Dear Editor,

In a study of patients undergoing moderate and tepid hypothermic hemodiluted cardiopulmonary bypass cerebral oxygen saturation (RsO(2)) and mixed venous oxygen saturation (SvO(2)) were continuously monitored with a cerebral oximeter via a surface electrode placed on the patient's forehead and with the mixed venous oximeter integrated in the CPB machine, respectively. There was a poor correlation between the two measurements. Indeed during moderate hypothermic bypass they changed in opposite directions, RsO(2) decreasing significantly from 76.0% +/- 9.6% to 58.9% +/- 6.4% and SvO(2) increasing significantly from 78.6% +/- 3.3% to 84.9% +/- 3.6% (1). "The temperature-uncorrected PaCO(2) was maintained at the normocapnic level throughout the study, whereas the temperature-corrected PaCO(2) was significantly lower during the moderate hypothermic phase (26.8 +/- 3.1 mmHg) compared with the tepid hypothermic phase (38.9 +/- 3.7 mmHg) of CPB. There was a significant and positive correlation between RsO(2) and temperature-corrected PaCO(2) during hypothermia"(1). The inference is that the RsO(2) rises as the pH falls and the magnitude of the protonmotive force driving ATP resynthesis increases.

In a study in which 18 patients regional oxygen saturation catheters (Baxter Healthcare Corporation, Edward Critical Care) were placed (2), however, longitudinal data regression showed that the overall slope of the regression between the catheter and blood values was 0.997 (p = 0.001).

In the alpha-stat protocol used in hypothermic cardiopulmonary bypass the PaCO2 is maintained at about 40 mm Hg using the measurement made at 37°C without temperature correction. In the pH-stat protocol, CO2 is added to the oxygenator inspired gas flow to maintain temperature-corrected pH at approximately 7.40 and PaCO2 at approximately 40 mm Hg. Thus "temperature correction" is an adjustment for the hypocarbic alkalosis that occurs in any aqueous solution that is cooled.

In an experimental hypothermic circulatory arrest model in piglets"the pH-stat protocol was associated with an increase in cerebral mixed vascular saturation measured by near-infrared spectroscopy" [i.e. RsO(2)] raising the possibility of an improvement in cerebral tissue energetics. (3). In a prospective randomized comparison of pH-stat and alpha-stat protocols in patients undergoing hypothermic bypass the pH- stat protocol promoted, relative to alpha stat protocol, "an increase in SJVO2 [jugular venous] and a decrease in arteriovenous oxygen and arteriovenous glucose differences. The authors concluded that, "These findings indicate an increased cerebral supply with pH-stat"(4). As a fall in pH inhibits glycolysis by inhibiting phosphofructokinase and thereby shifts substrate utilization from glycogen and glucose to fatty acids, a alternative explanation for the findings is that the pH-stat protocol improves the efficiency of ATP resynthesis by increasing the protonmotive force and thereby up-regulating oxidative phosphorylation. Indeed this might be interpreted as a corollary of the Bohr effect.

When the rate of blood flow increases in sepsis the SvO(2) increases. When instead SvO(2)s reduced by, for example, decreasing FiO(2), flow increases. The opposing changes in SvO(2) are, therefore, both functions of the rate of blood flow. ) the former the change in SvO(2) is a circulatory response to an impairment of oxygen uptake and utilization. The inference is that for RsO(2) to be of any value in assessing the adequacy of tissue energetics it would first have to be standardized for blood flow. It would also have to be standardized for intracerebral tissue pH.

We have reported that the intramucosal PO(2) was a stand-alone predictor from bleeding from stress ulceration but did not improve the predictive model derived from the intramucosal pH and number of risk factors, of dysfunctional organs, present (5). The PaO(2) in those who bled from stress ulcers was also higher, and thus the difference between PaO(2) and intramucosal PO(2), greater than that of the healthy controls. Our interpretation at the time was that the low intramucosal PO(2) was indicative of the presence of mucosal ischaemia. As the mucosa was bleeding actively this conclusion was, in retrospect, wrong. Might, rather, the low intramucosal PO(2) have been a reflection of the up- regulation of oxidative phosphorylation induced by the fall in pHi an increased extraction of oxygen from haemoglobin? In other words might a low RsO(2) in the brain which is accompanied by a low intracerebral pH be a refelction of the same?

