CLB-08866; No. of pages: 4; 4C: Clinical Biochemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients Gianfranco Cervellin a,⁎, Ivan Comelli a, Gianni Rastelli b, Alessandra Picanza c, Giuseppe Lippi c a b c
Emergency Department, Academic Hospital of Parma, Italy Emergency Department, Hospital of Vaio, Fidenza, Italy Laboratory of Clinical Chemistry and Haematology, Academic Hospital of Parma, Italy
a r t i c l e
i n f o
Article history: Received 3 July 2014 Received in revised form 1 September 2014 Accepted 17 September 2014 Available online xxxx Keywords: Lactate Carboxyhemoglobin Troponin Carbon monoxide Poisoning Hyperbaric therapy
a b s t r a c t Objective: The aim of this study was to assess the role of blood lactate levels at admission in carbon monoxide (CO)-poisoned patients for establishing severity of poisoning and short term prognosis. Method: All cases of CO poisoning visited in the emergency department during the years 2012 and 2013 were retrieved from the hospital database. The concentration of COHb and lactate was assessed in arterial blood in all patients with suspected CO poisoning, along with the plasma concentration of troponin I (TnI). The control population for TnI results consisted in 125 blood donors. Results: Twenty three (61%) out of 38 CO-poisoned patients underwent hyperbaric oxygen (HBO) treatment, and 10 (26%) were admitted to a hospital ward. A significant correlation was found between lactate and COHb (r = 0.54; p b 0.001), and between lactate and TnI (r = 0.44; p = 0.001). A significant correlation was also found between COHb and TnI (r = 0.38; p = 0.020). Blood lactate levels were higher in patients treated with HBO and hospital admission. In multivariate analysis, none of the parameters was associated with HBO treatment, whereas increased value of blood lactate (p = 0.036) was the only significant predictor of hospital admission. Twenty five (66%) patients had detectable TnI levels compared to 13% controls (p b 0.001), whereas 16% CO-poisoned patients had TnI levels N99th percentile compared to 2% controls (p = 0.003). The odds ratio for detectable TnI and TnI N 99th percentile in CO-poisoned patients were 13.1 (p b 0.001) and 7.6 (p = 0.006), respectively. Conclusion: Initial blood lactate level may be useful for risk stratification of CO-poisoned patients, especially for predicting hospitalization. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Carbon monoxide (CO) poisoning is one of the most frequent intoxications around the globe, accounting for more than one half of fatal poisonings reported in many countries [1], and more than 50,000 emergency department (ED) visits per year in the US [2]. The transient duration of symptoms in mild intoxication, the ubiquitous and often occult nature of exposure as well as the high frequency of misdiagnosis represent substantial challenges for quantifying the true incidence of CO poisoning. Although mild exposure often results in nonspecific symptoms such as headache, myalgia, dizziness or mild neuropsychological impairment [3], severe exposure causes neurological deterioration, including confusion and loss of consciousness, up to death [4]. The diagnosis of CO poisoning is mainly supported by clinical signs and symptoms. The commonly accepted definition requires a history of recent CO exposure, the presence of symptoms consistent with CO poisoning, ⁎ Corresponding author at: Emergency Department, Academic Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. E-mail address: [email protected] (G. Cervellin).
along with evidence of elevated blood levels of carboxyhemoglobin (COHb) [5]. The severity of poisoning is also related to environmental and human factors such as the relative concentration of CO in the air, duration of exposure, the respiratory function of the poisoned subject and the capacity to buffer acid–base derangements through metabolic and renal mechanisms [6]. The levels of COHb are generally defined as abnormal when exceeding the thresholds of 2% in nonsmokers and 9% in habitual smokers, respectively [7]. These elevated levels are highly suggestive for exposure to exogenous CO, thus supporting the clinical suspicion of poisoning. Elevated blood COHb levels are hence conventionally used to confirm a clinical suspicion of exposure to CO and help assessing the severity of poisoning [4]. Evidence has been provided that the degree of COHb increase in blood does not thoughtfully correlate with severity of clinical presentation, and its use for guiding clinical management is thereby currently discouraged [8]. According to this premise, the Undersea and Hyperbaric Medical Society recommends starting hyperbaric oxygen therapy for CO-poisoned individuals based on the clinical picture, irrespective of the COHb blood level [9].
