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Endogenous carbon monoxide production correlates weakly with severity of acute illness

Scharte, M.*; von Ostrowski, T. A.*; Daudel, F.*; Freise, H.*; Van Aken, H.*; Bone, H. G.*

European Journal of Anaesthesiology (EJA): February 2006 - Volume 23 - Issue 2 - p 117–122
doi: 10.1017/S0265021505002012
Original Article
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Background and objective: The enzyme haeme oxygenase-1 is highly inducible by oxidative agents. Its product carbon monoxide is thought to exert anti-inflammatory properties. We recently showed, that critically ill patients produce higher amounts of carbon monoxide compared to healthy controls. In the present study we compare endogenous carbon monoxide production with the severity of illness of intensive care unit patients.

Methods: Exhaled carbon monoxide concentration was measured in 95 mechanically ventilated, critically ill patients (mean age ± SD, 59.5 ± 15.7) on a carbon monoxide monitor. Measurements were taken every hour for 24 h in each patient. Data were analysed using Mann-Whitney rank sum test. Correlation analysis was performed with the Spearman's rank order correlation.

Results: Carbon monoxide production correlated weakly with the multiple organ dysfunction score (R = 0.27; P = 0.009). Patients suffering from cardiac disease (median 22.5, interquartile range 16.2-27.4 μL kg−1 h−1 vs. median 18.2, interquartile range 14.2-21.8 μL kg−1 h−1, P = 0.008) and critically ill patients undergoing dialysis (median 25.0, interquartile range 21.4-30.2 μL kg−1 h−1, vs. median 19.4, interquartile range 14.7-23.3 μL kg−1 h−1, P = 0.004) produced significantly higher amounts of carbon monoxide compared to critically ill controls.

Conclusion: The findings suggest that endogenous carbon monoxide production might reflect the severity of acute organ dysfunction.

*Universitätsklinikum Münster, Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Muenster, Germany

Correspondence to: Marion Scharte, Department of Anaesthesiology and Critical Care Medicine, University Hospital Muenster, Albert-Schweitzer-Strasse 33, D-48129 Muenster, Germany. E-mail: scharte@anit.uni-muenster.de; Tel: +49 251 83 47255; Fax: +49 251 83 48667

Accepted for publication 17 September 2005

First published online January 2006

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Introduction

Carbon monoxide (CO) is produced endogenously in human beings during haeme degradation. Haeme oxygenase (HO) is the rate-limiting enzyme in this degradation process, producing biliverdin, free iron (Fe2+), and CO. Biliverdin is immediately converted into bilirubin in mammals [1]. The inducible form HO-1 and the constitutive forms HO-2 and HO-3 have been identified as genetic isoforms [2]. All isoforms are highly conserved among species [3]. Under physiological conditions HO-2 and HO-3 are constitutively expressed in most tissues, while cells express only low or undetectable levels of HO-1. HO-1 gene expression is inducible by many diverse stimuli and involves different signalling pathways [4]. Among other stimuli HO-1 gene expression is strongly induced by agents that increase oxidative stress, including H2O2, cytokines, lipopolysaccharides, nitric oxide, ischaemia, heat shock, hypoxia and hyperoxia [5]. Its expression is mainly regulated at the transcriptional level and is cell type and species specific [6].

Elevated HO-1 expression has been found in different pathological conditions, including acute pancreatitis, asthma, atherosclerosis, cancer, diabetes and ischaemia/reperfusion [7]. Although the mechanisms are not fully understood yet, HO-1 and CO both have been demonstrated to exert cytoprotective and anti-inflammatory effects [5]. Beside the induction of HO-1, also increased CO concentrations in exhaled air have been reported in several conditions. Inflammatory airway disease is associated with higher CO levels in expired air [8-10]. Endogenous CO production was also significantly higher in patients suffering from severe sepsis compared to critically ill controls [11]. We could demonstrate a significantly higher CO production in critically ill patients compared to healthy controls [12]. In the present study we investigated the relationship between the severity of illness and endogenous CO production in critically ill patients.

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Methods

Population

The Local Ethics Committee approved the protocol and waived the need for informed consent, since the measurements of CO concentration in exhaled air were not invasive and blood gas analysis and other laboratory parameters were performed routinely for medical care. The study was performed on 95 mechanically ventilated critically ill patients from November 2000 to May 2002. Sepsis was defined according to the criteria of the American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) consensus conference [13]. Pneumonia was identified according to the clinical pulmonary infection score proposed by Singh and colleagues [14].

