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European Journal of Heart Failure 2004 6(4):403-407; doi:10.1016/j.ejheart.2004.03.002
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© 2004 European Society of Cardiology

Studies on intragastric PCO2 at rest and during exercise as a marker of intestinal perfusion in patients with chronic heart failure

Andreas Kracka,b,*, Barbara M. Richartza, Anja Gastmanna, Kasia Greima, Ulrich Lotzea, Stefan D. Ankerb,c and Hans R. Figullaa

a Department of Cardiology, Friedrich-Schiller University Erlanger Allee 101, D-07740, Jena, Germany
b Clinical Cardiology, NHLI, Imperial College School of Medicine London, UK
c Department of Cardiology, Charité Medical School at MDC Berlin, Germany

* Corresponding author. Tel.: +49-3641-9324101; fax: +49-3641-9324102. E-mail address: andreas.krack{at}med.uni-jena.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: The aim of this study was to investigate mesenteric ischaemia by determining intragastric PCO2 (iPCO2) with gastric tonometry during rest and exercise stress testing in patients with chronic heart failure (CHF). In CHF inflammatory immune activation is hypothesized to result from a chronic endotoxin challenge due to bacterial translocation of hypoperfused intestinal mucosa.

Methods and Results: In 10 patients with CHF and ten healthy controls a tonometry catheter was inserted into the stomach. IPCO2 was measured at rest and during bicycle exercise every 5 min. At rest arterial pCO2 (aPCO2), intragastric pCO2 (iPCO2) and the intragastric/arterial gap did not differ between patients and controls. During low level exercise (25 W), patients showed an increase in iPCO2 compared to resting iPCO2, whereas controls did not show an increase in iPCO2 (change in iPCO2: 12±2% vs. 1±0.4%, P<0.001). In CHF, iPCO2 during peak exercise was 25±3% higher than at rest, compared to controls (increase 2±1, P<0.0001).

Conclusions: Patients with CHF already at low level exercise develop an increase in iPCO2. This is likely to reflect hypoperfusion of the intestinal mucosa, which may contribute to the development of bacterial translocation.

Key Words: CHF, chronic heart failure • PCO2, partial pressure of carbondioxide • PO2, partial pressure of oxygen • NYHA, New York Heart Association • TNF{alpha}, tumor necrosis factor alpha

Received November 12, 2003; Revised January 12, 2004; Accepted March 3, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure (CHF) is characterised by a variety of cardiac and peripheral abnormalities including inflammatory immune activation [1] and peripheral hypoperfusion [2]. Gastric tonometry is an established technique to assess the severity of regional perfusion impairment in the gut [3,4]. The aim of this study was to investigate whether patients with CHF show gastrointestinal hypoperfusion.

In intensive care units, gastric tonometry is widely used to monitor intestinal microperfusion in patients after major cardiac surgery and in septic shock [5,6]. It has been shown that patients with cardiogenic shock develop high intragastric PCO2 (iPCO2) within the first 24 h, with persistently high levels of iPCO2 being indicative for prolonged hypoperfusion of the gut [7]. A high iPCO2 indicates gastrointestinal mucosal ischaemia [8].

Patients with chronic heart failure exhibit inflammatory immune activation [11]. Increased levels of inflammatory cytokines most often are found in patients with cardiac cachexia [1,9] and in patients with oedematous decompensation and in NYHA class IV [10,11]. The cause of TNF{alpha} activation in CHF is not yet known, but several hypotheses have been proposed [12]. According to the endotoxin hypothesis, increased bowel permeability in CHF patients may lead to bacterial translocation and endotoxin release [13]. An increased endotoxin challenge could cause inflammatory immune activation with increased TNF{alpha} production. Vonhof et al. [14] stimulated blood samples of decompensated CHF patients with lipopolysaccharides (LPS) in vitro and showed an increased TNF{alpha} release in response to LPS. Similar results were reported by Matsumori et al. [15].

Niebauer et al. [11] have shown that decompensated CHF patients show increased plasma levels of LPS. To date there is no evidence that intestinal hypoperfusion is present in CHF patients at rest or during low intensity exercise.

