indicator in CO-poisoned patients. The pathophysiologic mechanism of CO poisoning consists of a tissue hypoxia caused by CO-mediated circulatory failure [17]. After being inhaled, CO is easily absorbed from the lungs into the bloodstream and then forms a tight but slowly reversible complex with hemoglobin, known as CO-Hb. A high CO-Hb level usually indicates exogenous exposure to CO, but CO is also produced endogenously in states of rapid hemoglobin turnover such as severe hemolytic anemia. Intravascular hemolysis with associated endogenous CO production as a byproduct of heme metabolism results in the elevation of the CO-Hb levels to as high as 9.7% [18]. Carboxyhemoglobin being present in the bloodstream restricts erythrocyte oxygen transport and also lowers tissue oxygen availability, resulting in tissue hypoxia. Carbon monoxide raises cytosolic heme levels, leading to oxidative stress. It binds to platelet heme protein and cytochrome C oxidase, thus interrupting cellular respiration and leading to the production of reactive oxygen species, which in turn leads to neuronal necrosis and apoptosis. Cellular respiration impairment leads to a stress response, including hypoxiainducible factor 1α activation, which results in neurologic and cardiac protection or injury, depending on the level of CO involved, by means of gene regulation. Carbon monoxide exposure also causes inflammation through multiple pathways that are independent of those involved in hypoxia, leading to neurologic and cardiac injury [19]. Carbon monoxide poisoning symptoms may be the result of exposure either to low levels of CO for extended periods of time or, alternatively, to higher levels for a shorter period. Carbon monoxide poisoning may result in a wide variety of signs and symptoms. Because these are frequently nonspecific, CO poisoning may be overlooked [20]. Carbon monoxide poisoning symptoms, signs, and prognosis have a poor correlation with the CO-Hb level determined on arrival at hospital [21]. Numerous tables of symptom-associated CO-Hb levels are available; however,
680 most physicians recognize the poor correlation between COHb levels and the clinical presentation of patients with CO poisoning [22]. The reason is that there are wide variations in CO-Hb levels in CO-poisoned patients. This may be related to the time elapsing between exposure to CO ceasing and taking blood samples for measuring CO-Hb. Alternatively, variations in clinical presentation may be related to the duration of exposure to CO, its concentration, the basic health of the person concerned and their susceptibility to CO, or the amount and duration of supplemental oxygen administered before blood samples are taken [22]. As the related evidence ample, the risk factors for squeal from CO poisoning (including CO-Hb levels, loss of consciousness, etc) are now better documented, and a relation between the severity of CO-related illness and risk of squeal is categorized and guides the management of this cases [20,23]. However, relatively instability of the conventional marker during a long period, CO-Hb, necessitates discovery of a longer stable and sensitive markers such as IMA according to findings from this preliminary study. During acute ischemic conditions, the metal binding capacity of albumin is modified and reduces transition metal binding, generating a metabolic variant of protein. This change is quantifiable and commonly known as IMA [24]. Recently, IMA measurement has been proposed as a sensitive marker for the diagnosis of myocardial ischemia presenting with typical acute chest pain and licensed by the US Food and Drug Administration for diagnostic use in suspected myocardial ischemia [24]. However, high IMA concentrations do not seem to depend purely on myocardial involvement, and other organs seem to be responsible for the increase in IMA levels. Ischemia-modified albumin levels may rise during ischemia-reperfusion, affecting any organ, and cannot be considered together with oxidative stress [24]. According to available databases, this study is the first to examine IMA as a biochemical parameter of CO poisoning. Serum IMA levels were significantly higher in CO-poisoned patients compared with healthy individuals at both time of admission and at the third hour of treatment. That