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CRITICAL CARE AND TRAUMA

Supplemental Oxygen and Carbon Dioxide Each Increase Subcutaneous and Intestinal Intramural Oxygenation

Jebadurai Ratnaraj, MD^*, Barbara Kabon, MD^*, Michael R. Talcott, DVM, Daniel I. Sessler, MD, and Andrea Kurz, MD

Departments of *Anesthesiology and Veterinary Surgical Services, Washington University, St. Louis, MO; the Outcomes Research Institute and Departments of Anesthesiology and Pharmacology, University of Louisville, Louisville, KY; and the Department of Anesthesiology, University of Bern, Switzerland and the Department of Anesthesiology and Intensive Care Medicine, University of Vienna, Vienna, Austria

Address correspondence and reprint requests to Dr. Kurz, Department of Anesthesiology, University of Bern, 3010 Bern, Switzerland. Address email to kurza{at}notes.wustl.edu

	Abstract

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Oxidative killing by neutrophils, a primary defense against surgical pathogens, is directly related to tissue oxygenation. We tested the hypothesis that supplemental inspired oxygen or mild hypercapnia (end-tidal PCO₂ of 50 mm Hg) improves intestinal oxygenation. Pigs (25 ± 2.5 kg) were used in 2 studies in random order: 1) Oxygen Study: 30% versus 100% inspired oxygen concentration at an end-tidal PCO₂ of 40 mm Hg, and 2) Carbon Dioxide Study: end-tidal PCO₂ of 30 mm Hg versus 50 mm Hg with 30% oxygen. Within each study, treatment order was randomized. Treatments were maintained for 1.5 h; measurements were averaged over the final hour. A tonometer inserted in the subcutaneous tissue of the left upper foreleg measured subcutaneous oxygen tension. Tonometers inserted into the intestinal wall measured intestinal intramural oxygen tension from the small and large intestines. Oxygen 100% administration doubled subcutaneous oxygen partial pressure (PO₂) (57 ± 10 to 107 ± 48 mm Hg, P = 0.006) and large intestine intramural PO₂ (53 ± 14 to 118 ± 72 mm Hg, P = 0.014); intramural PO₂ increased 40% in the small intestine (37 ± 10 to 52 ± 25 mm Hg, P = 0.004). An end-tidal PCO₂ of 50 mm Hg increased large intestinal PO₂ approximately 16% (49 ± 10 to 57 ± 12 mm Hg, P = 0.039), whereas intramural PO₂ increased by 45% in the small intestine (31 ± 12 to 44 ± 16 mm Hg, P = 0.002). Supplemental oxygen and mild hypercapnia each increased subcutaneous and intramural tissue PO₂, with supplemental oxygen being most effective.

IMPLICATIONS: Tissue oxygenation is the primary determinant of oxidative killing rate by neutrophils. Increasing inspired oxygen concentration from 30% to 100% or increasing end-tidal PCO₂ from 30 mm Hg to 50 mm Hg increased both subcutaneous or intestinal intramural tissue oxygenation, with supplemental oxygen being most effective. Either treatment is thus likely to reduce the risk of infection.

	Introduction

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The primary defense against surgical pathogens is oxidative killing by neutrophils (1). Oxidative killing of bacteria depends on tissue oxygenation throughout the physiologic range (2–4). It is thus not surprising that infection risk is inversely related to subcutaneous tissue partial pressure of oxygen (PO₂) (5). Factors that improve subcutaneous tissue oxygenation reduce infection risk whether oxygenation is improved directly by providing supplemental inspired oxygen (6) or indirectly by maintaining perioperative normothermia, which increases tissue perfusion (7). In contrast, factors such as smoking (8) that reduce subcutaneous tissue oxygenation increase risk (7,9).

Inadequate gastrointestinal oxygenation is also associated with gut dysfunction, particularly a loss of barrier function. Failure of the intestinal barrier leads to systemic endotoxin absorption and bacterial translocation, which is clinically manifested as shock and sepsis (10). Hypoxic bowel also releases mediators that can injure distant organs, contributing to multiple organ failure (11). As might thus be expected, insufficient intestinal oxygenation increases mortality (10).

One of the easiest methods of improving subcutaneous oxygenation is simply providing supplemental inspired oxygen (6). Another is to permit mild hypercapnia, which improves cutaneous perfusion and, thus, oxygenation (12,13). However, the effects of supplemental oxygen or mild hypercapnia on intestinal intramural oxygenation remain unknown. We therefore tested the hypothesis that supplemental inspired oxygen or mild hypercapnia improves intestinal oxygenation.

	Methods

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After approval from the Washington University Animal Studies Committee, we studied 11 healthy female domestic pigs. Pigs were chosen because they are omnivores and the intestinal physiology of the pig closely approximates that of humans. They were 3 ± 1 mo old and weighed 25 ± 2.5 kg. All animals were fasted for 12–16 h and given 8.5 mg magnesium citrate solution orally the night before the study; a standard mechanical bowel preparation using an electrolyte solution was administered the morning of the study.