http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Cervellin G, et al, Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016
2
G. Cervellin et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Since oxygen accelerates the elimination of COHb and alleviates tissue hypoxia, it is widely acknowledged that all cases of CO poisoning should be treated with high-flow oxygen by mask or endotracheal tube as front-line treatment [4]. It is noteworthy, however, that the evidence that emerged from clinical trials does not unequivocally demonstrate superior efficacy of normobaric 100% oxygen over ambient air [4]. Nevertheless, due to limited availability and high cost of hyperbaric oxygen (HBO), several studies have tried to compare the efficacy of hyperbaric versus normobaric oxygen in the treatment of CO poisoning [10–13]. A cardiac involvement is also frequent in CO-poisoned patients, ranging from mild and transitory injury to myocardiocyte necrosis and severe contractile dysfunction [14]. This is probably attributable to the high sensitivity of myocardiocytes to oxygen deprivation, which is commonplace in CO-poisoned patients, and is further worsened by a direct CO-mediated injury at cellular and subcellular levels [14]. Severe metabolic acidosis is also associated with the highest short-term mortality rate in CO-poisoned patients and, especially when the source of CO is a building fire, is possibly caused by a concomitant cyanide intoxication [15,16]. It was recently shown that lactic acid, the product of anaerobic glycolysis in association with inadequate oxygen supply, may be a prognostic parameter in CO-poisoned patients, although published data are somewhat controversial. In fact, although some authors consider blood lactate at admission virtually meaningless in CO-poisoned patients [17], others concluded that its measurement may be useful as a prognostic biomarker [18,19], or reported controversial results [20]. As such, the aim of this study was to assess the role of blood lactate levels in CO-poisoned patients for establishing the severity of poisoning and short term prognosis. Materials and methods All cases of CO poisoning referred to the ED of the University Hospital of Parma during the years 2012 and 2013 were retrieved from the hospital database. According to a local protocol, the concentrations of COHb and lactate are assessed in arterial blood in all patients with suspected CO poisoning directly in the ED, using the blood gas analyzer Radiometer ABL 800-flex (Radiometer Medical ApS, Bronshoj, Denmark). The heparinized whole blood samples are transported to the instrument at ambient temperature, where blood gas analysis is typically completed within 5 min of draw time. The assessment of cardiospecific troponin I (TnI) is also routinely performed in all patients with suspected CO poisoning. A venous blood sample is collected in blood tubes containing K2EDTA and immediately sent to the core laboratory, where the specimen is centrifuged and TnI is assessed in EDTA plasma with Beckman Coulter AccuTni + 3 on Unicel DxI (Beckman Coulter, Brea, CA, USA). The lower limit of detection of this test is 10 ng/L, whereas the 99th percentile of the reference range is 30 ng/L [21]. For the purposes of this study, CO poisoning was defined as COHb levels N 2% in non smokers and N 9% in smokers, when the history was suggestive for CO exposure and clinical symptoms were consistent with CO poisoning. The possible hospital admission of patients is individually planned by the Emergency Physician, based on clinical judgment, whereas the treatment with HBO is decided according to the Guidelines of the American Thoracic Society, i.e., in poisoned patients with loss of consciousness, ischemic cardiac changes, neurological deficits, significant metabolic acidosis, or COHb N 25% [5]. The control population for TnI testing consisted in 125 non-smokers and healthy blood donors (77 males and 48 females, age range 21–54 years), who participated to a previous analytical evaluation of AccuTni + 3 during the same period [21]. The statistical analysis was based on the Wilcoxon–Mann–Whitney test (for continuous variables), Pearson's χ2 statistics with Yates' correction (for categorical variables), and Spearman's correlation. Results of measurements were expressed as median and interquartile range (IQR). Multivariate and receiver operating characteristics (ROC) curve analyses were also performed to identify potential associations of
demographical and laboratory data with clinical outcomes (i.e., HBO treatment or hospital admission). The statistical analysis was performed using Analyse-it (Analyse-it Software Ltd, Leeds, UK) and MedCalc Version 12.3.0 (MedCalc Software, Mariakerke, Belgium). The study was performed in accordance with the Declaration of Helsinki, under the terms of relevant local legislation. Results Complete clinical and biochemical information could be retrieved from the hospital database for 38 CO poisoned patients (23 females and 15 males; median age 37 years and IQR 26–47 years). Twenty three patients (61%) underwent HBO treatment due to clinical severity and/or the elevated COHb values, and 10 (26%) were subsequently admitted to a hospital ward for incomplete recovery after treatment and/or organ injury (most notably, for troponin elevation). The length of hospital stay was on average 2 days (range 1–4 days) for admitted patients, whereas the short-term clinical outcomes were evaluated as short-term (i.e., within 2 weeks) readmissions to the ED or death. Only one patient (female, 73 years; at presentation COHb 46.3%; lactate 3.3 mmol/L) returned to the ED complaining for mild headache. She was re-evaluated and discharged within 2 h, with acetaminophen prescription. No deaths were recorded in the 2 weeks after admission. In the whole population of CO-poisoned patients, a significant correlation was found between lactate and COHb (r = 0.54; p b 0.001), as well as between lactate and TnI (r = 0.44; p = 0.001). A modest but significant correlation was also found between COHb and TnI levels (r = 0.38; p = 0.020). Interestingly, blood lactate levels were found to be higher in patients with both HBO and hospital admission, albeit a stronger association was found in the second category of patients (Tables 1 and 2). Twenty five (i.e., 66%) CO poisoned patients had detectable levels of TnI compared to 13% healthy blood donors (p b 0.001), whereas 16% CO poisoned patients had TnI levels above the 99th percentile of the reference range compared to 2% healthy blood donors (p = 0.003). Accordingly, the odds ratio (OR) for detectable TnI and for TnI levels above the 99th percentile in CO-poisoned patients was 13.1 (95% CI, 5.6–30.7; p b 0.001) and 7.6 (95% CI, 1.8–32.2; p = 0.006). After stratification of patients for severity of poisoning according to COHb levels, TnI values were found to be marginally but significantly higher in patients with COHb N 25% than in those with lower values (p = 0.031). The values of COHb were also higher in patients refereed for HBO treatment, but not in those with hospital admission. Conversely, TnI values were higher in patients with hospital admission, but not in those refereed for HBO treatment (Tables 1 and 2). In multivariate analysis, in which the clinical outcome was entered as a dependent variable whereas age, sex, COHb, TnI, blood lactate, hemoglobin, the estimated glomerular filtration rate (eGFR) and lactate dehydrogenase (LDH) on admission were included as independent variables, none of the parameters was significantly associated with HBO treatment, whereas increased value of blood lactate on
Table 1 Values (median and interquartile range) of carboxyhemoglobin (COHb), blood lactate, troponin I (TnI), estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) formula and lactate dehydrogenase (LDH) in 38 patients with acute carbon monoxide poisoning, stratified according to hyperbaric oxygen (HBO) treatment.
