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(Chest. 2003;124:688-698.)
© 2003 American College of Chest Physicians

Effects of Dopexamine and Positive End-Expiratory Pressure on Intestinal Blood Flow and Oxygenation*

The Perfusion Pressure Perspective

Stefan Lehtipalo, MD, PhD; Björn Biber, MD, PhD; Rolf Fröjse, MD; Conny Arnerlöv, MD, PhD; Göran Johansson, MS and Ola Winsö, MD, PhD

* From the Anesthesiology and Intensive Care Unit (Drs. Lehtipalo, Biber, and Winsö, and Mr. Johansson) and the Surgery Unit (Drs. Fröjse and Arnerlöv), Department of Surgical and Perioperative Sciences, Umeå University Hospital, Umeå, Sweden.

Correspondence to: Stefan Lehtipalo, MD, PhD, Department of Surgical and Perioperative Sciences, Anesthesiology and Intensive Care, Umeå University Hospital, SE-901 85 Umeå, Sweden; e-mail: stefan. lehtipalo{at}vll.se


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: To evaluate the net effects of the concomitant use of positive end-expiratory pressure (PEEP) and dopexamine on intestinal tissue perfusion and oxygenation during predefined artificial reductions in intestinal perfusion pressure (IPP).

Design: Prospective, self-controlled, experimental study.

Setting: University hospital research laboratory.

Subjects: Seven female pigs.

Measurements: In barbiturate-anesthetized pigs, we measured mesenteric blood flow (QMES) [by transit-time ultrasonic flowmetry], jejunal mucosal perfusion (by laser Doppler flowmetry), and tissue PO2 (by microoximetry). Based on blood sampling, we calculated the intestinal net lactate production and oxygenation.

Interventions: These measurements and calculations were performed at three predefined and controlled IPP levels, which were obtained by an adjustable clamp around the superior mesenteric artery. At each IPP level, measurements were performed prior to and during PEEP (10 cm H2O), both with and without simultaneous dopexamine infusions (at 0.5 and 1.0 µg/kg/min).

Results: Within the IPP range of 77 to 33 mm Hg, intestinal perfusion and oxygenation were maintained irrespective of whether PEEP and/or dopexamine were applied or not. At IPP < 33 mm Hg, QMES and intestinal oxygenation deteriorated, resulting in regional net lactate production. At this IPP range, tissue oxygen perfusion was entirely pressure-dependent, and even small reductions in IPP led to prominent increases in intestinal net lactate production. Dopexamine did not modify this pattern.

Conclusions: We describe maintained intestinal tissue oxygen perfusion within a wide perfusion pressure range. Within this perfusion pressure range, PEEP did not induce any adverse regional circulatory effects. Below the perfusion pressure range for effective autoregulation, intestinal tissue oxygen perfusion deteriorated, and regional ischemia occurred. In this situation, dopexamine was unable to counteract IPP-dependent decreases in intestinal tissue oxygen perfusion. The regional ischemic threshold can be defined either as an IPP of < 33 mm Hg or as an intestinal tissue PO2 of < 45 mm Hg.

Key Words: dopexamine • lactate • oxygen uptake • positive end-expiratory pressure • splanchnic circulation • swine


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Tissue hypoxia due to insufficient blood flow or low arterial oxygen content is not uncommon in critically ill patients. Oxygen delivery, tissue oxygen transport, and oxygen uptake (O2) of the cells serve a functional entity (ie, tissue oxygen perfusion).1 The occurrence of tissue hypoxia during systemic circulatory failure and shock is presumed in the clinical setting. However, regional tissue hypoxia potentially can be present in patients who seem to be adequately resuscitated or are without signs of circulatory shock, as far as systemic hemodynamic parameters are concerned.2 Such regional hypoxia is not easily diagnosed, and the success of interventions to increase tissue oxygenation might be hard to evaluate.3 The assessment of regional tissue oxygen perfusion in clinical practice is usually based on indirect indicators, including traditional systemic hemodynamic indexes, and the evaluation of mixed venous saturation and lactate levels in the systemic circulation. Direct measurements of intestinal blood flow and oxygenation (ie, tissue oxygen perfusion) are invasive and time-consuming, and require special skills and instruments that are not readily available at the bedside.4

