critical care Tissue Hypercarbic Acidosis as a Marker of Acute Circulatory Failure (Shock)*

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1 critical care Tissue Hypercarbic Acidosis as a Marker of Acute Circulatory Failure (Shock)* Yoji Sato, MD; Max Harry Weil, MD, PhD, Master FCCP; and Wanchun Tang, MD, FCCP Measurement of ph of the stomach wall (gastric intramural ph) by the tonometric method has been utilized both experimentally and clinically as an indicator of the capability of the stomach to extract and utilize oxygen. As such, it serves as a metabolic marker of acute perfusion failure (circulatory shock). More recently, researchers have found that increases in the Pco 2 accounted for the decline in ph; this was documented in tissues other than the stomach wall, including the esophageal and sublingual mucosa. In this review, tissue Pco 2 is identified as a universal indicator of impaired perfusion and contrasted with conventional hemodynamic and metabolic markers of perfusion failure. (CHEST 1998; 114: ) Key words: circulatory shock; gastric intramural Pco 2 ; gastric intramural ph; ischemia; tissue Pco 2 Abbreviations: CPR=cardiopulmonary resuscitation; PcC0 2 =gastric wall Pco 2 ; PHC0 2 =hepatic Pco 2 ; phg= submucosal ph; phi=gastric intramural p:fl; PMC0 2 =myocardial tissue Pco 2 The measurement of intramural ph (phi) in the stomach by the tonometric method has been regarded as a quantitative metabolic indicator of the capability of the stomach to extract and utilize oxygen. 1 2 Earlier investigations anticipated that the stomach and intestines would be especially appropriate because blood flow to the viscera is markedly reduced during acutely life-threatening low-flow states of circulatory shock. 3 Fiddian-Green and Baker4 found that the onset of perfusion failure was detected earlier with gastric tonometric measurement than with alternative measurements in current use, namely arterial blood pressure, urine flow, *From The Institute of Critical Care Medicine (Drs. Sato, Weil, and!ang), Palm Springs, Calif, and the University of Southern Calilon1ia School of Medicine (Drs. Wei! and Tang), Los Angeles. Supported in part by a Grant-in-Aid from The American Heart Association and the Laerdal Foundation for Acute Medicine, Inc., Stavanger, Norway. Dr. Tang is an Established Investigator of the Society of Critical Care Medicine. Manuscript received August 7, 1997; revision accepted October 31, Reprint requests: Max Harry Weil, MD, PhD, Master FCCP, The Institute of Critical Care Medicine, 1695 North Sunrise Way, Building #3, Palm Springs, CA ; em.ail:weilm@ool.com cardiac output, and arterial ph. Other investigators confirmed that gastric intramural ph measurements predict the short-term outcome of patients who presented with perfusion failure (circulatory shock) Accordingly, the measurement of phi and, more specifically, the use of the commercially available tonometer (TRIP NGS catheter; Tonometries Division, Instrumentarium Corp; Helsinki, Finland) was viewed as a potentially valuable adjunct for diagnosis and monitoring of the severity of systemic perfusion deficits in critically ill patients. In this review we address both experimental and clinical data relating to the measurements of tissue Pco 2 for the diagnosis and quantitation of systemic perfusion failure (circulatory shock). Newer insights into the mechanisms that account for the increases in gastric wall Pco 2 (PcC0 2 ) and the ph of the stomach wall (phi) will be exposed. The concept has been expanded to include tissues remote from the stomach. Venous blood gases, the esophagus, the myocardium, liver, brain, and kidney tissue Pco 2 all reflect the same phenomenon (Table 1) Finally, we review the recognized benefits and limitations of tissue Pco 2 as a monitor of severity and a prognosticator of outcome of systemic perfusion failure CHEST I 114 I 1 I JULY,