n Age (years) Females COHb (%) Lactate (mmol/L) TnI (ng/L) Hemoglobin (g/L) eGFR (mL/min/1.73 m2) LDH (U/L)
No HBO
HBO
p
15 37 (20–47) 8/15 8.5 (5.0–20.5) 1.1 (1.0–1.6) 10 (10–20) 127 (120–139) 92 (78–101) 372 (328–418)
23 37 (28–47) 15/23 18.4 (12.2–26.8) 1.5 (1.3–1.9) 10 (b10 to 20) 132 (121–148) 95 (90–113) 377 (322–425)
0.416 0.352 0.032 0.003 0.318 0.326 0.056 0.383
Please cite this article as: Cervellin G, et al, Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016
G. Cervellin et al. / Clinical Biochemistry xxx (2014) xxx–xxx Table 2 Values (median and interquartile range) of carboxyhemoglobin (COHb), blood lactate, troponin I (TnI), estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) formula and lactate dehydrogenase (LDH) in 38 patients with acute carbon monoxide poisoning, stratified according to admission to a hospital ward.
n Age (years) Females COHb (%) Lactate (mmol/L) TnI (ng/L) Hemoglobin (g/L) eGFR (mL/min/1.73 m2) LDH (U/L)
No admission
Admission
p
28 35 (25–45) 18/28 15.0 (8.1–21.4) 1.2 (1.0–1.6) 0.01 (b0.01 to 0.01) 137 (121–147) 99 (90–109) 355 (323–402)
10 37 (46–75) 5/10 18.9 (12.4–30.1) 1.8 (1.4–2.0) 0.02 (0.01 to 0.04) 127 (120–137) 85 (73–94) 439 (397–491)
0.035 0.342 0.091 b0.001 0.002 0.274 0.002 0.008
eGFR, estimated glomerular filtration rate according to the Modification of Diet in Renal Disease (MDRD) formula; LDH, lactate dehydrogenase.
admission was the only significant predictor of hospital admission. The area under the curve (AUC) for predicting HBO treatment was 0.54 (95% CI, 0.31–0.78; p = 0.366) for blood lactate, 0.56 (95% CI, 0.31–0.80; p = 0.318) for TnI, and 0.64 (0.45–0.84; p = 0.078) for COHb, respectively. At variance with these findings, the AUC for predicting hospital admission was 0.85 (95% CI, 0.72–0.97; p b 0.001) for blood lactate, 0.71 (95% CI, 0.50–0.91; p = 0.026) for TnI, and 0.61 (95% CI, 0.39–0.84; p = 0.156) for COHb. A blood lactate concentration N 1.20 mmol/L was associated with 1.00 sensitivity and 0.57 specificity for predicting hospital admission, whereas a detectable value of TnI exhibited 0.80 sensitivity and 0.39 specificity for predicting hospital admission. Discussion The relationship between blood lactate and severity or prognosis of CO poisoning has been previously addressed. In a series of CO-poisoned patients Benaissa et al. found that plasma lactate is mildly elevated in pure CO-exposed patients but, due to the large overlap between the different groups of subjects, the usefulness of systematic lactate measurement in CO poisoning could not be confirmed [17]. At variance with this evidence, Inoue et al. reported that the initial blood lactate level correlated with patients' outcome and was proven to be a useful prognostic factor in a small series of suicidal, severely CO-poisoned patients [18]. Moon et al. also found that initial blood lactate level was independently associated with serious complications and the need for intensive medical treatment in 80 patients urgently admitted to the ED for CO poisoning [19]. More recently, Doğan et al. found that initial lactate levels were positively correlated with COHb values in 74 patients with severe CO poisoning [20]. Taken together, the published evidence about the clinical significance of blood lactate in CO-poisoned patients is scarce and somewhat controversial, so the results of our study may have some meaningful clinical implications. Besides confirming that heart involvement is frequent in patients with CO poisoning, the existence of significant associations between the values of lactate and those of COHb (r = 0.54; p b 0.001) or troponin (r = 0.44; p = 0.001) is indeed the first important finding of our retrospective investigation. It is also noteworthy that the correlation between TnI and lactate was greater than that found between TnI and COHb (r = 0.38; p = 0.020), and that increased blood lactate levels were independent predictors of hospital admission. This can be interpreted as meaning that the metabolic acidosis developing in COpoisoned patients is primarily responsible for the cardiac injury rather than the severity of the intoxication by itself. This important aspect has been hypothesized in some previous studies [15,16], and is also supported by the evidence that the myocardial tissue is highly vulnerable to oxygen deprivation, thus causing a substantial reduction of contractility and cardiac output, which ultimately contribute to worsen the direct
3
