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Intramucosal–arterial PCO2 gap fails to reflect intestinal dysoxia in hypoxic hypoxia
Critical Care volume 6, Article number: 514 (2002)
An elevation in intramucosal–arterial PCO2 gradient (ΔPCO2) could be determined either by tissue hypoxia or by reduced blood flow. Our hypothesis was that in hypoxic hypoxia with preserved blood flow, ΔPCO2 should not be altered.
In 17 anesthetized and mechanically ventilated sheep, oxygen delivery was reduced by decreasing flow (ischemic hypoxia, IH) or arterial oxygen saturation (hypoxic hypoxia, HH), or no intervention was made (sham). In the IH group (n = 6), blood flow was lowered by stepwise hemorrhage; in the HH group (n = 6), hydrochloric acid was instilled intratracheally. We measured cardiac output, superior mesenteric blood flow, gases, hemoglobin, and oxygen saturations in arterial blood, mixed venous blood, and mesenteric venous blood, and ileal intramucosal PCO2 by tonometry. Systemic and intestinal oxygen transport and consumption were calculated, as was ΔPCO2. After basal measurements, measurements were repeated at 30, 60, and 90 minutes.
Both progressive bleeding and hydrochloric acid aspiration provoked critical reductions in systemic and intestinal oxygen delivery and consumption. No changes occurred in the sham group. ΔPCO2 increased in the IH group (12 ± 10 [mean ± SD] versus 40 ± 13 mmHg; P < 0.001), but remained unchanged in HH and in the sham group (13 ± 6 versus 10 ± 13 mmHg and 8 ± 5 versus 9 ± 6 mmHg; not significant).
In this experimental model of hypoxic hypoxia with preserved blood flow, ΔPCO2 was not modified during dependence of oxygen uptake on oxygen transport. These results suggest that ΔPCO2 might be determined primarily by blood flow.
Tonometry is one of the few clinical tools available for the monitoring of tissue oxygenation . Decreases in gastrointestinal intramucosal pH (pHi) have usually been considered as indicators of dysoxia [2,3,4,5]; that is, as heralds of insufficient O2 to meet tissue demands. Recently, the intramucosal–arterial PCO2 gradient (ΔPCO2) has been claimed to be a better marker of gastrointestinal mucosal state of oxygenation . PCO2 can increase in intestinal lumen by two mechanisms . One is by bicarbonate buffering of protons from the breakdown of high-energy phosphates and metabolic acids generated anaerobically, such as lactate, in which case increased PCO2 would represent tissue dysoxia. Alternatively, in an aerobic state, it might be the result of hypoperfusion and decreased washout. In this latter case, oxygen metabolism could be preserved if the flow were adequate.
Grum et al.  found that pHi and intestinal oxygen uptake (VO2) were correlated in ischemia, in hypoxemia, and in a combination of both. However, in hypoxemic experiments, neither VO2 nor pHi fell. Hence, the value of tonometry in hypoxemia remains uncertain. If a rise in ΔPCO2 reflected only a decrease in blood flow, this gradient might not be altered in hypoxemia, in which cardiac output (CO) is usually maintained and even increased. Our hypothesis was that ΔPCO2 would not be modified in hypoxic hypoxia (HH) with preserved blood flow.
This study was approved by the local Animal Care Committee. Care of studied animals was in accordance with National Institutes of Health guidelines. Seventeen adult sheep (26.0 ± 9.1 kg [mean ± SD]) were anesthetized with 30 mg/kg sodium pentobarbital, tracheostomized and then ventilated (Harvard Pump Ventilator; Harvard Apparatus, South Natick, Massachusetts, USA) with a tidal volume of 15 ml/kg, a respiratory rate of 12 per minute, and a positive end-expiratory pressure of 5 cm H2O throughout the experiment. The starting fraction of inspired oxygen (FiO2) was 0.21. Additional pentobarbital was administered if necessary. Neuromuscular blockade was provided with a single dose of pancuronium (0.06 mg/kg). Catheters were placed into the femoral artery and vein and into the pulmonary artery (flow-directed thermod-ilution fiberoptic pulmonary artery catheter; Abbott Critical Care Systems, Mountain View, California, USA).
After performing a midline laparotomy, we performed splenectomy and a gastrostomy with drainage of gastric contents. We placed an electromagnetic blood flow transducer around the superior mesenteric artery. A catheter was advanced into the superior mesenteric vein, and a tonometer was inserted into the ileum.