It has been known for 17 years that a fall in intramucosal pH on the day of surgery is predictive of the development organ dysfunctions and death after cardiovascular operations(6) and indeed all critical illnesses. Although I had formerly attributed to unreversed ATP hydrolysis (7,8) I am now of the opinion that it is initially the product of proton retention from increased glycolytic turnover, and accompanying rise in NADH/NAD, and/or an active transport of protons from mitochondria into the cytosol associated with a reverse of the direction of action of the ATP synthase rotary pump. The fall in pH may be viewed as a cytoprotective effect one, aided by an inhibition of ATP-dependent cellular acitivities in accordance with the Daniel Atkinson energy charge hypothesis, designed to preserve enough ATP syntheis to maintain viablility (9). Thus a fall in intramucosal pH may be a sign both of reductive stress and the cytoprotective response to it.

Dantzker raised the possibility that the gastrointestinal tract might be the canary of the body, analogous to the canaries once used by coal miners to obtain early warning of potentially lethal concentrations of carbon monoxide (10). Maynard et al provided stronfg support for the hypothesis (11). But the canaries became unconscious and did not develop gastrointestinal problems! Indeed it has been proposed that the brain may be a better canary in ambulatory patients, mood and behavioural disorders preceding unconsciousness. Gologorsky et al have provided objectigve evidence in support of this hypothesis from a prospectiver randomized study of 200 pateints having elective coronary artery surgery (12). The patients were, "randomized to either intraoperative cerebral regional oxygen saturation (rSO2) monitoring with active display and treatment intervention protocol, or underwent blinded rSO2 monitoring. Predefined clinical outcomes were assessed by a blinded observer.

"Significantly more patients in the control group demonstrated prolonged cerebral desaturation (P = 0.014) and longer duration in the intensive care unit (P = 0.029) versus intervention patients. There was no difference in overall incidence of adverse complications, but significantly more control patients had major organ morbidity or mortality (death, ventilation >48 h, stroke, myocardial infarction, return for re -exploration) versus intervention group patients (P = 0.048). Patients experiencing major organ morbidity or mortality had lower baseline and mean rSO2, more cerebral desaturations and longer lengths of stay in the intensive care unit and postoperative hospitalization, than patients without such complications. There was a significant (r2 = 0.29) inverse correlation between intraoperative rSO2 and duration of postoperative hospitalization in patients requiring 10 days postoperative length of stay". That is the greater the degree of cerebral desaturation the longer the postoperative length of stay.

The design of the study and the findings are very simuilar to those of Gutierrez et al (13) who used the intramucosal pH as a supplementary endpopint in resuscitation. No other forms of monitoring have, to the best of my knowledge, ever been subjected to this kind of testing. For patients admitted with low pHi in the Gutierrez study, "survival was similar in the protocol and control groups (37% vs 36%), whereas for those admitted with normal pHi, survival was significantly greater in the protocol than in the control group (58% vs 42%; p less than 0.01)". There was no survival benefit in the Gologorsky study which included 30 fewer patients than the Gutierrez study, but statistical significiance in the Gutierrez study was found only after patients had been divided into two groups. Both studies might have been limited by current practices which, in some instances, oppose the logic of the interventions needed to achieve the best outcomes from these forms of monitoring.

These findings in the Gologorsky study raise the possibility that rSO2 might be a proxy for monitoring the intramucosal pH or visa versa placing NICE into the position of approving the one and not the other or even mandating a comparison before declaring one or the other cost- effective. What then of other candidates such as continuous monitoring of tissue and blood pH, PCO(2) and PO(2) with optodes, NMR spectroscopy and microdialysis to monitor tissue metabolites? Is NICE going to demand that each be shown to be effective in their own right and comparisons to be completed before approving any one of them? If that were their decision how long would it take for patients to benefit from any of the new technologies and the refinements that willl undoubtedly follow? Until we know how to use the information derived from any one form of monitoring to the best advantage can the possibility that any one of them should be excluded be justified despite the findings of any study? At the end of the day the information derived from different forms of monitoring is likely to be complemetary. Consider cerebral oxygen saturation.