injury of CO on cardiomyocytes [14]. This hypothesis seems to be confirmed by the findings of our investigation, in that blood lactate levels were significantly associated with TnI. It is also noteworthy that the rate of detectable TnI levels (i.e., N10 ng/L) using AccuTni + 3 was relatively low in healthy individuals (i.e., 13%). As such, the identification of a high rate of measurable TnI levels in our population of COpoisoned patients (i.e., 66%) should be considered as clinically meaningful, albeit not independently predictive of either HBO treatment or hospital admission. In conclusion, the results of this retrospective investigation on 38 patients presenting to the ED with acute CO poisoning suggest that initial blood lactate level may be an additional and useful parameter for risk stratification of patients, especially for predicting the need for hospitalization. Conflict of interest statement All authors do not have any potential conflicts of interest, and all authors have read the journal's policy on conflicts of interest. Moreover, all authors have read the journal's authorship agreement. Acknowledgments The authors acknowledge Drs. Marco Brambilla and Marco Mignani of the Academic Hospital of Parma for the kind support in extracting data from the electronic database of the Institution, and the Nurse Rosa Netti for the kind support in extracting hemogasanalyzer's data. References [1] Raub JA, Mathieu-Nolf M, Hampson NB, Thom SR. CO poisoning—a public health perspective. Toxicology 2000;145:1–14. [2] Hampson NB, Weaver LK. Carbon monoxide poisoning: a new incidence for an old disease. Undersea Hyperb Med 2007;34:163–8. [3] Amitai Y, Zlotogorski Z, Golan-Katzav V, Wexler A, Gross D. Neuropsychological impairment from acute low-level exposure to carbon monoxide. Arch Neurol 1998;55:845–8. [4] Weaver LK. Carbon monoxide poisoning. N Engl J Med 2009;360:1217–25. [5] Hampson NB, Piantadosi CA, Thom SR, Weaver LK. Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning. Am J Respir Crit Care Med 2012;186:1095–101. [6] Ryter SW, Otterbein LE. Carbon monoxide in biology and medicine. Bioessays 2004; 26:270–80. [7] Radford EP, Drizd TA. Blood carbon monoxide levels in persons 3–74 years of age: United States, 1976–80. In: Hyattsville MD, editor. US Dept of Health and Human Services; Advance Data 76; March 17, 1982. US Dept of Health and Human Services publication PHS; 1982. p. 82–1250. [8] 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. [9] Feldmeier JJ. Hyperbaric oxygen 2003: indications and results: the Hyperbaric Oxygen Therapy Committee report. Kensington, MD: Undersea and Hyperbaric Medical Society; 2003. p. 11–8. [10] Raphael JC, Elkharrat D, Jars-Guincestre MC, Chastang C, Chasles V, Vercken JB, et al. Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989;2:414–9. [11] Weaver LK, Hopkins RO, Chan KJ, Churchill S, Elliott CG, Clemmer TP, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 2002;347:1057–67. [12] Buckley NA, Juurlink DN, Isbister G, Bennett MH, Lavonas EJ. Hyperbaric oxygen for carbon monoxide poisoning (review). Cochrane Collaboration; 2011 [available online at http://www.thecochranelibrary.com]. [13] Wolf SJ, Lavonas EJ, Sloan EP, Jagoda AS. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Critical Issues in the Management of Adult Patients Presenting to the Emergency Department with Carbon Monoxide Poisoning. Ann Emerg Med 2008;51:138–52. [14] Lippi G, Rastelli G, Meschi T, Borghi L, Cervellin G. Pathophysiology, clinics, diagnosis and treatment of heart involvement in carbon monoxide poisoning. Clin Biochem 2012;45:1278–85. [15] Hampson NB, Hauff NM. Risk factors for short-term mortality from carbon monoxide poisoning treated with hyperbaric oxygen. Crit Care Med 2008;36:2523–7. [16] Anseeuw K, Delvau N, Burillo-Putze G, De Iaco F, Geldner G, Holström P, et al. Cyanide poisoning by fire smoke inhalation: a European expert consensus. Eur J Emerg Med 2013;20(1):2–9. [17] Benaissa LM, Mégarbane B, Borron SW, Baud FJ. Is elevated plasma lactate a useful marker in the evaluation of pure carbon monoxide poisoning? Intensive Care Med 2003;29:1372–5.
Please cite this article as: Cervellin G, et al, Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016
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[18] Inoue S, Saito T, Tsuji T, Tamura K, Ohama S, Morita S, et al. Lactate as a prognostic factor in carbon monoxide poisoning: a case report. Am J Emerg Med 2008; 26(966) [e1-966.e3]. [19] Moon JM, Shin MH, Chun BJ. The value of initial lactate in patients with carbon monoxide intoxication: in the emergency department. Hum Exp Toxicol 2011;30:836–43.