2 Table!-Average Tissue Pco 2 Normal Range, mm Hg Circulatory Shock, mm Hg Organ! Tissue Stomach Sublingual Esophagus Myocardium Liver Kidney Brain Pig Rat * Hemorrhagic Shock Pig Rat * * Cardiogenic Shock Sepsis Pig Rat Pig 76* 156* 117* *Unpublished data. Superscripted numbers represent references from which data were taken. 180* 88* Rat ll Anaphylactic Shock Pig Rat * 86* based on comparisons with present-day conventional hemodynamic and metabolic monitors. THE TONOMETRIC METHOD The Concept of the Tonometric Method The concept of the gastric tonometric method was reported approximately 40 years ago. Boda and M uninyil 7 advanced a balloon catheter through the nose into the stomach of human subjects. The balloon was filled with room air. Their intent was to estimate arterial Pco 2 from the Pco 2 of gas sampled from the gastric balloon after 2 h of equilibration. Gastric Pco 2 was closely related to end-tidal C0 2 and therefore to arterial Pco 2 in patients who had no respiratory disease. In 1964, Bergofsky 18 demonstrated that the gas tension of oxygen and carbon dioxide of saline instilled into the lumen of either the gallbladder or the urinary bladder equilibrated with that of the wall of the organ over an interval of 1 to 3 h. This method was subsequently adapted by Dawson et al 19 for the measurement of gas tensions in the mucosa of the small intestine. Pco 2 equilibrated more rapidly in the small intestine than in either the gallbladder or the urinary bladder. Fluid instilled into an ileal loop equilibrated over as little as 15 min. The Pco 2 of the fluid corresponded closely to that of the venous blood that drained the same ileal loop. 20 Fiddian-Green et al injected 200 ml of saline into the stomach of dogs. An aliquot of this fluid was aspirated after 30 min and the Pco 2 was measured on this aliquot. Arterial blood was concurrently sampled for measurement of ph and Pco 2. The bicarbonate concentration was computed from the arterial ph and Pco 2 with the Henderson-Hasselbach equation. This bicarbonate concentration was then utilized together with the Pco 2 measured on 264 the saline aspirated from the stomach to calculate what Fiddian-Green termed phi, once again utilizing the Henderson-Hasselbach equation. The Fiddian-Green adaptation of the Henderson-Hasselbach equation was as follows: where [HC0 3 - ] is the bicarbonate concentration calculated from arterial ph and Pco 2, [Pco 2 ] is the C0 2 tension measured on equilibrated saline aspirated from the isolated stomach, and k=0.031, representing the solubility coefficient of C0 2 in plasma. Fiddian-Green and coworkers 22 regarded the phi as a valid estimate of gastric wall ph. When the phi of the stomach of the dog was compared to the mucosal ph measured directly with a ph microelectrode, a linear correlation of 0.79 was demonstrated. The concept was then applied to measurements on 103 critically ill patients. A 30-mL volume of saline was instilled through a gastric tube into the stomach and allowed to equilibrate for 30 min. It was then aspirated and Pco 2 was measured. In seven patients, after massive bleeding the phi averaged This was in contrast to normal subjects, in whom phi exceeded In 1984, a balloon made of polytetrafluorethylene was adapted to the proximal end of a catheter. This catheter was inserted into a loop of ileum of dogs after celioenterotomy. 23 The balloon was then distended with 3 ml of normal saline and allowed to equilibrate. At 30-min intervals, aliquots of saline were aspirated for measurement of Pco 2. The phi of the ileum was then computed with the Fiddian Green equation. Blood flow, oxygen consumption, and the phi of the ileal loop were simultaneously measured. Ischemia was then induced by stepwise occlusion of the superior mesenteric artery. A linear correlation between phi and oxygen consumption Critical Care

3 was observed (r=0.68). These findings were cited as evidence that phi of the gut serves as a measurement that indicates critical decreases in oxygen consumption. As such, it serves as a quantitator of the severity of gut ischemia. The clinical application of this methodology was facilitated by a commercially available gastric tonometer, the TRIP NGS catheter. This device was a gastric tube modified to include a second channel, which terminated in a silicone balloon at the tip. The tube was intended for tonometric measurements in either the stomach or the intestine. After this tube had been advanced from the nose into the stomach, a 2.5-mL aliquot of normal saline was injected into the balloon. The position of this tube was checked with fluoroscopic image intensification. After an interval ranging from 30 to 90 min, 1 ml of saline was aspirated to clear the dead space of the catheter and an additional sample was then withdrawn for measurement of Pco 2 