elevation was thought to be in all likelihood related to the hypoxic condition already present in CO-poisoned patients and to increased oxidative stress. The impact on the patient's clinical status of the level of CO in the tissue may be equal or greater than that of CO in the blood [22]. Elevated levels of CO-Hb can produce sufficient tissue hypoxia for CO to bind to cytochrome C oxidase in a noncompetitive manner. Cytochrome C oxidase represents the terminal enzyme within the mitochondrial electrontransport chain. Carbon monoxide noncompetitive binding in local tissue hypoxia has also been observed in vivo in a heart preparation. The reduction in high-energy stores and intracellular acidosis during the course of CO-induced hypoxia can even be aggravated after CO exposure, even though CO-Hb has been eradicated. The worsening in energy metabolism during reoxygenation may be ascribed to CO uptake by cytochrome C oxidase. Human lymphocytic
S. Turedi et al. mitochondrial cytochrome C oxidase inhibition persisting for several days has been observed in the wake of acute CO poisoning, with CO-Hb levels varying from 11.6% to 22.3% [20]. The results of our study show that blood CO-Hb levels declined significantly with normobaric oxygen treatment. The CO-Hb half-life in patients with CO poisoning who are treated with 100% oxygen at atmospheric pressure is approximately 75 minutes [25]. Because this relatively short half-life of CO-Hb and CO-Hb levels of CO-poisoned patients should also be obtained as soon as possible. However, there was no significant reduction in IMA levels, regarded as a sensitive marker for ischemia; indeed, and even slightly higher IMA levels were determined than those at time of admission. This is in accordance with the information that IMA levels increases rapidly within minutes after ischemia and remains elevated 6 to 12 hours [26]. We did not expect significant decline on the IMA levels before clinical decision on discharge of our cases. Our findings have importance with regard to 2 points. One is significant to establish that the sensitive ischemia marker, IMA, is also elevated under hypoxia, although the contribution of associated oxidative stress should also be considered. Second, the longer turnover time of IMA may represent advantage compared with COHb, and this may have critical importance in the screening and management of CO poisoning. Although it would not be correct, in the light of these findings, to definitively conclude that IMA levels can be used as a clinical marker in CO poisoning, Ischemia-modified albumin may be a parameter that can be used clinically together with CO-Hb levels in terms of reflecting tissue hypoxia and oxidative burden to which tissues are exposed. This study also evaluated the severity of clinical status of CO-poisoned patients in the light of their PSS. Poisoning severity score as a grading of acute poisoning was described in the late 1990s and used in some toxicologic reports [27]. Cevik et al [27] determined significantly higher CO-Hb levels in PSS grade 3 patients that in patients with lower degrees. Similarly to the study of Cevik et al, we determined a significant correlation between CO-Hb levels and PSS at the time of admission. Also, CO-Hb levels in our PSS grade 3 patients were significantly higher than those in patients with lower grades. Serum IMA levels examined at admission exhibited no such correlation. However, because there was only 1 PSS grade 3 patient, it is not possible to say that these findings are completely clarificatory.
6. Conclusions Results from this pioneering study established high levels of IMA in CO-poisoned patients. Considering the rather preliminary nature of this current study, further studies targeting the significance of this biomarker in relation to brain or cardiac injury, immediate or late outcome, as well as its possible correlation with established biomarkers such as
IMA levels in CO poisoning troponin and SB-100 for the heart and brain, respectively, are warranted.