The therapeutic interventions that frequently are used in the clinical setting to improve tissue oxygen perfusion include positive-pressure ventilation with positive end-expiratory pressure (PEEP) to improve arterial oxygen content and certain vasoactive drugs (ie, inodilators) to increase arterial blood flow.5 6 PEEP ventilation improves pulmonary gas exchange abnormalities by increasing pulmonary compliance and functional residual capacity.7 Besides these desirable respiratory effects, PEEP also may exert adverse systemic and regional circulatory effects, which are related both to PEEP-induced increases in mean intrathoracic pressure8 9 10 11 and to the concurrent intravascular blood volume status.12 The net influence of PEEP on systemic oxygen transport is therefore dependent on the balance between cardiovascular and pulmonary effects.13 We have reported that PEEP decreased intestinal blood flow in proportion to the applied PEEP level.14 This pattern was also present when PEEP was applied at artificially reduced intestinal perfusion pressures (IPPs).14

The use of certain vasoactive drugs has been suggested as an adjunct to adequate fluid resuscitation in order to reduce the depression of cardiac output (CO) and intestinal blood flow caused by PEEP ventilation. However, data on the actual efficacy of different vasoactive drugs to mitigate PEEP-induced cardiovascular effects are sparse and divergent.15 16 Dopexamine, a synthetic catecholamine that acts mainly through the activation of dopaminergic (DA-1) and ß2-adrenoceptors,17 18 is frequently used to improve systemic circulation and oxygenation, and appears to possess particular beneficial effects on splanchnic perfusion.19 20 21 At present, we are only aware of a few experimental studies using dopexamine for such purposes.22 23 Thus, Steinberg and coworkers22 reported that dopexamine, when used in conjunction with PEEP, prevented the depression of mesenteric blood flow. Further, Scheeren and coworkers23 showed that dopexamine, but not dopamine, increased gastric mucosal oxygenation during PEEP ventilation. However, it is unknown whether these findings were dependent on alterations in IPP, or whether it is possible to extrapolate the findings to situations of hypotension. Analyses of the impact of regional perfusion pressures, as stated above, require a model with controlled perfusion pressures. Such study designs have been used previously by our research group and by others,24 25 26 27 and this design eliminates remote influences that may counterbalance intrinsic blood flow control. With this perspective, the present study was designed with the aim of evaluating the effects of PEEP and dopexamine on intestinal tissue perfusion and oxygen kinetics during artificially controlled reductions in IPP.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Seven female pigs, with a mean (± SEM) weight of 39.6 ± 0.7 kg, were used with the approval of the University Animal Experiment Ethics Committee. All procedures were carried out according to the guidelines of the National Institutes of Health guide for the care and use of laboratory animals.

Anesthesia
Animals were fasted overnight with free access to water. After premedication with ketamine (12 mg/kg IM), azaperon (2 mg/kg), and atropine (0.05 mg/kg), anesthesia was induced by sodium pentobarbital (15 mg/kg, followed by IV infusion at 15 to 20 mg/kg/h), with the addition of isoflurane during surgical procedures. No muscle relaxants were used. After tracheostomy, mechanical ventilation with oxygen in air (25 to 30% O2) was performed using a volume-cycled ventilator (model 900B; Siemens; Elema, Germany), with a minute ventilation of 7 L/min at a frequency of 20 breaths/min. A catheter at the proximal end of the endotracheal tube was used for the continuous monitoring of airway pressure, and PEEP was, in line with the protocol, adjusted according to these airway pressure measurements. Ventilation was initially adjusted to normocapnia (ie, 5.0 to 5.6 kPa), as judged by end-tidal CO2 levels (Artema; Artema Medical AB; Stockholm, Sweden) and intermittent arterial blood gas analyses (ABL-5 autoanalyzer; Radiometer; Brønshøj, Denmark), and was then kept constant throughout the experiment. Oxygen saturation was analyzed by a hemoglobin oximeter, using the animal mode for pig hemoglobin (OSM-3 hemoximeter; Radiometer). All blood gas data were within the normal range for the pig.28 Blood samples for lactate concentration were analyzed by an automated analyzer (Sport 2300 Stat Plus; Yellow Springs Instruments, Inc; Yellow Springs, OH). End-tidal concentrations of O2, CO2, and isoflurane were measured continuously by a gas analyzer (Artema; Artema Medical AB) with the sampling site at the proximal end of the endotracheal tube. All animals received IV infusions of Ringer acetate (600 mL as a bolus, followed by infusion of 20 mL/kg/h throughout the experiment). The core temperature was kept between 37°C and 39°C using heating blankets. Urine outflow was diverted through a cystostomy catheter and was assessed hourly. A three-lead ECG was used for monitoring the heart rate (HR).