Measurements and derived calculations
CO was measured in triplicate by the thermodilution technique, with 5 ml of iced saline (HP OmniCare Model 24 A 10; Hewlett Packard, Andover, Massachusetts, USA), and was referred to body weight. Superior mesenteric artery blood flow (intestinal blood flow) was measured by the electromagnetic method (Spectramed Blood Flowmeter model SP 2202 B; Spectramed Inc., Oxnard, California, USA) and indexed to intestinal weight.
Arterial mixed venous and mesenteric venous PO2, PCO2, and pH, and haemoglobin concentrations and saturations were measured with a blood gas analyzer and a co-oximeter, respectively (ABL 30 and OSM 3; Radiometer, Copenhagen, Denmark). Systemic and intestinal oxygen transport and uptake (DO2, VO2, intestinal DO2, and intestinal VO2 respectively) were calculated with standard formulae.
Intramucosal PCO2 was measured by saline tonometry (TRIP Sigmoid Catheter; Tonometrics, Inc., Worcester, Massachu-setts, USA) . After an equilibration period of 30 minutes, 1.0 ml was discarded. PCO2 was measured in the remnant (ABL 30; Radiometer). pHi and ΔPCO2 were calculated with a correction factor for the equilibration time. Kolkman et al.  showed that the variability of intramucosal PCO2 measurements is independent of dwell time. Assessments at short dwell times should therefore be reliable.
We calculated venoarterial and intramucosal–arterial CO2 content differences to evaluate the changes in the CO2 dissociation curve . To compute intramucosal CO2 content, intramucosal PCO2, pH, and mesenteric venous oxygen saturation were considered as representative of mucosal blood.
After a stabilization period of at least 30 minutes, we performed basal measurements (0 minutes). Sheep were then assigned to ischemic hypoxia (IH [n = 6]), HH (n = 6), or sham (n = 5) groups. In the IH group, bleeding was performed in three steps of 10 ml/kg at intervals of 30 minutes. In the HH group, 2 ml/kg 0.1 M hydrochloric acid was instilled into the trachea, and FiO2 was raised to 0.50. Saline solution was infused to keep intestinal blood flow constant. Measurements were repeated at 30, 60, and 90 minutes. Body temperature was maintained stable with a heating lamp.
Finally, animals were killed with supplemental pentobarbital and a KCl bolus. Indian ink was infused through the superior mesenteric artery, and dyed intestinal segments were dissected and weighed.
Data are expressed as means ± SD except where noted otherwise. Analysis within groups was performed with a repeated-measures analysis of variance (ANOVA) and a paired t-test with Bonferroni correction. One-way ANOVA and unpaired t-test with Bonferroni correction were used for one-time comparisons. In both cases, t-tests were used when ANOVA results were significant; P < 0.05 was considered significant.
Hemoglobin concentration, and arterial, mixed venous, and mesenteric venous blood gases and oxygen saturations in basal conditions, and during IH and HH and in the sham group are shown in Table 1.
Systemic and intestinal supply dependence was induced in both the IH and HH groups. There were no significant changes in systemic and intestinal DO2 and VO2 in the sham group (Figure 1). In the IH group, supply dependence appeared with critical decreases in CO and superior mesenteric artery blood flow (0.104 ± 0.024 versus 0.048 ± 0.006 l/min per kg, and 0.664 ± 0.227 versus 0.258 ± 0.082 l/min per kg, respectively; P < 0.0001). In the HH group it was due to a progressive decrease in arterial oxygenation. CO and intestinal blood flow were maintained (0.446 ± 0.085 versus 0.431 ± 0.140 ml/min per kg, respectively; not significant), owing to the administration of normal saline (median 630 ml; range 20–1310 ml). Arterial and intra-mucosal pH fell significantly in the IH and HH groups. In the HH group it was primarily related to systemic respiratory and metabolic acidosis (Tables 1 and 2), because ΔPCO2 did not increase. In addition, systemic and intestinal venoarterial PCO2 gradients were not modified. CO2 content differences also did not change (Table 2 and Figure 2). In contrast, in the IH group, ΔPCO2, systemic and intestinal venoarterial PCO2, and CO2 content gradients increased significantly (Table 2 and Figure 2). In the sham group, CO2 gradients and pHi remained unchanged.
