Coavriwht Acta AnurJthesz~l SLand I99S Artu Anuesthrsiol Scand 1995: 39: Supplementum 107, 77-80 Printed in Denmark ~ all rights reserved Acta Anaesthesiologica

Scandinavica ISSN 0515-2720

ISBN 87- 16.151 73-9

Bladder epithelial oxygen tension as a marker of organ perfusion M. SINGER, D. ROSSER AND R. STIDWILL Bloomsbury Institute of Intensive Care Medicine, University College London Medical School, Rayne Institute, London, UK

Key words: Bladder; hemodynamics; oxygen tension; organ pertusion; tissue oxygenation.

A tissue oxygen deficit can be both precursor and endpoint of multiple organ dysfunction. Shoemaker et al. (1) demonstrated how persistence and severity of a post- operative tissue oxygen debt correlated with subsequent complications. This group and others (2, 3) have shown how postoperative maintenance of adequate levels of global perfusion had a clearly demonstrable benefit on mortality, morbidity, hospital stay and costs. Circulatory manipulations were performed by fluid and dobutamine (I) , fluid and dopexamine (2), or fluid alone (3). Once the oxygen debt is established and the patient is critically ill, belated attempts to improve global blood flow and oxygen transport caused, if anything, a poorer outcome (4). Tissue hypoxia is a potent stimulator of inflamma- tory mediators including nitric oxide (5-7) while activa- tion of inflammatory cascades causing (i) microvascular obstruction by aggregated neutrophils and platelets, (ii) vasoconstriction from local release of vasoactive media- tors such as endothelins and thromboxanes, (iii) endo- thelial leak and interstitial oedema all contribute to tissue hypoxia. The high mixed venous oxygen saturation seen in sepsis in the face of a coexisting metabolic deficit is often ascribed to shunting of oxygenated blood away from nutrient capillaries (8- 10). However, definitive evidence for this hypothesis is lacking.

A further problem lies in monitoring of tissue hypoxia. Covert tissue hypoxia often passes unrecognised, despite a seemingly adequate circulation (1 1) while current means of early identification are also limited. Global indices of anaerobic respiration such as an increasing base deficit (acidaemia) or hyperlactataemia are used but, in terms of sensitivity and specificity, neither are perfect. High blood lactate levels may be found in accelerated aerobic glycolysis, liver dysfunction, post-seizures, and

with the use of lactate-buffered renal replacement fluid (12-14) while an elevated base deficit may reflect, for example, deteriorating renal function. A further problem arises when the area of ischaemia is localised, e.g., a segment of bowel or bowel mucosa. Lactate and hydro- gen ions draining from this region will be diluted in the central blood stream and only when hepatorenal and blood buffering mechanisms for clearing these ions are overwhelmed will abnormal blood levels be detected.

The Holy Grail of circulatory monitoring is to have a device that can monitor simply, reliably, with minimal invasiveness, and with a high degree of sensitivity, speci- ficity ... and affordability. It should be able to assess the adequacy of perfusion at a regional level and should also reflect the adequacy of perfusion of the vital organs. This detection should be as early as possible and it should serve as an appropriate treatment endpoint.

Tissue hypoxia can be measured locally either by as- sessing the level of substrate, i.e., oxygen, or by measur- ing of one or more of the consequences of altered metab- olism, e.g., intracellular acidosis, redox status, high energy phosphate status or C02 production. The latter is the principle underlying gut tonometry whereby acid production from anaerobic gut mucosal metabolism is buffered by tissue bicarbonate with subsequent release of carbon dioxide. The PCO, equilibrates with saline within the tonometer; this can be measured and used in a mod- ified Henderson-Hasselbalch equation to provide the gut mucosal pHi, a low value of which is indicative of local ischaemia (15, 16). As the splanchnic circulation is claimed to be the first area undergoing ischaemia during decreased blood flow (e.g., haemorrhage) (17, 18), the tonometer is touted as an early warning device though this has yet to be validated in clinical practice. Further-

0 Acta Anaesthesiologica Scandinavica 39 (1995)

78 M. SINGER ET AL.

renal a,- Doppler flow probo 1

urlnc drainage

Fig. 1

more, the derivation of pHi relies upon substitution of arterial bicarbonate for tissue bicarbonate, an assumption which appears to be seriously flawed (19, 20).