with a conventional blood gas analyzer. The phi was then calculated by the Fiddian-Green equation (Fig 1). The validity and reproducibility of gastric tonometry was examined more critically in experimental animals Antonsson et al 24 measured the ph of the mucosa of the ileum of pigs directly with an implanted microelectrode and compared it with the phi measured by the tonometric method. After intravenous injection of Escherichia coli endotoxin, the directly measured mucosal ph and the indirectly measured phi corresponded closely to each other (Fig 2). However, when blood flow through the mesenteric artery was partially or totally occluded, the directly measured mucosal ph was substantially lower. When hemorrhagic shock was induced in pigs, Montgomery et al 28 found a close relationship among the indirectly measured phi values of the stomach wall, intestine, and colon, and all three corresponded to the volume of blood loss. Neither gastric nor intestinal phi consistently returned to control levels after reinfusion of shed blood. In contrast, in the sigmoid colon phi returned to normal levels as soon as blood volume was restored. Accordingly, differences between mucosal ph measured directly with an electrode and phi measured indirectly with a saline-filled balloon were contingent on the etiology of the shock state, the site of measurement, and the time course of onset (and reversal) of circulatory shock. 1. Advance tonometer 2. Injection of 2.5ml saline 3. Equilibrium (30 to 90min) 4. withdraw 2.5ml GAS ANALYZER 5. Arterial sample 6. PC02 in saline 8. Compute phi 7. HC03. in arterial blood FIGURE l. Methods of gastric phi measurements with a balloon tonometer. CHEST I 114 I 1 I JULY,

4 CONTROL o ELECTRODE TONOMETER MINUTES OCCLUSION MINUTES 7.5 PARTIAL OCCLUSION * * * MINUTES ENDOTOXIN * * * * * MINUTES FIGURE 2. A comparison of phi measured by microelectrodes and estimated by tonometry in pigs. The directly measured mucosal ph and the indirectly measured phi corresponded closely to each other except after partial or total mesenteric artery occlusion. Values r epresent mean ± SD. Asterisk(*)=p< 0.05 when compared to baseline; double asterisk(**)=p< 0.05 between m ethods. Adapted from Antonsson et aj.2 4 Limitations of the Tonometric Method The gastric phi measurement was based on two key assumptions: (1) that the Pco 2 of the saline contained in the tonometric balloon after equilibration corresponded to that of gastric tissue Pco 2, and (2) that the tissue and arterial bicarbonate were the same. The evidence bearing on these two key assumptions was the subject of several reports. Tissues are highly permeable to C0 2. When fluid is instilled into the lumen of a hollow organ, the gaseous C0 2 equilibrates with the C0 2 in tissue fluid and cells in the superficial layers of the wall of the hollow organ However, the stomach may be an exception. The Pco 2 of gastric juice may in some instances exceed the Pco 2 of the gastric wall and gastric venous blood. 29 Pco 2 is also generated in the gastric lumen from neutralization of H+ by the bicarbonate contained either in the gastric juice or in the backflow of duodenal fluid. Back diffusion of C0 2 into the gastric mucosa itself increases gastric wall Pco 2 independently of gastric mucosal blood flow After H 2 blockade by cimetidine, H+ production by the stomach is reduced, and the Pco 2 of gastric luminal fluid and that of gastric venous blood approximate each other. Accordingly, the H+ of 266 gastric juice interferes with tonometric measurement of Pco2. Routine H 2 blockade is therefore recommended in conjunction with gastric tonometry to minimize this effect. 32 Although many critically ill patients are treated with H 2 receptor-blocking agents for prevention of stress ulceration, its benefits are disputed. There are adverse effects of H 2 blockade in such settings, especially an increased risk of nosocomial pneumonia. 34 A s econd assumption in the Fiddian-Green equation is that the HC03- concentration in the gastric wall is the same as that in the arterial blood. This is also unproven. To the contrary, there is evidence that the concentration of gastric wall H C03-, calculated with the conventional Henderson-Hasselbach equation from directly measured gastric tissue Pco 2 and gastric wall ph, is consistently greater than that of arterial blood HC0 3 - during shock states (Fig 3).U The time interval required for equilibration of C0 2 between the saline in the tonometer's balloon and the gastric wall imposes significant time limitations. Equilibration was only 80% complete after an average equilibration interval of 30 min, 85% after 45 min, and 88% after 60 min. 4 Experimentally, we Critical Care