Increased mucosal intestinal PCO2 is used as a tool to detect delivery can no tissue dysoxia, the condition in which O2 longer sustain O2 uptake . A great body of literature supports the role of intestinal PCO2 as an early marker of dysoxia and regional hypoperfusion. Early studies considered pHi as the reference parameter. Recently, some investigators have claimed that intramucosal PCO2, the variable actually measured by the tonometer, and ΔPCO2 could more adequately reflect mucosal oxygenation [6,12]. pHi is a calculated variable, from the Henderson–Hasselbach equation, with the assumption that arterial bicarbonate is representative of intra-mucosal bicarbonate. In a steady state, both values might be similar. However, in rapidly changing physiological situations, differences between arterial and mucosal CO2 might arise owing to slow CO2 equilibrium kinetics . Therefore, pHi values calculated from tonometry might differ from those directly measured with tissue electrodes . Moreover, acid–base states could influence in the absence of pHi altered mucosal oxygenation. As a result, the acid–base status of arterial blood will be reflected in both mucosal pHi and PCO2 [6,14]. In our experiments, pHi fell progressively during hydrochloric acid-induced lung injury and decreased DO2, reflecting ongoing systemic respiratory and metabolic acidosis. However, ΔPCO2 remained unchanged.
Another issue that has been discussed extensively is the relative impact on mucosal PCO2 of anaerobic production of CO2 in comparison with decreased washout of aerobically generated CO2 during low flow states. Many investigators [15,16,17] have ascribed increased PCO2 found in shock states to continuing aerobic CO2 production with decreased elimination; that is, to 'respiratory acidosis'. However, Schlichtig and Bowles  showed evidence supporting the role of intramu-cosal PCO2 as a marker of dysoxia in extreme hypoperfusion, when VO2 falls. In a dog model of cardiac tamponade, they demonstrated that mucosal PCO2 could rise because of anaerobic CO2 production below the critical DO2. These conclusions were drawn by using the Dill nomogram, which can theoretically detect anaerobic CO2 production from a comparison of the measured (%HbO2,v) and calculated (%HbO2,vDill) venous oxyhemoglobin, within a given venous PCO2 value. Because venous PCO2 is considered to be representative of tissue PCO2, Schlichtig and Bowles made the calculation with its intestinal equivalent, intramucosal PCO2. If %HbO2,vDill is lower than the measured %HbO2,v, anaerobic production of CO2 might be assumed. Similar values would represent aerobic CO2 generation. Notwithstanding the original contribution of Schlichtig and Bowles  to the analysis of these topics, the use of low flow to produce critical oxygen delivery and falling VO2 has been signaled as a potential confounding factor .
We studied these issues in a model of HH with preserved flow, because it allows a clear discrimination between hypoxia and hypoperfusion. There have been attempts to analyze pHi behavior in HH, but critical intestinal DO2 was not attained, and intestinal VO2 and pHi remained unchanged . Our model consisted of an acute lung injury produced by endotracheal instillation of hydrochloric acid that rapidly generated severe hypoxemia, shown by the decrease in arterial PO2 and pH. The acid also enhanced microvascular permeability [19,20,21], demonstrated by increased requirements of saline solution to maintain intestinal blood flow and by the increase in hemoglobin levels. However, other mechanisms could be acting to preserve blood flow, such as tachycardia and enhanced left ventricular contractility . Deep arterial hypoxemia caused significant reductions in systemic and intestinal DO2, but systemic and intestinal blood flow were preserved and hemoglobin concentration increased. Despite the increase in systemic and intestinal oxygen extraction, systemic and intestinal VO2 values decreased, and dependence of O2 uptake on transport ensued. Dependence of oxygen consumption on transport during HH has been described by Cain et al. in a classical study , and it has been considered an indicator of anaerobic metabolism. Additional evidence of tissue dysoxia was the appearance of metabolic acidosis. Cain  also showed that there is a correlation between pH and lactate/pyruvate relationship in HH.
Another potential confounding factor that could affect arterial and intestinal PCO2 and their differences is the shift of the CO2 dissociation curve. As Jakob et al.  have shown, there can be a lack of correlation of CO2 contents and PCO2, and, consequently, of their differences. Many determinants of the shifts of the CO2 dissociation curve, such as changes in pH, in hemoglobin concentrations, and especially in oxygen saturations (the Haldane effect), were present. To discard a possible increase in venoarterial and intramucosal–arterial CO2 contents without changes in PCO2 differences in the HH group, we calculated CO2 content differences. There were no increases in venoarterial and intramucosal–arterial CO2 content differences during the period of supply dependence, as there were no changes in both PCO2 differences. Shifts of the CO2 dissociation curve therefore do not seem to influence our results.