Studies involving oxygen tension measurement within tissue beds are numerous and include brain, skin, subcu- taneous tissue, conjunctiva, liver, kidney and gut (21-3 1). These are taken from serosal or mucosal surfaces, from a direct intra-parenchymal approach or from effluent drainage, e.g., urine, venous blood (34-36). Relationships have been shown experimentally between the adequacy of blood flow and tissue oxygen tension while in both patient studies and animal models, tissue oxygen tension appears to be a good and early indicator of the degree of blood loss. It has also been used to assess the viability of tissue grafts (37).

In performing studies in a rat model to evaluate changes in urine oxygen tension during various circulatory insults, a continuously monitoring Clark-type oxygen electrode was sited in the bladder lumen to facilitate monitoring. Changes in PO, occurred within seconds of a manoeuvre making it more likely that bladder rather than urine PO, was being measured, particularly as the bladder lumen was collapsed (urine was being drained continuously) and the active tip of the electrode (1 cm . 0.55 mm) was in direct contact with the bladder epithelium. As the data are contemporaneous and currently undergoing peer review, only a description of the model and an overview of results will be given to not jeopardise subsequent publication.

Male Sprague-Dawley rats are anaesthetized, tracheo- stomised and left spontaneously breathing on room air. In our initial experiments intraperitoneal thiobuta- barbitone was used for anaesthesia though, latterly, this has been replaced by halothane which was found to provide better haemodynamic stability. The animal is

b... I

Fig. 2.

placed on a heating table to maintain core temperature at 37 "C and instrumented with carotid and internal jugular lines for arterial and central venous pressure monitoring, intermittent sampling for blood gas analysis and infusion of drugs and fluid. A baseline fluid infusion of 2 mL/lOO g body wt/hr is commenced. A midline ab- dominal laparotomy is then performed for placement of Doppler flow probes around the left renal artery and infrarenal abdominal aorta. The bladder is cannulated directly to allow continuous free drainage of urine and to keep the bladder in a collapsed state. A continuous Clark-type electrode of Ag/AgCl design (Continucath, Biomedical Sensors, High Wycombe, UK) is introduced alongside the bladder cannula and coiled within the collapsed bladder lumen such that the active tip of the electrode is in contact with the bladder wall (Fig. 1). The abdominal cavity is then covered with clingfilm to decrease any evaporative and thermal losses. After a stabilisation period of at least 60 minutes and confirma- tion of cardiorespiratory stability, the rat undergoes one of a variety of manoeuvres. These have included haem- orrhage, hypoxaemia, vasoactive drugs (dobutamine, noradrenaline), and endotoxin (20 mgkg bolus and

BLADDER EPITHELIAL OXYGEN TENSION AS A MARKER OF ORGAN PERFUSION 79

10 mgkg infusion over 30 minutes to create hypo- and hyperdynamic models, respectively).

Fig. 2 shows a summary of findings to date. The oxy- gen tension in the bladder epithelium appears to be a very sensitive indicator of circulatory disturbance, chang- ing in line with arterial base deficit in all conditions other than sepsis. In this situation, creation of both hypo- and hyperdynamic endotoxaemic models produced a consistent rise in bladder epithelial oxygen tension des- pite marked metabolic acidosis. This implies that the tissue oxygen debt seen in sepsis may be related more to defects in utilization of oxygen at celluladmitochondrial level rather than microcirculatory oxygen delivery. More work is obviously needed and studies are currently ongoing in our laboratory.

CONCLUSION

Tissue hypoperfusion is often difficult to detect, especial- ly at an early stage where prompt correction may result in maintenance of organ function and an improved out- come. Current methodologies in clinical use for deter- mining the adequacy of organ perfusion all have limita- tions. Monitoring of tissue oxygenation has shown poten- tial for a number of years; perhaps the bladder epithelial approach may prove to be a clinically useful tool as it is relatively non-invasive and easily accessible in critically ill or high-risk patients via a Foley catheter. The finding of an increase in bladder epithelial oxygen tension in sepsis despite apparent anaerobic tissue metabolism war- rants further investigation.

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Address: Metvyn Singer, M.D. Bloomsbury Institute of Intensive Care Medicine University College London Medical School Rayne Institute University Street London WClE 6JJ, UK