5 _. 35 -C"" W25 E (A) HEMORRHAGE IPREI IHEMORRHAGEII REINF. I _. 35 -C"" W25 E (B) ANAPHYLAXIS OVALBUMIN, 1 mg t MINUTES MINUTES FIGURE 3. HC0 3 - of the gastric wall (solid bars) corresponded to that of arterial blood (hatched bars) during hemorrhagic shock (panel A) and after anaphylaxis (panel B). Values represent mean±sd of five animals in each group. Asterisk (*)=p<o.os; double asterisk (**)=p<o.ol vs gastric wall. Adapted from Tang et a!. 1 1 found that the level of tissue Pco 2 has little effect on the equilibration period This has two constraints. First, the measurement is time-delayed. Second, the corrections that are used on the advice of the manufacturer were intended to adjust for incomplete equilibration. However, these corrections represent average values rather than values indicating the time required for partial equilibration in an individual patient. An additional source of error was in the analysis of Pco 2 on the saline sample aspirated from the balloon When known C0 2 gas tensions in saline were measured with various blood gas analyzers in vitro, the Pco 2 values ranged from +9% to -66%, with larger errors at higher Pco 2 levels. The resulting bias was predominantly an underestimate of balloon Pco 2. When phosphate-bicarbonate buffer or 4% succinylated gelatin was utilized in lieu of saline in the balloon, the range of Pco 2 values was decreased to less than one half of the previous range In vivo studies on human patients yielded comparable ranges. 37 Phosphate buffer solutions were therefore identified as options for improving the accuracy and reliability of phi analyses. Facilitating Tonometric Measurement The concept that measurements may be performed on gas aspirated from the stomach was reinvestigated by Salzman et al. 38 Gas was sampled from the stomach 60 min after instillation of 200 ml of air. The Pco 2 of this gas was correlated with that measured on saline with a conventional balloon tonometer when perfusion failure was induced by pericardia! tamponade (r=0.73). During respiratory acidosis and in the absence of shock, there was a very high correlation between the Pco 2 of stomach gas and that of the saline sampled from the balloon (r=0.99). The concept of air tonometry was recently expanded by Guzman and Kruse, 39 who circulated gas through a gastric balloon and measured Pco 2 in that gas continuously with an infrared capnometer. More recently, capnometry and conventional balloon tonometry have been combined. Air is used in lieu of saline, and then gas is aspirated and analyzed automatically by infrared capnometry after 10 min of equilibration with a commercially available Tonocap (Datex-Engstrom; Tonometries; Tewksbury, Mass). 40 Limitations due to intermittency of measurements, errors of gas analysis on saline samples, and relatively labor-intensive manipulations are in part overcome by these new gas analysis methods. Tissue Pco 2 has also been measured with an ion-sensitive field effect (ISFET; Nihon Kohden; Tokyo, Japan) 10 and fiberoptic Pco 2 sensors. 41 These sensors have the advantage of direct and continuous CHEST I 114 I 1 I JULY,

6 measurements of tissue Pco2 without errors associated with equilibration or in vitro measurements on samples aspirated from an organ. TISSUE Pco2 AS A BIOCHEMICAL MARKER OF PERFUSION F AlLURE When oxygen delivery is critically reduced during acute perfusion failure, the hydrogen ion concentrations in venous blood increase and the phi declines. When tissue oxygen requirements can no longer be sustained, anaerobic metabolism is triggered. Anaerobic oxidation of glucose to pyruvate proceeds through the emergency pathway in which pyruvate is shunted to lactate. The excesses of hydrogen ions thus produced account, in part, for tissue acidosis Lesser amounts of acid are also produced by hydrolysis of high-energy phosphates and lipolysis. The quantitative relationships between circulatory failure and acid production in various tissues during circulatory shock have been examined recently in greater detail. The initial impetus came from coincidental observations on the ph and the Pco2 of mixed venous and arterial blood during cardiopulmonary resuscitation (CPR). Marked decreases in the ph of venous blood were identified during cardiac arrest, and the decreases were reversed after resuscitation. These decreases in venous blood ph were due primarily to increases in venous blood mmhg Pco2. 