A peripheral IV catheter was inserted for administration of fluids and medications. Lactated Ringer’s solution was given IV as a 10-mL/kg bolus, followed by an infusion at a rate of 7 mL · kg^–1 · h^–1; fluids were warmed to 37°C. The pigs were sedated with IM Telazol (2 mg/kg), ketamine (1 mg/kg), and xylazine (1 mg/kg). Anesthesia was induced by inhaled isoflurane and maintained with isoflurane (1.5%–2.0%) in 30% oxygen and 70% nitrogen. All pigs had endotracheal intubation, and their lungs were mechanically ventilated at 12 breaths/min with a tidal volume of 8 mL/kg. The animals were actively warmed with surface warming to maintain normothermia. A femoral arterial catheter was inserted for direct arterial blood pressure monitoring; a pulmonary artery catheter was inserted via the femoral vein. A urinary catheter was placed as well.

After induction of anesthesia, silastic tonometers were inserted into the lateral left upper arm for measurement of subcutaneous tissue oxygenation and temperature. Each tonometer consisted of a 15-cm tube filled with hypoxic saline; 10 cm of the tubing was tunneled subcutaneously. A Clark-type oxygen sensor and thermistor (Licox, Gesellschaft für Medizinische Sondensysteme, GmBH, Kiel, Germany) were inserted into the subcutaneous part of the tonometer as previously described (14).

In vitro accuracy of the optodes (in a water bath at 37°C) is ±3 mm Hg for the range from 0–100 mm Hg, and ±5% for the range 100–360 mm Hg. Temperature sensitivity is 0.25%/°C, but thermistors are incorporated into the probes and temperature-compensation is included in the subcutaneous tissue oxygen tension (PsqO₂) calculations. Optode calibration remains stable (within 8% of baseline value for room air) in vivo for at least 8 h. Optodes (oxygen sensors) were calibrated in room air (ambient PO₂ 154 mm Hg). For calibration purposes a calibration card was inserted into the Licox device. The calibration data of the connected optode and other data are electronically stored on this card (factory calibration setting). All PsqO₂ values measured before insertion were within 10% of 154 mm Hg.

To exclude a significant drift of the optode (>10%), probes were again exposed to room air after each investigation. No significant drift was observed throughout the entire study. At least 30 min were allowed for electrode equilibration. Values were subsequently recorded at 15-min intervals.

To measure intramural intestinal oxygen partial pressure (PimO₂), the abdomen was opened and similar intramural probes were inserted through 20-g cannulae into the small intestine and colon. The probes were inserted into the tissue plane between the serosa and mucosa. Great care was taken to minimize handling of the intestine and to return the bowel to a neutral position. Intestinal retractors were not used.

Each of the pigs was used in a study evaluating inspired oxygen concentration (oxygen study) and a separate study evaluating end-tidal carbon dioxide partial pressure (PCO₂) (carbon dioxide study). The order in which the protocols were performed was randomly assigned, and each protocol contained its own internal randomization. Each randomization was based on computer-generated codes maintained in sequentially numbered opaque envelopes until just before use.

In the oxygen study, the 2 study treatments were inspired oxygen concentrations of 30% or 100%. In each case, the concentration designated by the randomization was maintained for 30 min to establish steady-state conditions. Subsequently, PsqO₂ and PimO₂ were recorded for 1 h (treatment period). Measurements were then repeated during the alternative oxygen concentration, and again 30 min was allowed to elapse to establish steady-state conditions before measurements were taken. End-tidal PCO₂ was kept at 40 mm Hg throughout the oxygen study.

In the carbon dioxide study, the 2 study treatments were an end-tidal PCO₂ of 30 and 50 mm Hg. To achieve an end-tidal PCO₂ of 50 mm Hg, we removed the soda lime and slightly decreased the respiratory rate. In each case, the end-tidal concentration designated by the randomization was maintained for 30 min to establish steady-state conditions. Subsequently, PsqO₂ and PimO₂ were recorded for 1 h (treatment period). Measurements were then repeated at the alternative end-tidal PCO₂. The inspired oxygen concentration was kept at 30% throughout the carbon dioxide study.

Additional measurements in both studies included hemodynamic and respiratory values. Arterial blood for gas analysis was obtained at the beginning of each 1-h treatment period. Cardiac output was determined by thermodilution at the beginning and end of each treatment period. All other measurements, including tissue oxygenation, were recorded at 5-min intervals throughout each treatment period.

All values obtained during each treatment period were averaged in each animal. Our primary comparisons were between the 2 treatments in each study (i.e., 30% versus 100% oxygen and 30 mm Hg versus 50 mm Hg end-tidal PCO₂). Data were compared with two-tailed, paired Student’s t-tests. We similarly compared the effects of supplemental oxygen and changes in end-tidal PCO₂ on subcutaneous and intestinal oxygenation. Data are presented as mean ± SD; P < 0.05 was considered statistically significant.