Instrumentation and Measurements
A schematic illustration of the experimental set up is depicted in Figure 1 . All intravascular catheters were inserted via cutdowns to the appropriate vessels. The carotid artery and the external jugular vein were exposed through a right-sided neck dissection. Systemic arterial pressure was monitored continuously by a fluid-filled catheter with its tip in the proximal aorta. A flow-directed, thermistor-tipped, pulmonary artery catheter (7F Swan-Ganz catheter; Baxter Medical; Kista, Sweden) was inserted via the right external jugular vein and advanced into a distal branch of the pulmonary artery for measurements of CO and core body temperature. CO was measured by the antegrade thermodilution technique (Wetenschappelijk Technische Instituut; Eindhoven, the Netherlands) at end-expiration with 5 mL iced 0.9% solution of NaCl as the indicator. CO data are presented as the mean of three consecutive measurements obtained within 2 min, not differing > 10%. For continuous measurements of central venous pressure (CVP) and for the administration of fluids and drugs, a double-lumen central venous catheter was inserted via the left external jugular vein.



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  		Figure 1.. Schematic illustration of the experimental setup. PAORTA = denotes aortic BP.

 
A long midline laparotomy was performed with the animal in the supine position. The proximal part of the superior mesenteric artery was freed, and an adjustable clamp for graded occlusion was attached to this vessel near the aortic origin. The portal and mesenteric veins were identified in the hepatoduodenal ligament. A transit-time ultrasonic flowmetry probe was applied around the mesenteric vein (type 8SB; Transonic Systems Inc; Ithaca, NY) for the measurement of superior mesenteric venous blood flow (QMES) [Transonic T206D; Transonic Systems Inc]. In the pig, the portal vein is formed by the confluence of the mesenteric and the gastric (splenic) veins.29 Only a negligible part of the gastric and splenic splanchnic perfusion therefore was included in the QMES measurements. The superior mesenteric artery was directly punctured and a polyethylene catheter with an outer diameter of 0.67 mm was introduced downstream to the clamp for BP measurements (ie, superior mesenteric arterial pressure [PSMA]). A direct puncture was used for introducing a polyethylene catheter (outer diameter, 1.0 mm) for pressure measurement (ie, mesenteric venous pressure [PMES]) and blood sampling in the mesenteric vein. All pressure transducers (System DPT-6000, PvB; Codan Triplus; Kungsbacka, Sweden) were calibrated to atmospheric pressure at the level of the right atrium by a saline solution column.

Jejunal mucosal perfusion was measured using laser Doppler flowmetry (LDF) with a specially designed catheter fitted with two laser Doppler optical fibers of equal length, terminating at the tip and facing the mucosa perpendicular to the axial line of the catheter (probe 415–134; Perimed AB; Järfälla, Sweden). The data are presented from the most consistent optical fiber recording. According to this technique, blood flow is expressed in arbitrary perfusion units (PU) and is described as being equivalent to the number of RBCs contained in the volume of blood through which the laser light is passing and at the speed at which these cells are moving. The catheter was inserted intraluminally through a small antemesenteric incision 2 m proximal to the iliocecal valve. The intestinal incision then was closed, and the laser Doppler catheter was secured by an additional suture. Each fiber had a core diameter of 150 µm and a fiber separation of 250 µm. The wavelength of the emitted laser light was 780 nm, and the Doppler shift frequency was 20 kHz. The probe was connected to a base unit (PeriFlux 4001 Master; Perimed AB). Calibration was performed according to the manufacturer at 0 PU on a plastic disk at optical zero and at 250 PU using motility standard provided by the manufacturer. The LDF technique has been thoroughly evaluated by several investigators30 31 at well-known circulatory physiology laboratories.

