We welcome the Education and Debate article on Toxic Shock
Syndrome(1), which helps improve the profile of this potentially
devastating disease and enhances diagnostic recognition.
It is however important to highlight some specific areas in
prevention, diagnosis and therapy which are not fully discussed within
this review.
As the authors state, early diagnosis can be difficult but...
We welcome the Education and Debate article on Toxic Shock
Syndrome(1), which helps improve the profile of this potentially
devastating disease and enhances diagnostic recognition.
It is however important to highlight some specific areas in
prevention, diagnosis and therapy which are not fully discussed within
this review.
As the authors state, early diagnosis can be difficult but is crucial
to improving prompt intervention and therapy. Case definitions are
complex but are well established and importantly differentiate
staphylococcal from streptococcal toxic shock (2). It is important to
realise that streptococcal toxic shock does not always present with a
rash, nor is pyrexia included within the case definition, although
isolation of GAS is required. Rash is therefore not an essential
diagnostic criteria when assessing children initially before the results
of cultures are known.
Prevention is important and there was little expansion on the role of
prophylactic antibiotics in burns which has gathering evidence for
efficacy in the prevention of toxic shock syndrome(8,9).
The authors state that effective antitoxin therapy is considered an
essential part of management, but describe only the potential for
antitoxin blocking antibody. There is however a growing literature on the
specific antitoxin effect of antibiotics such as clindamycin,
aminoglycosides and linezolid which have been shown to reduce TSST 1 and
streptococcal exotoxin A (3,4,5). Clindamycin is now an accepted and
recommended adjunctive therapy for both staphylococcal and streptococcal
toxic shock (2-5).
Inhibition of T cell activation by blocking or inactivating
staphylococcal and streptococcal superantigens is theoretically attractive
(6). Its use in streptococcal toxic shock has suggested benefit,
(statistically significant results perhaps prevented by early termination
of this study because of slow recruitment) (7), but there have been no
such studies with FFP, which the authors suggest is useful. Although
specific anti-toxin antibody may be detected in FFP, the level of this
antibody is likely to be significantly lower than in IVIG and hence
passive immunity may not be achieved. There is no other evidence base for
FFP apart from the authors’ experience, and although it may well have been
successful for the authors is not consistent with other accepted
guidelines (2).
Management guidelines for Toxic shock are specifically outlined by
the American Academy of Pediatrics (2) as follows:
• Fluid management to maintain adequate venous return and cardiac filling
pressures to prevent end organ damage.
• Anticipatory management of multi system organ failure.
• Parental antimicrobial therapy at maximal doses for age.
o Kill organism with bactericidal cell wall inhibitor (e.g. beta-lactamase
resistant antistaphylococcal antimicrobials).
o Stop enzyme, toxin, or cytokine production with protein synthesis
inhibitor (e.g. clindamycin).
• Intravenous immune globulin may be considered for an infection
refractory to several hours of aggressive therapy, in the presence of an
undrainable focus, or where there is persistent oliguria with pulmonary
oedema.
The guidelines for the management of toxic shock syndrome should
include Clindamycin as an adjunctive treatment and IVIG where necessary.
FFP should not be used as a specific anti-toxin (without an evidence base)
but may be useful as part of volume expansion management.
References:
1. A Young, K Thornton. Toxic shock syndrome in burns: diagnosis and
management. Arch Dis Child Educ Pract Ed 2007;92:ep97-ep100.
2. American Academy of Pediatrics [Toxic Shock Syndrome]. In: Pickering
LK,ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th
edition. Elk Grove Village, IL: American Academy of Pediatrics;2000:p580.
3. Chuang et al. Toxic shock syndrome in children epidemiologic,
pathogenis, and management. Pediatric drugs. 2005;7(1):11-25.
4. Coyle E.A, Cha R, Rybak M J. Influences of linezolid, penicillin and
clindamycin alone and in combination on streptococcal pyrogenic ExotoxinA
release. Antimicrobial Agents and Chemotherapy. 2003;47(5);1752-1755.
5. Annane D, Clair B, Salomon J. Managing toxic shock syndrome with
antibiotics. Expert Opin. Pharmacother. 2004;5(8):1701-1709.