45 In contrast, in arterial blood there was mild hypocapnia with little change in ph. For instance, the Pco2 of mixed venous blood during CPR exceeded 70 mm Hg when concurrent PaC02 was less than 30 mm Hg. Accordingly, the venoarterial Pco2 gradient exceeded 40 mm Hg (Fig 4). Pco2 measurements on coronary venous blood during CPR demonstrated even more profound increases in Pco2 than were seen in mixed venous blood. The coronary venoarterial gradient of Pco2 typically exceeded 130 mm Hg A close relationship was subsequently documented between quantitative increases in systemic and regional venoarterial Pco2 gradients, the severity of the perfusion defect, and outcomes. Accordingly, failure of adequate oxygen delivery due to reduced tissue blood flow was followed not only by anaerobic generation of lactic acid but also by hypercarbia of both tissues and the venous effluent from ischemic tissues. In contrast, when blood lactic acid was assessed during circulatory shock, no meaningful differences behveen arterial and venous blood were found. 45 The first direct evidence of hypercarbia in tissue other than the GI tract and urinary bladder came from directly measured Pco2 of the myocardium. Myocardial tissue Pco2 (PMC02) increased in parallel with progressive constriction of the circumflex coronary artery. 49 Increases in PMC02 were correph, units P C ~, PRE DURING PRE DURING PRE DURING ?- NS --? FIGURE 4. Selective increases in Pco 2 and decreases in ph of mixed venous blood during cardiac arrest. There were no significant changes in arterial blood Pco 2 or in the calculated bicarbonate concentrations of either arterial or mixed v enous blood. Values r epresent mean::'::sd. Adapted from Wei! et al. 45 NS=not significant; PA=pulmonary artery. 268 Critical Care

7 lated with electrocardiographic ST segment elevations indicative of myocardial ischemia (r=0.8l). In studies on human patients, PMC0 2 initially was measured with the aid of mass spectrometry during open heart operations. 50 Intraoperative PMC0 2 was predictive of the severity of postoperative impairment in myocardial contractility. PMC0 2 increased during cross-clamping of the aorta after single-dose potassium cardioplegia. In contrast, multidose cardioplegia prevented myocardial ischemia and increases in PMC0 2. Subsequent observations were made in a porcine model of cardiac arrest and CPR. An ISFET sensor was utilized in this model for continuous measurement of PMC PMC0 2 progressively increased from 54 to 346 mm Hg and the intramyocardial hydrogen ion concentrations increased from 65 nmovl (ph 7.20) to 441 nmovl (ph 6.38) during CPR. The PMC0 2 was a more precise prognosticator of the success of CPR interventions than was myocardial tissue ph. PMC0 2 correlated inversely with coronary perfusion pressure ( r =0.94; p < O.Ol ), and both PMC0 2 and coronary perfusion pressure served as independent predictors of the likelihood of successful resuscitation (Fig 5). This was especially impressive because coronary perfusion pressure is recognized as the most consistent predictor of outcome CONTROL RESUSCITATION n= I II 7/ CONTROL 500 RESUSCITATION PC02, mmhg e NON RESUSC. (6) 0 R ESU SC. (8) [H+j, nmoi/l FIGURE 5. Top: increases in myocardial hydrogen i on [H +] ([H +]M ) and PMC0 2 were associated with increases in lactate content in blood sampled from tbe great cardiac vein. More moderate increases in lactate content of systemic blood were observed. Bottom: PMCO:?. related to outcome. Values represent mean±sd. PREC COMPRESS = precordial compression; [HC0 3 - ]M=myocarclial bicarbonate; AO=aorta; PA =pulmonary artery; GCV=great cardiac vein. Adapted from Kette e t aj. ld CHEST I 114 I 1 I JULY,