Tissue PO2 in the jejunal wall, 2 m proximal to the iliocecal valve, was measured by a tissue probe (Licox CC 1.2; Gesellschaft für Medizinische Sondentechnik; Kiel-Mielkendorf, Germany), was inserted from the serosal side into the intestinal wall, and was connected to a tissue oxygen pressure monitor (Licox CMP; Gesellschaft für Medizinische Sondentechnik). A tissue temperature probe (Licox C 8.1; Gesellschaft für Medizinische Sondentechnik) that was connected to the tissue oxygen pressure monitor measured the temperature in the jejunal wall. Urine outflow was diverted through a cystostomy catheter and was assessed hourly. A three-lead ECG was used for the monitoring of HR.

All BP, ECG, blood flow, LDF, and tissue PO2 data were recorded continuously using a 16-channel recording system (model TA-5000; Gould Inc; Eastlake, OH), as well as a computer-based, multichannel signal acquisition and analysis system (Acknowledge III; Biopac Systems Inc; Santa Barbara, CA). The software (Acknowledge; Biopac Systems Inc), using a sampling frequency of 50 Hz, continuously collected all signals. The data were extracted from this system as mean values, which were established during registration sequences of 30 s duration.

Experimental Protocol
The study protocol is schematically depicted in Figure 2 . Each data collection point included measurements of mean arterial pressure (MAP), HR, CVP, CO, PMES, PSMA, QMES, jejunal mucosal perfusion, and tissue PO2. Blood samples for blood gas analyses, oxygen saturation measurements, and lactate concentration analyses were drawn from the aortic and mesenteric venous catheters in conjunction with the hemodynamic recordings.



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  		Figure 2.. Study protocol illustrating data collection time points. 1 = ZEEP (C1); 2 = PEEP at 10 cm H2O (P); 3 = dopexamine infusion at 0.5 µg/kg/min (D1); 4 = dopexamine infusion at 0.5 µg/kg/min and PEEP at 10 cm H2O (D1P); 5 = dopexamine infusion at 1.0 µg/kg/min (D2); 6 = dopexamine infusion at 1.0 µg/kg/min and PEEP at 10 cm H2O (D2P); and 7 = end of a recovery period of 45 min (C2). The protocol includes three consecutive sets of measurements, at a freely variable PSMA with unrestricted IPP (A), at a PSMA of 50 mm Hg (B) and at a PSMA of 30 mm Hg (C).

 
After the instrumentation was completed, the isoflurane supply was discontinued. A stabilization period of 1 h during basal sodium pentobarbital anesthesia was allowed to elapse before the first data collection point. The protocol included the following three subsequent stages: (1) "freely variable PSMA"—This refers to the first part of the study, when the adjustable superior mesenteric arterial clamp was entirely open and the prevailing systemic arterial pressure was allowed to serve unhindered as the intestinal arterial driving force; (2) "PSMA of 50 mm Hg"—At this stage, the superior mesenteric arterial inflow pressure was kept constant at a predefined level of 50 mm Hg (corresponding to an IPP of 33 to 42 mm Hg) by adjustments of the clamp around the superior mesenteric artery. The intestinal arterial inflow pressure also was maintained during the ongoing dopexamine infusions. Similarly, inflow pressure was kept at 50 mm Hg immediately before PEEP was applied. Subsequent changes in systemic arterial pressure during PEEP were, however, not met by further adjustments of the superior mesenteric arterial clamp; (3) "PSMA of 30 mm Hg"—Superior mesenteric arterial inflow pressure was kept constant at a predefined level of 30 mm Hg (corresponding to an IPP of 17 to 22 mm Hg). In all other aspects, this stage was the same as the sequence using the PSMA of 50 mm Hg.