[20] Doğan N, Savrun A, Levent S, Günaydın G, Celik G, Akküçük H, et al. Can initial lactate levels predict the severity of unintentional carbon monoxide poisoning? Hum Exp Toxicol 2014 Jun 27 [pii: 0960327114538986. [Epub ahead of print]]. [21] Lippi G, Dipalo M, Avanzini P, Formentini A, Aloe R. Analytical assessment of the Beckman Coulter Unicel DxI AccuTnI + 3 immunoassay. Diagnosis 2014;1:195–7.
Please cite this article as: Cervellin G, et al, Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients Gianfranco Cervellin a,⁎, Ivan Comelli a, Gianni Rastelli b, Alessandra Picanza c, Giuseppe Lippi c a b c
Emergency Department, Academic Hospital of Parma, Italy Emergency Department, Hospital of Vaio, Fidenza, Italy Laboratory of Clinical Chemistry and Haematology, Academic Hospital of Parma, Italy
a r t i c l e
i n f o
Article history: Received 3 July 2014 Received in revised form 1 September 2014 Accepted 17 September 2014 Available online xxxx Keywords: Lactate Carboxyhemoglobin Troponin Carbon monoxide Poisoning Hyperbaric therapy
a b s t r a c t Objective: The aim of this study was to assess the role of blood lactate levels at admission in carbon monoxide (CO)-poisoned patients for establishing severity of poisoning and short term prognosis. Method: All cases of CO poisoning visited in the emergency department during the years 2012 and 2013 were retrieved from the hospital database. The concentration of COHb and lactate was assessed in arterial blood in all patients with suspected CO poisoning, along with the plasma concentration of troponin I (TnI). The control population for TnI results consisted in 125 blood donors. Results: Twenty three (61%) out of 38 CO-poisoned patients underwent hyperbaric oxygen (HBO) treatment, and 10 (26%) were admitted to a hospital ward. A significant correlation was found between lactate and COHb (r = 0.54; p b 0.001), and between lactate and TnI (r = 0.44; p = 0.001). A significant correlation was also found between COHb and TnI (r = 0.38; p = 0.020). Blood lactate levels were higher in patients treated with HBO and hospital admission. In multivariate analysis, none of the parameters was associated with HBO treatment, whereas increased value of blood lactate (p = 0.036) was the only significant predictor of hospital admission. Twenty five (66%) patients had detectable TnI levels compared to 13% controls (p b 0.001), whereas 16% CO-poisoned patients had TnI levels N99th percentile compared to 2% controls (p = 0.003). The odds ratio for detectable TnI and TnI N 99th percentile in CO-poisoned patients were 13.1 (p b 0.001) and 7.6 (p = 0.006), respectively. Conclusion: Initial blood lactate level may be useful for risk stratification of CO-poisoned patients, especially for predicting hospitalization. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Carbon monoxide (CO) poisoning is one of the most frequent intoxications around the globe, accounting for more than one half of fatal poisonings reported in many countries [1], and more than 50,000 emergency department (ED) visits per year in the US [2]. The transient duration of symptoms in mild intoxication, the ubiquitous and often occult nature of exposure as well as the high frequency of misdiagnosis represent substantial challenges for quantifying the true incidence of CO poisoning. Although mild exposure often results in nonspecific symptoms such as headache, myalgia, dizziness or mild neuropsychological impairment [3], severe exposure causes neurological deterioration, including confusion and loss of consciousness, up to death [4]. The diagnosis of CO poisoning is mainly supported by clinical signs and symptoms. The commonly accepted definition requires a history of recent CO exposure, the presence of symptoms consistent with CO poisoning, ⁎ Corresponding author at: Emergency Department, Academic Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. E-mail address: [email protected] (G. Cervellin).
along with evidence of elevated blood levels of carboxyhemoglobin (COHb) [5]. The severity of poisoning is also related to environmental and human factors such as the relative concentration of CO in the air, duration of exposure, the respiratory function of the poisoned subject and the capacity to buffer acid–base derangements through metabolic and renal mechanisms [6]. The levels of COHb are generally defined as abnormal when exceeding the thresholds of 2% in nonsmokers and 9% in habitual smokers, respectively [7]. These elevated levels are highly suggestive for exposure to exogenous CO, thus supporting the clinical suspicion of poisoning. Elevated blood COHb levels are hence conventionally used to confirm a clinical suspicion of exposure to CO and help assessing the severity of poisoning [4]. Evidence has been provided that the degree of COHb increase in blood does not thoughtfully correlate with severity of clinical presentation, and its use for guiding clinical management is thereby currently discouraged [8]. According to this premise, the Undersea and Hyperbaric Medical Society recommends starting hyperbaric oxygen therapy for CO-poisoned individuals based on the clinical picture, irrespective of the COHb blood level [9].