6. Darenberg J et al. Differences in potency of Intravenous polyspecific
immunoglobulin G against streptococcal and staphylococcal superantigens:
implications for therapy of toxic shock syndrome. CID. 2004:38:836-842.
7. Darenberg J et al. Intravenous immunoglobulin G therapy and
streptococcal toxic shock syndrome. CID. 2003;37:333-40.
8. Abid Rashid, Alastair P. Brown, Khalid Khan. On the use of
prophylactic antibiotics in prevention of toxic shock syndrome. Burns 31
(2005) 981–985.
9. Edwards-Jones V, Dawson MM, Childs C. A survey into toxic shock
syndrome (TSS) in UK burns units. Burns 26 (2000) :323–33.
We read this article with concern. Incorrect and potentially harmful
messages may be relayed to paediatricians, especially to those in training
and other healthcare professionals.
Dr Lio asserts that Evidence-based Medicine (EBM) leads to stagnation
in medicine and therapeutic nihilism, and expresses his concerns of EBM as
a “philosophy in treating actual human beings”. Unfortunately this is
rath...
We read this article with concern. Incorrect and potentially harmful
messages may be relayed to paediatricians, especially to those in training
and other healthcare professionals.
Dr Lio asserts that Evidence-based Medicine (EBM) leads to stagnation
in medicine and therapeutic nihilism, and expresses his concerns of EBM as
a “philosophy in treating actual human beings”. Unfortunately this is
rather missing the point. The cornerstone of EBM is reviewing the wealth
of data and applying this to the individual patient.
In 2006 there were comprehensive Cochrane reviews of treatment of
warts and molluscum in otherwise healthy individuals.[1,2] These had
simple and easy-to-understand recommendations; firstly, awaiting
spontaneous resolution of molluscum and secondly, topical preparations
containing salicylic acid are safe and effective for warts. No randomised
controlled trials address physical destructive methods for molluscum.
Cantharidin causes pain and blistering with multiple treatments often
required.[3] Regarding warts, cryotherapy appears to be no more effective
than simple topical preparations.[1] Balneotherapy is potentially
dangerous due to risk of burns. Up to 85% children using imiquimod have
side effects.[4] Doctors registered with the General Medical Council have
a duty to provide effective treatments based on best available
evidence.[5] In the absence of a clearly demonstrable superior efficacy of
a given treatment compared to placebo or no treatment we should not
persist with such treatments.
Additionally to physical side effects, we should consider that for a
child distressing treatments may lead to longlasting phobias and distrust
of healthcare professionals and hospitals. Treatment of molluscum and
warts is appropriate when clearly troubling or impairing the child, and in
the child’s best interests. However, the front cover picture of August
2007 Education and Practice depicting cantharidin treatment in infants is
worrisome. Doctors may feel pressured to offer treatment based on parental
anxiety and expectations but frequently all that is required is simple
reassurance for common, asymptomatic and self-limiting conditions.
References:
1.Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane Database of Syst Rev 2006:3:CD001781.
2.Van Dr Wouden JC, Menke J, Gajadin S et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database of Syst Rev 2006;2:CD004767.
3.Hanna D, Hatami A, Powell J et al. A prospective randomised trial compating the efficacy and adverse effects of four recognised treatments of molluscum contagiosum in children. Pediatr Dermatol 2006;23:574-9.
4.Bayerl C, Feller G, Goerdt S. Experience in treating molluscum contagiosum in children with imiquimod 5% cream. Br J Dermatol 2003;149:25-8.
5.The General Medical Council. Good Medical Practice. London, GMC 2006.
Dr Helen M Goodyear
Consultant Paediatrician Heart of England NHS
Foundation Trust Bordesley Green East Birmingham B9 5SS
Keady S (1) provides some updated guidelines on the drug treatment of
gastro-oesophageal reflux (GOR) and gastro-oesophageal reflux disease
(GORD).
However, in order to give clear management guidelines, we believe that the
review should have first addressed the definition of GOR (ie,
physiological) versus GORD (ie, pathological). In fact, the results of a
recent survey on the knowledge, attitudes a...
Keady S (1) provides some updated guidelines on the drug treatment of
gastro-oesophageal reflux (GOR) and gastro-oesophageal reflux disease
(GORD).