Our model of HH is useful for discriminating the effects of hypoxia and low blood flow, because this last factor was kept constant throughout the experiment. ΔPCO2 remained stable, although there were signs of anaerobic metabolism. Systemic and venoarterial PCO2 differences also remained unchanged. Conversely, during supply dependence of VO2 induced by hemorrhage, ΔPCO2 and systemic and intestinal venoarterial PCO2 differences widened, as well as the respective ΔPCO2 content differences. Moreover, these parameters increased before any change in VO2, as we have described previously . These results suggest that, at least in our experiments, tissue perfusion is a key determinant of increased ΔPCO2.
Nevière et al.  tested a similar hypothesis in pigs. They compared the effects of diminished blood flow with diminished inspired fraction of oxygen. In IH, ΔPCO2 increased to 60 mmHg. In HH, ΔPCO2 increased to 30 mmHg only in the last step of hypoxemia, although mucosal blood flow measured by laser Doppler flowmetry was preserved. The authors concluded that elevated intramucosal PCO2 indicated local CO2 generation. However, in the two previous stages of reduced FiO2 there was supply dependence, and ΔPCO2 remained unchanged. In our HH model, ΔPCO2 was also stable. The differences between our data and those of Nevière et al.  could be ascribed to distinct microvascular features of the experimental subjects (pigs and sheep) or to different degrees of hypoxemia. In addition, as Nevière et al. pointed out, some degree of decrease in gut mucosal blood flow and heterogeneity might have been present, because only global microvascular blood flow changes can be assessed by laser Doppler flowmetry. Nevertheless, both studies show that ΔPCO2 could fail to reflect tissue dysoxia at some time during HH. In results similar to ours, Vallet et al.  showed that perfusion is a major determinant of venoarterial PCO2 difference during critical IH or HH in isolated hindlimb. This gradient increases in ischemia and is preserved in hypoxia.
Venoarterial and intramucosal–arterial PCO2 gradients are the result of interactions of changes in aerobic and anaerobic CO2 production, the CO2 dissociation curve, and blood flow to tissues. During oxygen supply dependence induced by hemorrhage, opposite changes in aerobic and anaerobic CO2 production are present: aerobic CO2 production decreases as a consequence of depressed aerobic metabolism, but anaerobic CO2 production starts because of bicarbonate buffering of protons from fixed acids. Total CO2 production might not increase, but O2 consumption falls, so there is an increase in respiratory quotient [29,30]. This increase in VCO2 relative to VO2 might generate tissue and venous hypercarbia only in low flow states, in which there is diminished CO2 removal. Other situations in which intramucosal acidosis could arise with preserved tissue perfusion are reperfusion injury  and cytopathic hypoxia generated by endotoxemia , with cellular damage and metabolic abnormalities as underlying mechanisms. However, impaired villous microcirculation has been advocated as the causal phenomenon in the latter .
To our knowledge, this is the first study showing that ΔPCO2 fails to mirror intestinal tissue dysoxia. Our findings also suggest that blood flow might be the main determinant of ΔPCO2. Tonometry seems to be a useful method for monitoring perfusion, with rather limited value in detecting anaerobic metabolism when blood flow is preserved. Additional studies in other models of hypoxic and anemic hypoxia are needed to confirm our findings and to resolve discrepancies between studies.
The intramucosal–arterial PCO2 gradient fails to reflect intestinal oxygen supply dependence during hypoxic hypoxia
Blood flow seems to be the main determinant of venoarterial and intramucosal–arterial PCO2 gradients
Tonometry seems to be a useful method for monitoring perfusion, with limited value in detecting anaerobic metabolism when flow is preserved
ANOVA = analysis of variance
CO = cardiac output
DO2 = oxygen transport
ΔPCO2 = intramucosal–arterial PCO2 gradient
FiO2 = fraction of inspired oxygen
HH = hypoxic hypoxia
IH = ischemic hypoxia
pHi = intramucosal pH
VO2 = oxygen uptake.
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Dubin, A., Murias, G., Estenssoro, E. et al. Intramucosal–arterial PCO2 gap fails to reflect intestinal dysoxia in hypoxic hypoxia. Crit Care 6, 514 (2002) doi:10.1186/cc1813
- blood flow
- carbon dioxide
- oxygen consumption