INTRODUCTION

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EARLIER STUDIES ESTABLISHED that increases in PCO₂ of the stomach and esophagus represented a consistent finding in critical low-flow states of circulatory shock (4, 16, 17). The PCO₂ of the stomach wall, the liver parenchyma, the kidneys, myocardium, and the cerebral cortex were each increased early, and tissue hypercarbia was promptly reversed, with restoration of normal blood flows (3, 10, 11, 17). We recognized hypercarbia as a universal phenomenon of circulatory shock states. We thereupon searched for an even more practical, noninvasive method of monitoring PCO₂. Accordingly, we investigated the feasibility of measurements under the tongue, not unlike those obtained with an oral thermometer. Sublingual PCO₂ proved to be a quantitative indicator comparable to measurements obtained from gastric and esophageal sites (13). In the present study, we tested our hypothesis that increases in sublingual PCO₂ are a sensitive indicator of decreases in blood flow, not only to the tongue and sublingual tissues but also to blood flows in the viscera and specifically in stomach, jejunum, colon, and kidneys.

	METHODS

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Experiments were performed in an established rodent model of hemorrhagic shock (14, 17, 18). All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals formulated by the National Research Council and published by National Academy Press in 1996.

Animal preparation. Ten Sprague-Dawley rats, weighing 450-550 g, were fasted overnight except for free access to water. The animals were anesthetized with intraperitoneal injection of 45 mg/kg pentobarbital sodium and were restrained on a surgical board in the supine posture. The trachea was surgically exposed at a site 2 cm caudal to the larynx. A 14-gauge cannula (Abbocath-T; Abbott Hospital Division, North Chicago, IL) was then advanced into the trachea for a distance of 1 cm. End-tidal CO₂ was continuously monitored with a sidestream infrared CO₂ analyzer (End-Tid IL 200; Instrumentation Laboratory, Lexington, MA). Through the left carotid artery, a polyethylene catheter (PE50; Becton-Dickinson, Franklin Lakes, NJ) was advanced into the ascending thoracic aorta to measure aortic pressures and to sample aortic blood for laboratory analyses. Through the left jugular vein, a polyethylene catheter was advanced into the right atrium for measurement of right atrial pressure. This catheter was also used as a site for injection of a thermal indicator for measurement of cardiac output. Intravascular pressures were measured with high-sensitivity transducers (model 42584-01, Abbott Critical Care System, North Chicago, IL) and with reference to the midchest of the animal. An additional polyethylene catheter was advanced through the right carotid artery into the left ventricle, as guided by the morphology of the pressure pulses during transit from the aorta to the left ventricle. This catheter served as the injection site for colored microspheres. A polyethylene catheter also was inserted through the left femoral artery into the abdominal aorta. The catheter was connected to a three-way stopcock which allowed for bleeding. Blood was collected into a reservoir (the barrel of a standard 30-ml plastic syringe). A venous catheter was surgically inserted into the left femoral vein and was advanced into the inferior vena cava. This catheter served as a site for infusion of donor blood. For the measurement of cardiac output, a 1.5-Fr thermocouple microprobe (9030-12-D-34, Columbus Instruments, Columbus, OH) was advanced into the thoracic aorta through a surgically exposed right femoral artery. Blood temperature was monitored with this sensor. The temperature was maintained between 36.5 and 37.5°C by utilizing infrared heating lamps.

Experimental procedure. The animals were randomized to hemorrhage or sham-hemorrhage control groups by the sealed envelope method. A modification of previously described methods for producing hemorrhagic shock in rats was utilized (14, 17, 18). Blood from the left femoral artery was allowed to flow into the barrel of the syringe reservoir. The reservoir was pressurized (to 100 mmHg for 10 min, to 80 mmHg for the next 20 min, to 70 mmHg for the subsequent 20 min, and to 50 mmHg for the ensuing 70 min) by utilizing a pressure regulator (model 10; Fairchild, Winston-Salem, NC) in parallel with a conventional mercury manometer. After 2 h, the pressure in the reservoir was increased to 200 mmHg, such that shed blood was reinfused; this procedure was completed over an average interval of 10 min. The animals were observed for an additional 50 min and then euthanized with injection of pentobarbital sodium (100 mg/kg iv). An autopsy was routinely performed on all animals, with gross inspection of thoracic and abdominal organs to identify any adverse effects of the interventions. In control animals, the procedures were identical, except that no blood was allowed to flow from the femoral arterial catheter into the reservoir.

Measurements. End-tidal CO₂, aortic pressures, and sublingual PCO₂ were continuously recorded with the aid of a PC-compatible 486 computer utilizing data-acquisition hardware/software (DATAQ Instruments, Akron, OH). Cardiac output and aortic blood lactate measurements were obtained before hemorrhage and at 30, 60, 90, 120, 150, and 180 min after the start of hemorrhage. Cardiac output was measured by a thermodilution technique in which a bolus of 200 µl of saline at a temperature of 15°C was injected into the right atrium. With the aid of a cardiac-output computer (CO-100; Institute of Critical Care Medicine, Palm Springs, CA), cardiac index was computed as the cardiac output per kilogram body weight. Lactate concentration was measured from aortic blood by utilizing a lactate analyzer (model 23L, Yellow Springs Instruments, Yellow Springs, OH). After withdrawal of aortic blood for laboratory measurements, an equal amount of blood from an anesthetized donor rat was injected into the left femoral venous catheter.

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Statistical analyses. Measurements were reported as means ± SD. Baseline measurements between the groups and time-based measurements within a group were compared by ANOVA for repeated measurements. A P value of <0.05 was considered significant.