The measurements were first done during zero end-expiratory pressure (ZEEP) [ie, the control measurements at each perfusion pressure level] and then, after a 10-min steady-state period, with PEEP at 10 cm H2O. Thereafter, PEEP was discontinued and replaced by ZEEP. After a 5-min recovery period during ZEEP, dopexamine was administered at a rate of 0.5 µg/kg/min, and data collection was performed after a stabilization period of 15 min (still with ZEEP). A PEEP of 10 cm H2O was then reinstituted, and measurements were repeated at the end of a 10-min steady-state period. Finally, PEEP was discontinued for 5 min before the rate of dopexamine infusion was increased to 1.0 µg/kg/min, and a similar ZEEP-PEEP measuring sequence was performed at this higher dopexamine dose. The duration of the entire measurement sequence at each perfusion pressure level was 125 min, including a 45-min recovery period without controlled perfusion pressure or dopexamine infusion at ZEEP. The animals were killed during deepened sodium pentobarbital anesthesia with an IV bolus of potassium chloride. The correct positions of all catheters were verified, and flow probes were checked in situ for zero blood flow recordings.

Calculations

Statistical Analysis
All values are given as mean ± SEM (n = 7). Data were analyzed using repeated-measures analyses of variance. When significant main effects were found, simple contrasts were made using the Student two-tailed t test for paired data. A p value of < 0.05 was considered to be significant. The statistical analysis was performed with a statistical software package (SPSS, version 10.0; SPSS Inc; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Systemic Effects of Dopexamine and PEEP
For background information, systemic hemodynamic parameters are presented at ZEEP and PEEP, both with and without dopexamine (Table 1 ). These parameters are presented to understand better the systemic hemodynamic alterations that were induced by PEEP and/or dopexamine. However, we would like to emphasize that the alterations in systemic hemodynamics are of less importance for the interpretation of our results, since we used a controlled perfusion pressure model.


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  		Table 1.. Hemodynamic Effects of Dopexamine Infusion During ZEEP and PEEP at 10 cm H2O at a Freely Variable PSMA*

 
Regional Effects of Dopexamine and PEEP
At each applied IPP level, the situation at ZEEP was defined as the control and was used as the reference point.

Effects on IPP
At the stage of freely variable PSMA (see "Materials and Methods" section), the mean IPP was 77 ± 4 mm Hg at ZEEP (control point) and was significantly decreased by PEEP to 61 ± 4 mm Hg. Dopexamine dose infused at a rate of 0.5 µg/kg/min induced no significant change in IPP, while the dose infused at 1.0 µg/kg/min decreased the IPP to 53 ± 3 mm Hg. In comparison with the control, the concomitant use of dopexamine and PEEP decreased the IPP even further. Thus, the lowest IPP level (46 ± 3 mm Hg) was observed during PEEP and dopexamine infusion at 1.0 µg/kg/min (Fig 3 ).



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  		Figure 3.. IPP at a freely variable PSMA, at a PSMA of 50 mm Hg, and at a PSMA of 30 mm Hg. C = control; # = simple contrasts in comparison with C within each IPP range. See the legend for Figure 2 for other abbreviations not used in the text. Values are given as the mean ± SEM, and p < 0.05 was considered to be significant.

 
At the stages PSMA of 50 mm Hg and PSMA of 30 mm Hg (see "Materials and Methods" section), the PEEP per se did not influence IPP significantly, while the combined use of PEEP and dopexamine induced a significant decrease in IPP at both dopexamine doses (Fig 3) .

Effects on Intestinal Blood Flow
Within the IPP range 77 to 33 mm Hg (mean values, present during freely variable PSMA and PSMA of 50 mm Hg), there were, despite the wide IPP pressure range, only two significant alterations in QMES (compared to the initial control value at a mean IPP of 77 mm Hg). Thus, decreases were observed at the freely variable PSMA during PEEP alone (by about 215 mL/min) and during PEEP and dopexamine, 0.5 µg/kg/min (by about 165 mL/min). At an IPP < 33 mm Hg, QMES was, for all measuring points besides during dopexamine infusion at 1.0 µg/kg/min, significantly decreased compared to the initial control value at a mean IPP of 77 mm Hg (Fig 4 ). Jejunal mucosal perfusion was maintained at IPP levels of > 45 mm Hg but showed a pattern of gradual decrease that paralleled the reduction in IPP below this perfusion pressure level. This response was not influenced significantly by the dopexamine or PEEP interventions (Fig 4) .