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Measurement of endogenous CO production

The patients were ventilated either with EVITA 4 or 2 (Draeger-Werke, Luebeck, Germany). They had been mechanically ventilated for 5.5 ± 0.2 days prior to the first measurement. Exhaled CO was determined electrochemically with a CO-monitor equipped with a polytron cell (Draeger-Werke, Luebeck, Germany). Sensitivity (≤ ±3% of the measured value) and specificity parameters of CO measurements were provided by the manufacturer (Draeger-Werke, Luebeck, Germany) (Draeger-Sicherheitstechnik, 1997 #41) [15]. A number of substances were tested for their reaction on the sensor (cross sensitivities). Among the tested substances, ammonia, carbon dioxide and nitrogen monoxide (NO) are of interest for the measurements taken in the patients. Ammonia and carbon dioxide did not interfere with the CO measurements. NO with a test gas concentration of 25 ppm resulted in a ≤8 ppm deviation from the CO value measured without NO (Draeger-Sicherheitstechnik, 1997 #41). Thus patients with NO inhalation therapy were excluded from the study. The intra-assay coefficient of variation (CV) was 2.3%; the inter-assay CV based on CO measurements taken in six healthy subjects was 12.1%. At the beginning of the study the sensor was calibrated by the manufacturer. Exhaled air was directed from the respirator into a compartment (1.5 L volume), from which gas was sampled continuously by the suction unit of the CO monitor. Thus a continuous measurement of CO concentration in exhaled air was possible. In each patient CO concentration in exhaled air was measured continuously for 24 h. Every hour the CO concentration was noted. The mean of all 24 measurements was calculated for each patient. To control for differences in minute ventilation CO production was calculated by CO concentration in exhaled air multiplied by minute ventilation: VCO (mL min−1) = eCO (ppm) × minute ventilation (L min−1). To take the body weight into consideration the CO production in mL min−1 was further divided by kilogram body weight: VCO (μL kg−1 h−1) = eCO (ppm) × minute ventilation (L min−1) × 60 (min)/body weight (kg).

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Laboratory parameters

Arterial blood was drawn before the first and after the last measurement of exhaled CO concentration and sampled in heparinized tubes (Sarstedt, Nümbrecht, Germany). It was immediately analysed for PaO2, PaCO2 and haemoglobin by a blood gas analyser/ oxymeter (ABL 620; Radiometer AB, Copenhagen, Denmark). The mean of the two measured values of PaO2, PaCO2 and haemoglobin was taken for statistical analysis. The analysis of serum from arterial blood drawn once a day for routine medical care was performed in the hospital laboratory according to standard laboratory procedures.

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Data analysis

Data are expressed as mean ± SD or as median and interquartile range (IQ). Differences in multiple organ dysfunction score (MODS) between patients with normal and increased CO production was analysed with the t-test, differences in serum creatinine concentrations, lactate dehydrogenase concentrations and white blood cell counts between both groups were analysed using the Mann-Whitney rank sum test. Statistical analysis of CO production in different subgroups was performed using Mann-Whitney rank sum test. Correlations between endogenous CO production and disease scores or laboratory parameters were analysed using the Spearman's rank correlation.

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Results

Ninety-five mechanically ventilated and critically ill patients were included in the study. Patient characteristics data are given in Table 1. Twenty-four of the patients suffered from a pulmonary disease (COPD, pneumonia, obstructive sleep apnoea, pulmonary oedema, cystic fibrosis). Fifty-four out of 95 patients had at least one pre-existing cardiovascular disease (Table 2).

Table 1

Table 1

Table 2

Table 2

CO concentration of the patients varied between 0.86 and 8.47 ppm (median 2.9, IQ 2.2-3.7 ppm). Patients produced endogenous CO in the range of 7.8-115 mL min−1 (median 24.6, IQ 19.15-30.8). Considering the body weight, patients produced endogenous CO between 7.3 and 97.9 μL kg−1 h−1 (median 20.6, IQ 15.7-25.3).

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Differences between patients with normal and elevated endogenous CO production

Twenty-three of the critically ill patients showed a CO production (7-18.7 mL min−1) comparable with healthy subjects (median 13.5, 95% CI 11-19), in whom we measured CO production in a previous study [12]. Seventy-two patients produced increased levels of CO (19.15-115 mL min−1). Patients with a CO production in the normal range had significantly lower MODS (mean ± SE; 8.09 ± 0.54) compared to patients with increased CO production (mean ± SE; 9.79 ± 0.45) (P = 0.047). Furthermore, patients with normal VCO had significantly lower creatinine serum concentrations (median 1.0, IQ 0.6-1.2 mg dL−1) compared to patients with elevated CO production (median 1.4, IQ 0.8-1.9) (P = 0.005). There was no difference in white blood cell count as well as in lactate dehydrogenase serum levels between both groups (P > 0.05).