	Results

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Bowel at the tonometer insertion sites appeared entirely normal at the end of the studies and was not edematous, nor were any hematomas observed. Arterial and end-tidal PCO₂ values were similar. Initial hemoglobin concentration was 10.1 ± 1.4 g/dL, and the concentration did not change significantly during the study.

Heart rate, arterial blood pressure, pulmonary arterial pressure, cardiac output, and systemic and pulmonary vascular resistances did not differ significantly during 30% and 100% inspired oxygen. The pH, PCO₂, base excess, and HCO₃– were similar during the 30% and 100% oxygen treatments. As might be expected, arterial PO₂ was 108 ± 21 mm Hg with 30% inspired oxygen and 454 ± 53 mm Hg with 100% oxygen.

Subcutaneous tissue oxygenation increased by 50 ± 41 mm Hg during 100% oxygen (P = 0.006). Supplemental oxygen increased small intestine PO₂ by 15 ± 11 mm Hg (P = 0.004). Supplemental oxygen increased large intestine intramural PO₂ considerably more, by 65 ± 62 mm Hg (P = 0.014) (Table 1).

	Discussion

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When the pigs were subjected to an end-tidal PCO₂ of 50 mm Hg, hemodynamic changes occurred, including significant increases in pulmonary arterial pressure, cardiac output, and stroke volume. However, systemic vascular resistance decreased, presumably because of peripheral vascular dilation. Heart rate and arterial blood pressure thus remained essentially unchanged.

Interestingly, increasing end-tidal PCO₂ to 50 mm Hg similarly increased intramural oxygenation in both the small and large intestines, whereas supplemental oxygen was considerably more effective in the large intestine. Overall, supplemental oxygen was far more effective than increasing end-tidal PCO₂ from 30 to 50 mm Hg. It also had the advantage of being easier to implement. Although it is likely that the combining supplemental oxygen and mild hypercapnia would further improve tissue PO₂, we did not specifically test this theory.

In contrast to previous studies, oxygen tension in the large intestine was significantly more than in the small intestine during all conditions (16,17). Although oxygenation of both the small and large intestines are of interest, anastomotic leaks are more common in the large intestine (18), and large-intestinal surgery entails a far greater infection risk. It was thus encouraging to observe that tissue oxygenation in the large intestine and skin were remarkably similar under each study circumstance. In contrast, tissue oxygenation in the small intestine was consistently less than subcutaneous oxygen tension, usually by approximately 40%. Nevertheless, it should be noted that our experiments were performed on healthy, normovolemic animals. Oxygenation in the large intestines and the subcutaneous tissue might be different under certain pathologic conditions (e.g., bowel surgery, hypovolemia or shock).

Microelectrodes were inserted directly into the tissue plane separating the mucosal and serosal surfaces of the intestines to avoid tissue damage and interference with the microcirculation. In this respect, our technique differed from previous studies that evaluated intestinal oxygenation with Clark-type multiwire electrodes placed onto the serosal or mucosal surfaces (19–21) or with serosal and mucosal surface tonometers, which were introduced through needle enterostomies (22). Our concern about these methods is that measurements can be confounded by air or fecal contamination or by poor contact between the electrode and the tissue surface. Our baseline values for intestinal PO₂ were nonetheless similar to those reported previously (16). Although we did not observe edema or hematomas at the insertion sites, some tissue damage is inevitable. In this respect, insertion of the electrode served as a surrogate wound, much as subcutaneous measurements in the arm deliberately mimic surgical incisions.

An obvious limitation of our study is that we evaluated swine rather than humans. The gut in pigs, however, approximates the human intestinal system. Consistent with this theory, subcutaneous oxygenation with 30% oxygen was similar to that observed in humans, as was the effect of supplemental oxygen (15). Our study was restricted to minimally disturbed intestine; the effects of supplemental oxygen and end-tidal PCO₂ on intramural oxygenation may differ after intestinal manipulation and, especially, after intestinal anastomosis.

Another limitation was that during the CO₂ study, the PaO₂ was significantly less during an end-tidal PCO₂ of 50 mm Hg than during an end-tidal PCO₂ of 30 mm Hg. This could explain why the increase in tissue oxygenation with a PCO₂ of 50 mm Hg was slightly less than observed previously in humans (12).

In summary, tissue oxygenation in the large intestine and skin were similar, whereas tissue oxygenation in the small intestine was consistently less than PsqO₂, usually by approximately 40%. Administration of 100% oxygen nearly doubled subcutaneous and large intestinal intramural oxygenation, whereas intramural oxygenation increased 40% in the small intestine. Changing the end-tidal PCO₂ from 30 to 50 mm Hg increased tissue oxygenation approximately 20% in the subcutaneous tissue and in the large intestine, whereas intramural oxygenation increased by 45% in the small intestine. Supplemental oxygen and mild hypercapnia thus each increased subcutaneous and gut tissue PO₂, with supplemental oxygen being most effective.

	Acknowledgments

 
Supported, in part, by NIH Grants GM 58273 and GM 061655 (Bethesda, MD), the Joseph Drown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).

	References

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