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  		Figure 4.. The relationship between QMES and IPP (top) and jejunal mucosal perfusion and IPP (bottom). See the legend for Figure 2 for other abbreviations not used in the text. Values are given as the mean ± SEM. For statistical comparisons, see text.

 
Effects on Intestinal Oxygenation and Metabolism
The vp-DO2 level reflected the above mentioned QMES changes, with significant decreases observed only at freely variable PSMA during PEEP alone (by about 25 mL/min) and during the combined use of PEEP and dopexamine, 0.5 µg/kg/min (by about 19 mL/min). The overall pattern was thus an essentially maintained vp-DO2 at IPP levels of > 33 mm Hg.

However, at an IPP < 33 mm Hg, the vp-DO2 decreased significantly (Fig 5 ), while oxygen extraction increased (Fig 5) . The vp-O2 was maintained as long as the IPP was > 33 mg Hg (Fig 5) . Once the IPP decreased to < 33 mg Hg, the significant decrease in vp-DO2 was associated with a gradually lowered vp-O2.



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  		Figure 5.. The relationship among vp-DO2 and IPP (top), mesenteric oxygen extraction (vp-O2 EXTR) and IPP (middle), and vp-O2 and IPP (bottom). See the legend for Figure 2 for other abbreviations not used in the text. Values given as the mean ± SEM. For statistical comparisons, see text.

 
Intestinal tissue PO2 decreased gradually in proportion to reductions in IPP (Fig 6 ). Furthermore, mesenteric lactate production occurred at an IPP of < 33 mm Hg (Fig 6) . At this low IPP level, even minimal additional reductions in IPP (mean decreases, < 5 mm Hg) were associated with significant increases in lactate production (Fig 7 ). The relationship between intestinal tissue PO2 and mesenteric lactate production (Fig 6) illustrates that the ischemic threshold in this study can be defined as either an approximate IPP of < 35 mm Hg or an approximate intestinal tissue PO2 of < 45 mm Hg.



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  		Figure 6.. The relationship among intestinal tissue PO2 (PO2 TISSUE) and IPP (top), between vp-lactate flux and intestinal PO2 TISSUE (middle), and between vp-lactate flux and IPP (bottom). See the legend for Figure 2 for other abbreviations not used in the text. Values given as the mean ± SEM. For statistical comparisons, see text.

 


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  		Figure 7.. Changes in vp-lactate flux (top) and changes in IPP (bottom) at a PSMA of 30 mm Hg under different conditions. # = simple contrasts in comparison with the control at a PSMA of 30 mm Hg. See the legend for Figure 2 for other abbreviations not used in the text. Values given as the mean ± SEM, and p < 0.05 was considered to be significant.

 
Stability of the Model
In this study, the stability of the intestinal preparation was examined repeatedly by control measurements. Such control measurements were performed prior to PEEP and at the end of a 45-min recovery period (with the arterial clamp fully released) following a data collection sequence at a freely variable PSMA and at a PSMA of 50 mm Hg. We observed no significant changes over time in intestinal PO2 or in intestinal lactate flux (ie, there was no net lactate production) among the control stages throughout the study protocol.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main finding of this study was that the prevailing perfusion pressure is the main determinant for intestinal tissue oxygen perfusion during the application of PEEP. Within the perfusion pressure range of 77 to 33 mm Hg, intestinal tissue oxygen perfusion was maintained despite the application of PEEP. In this situation, the regional vascular effects of dopexamine were minimal. Expressed differently, the need for pharmacologic vasoactive support of the intestinal circulation was nonexistent, probably due to the powerful autoregulation of this vascular bed.32 At IPPs of < 33 mm Hg, intestinal net lactate production was observed already at ZEEP, and even minimal reductions in IPP, as induced by PEEP, were associated with increased intestinal net lactate production. In this situation, dopexamine was unable to counteract the perfusion pressure-related oxygen debt. On the contrary, dopexamine was associated with increased regional net lactate production. Our data suggest that the regional ischemic threshold can be defined either as an approximate IPP of < 35 mm Hg or an approximate intestinal tissue PO2 of < 45 mm Hg.