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Correlation between endogenous CO production and disease scores

In order to evaluate the severity of illness different scores were calculated at the beginning of the protocol, immediately before the first measurements of CO concentration in exhaled air were taken. The Acute Physiology and Chronic Health Evaluation II score (APACHE II score) was chosen as an outcome score. To estimate the severity of organ dysfunction the MODS was calculated. Endogenous CO production (VCO (μL kg−1 h−1)) correlated significantly though fairly with the MODS (R = 0.266; P = 0.009) (Fig. 1). The highest three readings for CO production are substantially higher compared to the measurements taken of the other 92 patients and might be regarded as outliers. When omitting these three readings, still a significant but weak correlation existed between endogenous CO production and MODS (R = 0.23; P = 0.026; n = 92). No correlation was found between APACHE II score and CO production (VCO (μL kg−1 h−1)) (R = 0.04; P = 0.699).

Figure 1.

Figure 1.

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Differences in endogenous CO production between subgroups

Patients with a pre-existing cardiac disease (n = 54) produced significantly higher amounts of endogenous CO compared to patients without a pre-existing cardiac condition (n = 41) (median 22.5, IQ 16.2- 27.4 μL kg−1 h−1 vs. median 18.2, IQ 14.2-21.8 μL kg−1 h−1; P = 0.008) (Fig. 2). In pre-existing cardiac disease MODS (median 11, IQ 8-13 vs. median 7, IQ 5-8) and APACHE II scores (median 24, IQ 20-26 vs. median 20, IQ 17-24) were significantly higher compared to intensive care unit (ICU) controls (P < 0.001 and P = 0.002, respectively).

Figure 2.

Figure 2.

Furthermore, patients with renal failure, who had to undergo dialysis (n = 14), exhibited a significantly higher endogenous CO production compared to patients without renal failure (n = 81) (median 25.0, IQ 21.4-30.2 μL kg−1 h−1 vs. median 19.4, IQ 14.7-23.3 μL kg−1 h−1; P = 0.004) (Fig. 3). Similar to patients with a pre-existing cardiac condition critically ill dialysis patients demonstrated significantly higher MODS (median 13.5, IQ 10-15 vs. median 8, IQ 6-11) and APACHE II scores (median 25.5, IQ 20-30 vs. median 22, IQ 19-24) compared to critically ill patients without acute renal failure (P < 0.001 and P = 0.01, respectively).

Figure 3.

Figure 3.

Interestingly, critically ill patients with sepsis (n = 10) produced similar amounts of endogenous CO compared to ICU patients without sepsis (n = 85) (median 20.4, IQ 17.4-27.9 μL kg−1 h−1 vs. median 20.6, IQ 15.2-22.9 μL kg−1 h−1; P > 0.05) despite a significantly higher MODS in sepsis (median 12, IQ 10-16 vs. median 8, IQ 7-12; P = 0.009).

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Correlation between endogenous CO production and laboratory parameters

As haemoglobin is degraded by haeme oxygenase, resulting in the production of equal amounts of CO and biliverdin, which is converted into bilirubin, the correlation between serum bilirubin and endogenous CO production was analysed as a control for the validity of CO concentration measurements. There was a significantly positive correlation between endogenous CO production and serum bilirubin (R = 0.378; P = 0.00). No significant correlation existed between CO production and haemoglobin levels (R = 0.031; P > 0.05) or CO production and number of red blood cell concentrates given during the previous 7 days (R = 0.162; P > 0.05). Furthermore, no correlation was found between endogenous CO production and PaCO2 or PaO2 (R = −0.076 and −0.105, respectively; P > 0.05). Endogenous CO production did not correlate with white blood cell count (R = 0.08; P > 0.05), but correlated significantly with serum lactate dehydrogenase (R = 0.226; P = 0.03). In line with a significantly higher CO production found in patients with renal failure compared to critically ill controls, a significantly positive correlation existed between serum creatinine and CO production (R = 0.272; P = 0.01).

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Discussion

In this study we have demonstrated, to our knowledge for the first time, a significant though weak correlation between MODS and endogenous CO production. Furthermore, patients with a CO production in the normal range had significantly lower MODS compared to patients with increased CO production. Serum creatinine levels were significantly lower in patients with normal CO production compared to those with increased CO production; CO production correlated significantly with serum creatinine concentration. Patients, who developed severe renal failure and had to undergo dialysis as well as patients with a pre-existing cardiac condition produced significantly more CO compared to critically ill controls.