8 of cardiac resuscitation in each of the species in which it has been examined.lo,l2,5l-53 Other tissues have been examined. Hepatic Pco2 (PHC02) was investigated in large Sprague-Dawley rats after an ISFET Pco2 sensor was surgically implanted into the left lobe of the liver. 7 PHC02 increased from 55 mm Hg to 160 mm Hg during cardiac arrest and was promptly reversed after restoration of spontaneous circulation. When resuscitation attempts failed, PHC02 had consistently increased to levels exceeding 200 mm Hg. Accordingly, PHC0 2, like PMC0 2, served as a quantitative indicator of the severity of perfusion failure. 7 The PHC0 2 was inversely correlated with coronary perfusion pressure (r=0.92; p<0.01). Based on evidence obtained from both porcine and rodent models of cardiac arrest, Pco 2 predicted outcome better than phi. During septic shock, tissue Pco 2 increased not only in the stomach but also in the liver, in the kidneys, and in the cerebral cortex. 9 Accordingly, tissue hypercarbia emerged as a universal phenomenon during the low flow states of circulatory shock associated with cardiac failure, hemorrhage, anaphylaxis, and sepsis. The Pco 2 of the stomach wall increased very predictably during both hemorrhagic and anaphylactic shock.l 1 When submucosal tissue Pco 2 (PcC0 2 ) and ph (phc) were measured directly with an ISFET Pco 2 sensor and a glass ph electrode, decreases in gastric blood flow, decreases in phc, and increases in PcC0 2 were closely related (Table 2). After anaphylactic shock was induced in animals sensitized to crystalline egg albumin, decreases in mean aortic pressure were associated with increases in PcC0 2 and decreases in phc. These increases in PcC0 2 were highly correlated with decreases in gastric blood flow measured by the microsphere method. Directly measured gastric tissue Pco 2 again served as a more precise and sensitive monitor of perfusion failure than the computed gastric phi. 11 After it was apparent that the gastric wall served as an appropriate site for direct clinical measurements of tissue Pco 2, the esophagus was examined as a more proximal and potentially even less invasive site Earlier investigators had assumed that decreases in tissue ph during shock and, by implication, increases in Pco 2 were limited to the splanchnic circuit. Because the esophagus is supplied by arterial branches from the aorta and venous drainage is into systemic veins, the expectation was that the esophagus would not be a suitable site. Yet, increases in esophageal Pco 2, like gastric wall Pco 2, correlated impressively with decreases in esophageal blood flow (p<0.001) and with increases in PcC0 2 (r=0.90; p<0.001) during hemorrhagic shock. In 1997, an additional alternative site for the measurement of visceral Pco 2 was identified. Pco 2 was directly and continuously measured in the soft tissues under the tongue. During hemorrhagic 15 and septic shock 16 in rats, there were striking increases in sublingual Pco 2, comparable to those measured in the gastric wall. These observations were confirmed on pigs and subsequently in human patients during cardiogenic, hemorrhagic, and septic shock. This new option has potential advantages because it is disarmingly simple. Equilibration is typically complete at between 2 and 3 min. The potential application of the technique extends to triage in both civilian disasters and military settings. Table 2-Hemorrhagic Shock Baseline Shock Recovery Group -15 min 60 min 120 min 180 min PcC0 2, mm Hg c H phg c H t * Lactate, mmol!l c H ' 3.4* GBF, mumin/100 g H Values are mean± SO; n=5 rats. C=control group; H=hemorrhagic shock group; lactate=arterial blood lactic acid; GBF=gastric blood flow. *p< p<o.ol. Mechanisms of Tissue Hypercarbic Acidosis The source of hypercarbic acidosis was initially investigated in the myocardium. When the PMC0 2 increased from an average of 60 to 210 mm Hg during a 4-min interval of cardiac arrest, myocardial tissue ph simultaneously decreased from an average of 7.03 to However, there were no detectable increases in the total C0 2 content of the heart muscle. Accordingly, the buffering of metabolic acids by tissue bicarbonate, rather than by increases in total C0 2 production or decreases in C0 2 removal, accounted for the increases in PMC0 2. This further supported the concept that anaerobically generated acids and especially lactic acid together with [H+] generated by the accelerated hydrolysis of highenergy phosphate compounds and by lipolysis supplied the [H+]. The [H+] then combined with HC03- to produce C0 2. Myocardial hypercarbia therefore represented the end effect of excess pro- 270 Critical Care