However, in order to give clear management guidelines, we believe that the
review should have first addressed the definition of GOR (ie,
physiological) versus GORD (ie, pathological). In fact, the results of a
recent survey on the knowledge, attitudes and practice styles of North
American Pediatricians regarding GOR show that still many infants are
inappropriately treated for GORD when all they have is physiological GOR
(2). The first important goal of future educational efforts should be
therefore directed to avoid overtreatment of “happy spitters” (ie, GOR).
Second, in his conclusions Keaty correctly underlines that “the majority
of drugs used have limited robust data supporting their use”. However,
some evidence from randomised controlled trials (RCTs) is now available
but it is not clearly reflected by the practice guidelines Keaty
suggested. An example of this is the use of prokinetic drugs (domperidone
or erythromycin), in association with an appropriate acid suppressant,
recommended for the treatment of moderate o severe GORD. A recent
systematic review of RCTs showed that, even if from the limited evidence
available (the 4 RCTs named by the same Keaty), domperidone does not
appear to be more effective than placebo in reducing symptoms of GOR and
GORD (3). Given the usually benign nature of GOR, the widespread use of
prokinetic drugs is therefore not indicated. In severe cases of GORD,
where medical management is required, available evidence suggest that
domperidone is yet not indicated. Its use may be re-considered if further
data was to provide robust evidence of a favourable benefit-risk profile.
The overall variability in practice style and lack of conformity to
Naspghan GORD guidelines (4) merit further efforts in education and in
terms of guideline availability based on the results of good clinical
trials with relevant outcome measures.
Federico Marchetti, Jenny Bua, Alessandro Ventura
Department of Paediatrics, Institute of Child Health, IRCCS Burlo
Garofolo, Trieste, Italy
e-mail: fedemarche@tin.it
Competing interests: None declared
References:
1.Keady S. Update on drugs for gastro-oesophageal reflux disease.
Arch Dis Child Educ Pract 2007;92:ep114-ep118
2.Diaz DM, Winter HS, Colletti RB, Ferry GD, Rudolph CD, Czinn SJ,
Cochran W, Gold BD; NASPGHAN/CDHNF Scientific Advisory Board. Knowledge,
attitudes and practice styles of North American pediatricians regarding
gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr
2007;45(1):56-64.
3.Pritchard DS, Baber N, Stephenson T. Should domperidone be used for
the treatment of gastro-oesophageal reflux in children? Systematic review
of randomized controlled trials in children aged 1 month to 11 years old.
Br J Clin pharmacol 2005;59(6):725-9
4.Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation
and treatment of gastroesophageal reflux in infants and children.
Recommendations of the North American Society for Pediatric
Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32
(Suppl 2) :S1–S31
I enjoyed this excellent review on malrotation. The title, however,
implies that the key alerting sign for clinicians is that the vomit is
green, and the paper fails to address the issue of the lack of consensus
regarding the colour of ‘bile’. This topic has been the subject of a
recent study involving hospital and community nurses, parents and GPs (1).
Participants were sent a questionnaire with colour...
I enjoyed this excellent review on malrotation. The title, however,
implies that the key alerting sign for clinicians is that the vomit is
green, and the paper fails to address the issue of the lack of consensus
regarding the colour of ‘bile’. This topic has been the subject of a
recent study involving hospital and community nurses, parents and GPs (1).
Participants were sent a questionnaire with colour chart showing 8 colours
from pale yellow to green. Interestingly, parents often felt that food
residue alone in the vomit indicated ‘bilious’ vomiting, with many of both
parents and GPs not even categorising green as bile. Importantly, I
suspect a range of different opinions would also have been given by
paediatric surgeons had they been included in the study. The authors
(paediatric surgeons themselves) point out that a detailed history in some
of their patients with bowel obstruction reveals only yellow vomit. The
Shorter Oxford English Dictionary defines bile as “yellow, brown or green
fluid secreted by the liver”. In fact, bile staining involves a spectrum
of colour, similar to the range of pale yellow to dark green found when
small bowel contents are aspirated in the course of pancreatic function
testing before and after stimulation of gall bladder contraction. I agree
with Walker et al (1) that “yellow vomiting in babies should not be
disregarded”. Since ‘yellow, brown or green’ stained vomit may be the only
sign early on in malrotation with volvulus, and delay in investigation
have disasterous consequences, it is not only ‘green’ for danger.