http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Cervellin G, et al, Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016
2
G. Cervellin et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Since oxygen accelerates the elimination of COHb and alleviates tissue hypoxia, it is widely acknowledged that all cases of CO poisoning should be treated with high-flow oxygen by mask or endotracheal tube as front-line treatment [4]. It is noteworthy, however, that the evidence that emerged from clinical trials does not unequivocally demonstrate superior efficacy of normobaric 100% oxygen over ambient air [4]. Nevertheless, due to limited availability and high cost of hyperbaric oxygen (HBO), several studies have tried to compare the efficacy of hyperbaric versus normobaric oxygen in the treatment of CO poisoning [10–13]. A cardiac involvement is also frequent in CO-poisoned patients, ranging from mild and transitory injury to myocardiocyte necrosis and severe contractile dysfunction [14]. This is probably attributable to the high sensitivity of myocardiocytes to oxygen deprivation, which is commonplace in CO-poisoned patients, and is further worsened by a direct CO-mediated injury at cellular and subcellular levels [14]. Severe metabolic acidosis is also associated with the highest short-term mortality rate in CO-poisoned patients and, especially when the source of CO is a building fire, is possibly caused by a concomitant cyanide intoxication [15,16]. It was recently shown that lactic acid, the product of anaerobic glycolysis in association with inadequate oxygen supply, may be a prognostic parameter in CO-poisoned patients, although published data are somewhat controversial. In fact, although some authors consider blood lactate at admission virtually meaningless in CO-poisoned patients [17], others concluded that its measurement may be useful as a prognostic biomarker [18,19], or reported controversial results [20]. As such, the aim of this study was to assess the role of blood lactate levels in CO-poisoned patients for establishing the severity of poisoning and short term prognosis. Materials and methods All cases of CO poisoning referred to the ED of the University Hospital of Parma during the years 2012 and 2013 were retrieved from the hospital database. According to a local protocol, the concentrations of COHb and lactate are assessed in arterial blood in all patients with suspected CO poisoning directly in the ED, using the blood gas analyzer Radiometer ABL 800-flex (Radiometer Medical ApS, Bronshoj, Denmark). The heparinized whole blood samples are transported to the instrument at ambient temperature, where blood gas analysis is typically completed within 5 min of draw time. The assessment of cardiospecific troponin I (TnI) is also routinely performed in all patients with suspected CO poisoning. A venous blood sample is collected in blood tubes containing K2EDTA and immediately sent to the core laboratory, where the specimen is centrifuged and TnI is assessed in EDTA plasma with Beckman Coulter AccuTni + 3 on Unicel DxI (Beckman Coulter, Brea, CA, USA). The lower limit of detection of this test is 10 ng/L, whereas the 99th percentile of the reference range is 30 ng/L [21]. For the purposes of this study, CO poisoning was defined as COHb levels N 2% in non smokers and N 9% in smokers, when the history was suggestive for CO exposure and clinical symptoms were consistent with CO poisoning. The possible hospital admission of patients is individually planned by the Emergency Physician, based on clinical judgment, whereas the treatment with HBO is decided according to the Guidelines of the American Thoracic Society, i.e., in poisoned patients with loss of consciousness, ischemic cardiac changes, neurological deficits, significant metabolic acidosis, or COHb N 25% [5]. The control population for TnI testing consisted in 125 non-smokers and healthy blood donors (77 males and 48 females, age range 21–54 years), who participated to a previous analytical evaluation of AccuTni + 3 during the same period [21]. The statistical analysis was based on the Wilcoxon–Mann–Whitney test (for continuous variables), Pearson's χ2 statistics with Yates' correction (for categorical variables), and Spearman's correlation. Results of measurements were expressed as median and interquartile range (IQR). Multivariate and receiver operating characteristics (ROC) curve analyses were also performed to identify potential associations of
demographical and laboratory data with clinical outcomes (i.e., HBO treatment or hospital admission). The statistical analysis was performed using Analyse-it (Analyse-it Software Ltd, Leeds, UK) and MedCalc Version 12.3.0 (MedCalc Software, Mariakerke, Belgium). The study was performed in accordance with the Declaration of Helsinki, under the terms of relevant local legislation. Results Complete clinical and biochemical information could be retrieved from the hospital database for 38 CO poisoned patients (23 females and 15 males; median age 37 years and IQR 26–47 years). Twenty three patients (61%) underwent HBO treatment due to clinical severity and/or the elevated COHb values, and 10 (26%) were subsequently admitted to a hospital ward for incomplete recovery after treatment and/or organ injury (most notably, for troponin elevation). The length of hospital stay was on average 2 days (range 1–4 days) for admitted patients, whereas the short-term clinical outcomes were evaluated as short-term (i.e., within 2 weeks) readmissions to the ED or death. Only one patient (female, 73 years; at presentation COHb 46.3%; lactate 3.3 mmol/L) returned to the ED complaining for mild headache. She was re-evaluated and discharged within 2 h, with acetaminophen prescription. No deaths were recorded in the 2 weeks after admission. In the whole population of CO-poisoned patients, a significant correlation was found between lactate and COHb (r = 0.54; p b 0.001), as well as between lactate and TnI (r = 0.44; p = 0.001). A modest but significant correlation was also found between COHb and TnI levels (r = 0.38; p = 0.020). Interestingly, blood lactate levels were found to be higher in patients with both HBO and hospital admission, albeit a stronger association was found in the second category of patients (Tables 1 and 2). Twenty five (i.e., 66%) CO poisoned patients had detectable levels of TnI compared to 13% healthy blood donors (p b 0.001), whereas 16% CO poisoned patients had TnI levels above the 99th percentile of the reference range compared to 2% healthy blood donors (p = 0.003). Accordingly, the odds ratio (OR) for detectable TnI and for TnI levels above the 99th percentile in CO-poisoned patients was 13.1 (95% CI, 5.6–30.7; p b 0.001) and 7.6 (95% CI, 1.8–32.2; p = 0.006). After stratification of patients for severity of poisoning according to COHb levels, TnI values were found to be marginally but significantly higher in patients with COHb N 25% than in those with lower values (p = 0.031). The values of COHb were also higher in patients refereed for HBO treatment, but not in those with hospital admission. Conversely, TnI values were higher in patients with hospital admission, but not in those refereed for HBO treatment (Tables 1 and 2). In multivariate analysis, in which the clinical outcome was entered as a dependent variable whereas age, sex, COHb, TnI, blood lactate, hemoglobin, the estimated glomerular filtration rate (eGFR) and lactate dehydrogenase (LDH) on admission were included as independent variables, none of the parameters was significantly associated with HBO treatment, whereas increased value of blood lactate on
Table 1 Values (median and interquartile range) of carboxyhemoglobin (COHb), blood lactate, troponin I (TnI), estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) formula and lactate dehydrogenase (LDH) in 38 patients with acute carbon monoxide poisoning, stratified according to hyperbaric oxygen (HBO) treatment.