The main problem in determining whether CHF patients show intestinal hypoperfusion is the lack of functional tests that can identify and grade the severity of gastrointestinal ischaemia [16,17]. We used tonometry in combination with an exercise test. Exercise stresses the abdominal vasodilator reserve by diverting blood flow from the splanchnic circulation to the exercising muscles.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Participants
We studied prospectively ten patients with CHF and ten healthy volunteers of similar age and body mass index (BMI) (Table 1). All patients were inpatients admitted to University Hospital, Jena (eight NYHA class III, two class IV). Assessments were performed after clinical recompensation prior to discharge from hospital. Healthy volunteers were recruited from a local sports club; they had no evidence of cardiac disease, and all showed normal ECG, bicycle exercise test and echocardiography. The etiology of CHF was ischaemic in five patients and non-ischaemic in the other five patients as established by cardiac catheterisation. No patient or control subject showed clinical signs of infection, rheumatoid arthritis, inflammatory bowel disease, liver cirrhosis or cancer. Patients were treated with diuretics (n=10), angiotensin-converting-enzyme inhibitors or angiotensin-receptor antagonists (n=10), beta blockers (n=7), digitalis (n=8), aspirin (n=5), spironolactone (n=1), and nitrates (n=2) in various combinations. The protocol was approved by the institutional ethical committee. Written informed consent was obtained from all participants. The procedures followed were in accordance with institutional guidelines.


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  		Table 1 Characteristics of patients with chronic heart failure and healthy volunteers

 
2.2. Tonometry
Forty milligrams of Pantoprazol (Pantozol, Byk Gulden, Konstanz, Germany) was administered twice daily orally for 3 days prior to the study to suppress gastric acid secretion. The latter is considered to be a standard procedure in gastric tonometry [18]. A gastric juice pH>4 considerably reduces interindividual variability of the tonometric measurements [19]. All participants were fasting for at least 12 h. For assessing intragastric pressure of carbon dioxide (iPCO2) a Tonocap monitor (Datex-Engstrom, Helsinki, Finland) was used. A Trip tonometry catheter (Datex-Engstrom, Helsinki, Finland) was introduced through the mouth and advanced into the stomach. This tonometry catheter consists of a polyurethane, CO2 impermeable nasogastric tube with a silicone CO2 permeable balloon at the tip. The CO2 can freely equilibrate between the gastric mucosa, the lumen, and the air in the balloon. The Tonocap monitor analyses air samples from the balloon every 5 min, therefore this modality is called air tonometry. The monitor automatically analyses the sample with an infrared sensor for CO2. Additionally, arterial pCO2 was assessed from arterialised blood from earlobe according to standard procedures. The intragastric PCO2 (iPCO2) to arterial PCO2 (aPCO2) difference (gap) is determined according to the formula gap=iPCO2–aPCO2, where gap is measured in mm Hg. Gap is thought to provide a measure of the degree of intestinal perfusion failure [20]. We defined ‘gap difference’ as the difference between gap values at rest and at peak exercise level. After an equilibration period of 45 min, a bicycle exercise was performed. The workload was increased 25 W every 5 min, and iPCO2 was determined during each exercise level. Exercise testing was terminated when the participant showed fatigue, shortness of breath, or reached maximal predicted heart rate [21].

2.3. Assays
At baseline, blood samples for TNF{alpha}, sCD14, lactate, full blood count, urea and electrolytes and an arterialised capillary blood gas sample were taken after supine rest of at least 15 min. Arterialised capillary blood gas samples and lactate were also measured at peak exercise and after recovery 120 min after the end of exercise test. Blood samples for TNF{alpha} and sCD14 were collected 120 min after exercise [22]. Blood samples for TNF{alpha} and sCD14 analysis were placed on ice, separated immediately, and stored at –78 °C until assessment. ELISA kits were used to measure TNF{alpha} (QuantiGlo human TNF{alpha} chemiluminiscent immunoassay, R&D Systems, Minneapolis, MN, USA; sensitivity 0.5 pg/ml) and sCD14 (sCD14 ELISA, IBL, Hamburg, Germany; sensitivity 0.5 ng/ml).

2.4. Statistical analysis
Results are presented as mean value±S.E. Comparison between patients and control subjects was made using unpaired Student t-test. Abnormally distributed variables were log-transformed for statistical analyses. Changes over time were analysed by paired t-test or repeated measures analysis of variance (ANOVA) as appropriate. We used univariate and multivariate regression analysis to establish the relationship between variables. A P-value less than 0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Gastric tonometry at rest and after exercise
Baseline arterial pCO2 (aPCO2), intragastric pCO2 (iPCO2) and the gap did not differ between patients and control subjects (Table 2). All subjects managed to exercise for at least 5 min at 25 W. During low level exercise (25 W), patients showed an increase in iPCO2 compared to resting iPCO2, whereas controls did not show an increase in iPCO2 (change in iPCO2: 12.4±1.7% vs. 1.1±0.4%, P<0.0001).