What is the potential for cytokines misleading clinicans by interfering with oxygen uptake and utilization? I am reminded of the pigs in which we were monitoring intramucosal PO(2) and pH. Both fell with acute vascular occlusion and in all but one case rose with reperfusion one hour later. In the one case the intramucosal pH remainded low whilst the PO(2) rebounded to supranormal levels. The same kind of phenomenon might occur in sepsis and endotoxaemia. I suspect, therefore, that there will be cases in which cerebral oxygen saturation diverges from intracerebral pH and provides clinicans potentially misleading information. At the end of the day the availability of oxygen does not seem to be a rate limiting factor in ATP resynthesis in patient (14) except in extremis. That does not exclude the possiblity that the measurement might be very helpful especially in evaluating mood and behavioural disorders in subjects in whom invasive monitoring is undesirable or likely to be refused.

Clinicians need to gain experience with these newer forms of monitoring and, more importantly, gain some insight to the metabolic issues involved. If the brain is to be used as a canary it would seem that the intracerebral pH needs to be monitored for monitoring the rSO2 alone could miss the presence of metabolic stress especially in sepsis and some forms of poisoniong such as CO poisoning. Having identified a low intracerebral pH and/or low rSO2 and/or intramucosal pH and being made aware of the probability of impending complications information about individual enzyme activity, notably the regulatory enzymes which include the pyruvate dehydrogenase complex, pyruvate decarboxylase and phosphofructokinase, may be needed to make and implement rational decisions in patient management.

References:

1. Baraka A, Naufal M, El-Khatib M. Correlation between cerebral and mixed venous oxygen saturation during moderate versus tepid hypothermic hemodiluted cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2006 Dec;20(6):819-25.

2. Ann M. Ritter1, Shankar P. Gopinath1, Charles Contant1 Raj K. Narayan1 and Claudia S. Robertson1 Evaluation of a regional oxygen saturation catheter for monitoring SJVO2 in head injured patients Journal of Clinical Monitoring and Computing Volume 12, Number 4 / July, 1996 285-291

3. Kurth CD, O’Rourke MM, O’Hara IB. Comparison of pH-stat and alpha- stat cardiopulmonary bypass on cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets. Anesthesiology 1998; 89: 110–8.

4. H. Tarik Kiziltan, Mehmet Baltal, Ahmet Bilen, Gülah Seydaoglu, Muzaffer Incesoz, Atlay Tasdelen, and Sait Aslamaci. Comparison of Alpha- Stat and pH-Stat Cardiopulmonary Bypass in Relation to Jugular Venous Oxygen Saturation and Cerebral Glucose-Oxygen Utilization Anesth Analg 2003;96:644-650

5. Fiddian-Green RG, McGough E, Pittenger G, Rothman E. Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterology. 1983 Sep;85(3):613-20

6. Fiddian-Green RG. 6. Gut mucosal ischemia during cardiac surgery. Semin Thorac Cardiovasc Surg. 1990 Oct;2(4):389-99.

7. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-base balance. Br J Anaesth. 1995 May;74(5):591-606.

8. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement. Chest. 1999 Dec;116(6):1839-41.

9. Richard G Fiddian-Green Monitoring tissue pH vs lactate and ATP degradation products in sepsis http://adc.bmj.com/cgi/eletters/78/2/155#2830, 14 Dec 2006

10. Dantzker DR. The gastrointestinal tract. The canary of the body? 1: JAMA. 1993 Sep 8;270(10):1247-8

11. Maynard N, Bihari D, Beale R, Smithies M, Baldock G, Mason R, McColl I. Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. 1: JAMA. 1993 Sep 8;270(10):1203 -10

12. Gologorsky E, Gologorsky A, Akins C, Murtha S. Regional cerebral oxyhemoglobin saturation-guided resuscitation. Anesth Analg. 2006 Dec;103(6):1608-9.

13. Gutierrez G, Palizas F, Doglio G, Wainsztein N, Gallesio A, Pacin J, Dubin A, Schiavi E, Jorge M, Pusajo J, et al. Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet. 1992 Jan 25;339(8787):195-9.

14. Fiddian-Green RG. Oxygen administration can reverse neurological deficit following carotid cross-clamping. Br J Anaesth. 2005 Aug;95(2):274 -5