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

Dear Editor,

Drugs that cause acne include those that can impair oxidative phosphorylation such as antidepressants, anti-seizure medications, and cyclosporin which closes the permeability transition pore on mitochondrial membranes. Impairment of oxidative phosphorylation should be accompanied by a fall in cutaneous tissue pH and energy charge. Drugs that aggravate acne include testosterone, corticosteroids, and anabolic steroids. Might they do so by causing a fall in cutaneous tissue pH and/or energy charge?

The superficial layers of skin must be alkalotic because they exist in an hypocarbic hyperoxic environment (1). In decreasing the magnitude of the protonmotive force this should down-regulate ATP resynthesis by oxidative phosphorylation and up-regulate that by glycolysis alone. As the temperature of skin is also lower than core temperature and ATP yield increases as the temperature increases skin is at a metabolic disadvantage. Fetal skin, which does not scar, is much better off. It is exposed to a much higher pCO2, 40 mmHg, the core temperature and a much lower pO2, one less likely to generate free radicals. Fetal skin has, therefore, a metabolic advantage over normal skin. Increasing the pCO2 to which skin is exposed, decreasing the pO2 and increasing its temperature might all be of benefit in acne sufferers because of an improvement in tissue energetics. This is not a practical solution.

In myocytes testosterone induces cytoprotection by activation [opening] of mitoKATP channel (2). It appears to do so by decreasing myocardial contractility and hence workload. Myocardial dysfunction, commonly achieved at surgery with potassium cardioplegia, is cytoprotective to myocytes. Indeed the electrochemical effects of opening the mitoKATP channel would seem to be very similar to that of potassium cardioplegia. This is of interest for the primary determinants of ATP resynthesis appear to be the primary determinants of the degree of H+(atp) channel openess. In other words the cytoprotection, or therapeutic dysfunction, induced in the heart by opening the mitoKATP channel with testosterone might be due to a fall in tissue pH and accompanying decline in energy charge and its inhibition of ATP-dependent enzyme activity in accordance with the Daniel Atkinson hypothesis (3). Might this be how testosterone increases the risk of developing acne?

If so glibenclamide, a mitoKATP closer, and even pinacidil, a mitoKATP opener, might improve cutaneous tissue energetics and be effective treatments in patients with acne . Glibenclamide might increase the energy charge by increasing the rate of ATP resynthesis and pinacidil by decreasing the rate of ATP utilization. Pinacidil, the opener, might also make matters worse by increasing the dysfunction to a degree that precipitates harmful effects including apoptosis and even necrosis with its accompany inflammatory response. Glibenclamide would seem, therefore, the safer option. In opposing the action of testosterone glibenclamide might even be an ideal choice of drug to treat acne if indeed it is the product of a decline in pH and energy charge induced partially or wholly by testosterone and other androgens.

Diabetics are at added risk of developing infections and glibenclamide is used to increase insulin release in insulin-dependent diabetics. It does so by closing the mitoKATP channel which induces an influx of Ca++ in beta cells which causes stored insulin to be released from its vesicles. Insulin release is normally triggered by a rise in ATP/ADP and, therefore, rise in pH and energy charge. In so doing it inhibits ATP resynthesis both be decreasing the availability of glucose and by inhibiting lipolysis and promoting the storage of fat in adipocytes. A rise in glucose also stimulates insulin secretion by causing an influx of Ca++ into beta cells. Thus a rise in fasting glucose, which is associated with adverse outcomes, might indeed be an indication of impaired tissue energetics (4). Diabetes is a disease characterised by impaired tissue energetics (5). That, rather than the elevated concetration of glucose in tissue fluids per se, is the most likely cause for the increased risk of infections in these patients.

The easiest way to test the hypothesis that glibenclamide might be effective treatment for patients with acne would be to look at patients with acne who have been given the drug for insulin-dependent diabetes.

References:

1. Product of a tissue alkalosis induced by hypocarbia? Richard G Fiddian-Green CJA Online, 21 Dec 2004 re: T Tsubo, T Kudo, A Matsuki and T Oyama Decreased glucose utilization during prolonged anaesthesia and surgery Canadian Journal of Anesthesia, Vol 37, 645-649

2. Fikret Er, MD*; Guido Michels, MD*; Natig Gassanov, MD; Francisco Rivero, MD; Uta C. Hoppe, MD Testosterone Induces Cytoprotection by Activating ATP-Sensitive K+ Channels in the Cardiac Mitochondrial Inner Membrane. Circulation. 2004;110:3100-3107

3. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001 Dec;23(12):1112-9.

4. Richard G Fiddian-Green Hyperglycaemia = anaerobic threshold has been reached? http://www.heartjnl.com/cgi/eletters/89/5/512#634, 3 Mar 2005

5. Richard G Fiddian-Green Grounds for abandoning "diabetes" as a diagnosis? http://www.postgradmedj.com/cgi/eletters/81/952/103#246, 3 Mar 2005

Dear Editor,

Richard Bowker and the Paediatric Accident and Emergency Research Group are to be congratulated on their excellent guideline [1]. It appears comprehensive enough to detect all possible diagnoses while being concise enough to be workable. It does appear vulnerable in the area of poisoning, however.