	RESULTS

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Baseline measurements of mean aortic pressure, cardiac index, end-tidal PCO₂, and aortic blood lactate in both experimental and control animals were within the physiological ranges previously reported (14, 16, 17). During the 120-min interval of hemorrhage, the mean aortic pressure decreased from an average of 151 to 49 mmHg, and cardiac index decreased from 282 to 76 ml · min¹ · kg¹. Reinfusion of the shed blood restored mean aortic pressure and cardiac index to near- baseline levels within 30 min (Fig. 1). These hemodynamic changes were accompanied by increases in aortic blood lactate concentration from 0.9 to 11.2 mmol/l, and a return to near-baseline values was observed after reinfusion (Fig. 1).

View larger version (30K): [in this window] [in a new window]   Fig. 1.   Hemodynamic and arterial lactate measurements observed at baseline, during hemorrhage, and after reinfusion of shed blood. Means ± SD are shown for 5 shock and 5 sham-hemorrhage control animals. MAP, mean aortic pressure; CI, cardiac index; LAC, arterial blood lactate; BL, baseline.

During hemorrhage, sublingual PCO₂ increased from 50 to 127 Torr. This was associated with decreases in end-tidal PCO₂ from 40 to 12 Torr (Fig. 2). Maximal baseline drift in the sublingual PCO₂ sensors over the 3-h interval of measurement was 10%, but the slope of the two-point PCO₂ calibration remained within 2% of its initial value. The sublingual and arterial PCO₂ gradient was increased from 17 to 116 Torr during hemorrhagic shock (Table 1).

View larger version (32K): [in this window] [in a new window]   Fig. 2.   Changes in sublingual PCO2 (SLPCO2) and end-tidal PCO2 (ETPCO2) before and during hemorrhagic shock and after reinfusion of shed blood.

Sublingual blood flow decreased from 22 to 7 ml · min¹ · 100 g¹ and remained at 7 ml · min¹ · 100 g¹ at the end of the 120-min hypovolumic interval. There were corresponding decreases in blood flow to the sublingual tissues, tongue, stomach, jejunum, colon, and kidneys. These flows ranged from an average of 33 to 53% of preshock values (Fig. 3 and Table 2). Progressive increases in sublingual PCO₂ were highly correlated with decreases in sublingual blood flow (r = 0.80, P < 0.01; Fig. 4), tongue blood flow (r = 0.81, P < 0.01), and gastric blood flow (r = 0.74, P < 0.01). Jejunal blood flow (r = 0.65, P < 0.01), colon blood flow (r = 0.80, P < 0.01), and renal blood flow (r = 0.75, P < 0.01) were also correlated with simultaneously measured sublingual PCO₂. There were no statistically significant differences in the quantitative reductions in blood flow among the various organs. At 60 min after reinfusion of shed blood, sublingual PCO₂ had returned to baseline levels, and sublingual blood flow increased to ~70% of preshock values (Fig. 3).

View larger version (30K): [in this window] [in a new window]   Fig. 3.   Tissue blood flows relative to 7 sites during hemorrhagic shock (60 and 120 min) and after reinfusion of shed blood (180 min). L and R, left and right, respectively.

View larger version (20K): [in this window] [in a new window]   Fig. 4.   Linear correlations between and sublingual blood flow (BFSL) and between SLPCO2 and stomach blood flow (BFST); n, no. of animals.

These findings contrasted with those in simultaneously measured in anesthetized control animals. Neither sublingual PCO₂ nor blood flow to the various organs was significantly altered during the 180-min interval of sham hemorrhage (Figs. 1 and 2; Tables 1 and 2).

	DISCUSSION

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Earlier studies had demonstrated that sublingual tissue PCO₂ was highly correlated with gastric PCO₂ during hemorrhagic shock in the rat (13). The measured increases in sublingual PCO₂ were numerically greater than those of gastric PCO₂, although the relative changes were comparable.

The present study established that increases in sublingual PCO₂ were highly correlated with decreases in sublingual and tongue blood flows and of magnitudes in these experiments exceeding that of the stomach wall. Gastric PCO₂ that was measured with gastric tonometry had previously served as the primary reference for tissue PCO₂ measurements in settings of circulatory shock (6, 7, 14, 17). Comparable decreases in blood flow were also demonstrated in the stomach, jejunum, colon, and kidneys. Blood flows at each of these sites increased to between 69 and 82% of baseline values after reinfusion of shed blood. Sublingual PCO₂ mirrored the PCO₂ of the gastric wall (13).

During the last decade, gastric tonometry has emerged as an option for estimating the severity of visceral ischemia during circulatory shock states (2, 6, 7). The rationale for that method was that blood flow to the stomach and intestines is reduced early and disproportionately during low-flow states of circulatory shock (1, 12, 15). However, our more recent studies have demonstrated that this assumption is not fully sustained. In rats, both the esophagus and the sublingual sites have comparable reductions in blood flow (16). The present data lend additional support to the concept that the abdominal viscera do not deserve to be heralded as the "canary" of systemic blood flow (2).

The practical implications are substantial. Sublingual tonometry is a disarmingly facile and noninvasive option for continuous measurement of tissue PCO₂ during low-flow states of circulatory shock. This method contrasts with gastric tonometry, which provides intermittent measurements. Gastric tonometry is not only a more invasive procedure, it requires more elaborate and costly instrumentation. It also requires administration of H₂-receptor-blocking drugs if interference by gastric acid secretion is to be prevented, as well as the acceptance of the side effects of the drugs (9).

Therefore, we conclude that increases in sublingual PCO₂ reflect decreases in systemic blood flow. These are reflected in decreases of sublingual tissue blood flow of magnitudes that are comparable with or greater than those measured in the stomach and jejunum in the rat model. Accordingly, the rationale for sublingual PCO₂ measurements for diagnosis of systemic perfusion failure, for estimation of its severity, and as a monitor of the response to treatment of circulatory shock is supported by the present studies.