9 duction of hydrogen ions. C0 2 was generated from the excess of [H+] acting on HC0 3 - such that there were no increases in the sum of C0 2 and HC0 3 -, represented by the total C0 2 content. 54,5 5 Clinical Applications Tonometric measurements are recognized as early and clinically useful indicators of oxygen deficit accompanying the perfusion failure of circulatory shock states Of 85 patients who were monitored after open heart surgery, eight presented with life-threatening perfusion failure due to acute myocardial infarction, heart failure, pulmonary embolism, or acute pancreatitis within 72 h after completion of the surgical procedure. 4 Declines in gastric phi ( <7.32) preceded a fall in arterial blood pressure, cardiac output, and urine flow. The phi therefore served as an early predictor of perfusion failure. The measurement of sigmoid phi was also useful for detecting intestinal ischemia during or after surgical procedures on the abdominal aorta.56,58,59 When phi in the colon was <7.10, it served as an early warning of mucosal ischemia. When phi was <6.86, it prognosticated major ischemic injury and death. An impressive number of clinical studies support the correlations between low gastric phi and increased patient mortality. In 80 consecutive patients in whom gastric phi was measured on admission and 12 h after admission to a multidisciplinary ICU, a highly significant increase in mortality was observed when the phi declined to < In a study of 83 patients with both surgical and medical crises, a phi of <7.35 was prognostic for increased mortality. 2 When phi is reduced within the first 24 h in patients with sepsis, there is an increased likelihood that sepsis will progress to multiorgan failure. 5 1 After multisystem trauma, phi also serves as a good predictor of multiple organ failure and mortality There were no deaths when phi exceeded 7.32 after 24 h. When phi was ::::;7.32 at 24 h, the mortality was 50%. All patients in whom phi declined to <7.1 developed multiple organ dysfunction. 62 The phi was therefore viewed by its proponents as a more precise predictor of outcome than a single measurement of heart rate, mean arterial pressure, cardiac output, arterial blood lactate concentration, or measurements of systemic oxygen delivery and oxygen consumption. 2,61,64 Tissue gradient between tissue Pco 2 and arterial Pco2 may further refine the prognostic value of the Pco2 measurements Measurement of gastric Pco2 was not as sensitive as phi for predicting mortality, but it was more specific. Direct measurement of Pco2 in the stomach also eliminates the additional invasiveness, complexity, cost, and errors of arterial blood sampling for calculation of arterial bicarbonate. 6 CLINICAL UTILITY OF GASTRIC TONOMETRY There is persuasive evidence in support of monitoring gastric phi or Pco2 to estimate severity and prognosticate outcome after perfusion failure has appeared. Of equal or greater importance, however, is its value as a monitor to guide treatment to reverse perfusion failure Gutierrez et al 67 investigated 260 critically ill patients who were randomized to either conventional therapy or a protocol of management intended to increase systemic oxygen delivery or reduce oxygen demand. Patients were selected for intervention whenever the gastric phi declined to <7.35 or decreased by more than 0.10 ph units over an interval of 6 h. Interventions included generous infusion of fluid and administration of dobutamine to augment cardiac output and oxygen delivery. In patients in whom gastric mucosal ph was <7.35 at the time of admission, no differences in outcome were observed by these investigators. However, benefits accrued to patients who had a phi >7.35 on admission, who were treated aggressively with fluids and dopamine and in whom decreases in phi were prevented. The authors attributed the improvement in this subset's survival to these interventions, which were presumed to fulfill demands for oxygen at the tissue level These observations prompted socalled supernormal levels of cardiac output and oxygen delivery to become general principles of treatment in patients with perfusion failure and especially circulatory shock Yet, more recent controlled studies in patients failed to sustain such interventions as routine practice for