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  		Table 2 Tonometric data of patients with chronic heart failure and healthy volunteers

 
The workload was increased every 5 min. At peak exercise level, which was 25–75 W in patients (mean 55±5 W) and 100–150 W in controls (mean 118±10 W), patients showed an increase in iPCO2 of 24.9±3.1% vs. 1.7±1.1% in controls (P<0.0001) (Figs. 1 and 2). Patients showed an increase in the iPCO2–aPCO2 gap (gap difference) from rest to peak exercise of 1.52±0.19 kPa, compared with 0.49±0.14 kPa in controls (P=0.0003) (Table 2).


Figure 1
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  		Fig. 1 iPCO2 in patients.

 


Figure 2
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  		Fig. 2 iPCO2 in controls.

 
3.2. Humoral assessments
Baseline TNF{alpha} levels were higher in patients (5.49±0.78 pg/ml) than in controls (1.87±0.27 pg/ml) (P<0.0001, Table 1). Two hours after exercise TNF{alpha} levels had not changed significantly in patients (P>0.2), but had decreased in controls by 21±10% (P=0.0482). Baseline sCD14 levels were higher in patients (82.3±12.4 ng/ml) than in controls (39.5±2.6 ng/ml) (P=0.0033). Two hours after exercise sCD14 levels did not change significantly, neither in patients nor in controls (Table 1).

Baseline lactate was similar in both groups (1.0±0.06 vs. 1.3±0.09 mmol/l in patients vs. controls, P>0.2). At peak exercise, lactate in patients rose up to 3.1±0.16 mmol/l, compared to 7.2±0.38 mmol/l in controls (P<0.0001).

3.3. Regression analyses
Plasma levels of TNF{alpha} or sCD14 did not relate to iPCO2 or gap, neither at rest, nor after exercise. In CHF patients, plasma sodium levels strongly and inversely related to the difference in intragastric-arterial PCO2 gap between peak exercise to baseline (i.e. gap difference) (r=–0.83, P=0.0031, Fig. 3). Potassium levels positively related to gap difference (r=0.76, P=0.0102).


Figure 3
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  		Fig. 3 Correlation between gap difference and sodium in patients.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our study shows that patients with chronic heart failure already at low level exercise develop a rise in intragastric PCO2. This is likely to reflect splanchnic hypoperfusion, i.e. mesenteric ischaemia. Bicycle exercise at 25 W reflects a degree of physical activity that frequently occurs during the daily life of a CHF patient. Level walking at 2.5 miles per hour is equivalent to bicycle exercise at 25 W [23]. Therefore, the gut of CHF patients (in contrast to that of healthy persons) may frequently be exposed to ischaemic stress, which could contribute to the development of an impaired barrier function of the gut with subsequent bacterial translocation and uptake of endotoxin into the circulation. We have studied patients in NYHA class III and IV, who are known to show inflammatory immune activation (also documented in the present study) as well as elevated endotoxin plasma levels. Mesenteric ischaemia may contribute to immune activation in CHF, but the intermittent nature of this phenomenon prevents us to find a direct relationship to plasma cytokine levels that are regulated much slower than gut perfusion. Tonometry has not been used before to study CHF patients. In patients with unexplained abdominal symptoms, Kolkman et al. [24] evaluated the potential value of gastric tonometry during 10 min of submaximal exercise for diagnosing gastrointestinal ischaemia, as compared to angiography. They found a significant correlation between peak PCO2 gradient and the clinical and gastroscopic severity of ischaemia. This indicates that exercise tonometry could be used to grade the severity of mesenteric ischaemia. The provocation of gastric ischaemia during peak exercise in patients with stenotic lesions of the intestinal arteries most probably resulted from the diversion of blood flow away from the splanchnic area to the exercising muscles [25]. Our study suggests that intestinal hypoperfusion is present in CHF. This may lead to bacterial translocation with chronic cytokine activation. Further investigations should include lipopolysaccharide levels under exercise stress testing to prove the hypotheses of acute endotoxin challenge.

There are several mechanisms that could be important causing intestinal hypoperfusion during exercise. NO release plays an important role in splanchnic perfusion [26]. In the peripheral circulation, CHF patients show vasomotor dysfunction due to increased NO degradation by oxygen radicals [27]. CHF is known to be associated with general endothelial dysfunction [28], and there is no reason why this should not be present in splanchnic vasculature as well.

There was a strong correlation between low sodium levels and high gap difference. Hyponatremia is known to be a risk factor for increased mortality in CHF [29]. Our study was not designed to look at mortality. It remains to be investigated whether a high gap difference, indicating poor intestinal perfusion, is a prognostic marker for advanced CHF.

In conclusion, our study suggests that gastric tonometry in patients with CHF indicates hypoperfusion of the intestinal mucosa by an increase in iPCO2 under exercise stress testing.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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