Reference:
Walker GM, Neilson A, Young P, Raine PAM. Colour of bile vomiting in
intestinal obstruction in the newborn: a questionnaire study. BMJ
2006;332:1363-5.
Dr Embleton et al, have highlighted the issues, especially of immediate
management and communication that arise whilst managing children with
unknown or impending clinical diagnosis. There are some clinical markers
which are characteristic of well recognised syndromes, some of which may
be incompatible with life. As expressed in the article, it is worthwhile
informing parents. This particular case how...
Dr Embleton et al, have highlighted the issues, especially of immediate
management and communication that arise whilst managing children with
unknown or impending clinical diagnosis. There are some clinical markers
which are characteristic of well recognised syndromes, some of which may
be incompatible with life. As expressed in the article, it is worthwhile
informing parents. This particular case however highlights the
consideration of alternative diagnosis which may be life limiting
eventually, but can present with life threatening emergencies. There is a
dilemma whether to intervene or not and to what extent. Perhaps the safer
option may be to attend to the life sustaining measures, for example in
this case, securing airways which can potentially prevent the occurence of
cardiac arrest, more so as this baby has been recognised by the staff as
one which requires intensive care. Should a diagnosis of life limiting
syndrome be confirmed, a discussion with family then may be more
appropriate. It will surely help the family's grieving process to believe
all that was possible was done in the best interest of the child. Should
life limiting diagnosis be nulled on further investigations, best care
will have been provided.
The prescence of a risk factor is not evidence of causality. Reading
this fictious case presentation my interpretation was that this boy has an
autism spectrum disorder probably caused by heredity from the father. My
hypothesis would be as impossible to prove as the hypothesis presented by
the authors that his problems are caused by drinking during pregnancy and
attachment disorder, but at least my theo...
The prescence of a risk factor is not evidence of causality. Reading
this fictious case presentation my interpretation was that this boy has an
autism spectrum disorder probably caused by heredity from the father. My
hypothesis would be as impossible to prove as the hypothesis presented by
the authors that his problems are caused by drinking during pregnancy and
attachment disorder, but at least my theory does not place guilt on the
parents.
In order to widen the scope of diagnosis and treatment of
tuberculosis in children(1), due cognisance should be taken of diagnostic
modalities for tuberculous pleural and pericardial disease, previously
dealt with under the umbrella of the polymerase chain reaction(PCR) and
adenosine deaminase assay(2), but now also dealt with through the medium
of the assay of the interferon-gamma content of either of...
In order to widen the scope of diagnosis and treatment of
tuberculosis in children(1), due cognisance should be taken of diagnostic
modalities for tuberculous pleural and pericardial disease, previously
dealt with under the umbrella of the polymerase chain reaction(PCR) and
adenosine deaminase assay(2), but now also dealt with through the medium
of the assay of the interferon-gamma content of either of those
fluids(3)(4). For a suspected tuberculous aetiology an interferon-gamma
concentration of 138 pg/ml or more in the pleural fluid confers
sensitivities and specificities of 90.2% and 97.3%, respectively(3), and,
for suspected tuberculous pericarditis, a pericardial fluid interferon-
gamma concentration of 50 pg/ml or more confers a sensitivity of 92% and a
specificity of 100%(4). By its very nature, however, the interferon-gamma
assay is specific for mycobacterium tuberculosis(5), other diagnostic
modalities being required for suspected mycobacterium avium complex(MAC)-
related pleural or pericardial effusion(6)(7). These include evaluation
of PCR in the relevant fluid , culture of the fluid itself, and blood
culture(6)(7).
References:
(1)Shingada DV and Baumer JH
Tuberculosis; diagnosis, management and prevention
Archives of Disease in Childhood; education and practice 2007:92:ep 27-
ep29.
(2)Mishra OP., Kumar R., Ali Z., Prasad R., Nath G
Evaluation of polymerase chain reaction and adenosine deaminase assay for
the diagnosis of tuberculous effusions in children
Archives of Disease in Childhood 2006:91:985-9.