Carbon monoxide remains the most common cause of fatal poisoning in the UK [2], and should be considered in children presenting to the Emergency Department with a decreased conscious level. Symptoms progress from lethargy, headache and vomiting, to convulsions, coma and cardiovascular collapse [3]. Moreover for every case that comes to the attention of a clinician several may be missed, either because the patient or their carer does not report their vague symptoms or because the physician does not consider the diagnosis [4]. Although not completely sensitive or specific, a carboxyhaemoglobin (COHb) level may provide useful information in the search for a cause of reduced conscious level. COHb may be measured accurately on a venous sample [5] using an automated blood gas analyser.

I therefore recommend the following alteration to the algorithm: In Part III (Identify all problems) “Cause unknown” box, change “consider drug ingestion” to “consider poisoning (including drug ingestion and carbon monoxide exposure)”.

References:

1. Bowker RP, Stephenson TJ, Baumer JH. Evidence-based guideline for the management of decreased conscious level. Arch Dis Child Educ Pract 2006;91:ep115-ep122

2. Parfitt A, Henry JA. Troublesome toxins. Emerg Med J 2002; 19:192-193

3. Skinner D, Swain A, Peyton R, Robertson C (Eds). Cambridge textbook of accident and emergency medicine. Cambridge University Press, Cambridge, UK (1997) page 216

4. Wright J. Chronic and occult carbon monoxide poisoning: we don’t know what we’re missing. Emerg Med J 2002;19:386-390

5. Touger M, Gallagher EJ, Tyrell J. Relationship between venous and arterial carboxyhemoglobin levels in patients with suspected carbon monoxide poisoning. Annals Emergency Med 1995; 25: 481–3

Dear Editor,

In the UK we are presently in the middle of a significant heatwave with July 2006 declared the UK's hottest month on record (1). Both the Department of Health and NHS direct have been quick to disseminate health advice (2) particularly to parents and healthcare workers responsible for the care of children, about the dangers of heat exposure and dehydration. This advice has emphasised the need for adequate fluid intake, particularly that of water. Notably parents have been encouraged to ‘give babies plenty of cooled boiled water throughout the day’ (3) Although we believe this to be sound advice to parents in the majority of situations, we believe it is important for clinicians to be aware of the risks of water intoxication, especially in infants. Water intoxication in children has previously been well described (4) and as being on the increase, if not reaching epidemic proportions in the United States (5). It can cause significant morbidity and mortality from hyponatraemia, brain swelling and seizures. Primarily associated with inappropriate dilution of formula feeds, bottled water has previously been described as a significant cause (6,7). Children are at particular risk as it is thought that as well as renal function being immature, infants have a powerful thirst drive which may impede their ability to curb intake. Bhalla et al reported 4 cases in the UK of hyponatreamic seizures that were secondary to excessive solute ingestion in 1999 (8). As a paediatric intensive care retrieval service we have recently dealt with a previously normal hyponatraemic child presenting with abnormal neurology and seizures. A one-year-old child presented in status epilepticus following a 2 day history of vomiting during which time hypotonic fluids where administered. The child required iv lorazepam and one dose of rectal paraldehyde to terminate the seizure and was intubated, ventilated and transferred to a regional paediatric intensive care unit. Serum sodium on attendance was 116 mmol/L. The child was subsequently fluid restricted for 48 hours. Although we have insufficient evidence at present to implicate water intoxication in their pathogenesis we feel it is an issue that has not been addressed in the current DOH literature. This situation also emphasises the importance of parental education to the potential risks of this conditon.

Dr R M Kayani Retrieval Fellow Dr P Ramnarayan Consultant Paediatric Intensivist Children’s Acute Transport Service, Great Ormond Street Hospital, London

References:

1. Meteorological Office Press Release http://www.meto.gov.uk/corporate/ pressoffice/2006/pr20060801.html

2. ‘ Heatwave’ -A guide to looking after yourself and others during hot weather. Department of Health http://www.dh.gov.uk/assetRoot/ 04/13/53/04/04135304.pdf

3. Department of Health Website - http://www.nhsdirect.nhs.uk/articles/ article.aspx?ArticleId=1955

4. Dugan S, Holliday MA. Water intoxication in two infants following the voluntary ingestion of excessive fluids. Pediatrics 1967;39:418-20.

5. Keating JP,Schears GJ, Dodge PR. Oral water intoxication in infants. An American epidemic. Am J Dis Child. 1991 Sep;145(9):985-90.

6. Bruce RC , Kliegman RM Hyponatremic seizures secondary to oral water intoxication in infancy: association with commercial bottled drinking water. Pediatrics. 1997 Dec;100(6):E4. Review

7. From the Centers for Disease Control and Prevention-Hyponatremic Seizures Among Infants Fed With Commercial Bottled Drinking Water-- Wisconsin, 1993. JAMA 272(13),October 1994, pp 996-997

8. P Bhalla, F E Eaton, J B S Coulter, F L Amegavie, J A Sills and L J Abernethy

Lesson of the week: Hyponatraemic seizures and excessive intake of hypotonic fluids in young children 1999;319;1554-1557 BMJ