n Age (years) Females COHb (%) Lactate (mmol/L) TnI (ng/L) Hemoglobin (g/L) eGFR (mL/min/1.73 m2) LDH (U/L)
No HBO
HBO
p
15 37 (20–47) 8/15 8.5 (5.0–20.5) 1.1 (1.0–1.6) 10 (10–20) 127 (120–139) 92 (78–101) 372 (328–418)
23 37 (28–47) 15/23 18.4 (12.2–26.8) 1.5 (1.3–1.9) 10 (b10 to 20) 132 (121–148) 95 (90–113) 377 (322–425)
0.416 0.352 0.032 0.003 0.318 0.326 0.056 0.383
Please cite this article as: Cervellin G, et al, Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016
G. Cervellin et al. / Clinical Biochemistry xxx (2014) xxx–xxx Table 2 Values (median and interquartile range) of carboxyhemoglobin (COHb), blood lactate, troponin I (TnI), estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) formula and lactate dehydrogenase (LDH) in 38 patients with acute carbon monoxide poisoning, stratified according to admission to a hospital ward.
n Age (years) Females COHb (%) Lactate (mmol/L) TnI (ng/L) Hemoglobin (g/L) eGFR (mL/min/1.73 m2) LDH (U/L)
No admission
Admission
p
28 35 (25–45) 18/28 15.0 (8.1–21.4) 1.2 (1.0–1.6) 0.01 (b0.01 to 0.01) 137 (121–147) 99 (90–109) 355 (323–402)
10 37 (46–75) 5/10 18.9 (12.4–30.1) 1.8 (1.4–2.0) 0.02 (0.01 to 0.04) 127 (120–137) 85 (73–94) 439 (397–491)
0.035 0.342 0.091 b0.001 0.002 0.274 0.002 0.008
eGFR, estimated glomerular filtration rate according to the Modification of Diet in Renal Disease (MDRD) formula; LDH, lactate dehydrogenase.
admission was the only significant predictor of hospital admission. The area under the curve (AUC) for predicting HBO treatment was 0.54 (95% CI, 0.31–0.78; p = 0.366) for blood lactate, 0.56 (95% CI, 0.31–0.80; p = 0.318) for TnI, and 0.64 (0.45–0.84; p = 0.078) for COHb, respectively. At variance with these findings, the AUC for predicting hospital admission was 0.85 (95% CI, 0.72–0.97; p b 0.001) for blood lactate, 0.71 (95% CI, 0.50–0.91; p = 0.026) for TnI, and 0.61 (95% CI, 0.39–0.84; p = 0.156) for COHb. A blood lactate concentration N 1.20 mmol/L was associated with 1.00 sensitivity and 0.57 specificity for predicting hospital admission, whereas a detectable value of TnI exhibited 0.80 sensitivity and 0.39 specificity for predicting hospital admission. Discussion The relationship between blood lactate and severity or prognosis of CO poisoning has been previously addressed. In a series of CO-poisoned patients Benaissa et al. found that plasma lactate is mildly elevated in pure CO-exposed patients but, due to the large overlap between the different groups of subjects, the usefulness of systematic lactate measurement in CO poisoning could not be confirmed [17]. At variance with this evidence, Inoue et al. reported that the initial blood lactate level correlated with patients' outcome and was proven to be a useful prognostic factor in a small series of suicidal, severely CO-poisoned patients [18]. Moon et al. also found that initial blood lactate level was independently associated with serious complications and the need for intensive medical treatment in 80 patients urgently admitted to the ED for CO poisoning [19]. More recently, Doğan et al. found that initial lactate levels were positively correlated with COHb values in 74 patients with severe CO poisoning [20]. Taken together, the published evidence about the clinical significance of blood lactate in CO-poisoned patients is scarce and somewhat controversial, so the results of our study may have some meaningful clinical implications. Besides confirming that heart involvement is frequent in patients with CO poisoning, the existence of significant associations between the values of lactate and those of COHb (r = 0.54; p b 0.001) or troponin (r = 0.44; p = 0.001) is indeed the first important finding of our retrospective investigation. It is also noteworthy that the correlation between TnI and lactate was greater than that found between TnI and COHb (r = 0.38; p = 0.020), and that increased blood lactate levels were independent predictors of hospital admission. This can be interpreted as meaning that the metabolic acidosis developing in COpoisoned patients is primarily responsible for the cardiac injury rather than the severity of the intoxication by itself. This important aspect has been hypothesized in some previous studies [15,16], and is also supported by the evidence that the myocardial tissue is highly vulnerable to oxygen deprivation, thus causing a substantial reduction of contractility and cardiac output, which ultimately contribute to worsen the direct