management of circulatory shock Accordingly, increases in tissue Pco 2, like those of arterial blood lactate, indicate decreases in oxygen availability. However, they do not at this time serve as an indication for specific therapy other than treatment of the underlying cause. The evidence at present is that tissue hypercarbia, and only secondarily tissue acidosis, are inevitable accompaniments of tissue ischemia. This is not specifically limited to the viscera. Also at issue is the implication that a low phi during visceral ischemia is associated with increases in mucosal permeability to pathogenic bacteria This has been cited as an explanation for "secondary sepsis," which some investigators consider to be the cause of multisystem organ failure. CHEST/114/1/JULY,

10 CONCLUSIONS Measurements of tissue Pco 2 and phi are currently viewed as indicators of the adequacy of perfusion, oxygen delivery, and oxygen utilization. As such, these measurements are potentially valuable adjuncts for quantitation of severity and for prognostication of outcomes of systemic perfusion deficits. Tissue hypercarbia during perfusion failure is best explained by the buffering of metabolic acids by tissue bicarbonate rather than increases in total C0 2 production or decreases in C0 2 removal. Accordingly, we recognize ischemia as a dual defect of both 0 2 deficit and Pco 2 excess. Since increases in tissue Pco 2 were observed not only in the GI tract but also in mixed venous blood, coronary venous effluent, myocardium, esophagus, brain, liver, kidney, and urinary bladder during low flow states of circulatory shock, tissue hypercarbia is now recognized as a general phenomenon of perfusion failure. Tissue C0 2 measurements, including those on the stomach wall utilizing conventional tonometry, have been used as clinical indicators of perfusion failure. When it was initially introduced, gastric tonometry was intended to measure phi, which was calculated from Pco 2 measured from the saline in the gastric balloon after equilibration and from the bicarbonate content of arterial blood. Although decreases in phi were documented by these techniques during shock states of diverse etiologies in experimental animals and human patients, the method was labor-intensive and relatively costly. It required that a gastric tube be advanced into the stomach, time delays for equilibration, and separate in vitro analyses of saline samples from the balloon and blood gas measurements on arterial blood. Substantial analysis errors were identified when Pco 2 was measured after a saline sample was aspirated from the gastric balloon. Several of these disadvantages have been resolved by the newly introduced Tonocap, a commercially available device that utilizes a combination of capnometry and tonometry. Direct and continuous measurements of esophageal Pco 2 have been investigated. If initial experimental and clinical reports are confirmed, this approach would minimize interference by gastric acid and the need for H 2 blockade. Most recently, sublingual tonometry has emerged as a promising, noninvasive option that is disarmingly simple. It may provide an even less invasive alternative to clinical gastric and esophageal tonometry, with potential application for quantitation of severity in emergency and disaster settings and for triage of critically ill and injured patients. These new developments further secure the practical implications of increases in tissue Pco 2 for diagnosing and monitoring the ade- 272 quacy of circulation and their application to diagnosis, monitoring, and management of circulatory shock states. REFERENCES 1 Gutierrez G, Bismar H, Dantzker DR, et al. Comparison of gastric intramucosal ph with measures of oxygen transport and consumption in critically ill patients. Crit Care Med 1992; 20: Maynard N, Bihari D, BealeR, et al. Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. JAMA 1993; 270: Kivilaakso E, Ahonen J, Aronsen K-F, et al. Gastric blood flow, tissue gas tension and microvascular changes during hemorrhage-induced stress ulceration in the pig. Am J Surg 1982; 143: I 4 Fiddian-Green RG, Baker S. Predictive value of the stomach wall ph for complications after cardiac operations: comparison with other monitoring. Crit Care Med 1987; 15: Gys T, Rubens A, Neels H, et al. 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