Despite the wide IPP pressure range (ie, 77 to 33 mm Hg) at freely variable PSMA and PSMA of 50 mm Hg, there were only two significant decreases in QMES, which indicates that autoregulation was active within this IPP range. This important local control of the blood supply probably was achieved by an interaction between myogenic and metabolic components.32 According to the myogenic theory, a decrease in perfusion pressure reduces transmural pressure and vascular wall tension, and consequently elicits a decreased arteriolar tone (ie, vasodilation).33 34 The metabolic theory is based on the assumption that tissue metabolism and arteriolar smooth muscle constitute a local control system that provides the necessary coupling between blood flow and tissue nutritional requirements.35 According to this theory, decreased IPP induces arteriolar and precapillary sphincter relaxation to maintain blood flow to meet the need of the tissue for oxygen and nutrient delivery. Data from the literature indicate that increased oxygen extraction (ie, capillary recruitment) is of greater quantitative significance than the myogenic aspect of blood flow autoregulation at severely depressed IPP levels.36 In line with this metabolic theory of autoregulation, we observed no significant alterations in O2, indicating adequate intestinal tissue oxygen perfusion at a PSMA of 50 mm Hg, compared to a freely variable PSMA.

The relationships among oxygen delivery, oxygen extraction, and O2 have been described in terms of blood flow dependence and independence. Normally, tissue O2 can be maintained during limitations in oxygen delivery due to an increased oxygen extraction ratio (ie, flow-independent O2). However, if oxygen delivery is reduced below a critical level, O2 begins to decrease due to critical oxygen extraction, and O2 thus becomes flow-dependent. At this point, capillary density is maximized and local regulatory mechanisms cannot further increase oxygen extraction.37 In this study, at a PSMA of 50 mm Hg, intestinal tissue PO2 was decreased but was still sufficient to maintain adequate intestinal oxygenation, indicating the presence of flow-independent O2.

With a PSMA of 30 mm Hg, a different pattern was observed. At this IPP level, which is below the perfusion pressure range for effective autoregulation, a significant drop in mesenteric blood flow was observed, and consequently the O2 decreased. The presence of mesenteric tissue net lactate production at this IPP level illustrates that oxygen extraction had reached a critical level of 45%, and, accordingly, O2 became flow-dependent. This oxygen extraction ratio could be compared with a mean oxygen extraction ratio of 33 ± 5% during normal conditions in the pig38 and an oxygen extraction ratio of 64% 30 min after hemorrhage to a MAP of 40 mm Hg.39 Furthermore, Heino and coworkers40 have reported, in a model of gradual splanchnic ischemia in the pig, increased splanchnic oxygen extraction from a mean 44 ± 3% at baseline to 60 ± 3% obtained after 30 min of total occlusion of superior mesenteric arterial blood flow. Our observed critical oxygen extraction ratio of 45% is lower than the above-described maximal oxygen extraction ratios, suggesting that maximal extraction may not have been reached in our model. However, our observation of significant net lactate production across the preportal vascular bed and a prompt decrease in intestinal tissue PO2 suggests that oxygen extraction tended to reach maximal levels.