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injury of CO on cardiomyocytes [14]. This hypothesis seems to be confirmed by the findings of our investigation, in that blood lactate levels were significantly associated with TnI. It is also noteworthy that the rate of detectable TnI levels (i.e., N10 ng/L) using AccuTni + 3 was relatively low in healthy individuals (i.e., 13%). As such, the identification of a high rate of measurable TnI levels in our population of COpoisoned patients (i.e., 66%) should be considered as clinically meaningful, albeit not independently predictive of either HBO treatment or hospital admission. In conclusion, the results of this retrospective investigation on 38 patients presenting to the ED with acute CO poisoning suggest that initial blood lactate level may be an additional and useful parameter for risk stratification of patients, especially for predicting the need for hospitalization. Conflict of interest statement All authors do not have any potential conflicts of interest, and all authors have read the journal's policy on conflicts of interest. Moreover, all authors have read the journal's authorship agreement. Acknowledgments The authors acknowledge Drs. Marco Brambilla and Marco Mignani of the Academic Hospital of Parma for the kind support in extracting data from the electronic database of the Institution, and the Nurse Rosa Netti for the kind support in extracting hemogasanalyzer's data. References [1] Raub JA, Mathieu-Nolf M, Hampson NB, Thom SR. CO poisoning—a public health perspective. Toxicology 2000;145:1–14. [2] Hampson NB, Weaver LK. Carbon monoxide poisoning: a new incidence for an old disease. Undersea Hyperb Med 2007;34:163–8. [3] Amitai Y, Zlotogorski Z, Golan-Katzav V, Wexler A, Gross D. Neuropsychological impairment from acute low-level exposure to carbon monoxide. Arch Neurol 1998;55:845–8. [4] Weaver LK. Carbon monoxide poisoning. N Engl J Med 2009;360:1217–25. [5] Hampson NB, Piantadosi CA, Thom SR, Weaver LK. Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning. Am J Respir Crit Care Med 2012;186:1095–101. [6] Ryter SW, Otterbein LE. Carbon monoxide in biology and medicine. Bioessays 2004; 26:270–80. [7] Radford EP, Drizd TA. Blood carbon monoxide levels in persons 3–74 years of age: United States, 1976–80. In: Hyattsville MD, editor. US Dept of Health and Human Services; Advance Data 76; March 17, 1982. US Dept of Health and Human Services publication PHS; 1982. p. 82–1250. [8] 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. [9] Feldmeier JJ. Hyperbaric oxygen 2003: indications and results: the Hyperbaric Oxygen Therapy Committee report. Kensington, MD: Undersea and Hyperbaric Medical Society; 2003. p. 11–8. [10] Raphael JC, Elkharrat D, Jars-Guincestre MC, Chastang C, Chasles V, Vercken JB, et al. Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989;2:414–9. [11] Weaver LK, Hopkins RO, Chan KJ, Churchill S, Elliott CG, Clemmer TP, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 2002;347:1057–67. [12] Buckley NA, Juurlink DN, Isbister G, Bennett MH, Lavonas EJ. Hyperbaric oxygen for carbon monoxide poisoning (review). Cochrane Collaboration; 2011 [available online at http://www.thecochranelibrary.com]. [13] Wolf SJ, Lavonas EJ, Sloan EP, Jagoda AS. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Critical Issues in the Management of Adult Patients Presenting to the Emergency Department with Carbon Monoxide Poisoning. Ann Emerg Med 2008;51:138–52. [14] Lippi G, Rastelli G, Meschi T, Borghi L, Cervellin G. Pathophysiology, clinics, diagnosis and treatment of heart involvement in carbon monoxide poisoning. Clin Biochem 2012;45:1278–85. [15] Hampson NB, Hauff NM. Risk factors for short-term mortality from carbon monoxide poisoning treated with hyperbaric oxygen. Crit Care Med 2008;36:2523–7. [16] Anseeuw K, Delvau N, Burillo-Putze G, De Iaco F, Geldner G, Holström P, et al. Cyanide poisoning by fire smoke inhalation: a European expert consensus. Eur J Emerg Med 2013;20(1):2–9. [17] Benaissa LM, Mégarbane B, Borron SW, Baud FJ. Is elevated plasma lactate a useful marker in the evaluation of pure carbon monoxide poisoning? Intensive Care Med 2003;29:1372–5.
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Please cite this article as: Cervellin G, et al, Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.09.016