Haeme is degraded by haeme oxygenase into equal amounts of Fe2+, CO and biliverdin. The latter undergoes further metabolism to bilirubin. Thus the highly significant correlation between endogenous CO production and serum bilirubin levels was expected. Bilirubin concentration can be considered as one parameter to estimate the validity of the measurement of endogenous CO production.

Oxidative stress is a strong stimulus for the induction of HO-1, which might result in an increase in endogenous CO production. Organ dysfunction and failure is often accompanied by oxidative stress, which might have caused the increase in endogenous CO production in organ dysfunction like renal failure. The correlation between MODS and endogenous CO production, though only weak, as well as the significantly higher MODS in patients with increased CO production might suggest a relationship between organ dysfunction and organ failure on the one hand and endogenous CO production on the other hand. Beside parameters reflecting the acute disease status, the APACHE II score includes other parameters which can influence outcome, but do not reflect acute organ dysfunction, e.g. age. The latter might explain that no correlation was found between APACHE II score and endogenous CO production.

Oxidative stress is also present in severe sepsis and septic shock. Zegdi and colleagues found a significantly higher endogenous CO production in patients suffering from severe sepsis compared to critically ill controls [11]. In contrast, we could not demonstrate a difference in CO production in septic and non-septic critically ill patients. We included critically ill patients into the sepsis group according to the definition of sepsis of the ACCP/SCCM consensus conference [13], while Zegdi and colleagues only included patients who fulfilled the criteria of severe sepsis and septic shock [11]. The difference in inclusion criteria might explain partly the discrepant findings.

In inflammation of the respiratory tract increased CO concentrations in exhaled air have been found. Thus asthmatic patients [10] as well as patients with infection of the upper respiratory tract [16] exhaled higher concentrations of CO compared to controls. The increased CO production is thought to be caused by the induction of HO-1 by inflammatory mediators. In a rat model of asthma allergic agents causing an inflammation of the airway-induced HO-1 [17].

Not only in inflammation of the respiratory tract but also in various other inflammatory conditions such as ischaemia/reperfusion injury [18], atherosclerosis [19] and acute renal failure [20] increased HO-1 expression have been shown. The increased endogenous CO production in patients with acute renal failure demonstrated in the present study might therefore be caused by the induction of HO-1. The positive correlation between CO production and serum creatinine as well as the significantly higher creatinine concentration in patients with increased CO production further suggests a coherence between renal insufficiency and CO production. Furthermore, atherosclerosis is commonly found and often the underlying cause of a wide variety of cardiac diseases. Ischaemia/reperfusion injury plays an important role in the pathology of myocardial infarction and coronary heart disease. This suggests that the increased CO production found in patients with cardiac disease compared to critically ill controls might also be caused by increased levels of HO-1 due to induction of the enzyme by inflammatory mediators, such as pro-inflammatory cytokines.

The induction of HO-1 seems to have a protective effect on cells and tissues. In animal models of oxidant injury and acute inflammation [21-23] elevated levels of HO-1 resulted in resistance to cell injury and lipopolysaccharide-induced death, while inhibition of HO-1 blocked the protective effect. Furthermore, pharmacological induction of HO-1 suppressed the inflammatory response [18,24]. The exact mechanism by which HO-1 exerts its anti-inflammatory and cytoprotective effect is not fully understood. One mechanism might be the downregulation of adhesion molecule expression and leucocyte adhesion [25-27]. Similar to the effect of HO-1 overexpression on inflammation low doses of exogenous CO inhibit pro-inflammatory genes and augment anti-inflammatory cytokine production. The anti-inflammatory effect of CO is thought to be mediated, at least in part, by the activation of p38 mitogen-activated protein kinase signalling pathway [28-30]. Low doses of exogenous CO also exert an anti-inflammatory effect by suppression of T-cell proliferation [31,32]. Recently anti-inflammatory effects of low concentrations of inhaled CO could be demonstrated in a rat model of ventilator-induced lung injury [33]. Apart from its anti-inflammatory effect CO also shows anti-apoptotic properties in vitro and in vivo [34-36].

The increased production of CO found in critically ill patients, especially in patients with organ dysfunction, might therefore be regarded as a means of the body to protect its cells and tissues against oxidative stress and inflammatory injury. As the correlation between CO production and MODS was only weak, the results should be interpreted with care. The amount of endogenously produced CO might be helpful as an additional parameter among others to estimate the severity of illness. Whether increased endogenous CO production might predict morbidity and mortality, should be investigated in outcome studies.

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Keywords:

CARBON MONOXIDE; endogenous production; CRITICAL ILLNESS; HAEME OXYGENASE-1; MULTIPLE ORGAN FAILURE; INFLAMMATION

© 2006 European Society of Anaesthesiology