References [1] Hampson NB, Weaver LK. Carbon monoxide poisoning: a new incidence for an old disease. Undersea Hyperb Med 2007;34:163-8. [2] Buckley NA, Isbister GK, Stokes B, Juurlink DN. Hyperbaric oxygen for carbon monoxide poisoning: a systematic review and critical analysis of the evidence. Toxicol Rev 2005;24:75-92. [3] Hampson NB, Scott KL, Zmaeff JL. Carboxyhemoglobin measurement by hospitals: implications for the diagnosis of carbon monoxide poisoning. J Emerg Med 2006;31:13-6. [4] Hampson NB, Hauff NM. Carboxyhemoglobin levels in carbon monoxide poisoning: do they correlate with the clinical picture? Am J Emerg Med 2008;26:665-9. [5] Wolf SJ, Lavonas EJ, Sloan EP, Jagoda AS, American College of Emergency Physicians. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. Ann Emerg Med 2008;51: 138-52. [6] Davutoglu V, Gunay N, Kocoglu H, Gunay NE, Yildirim C, Cavdar M, et al. Serum levels of NT-ProBNP as an early cardiac marker of carbon monoxide poisoning. Inhal Toxicol 2006;18:155-8. [7] Sinha MK, Roy D, Gaze DC, Collinson PO, Kaski JC. Role of “Ischemia modified albumin,” a new biochemical marker of myocardial ischaemia, in the early diagnosis of acute coronary syndromes. Emerg Med J 2004;21:29-34. [8] Turedi S, Gunduz A, Mentese A, Karahan SC, Yilmaz SE, Eroglu O, et al. Value of ischemia-modified albumin in the diagnosis of pulmonary embolism. Am J Emerg Med 2007;25:770-3. [9] Turedi S, Gunduz A, Mentese A, Topbas M, Karahan SC, Yeniocak S, et al. The value of ischemia-modified albumin compared with D-dimer in the diagnosis of pulmonary embolism. Respir Res 2008;9:49. [10] Gunduz A, Turedi S, Mentese A, Karahan SC, Hos G, Tatli O, et al. Ischemia-modified albumin in the diagnosis of acute mesenteric ischemia: a preliminary study. Am J Emerg Med 2008;26:202-5. [11] Gunduz A, Turkmen S, Turedi S, Mentese A, Yulug E, Ulusoy H, et al. Time-dependent variations in ischemia-modified albumin levels in mesenteric ischemia. Acad Emerg Med 2009;16:539-43. [12] Mentese A, Mentese U, Turedi S, Gunduz A, Karahan SC, Topbas M, et al. Effect of deep vein thrombosis on ischaemia-modified albumin levels. Emerg Med J 2008;25:811-4.
681 [13] Gunduz A, Mentese A, Turedi S, Karahan SC, Mentese U, Eroglu O, et al. Serum ischaemia-modified albumin increases in critical lower limb ischaemia. Emerg Med J 2008;25:351-3. [14] Gunduz A, Turedi S, Mentese A, Altunayoglu V, Turan I, Karahan SC, et al. Ischemia-modified albumin levels in cerebrovascular accidents. Am J Emerg Med 2008;26:874-8. [15] Persson HE, Sjöberg GK, Haines JA, Pronczuk de Garbino J. Poisoning severity score. Grading of acute poisoning. J Toxicol Clin Toxicol 1998;36:205-13. [16] Bar-Or D, Lau E, Winkler JV. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia—a preliminary report. J Emerg Med 2000;19:311-5. [17] Atalay H, Aybek H, Koseoglu M, Demir S, Erbay H, Bolaman AZ, et al. The effects of amifostine and dexamethasone on brain tissue lipid peroxidation during oxygen treatment of carbon monoxide-poisoned rats. Adv Ther 2006;23:332-41. [18] Hampson NB. Carboxyhemoglobin elevation due to hemolytic anemia. J Emerg Med 2007;33:17-9. [19] Weaver LK. Clinical practice. Carbon monoxide poisoning. N Engl J Med 2009;360:1217-25. [20] Weaver LK. Carbon monoxide poisoning. Crit Care Clin 1999;15: 297-317. [21] Thom SR, Taber RL, Mendiguren II, Clark JM, Hardy KR, Fisher AB. Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995;25:474-80. [22] Raub JA, Mathieu-Nolf M, Hampson NB, Thom SR. Carbon monoxide poisoning—a public health perspective. Toxicology 2000; 145:1-14. [23] Weaver LK, Valentine KJ, Hopkins RO. Carbon monoxide poisoning: risk factors for cognitive sequelae and the role of hyperbaric oxygen. Am J Respir Crit Care Med 2007;176:491-7. [24] Turedi S, Gunduz A, Mentese A, Dasdibi B, Karahan SC, Sahin A, et al. Investigation of the possibility of using ischemia-modified albumin as a novel and early prognostic marker in cardiac arrest patients after cardiopulmonary resuscitation. Resuscitation 2009;80:994-9. [25] Weaver LK, Howe S, Hopkins R, Chan KJ. Carboxyhemoglobin halflife in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure. Chest 2000;117:801-8. [26] Lippi G, Montagnana M, Salvagno GL, Guidi GC. Potential value for new diagnostic markers in the early recognition of acute coronary syndromes. CJEM 2006;8:27-31. [27] Cevik AA, Unluoglu I, Yanturali S, Kalkan S, Sahin A. Interrelation between the Poisoning Severity Score, carboxyhaemoglobin levels and in-hospital clinical course of carbon monoxide poisoning. Int J Clin Pract 2006;60:1558-64.