In addition to the above-described relationship between IPP and intestinal net lactate production, our measurements of intestinal tissue PO2 allow us to further analyze the threshold, below which intestinal net lactate production occurs, that is indicative of regional ischemia. This threshold limit for intestinal tissue PO2 has been reported previously41 to be 1.9 mm Hg in a study in which intestinal tissue PO2 was correlated to histologically observed intestinal damage. We, on the other hand, have reported an intestinal tissue PO2 limit of 45 mm Hg, below which intestinal net lactate production occurs. When comparing our results with data obtained by Sheridan and coworkers,41 it must be emphasized that we used different species and also had different end points. The main focus of our study was the evaluation of the effects of alterations in IPP on intestinal tissue oxygen perfusion, while Sheridan et al41 focused on the histologic examination of the rat bowel. As illustrated by Figure 7 , we have deepened our analyses of the relationship between IPP, below the threshold of 33 mm Hg, and intestinal tissue net lactate production. Below this critical limit, our data indicate that only minor decreases in IPP, such as 2 to 5 mm Hg, induced significant increases in net lactate production, irrespective of whether PEEP and/or dopexamine were used. Thus, the perfusion pressure is the main determinant for intestinal net lactate production.

The level of PEEP that was chosen in this study (10 cm H2O) is in accordance with common clinical ICU practice. Several mechanisms have been suggested to explain the cardiovascular effects of PEEP. Thus, PEEP exerts direct effects on the heart, by reducing right and left ventricular function.42 43 Furthermore, PEEP increases intrathoracic pressure, thereby reducing venous return and CO. This increase in intrathoracic pressure results in the unloading of cardiopulmonary volume receptors, which usually elicits reflex sympathetic activation, increased norepinephrine release, and regional vasoconstriction.44 45 However, increased plasma norepinephrine levels,46 as well as unchanged systemic and regional norepinephrine levels,47 have been reported during PEEP ventilation.

Based on our observations, one could theoretically speculate whether vasoconstrictor therapy would be beneficial in a situation of severe intestinal hypotension similar to that produced in this study. If vasoconstrictor therapy does not increase perfusion pressure, and assuming that the vasoconstriction also encompasses the intestinal vascular bed, it seems probable that a deleterious reduction in intestinal tissue oxygen perfusion would occur. On the other hand, if such vasoconstrictor therapy really increases IPP, our data indicated that the intestinal vascular bed would benefit from such therapy. However, one must bear in mind that the net effects of vasoconstrictor therapy on intestinal tissue oxygen perfusion are not easily deduced from systemic BP measurements.3 In this study, we also measured jejunal mucosal perfusion. In situations of reduced intestinal blood flow, it has been suggested37 39 that a redistribution of blood flow occurs, preserving intestinal mucosal perfusion better than serosal perfusion. It is noteworthy that our data show a somewhat different pattern, with less well-maintained jejunal mucosal perfusion. The mechanisms behind this discrepancy cannot be elucidated from the present results, meriting further investigation.

To conclude, we have described the maintenance of intestinal tissue oxygen perfusion within a wide perfusion pressure range. Within this perfusion pressure range, PEEP did not induce any adverse regional circulatory effects. At a PSMA of 30 mm Hg, which is below the perfusion pressure range for effective autoregulation, intestinal tissue oxygen perfusion deteriorated and regional ischemia occurred. In this situation, dopexamine infusion was unable to counteract perfusion pressure-dependent decreases in intestinal tissue oxygen perfusion. The regional ischemic threshold can be defined either as an IPP of < 33 mm Hg or an intestinal tissue PO2 of < 45 mm Hg.


   Acknowledgements
 
The authors thank Marita Alquist, Anna-Maja Sundin, and Thomas Ekman for excellent technical assistance throughout the study.


   Footnotes
 
Abbreviations: CaO2 = systemic arterial oxygen content; CO = cardiac output; CVP = central venous pressure; HR = heart rate; IPP = intestinal perfusion pressure; LDF = laser Doppler flowmetry; MAP = mean arterial pressure; PEEP = positive end-expiratory pressure; PMES = mesenteric venous pressure; PSMA = superior mesenteric arterial pressure; PU = perfusion units; QMES = mesenteric venous blood flow; O2 = oxygen uptake; vp-DO2 = mesenteric oxygen delivery; vp-lactate flux = mesenteric lactate flux; vp-O2 = mesenteric oxygen uptake; ZEEP = zero end-expiratory pressure

This research was supported by grants from the Swedish Medical research council, project No. 06575, and the Medical Faculty at Umeå University.

Received for publication September 24, 2002. Accepted for publication January 9, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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