(3)Sharma SK and Banga A
Diagnostic utility of pleural fluid IFN-gamma in tuberculosis pleural
effusion
Journal of Interferon and Cytokine Reasearch 2004:24:213-7.
(4) Reuter H., Burgess L., van Vuuren W., Doubell A
Diagnosing tuberculous pericarditis
Quarterly Journal of Medicine 2006:99;827-39.
(5) Pai M., Riley LW., Colford JM
Interferon-gamma assays in th immunodiagnosis of tuberculosis: a
systematic review
Lancet Infectious Diseases 2004:4:761-6.
(6)Yanagihara K., Tomono K., Sawai T et al
Mycobacterium avium complex pleuritis
Respiration 2002:69:547-9.
(7) Choo PS., McCormack JG
Mycobacterium avium: a potentially treatable cause of pericardial
effusions
Journal of Infection 1995:30:55-8.
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...
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.
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
In Duke et al' study of twenty consecutive children receiving
extracorporeal life support for cardiovascular or respiratory failure the
area under the ROC curve was 0.95 for DCO2 (and 0.88 for pHi). pHi and
DCO2[difference between PCO2 in tonometer saline solution and arterial
blood] predicted survival better than base deficit (area under ROC curve,
0.82), blood lactate level (0.29), arterial pH (0.65)...
In Duke et al' study of twenty consecutive children receiving
extracorporeal life support for cardiovascular or respiratory failure the
area under the ROC curve was 0.95 for DCO2 (and 0.88 for pHi). pHi and
DCO2[difference between PCO2 in tonometer saline solution and arterial
blood] predicted survival better than base deficit (area under ROC curve,
0.82), blood lactate level (0.29), arterial pH (0.65), heart rate (0.62),
and mean arterial pressure (0.74) (1). This implies that the principle
cause of death in these children was pefusion failure rather than an
impairment of substrate extraction and utilization.
Had these children had CO poisoning I would not have expected the
same results for an increase in DO2 is not a feature in endtoxaemia, which
is said to impair oxygen extraction and utilization, in volume
resuscitated pigs whereas a profound fall in pHi is a striking feature(2).
Hence our inclusion of a normal pHi in our modified goals of resuscitation
(3) and my subsequent proposal that the normalization of the DCO2 should
be included in goal C and precede goal E, a normal pHi(4).
I know of no animal study that has examined the hypothesis that CO
poisoning will cause a fall in pHi without causing a rise in DCO2 in a
volume resuscitated large animal model. If CO poisoning does cause a fall
in pHi measuring it would be of value in assessing children with a
decreased level of consciousness.
References:
1. Duke T, Butt W, South M, Shann F. The DCO2 measured by gastric
tonometry predicts survival in children receiving extracorporeal life
support. Comparison with other hemodynamic and biochemical information.
Royal Children's Hospital ECMO Nursing Team. Chest. 1997 Jan;111(1):174-
9.
2. Fink MP, Cohn SM, Lee PC, Rothschild HR, Deniz YF, Wang H, Fiddian
-Green RG. Effect of lipopolysaccharide on intestinal intramucosal
hydrogen ion concentration in pigs: evidence of gut ischemia in a
normodynamic model of septic shock.
Crit Care Med. 1989 Jul;17(7):641-6.
3. Fiddian-Green RG, Haglund U, Gutierrez G, Shoemaker WC. Goals
for the resuscitation of shock. Crit Care Med. 1993 Feb;21(2 Suppl):S25-
31
4. Fiddian-Green RG. In pursuit of the Holy Grail: complete
resuscitation in one hour. Trauma and Emergency Medicine. Cannon Medical
Media (South Africa). April 2000.
5. Fiddian-Green eLetters re: M Hatherill, S M Tibby, R Evans, and I
A Murdoch
Gastric tonometry in septic shock
Arch Dis Child 1998; 78: 155-158
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 an...
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,
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Dear Editor,
In Duke et al' study of twenty consecutive children receiving extracorporeal life support for cardiovascular or respiratory failure the area under the ROC curve was 0.95 for DCO2 (and 0.88 for pHi). pHi and DCO2[difference between PCO2 in tonometer saline solution and arterial blood] predicted survival better than base deficit (area under ROC curve, 0.82), blood lactate level (0.29), arterial pH (0.65)...
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 an...
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