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I read with interest the review article by Thanvi and Lo on the
long term motor complications of levodopa.[1] The authors describe the role
of pulsatile stimulation of the post-synaptic dopamine receptors as a
possible mechanism for these complications and describe the various
strategies currently in use to prevent them. They however fail to
acknowledge the role of a multidisciplinary team in the ma...
I read with interest the review article by Thanvi and Lo on the
long term motor complications of levodopa.[1] The authors describe the role
of pulsatile stimulation of the post-synaptic dopamine receptors as a
possible mechanism for these complications and describe the various
strategies currently in use to prevent them. They however fail to
acknowledge the role of a multidisciplinary team in the management and
possibly prevention of these motor complications. It is clear that
Parkinson's disease is a progressive neurological disorder that results in
a number of disabilities which can only be partially treated with the
currently available oral medication. It is therefore important to involve
the physiotherapist and occupational therapist in the rehabilitation of
Parkinson's patients. The medicines management can then be tailored to a
"goal oriented approach" to counter the disability rather than relying
solely on increasing dosage of levodopa or its adjuncts which will never
achieve the desired objective on their own and lead to an increasing
incidence of complications. The "goal oriented approach" will also help
the patient to better accept his disability and understand the clear
limitations in the efficacy of anti-parkinsonian medication. I cannot
however site a randomised controlled trial to support the above comments
but it would defy logic to believe otherwise.
References
1. Thanvi B R, Lo T C N. Long term motor complications of levodopa:
clinical features, mechanisms, and management strategies. Postgrad Med J
2004; 80: 452-458
I would like to mention a few interesting points about the urine in
alkaptonuria.[1] When testing for the presence urine sugar by Benedict's
method, an alkaptonuric specimen gives a strongly positive (falsely, of
course) reaction, producing an orange precipitate. However, the clue lies
in the supernatant which turns black. Glucose oxidase-based test does not
give a positive reaction in this setting....
I would like to mention a few interesting points about the urine in
alkaptonuria.[1] When testing for the presence urine sugar by Benedict's
method, an alkaptonuric specimen gives a strongly positive (falsely, of
course) reaction, producing an orange precipitate. However, the clue lies
in the supernatant which turns black. Glucose oxidase-based test does not
give a positive reaction in this setting. Such a discrepancy if
encountered, one should be astute enough to strongly consider
alkaptonuria.
Interestingly, alkaptonuric mice neither pass black urine nor do they
develop pigmentation. Thanks to their ability to synthesise vitamin-C on
their own, which we humans have lost during evolution.
References
1. Mishra V, Ranganath L R. Pigmented sclera: a diagnostic challenge? Postgraduate Medical Journal 2004;80:491.
Is it feasible to extrapolate animal findings to human medicine? We did not evolve (see http://www.kean.edu/~breid/chrom2.htm ). These chromosome numbers certainly do not support any evolutionary
suppositions. Furthermore the mechanisms of meiosis serve to "fix" the
chromosome numbers of sexually reproducing species.
Is it not, therefore, dange...
Is it feasible to extrapolate animal findings to human medicine? We did not evolve (see http://www.kean.edu/~breid/chrom2.htm ). These chromosome numbers certainly do not support any evolutionary
suppositions. Furthermore the mechanisms of meiosis serve to "fix" the
chromosome numbers of sexually reproducing species.
Is it not, therefore, dangerous to read too much into animal
experiments? What is the rationale for applying animal findings to human
therapeutics?
References
Unnikrishnan A G. Tissue-specific insulin resistance. Postgrad Med J 2004;80:435.
Heart failure is a complex clinical syndrome that can result from
any
structural or functional cardiac abnormality that impairs the ability of
the left ventricle to fill with or pump blood.
The cardinal
manifestations
of heart failure are dyspnoea and fatigue, which may limit exercise
tolerance, and fluid retention, which may lead to pulmonary congestion
and
peripheral oedema. Heart failure is cha...
Heart failure is a complex clinical syndrome that can result from
any
structural or functional cardiac abnormality that impairs the ability of
the left ventricle to fill with or pump blood.
The cardinal
manifestations
of heart failure are dyspnoea and fatigue, which may limit exercise
tolerance, and fluid retention, which may lead to pulmonary congestion
and
peripheral oedema. Heart failure is characterised by inadequate tissue
perfusion to meet the metabolic demands of the body. In systolic heart
failure, there is reduced myocardial contractility, whereas in diastolic
heart failure, there is impaired relaxation and abnormal filling of the
left ventricle.
Modern therapy of heart failure is based on inhibition
of
the neurohormonal systems that may be initially beneficial but
eventually
become deleterious. The sympathetic nervous system increases heart rate,
myocardial contractility and cardiac output but also causes arteriolar
vasoconstriction and increased afterload. Increased circulating
catecholamines aggravate myocardial ischaemia, potentiate arrhythmias,
cause cardiac remodeling, and are directly toxic to the myocytes.[2]
Stimulation of the renin-angiotensin-aldosterone system as a result of
sympathetic stimulation and decreased renal perfusion results in further
arteriolar vasoconstriction and increased aldosterone production.
Increased aldosterone levels lead to sodium and water retention,
vascular
endothelial dysfunction and myocardial fibrosis [3].
Neurohormonal
antagonists (including ACE inhibitors, B-blockers and aldosterone
antagonists) have been shown in several randomised controlled studies to
reduce mortality, alleviate symptoms and improve the functional class of
heart failure. In the long term, ACE inhibitors and B-blockers also
improve left ventricular performance and ejection fraction [3-4-5].
Despite recent advances in the management of heart failure, mortality
remains high, with an estimated 5-year mortality rate of 50%. The
mortality is higher among patients with severe heart failure (NYHA class
4) who have a 20% annual mortality rate. Patients with severely
depressed
myocardial contractility may not tolerate ACE inhibitors because of
hypotension or renal impairment. This is due to peripheral
vasodilatation
and decreased systemic vascular resistance without a compensatory
increase
in cardiac output, especially when large doses of diuretics are being
used. In addition, severely distressed patients have abnormally
increased
cost of breathing with up to 40 - 50 % of cardiac output being shifted
to
the overacting respiratory muscles that further compromise systemic
perfusion. As a result of low cardiac output and systemic hypoperfusion,
the body activates several neurohormonal pathways, leading to cardiac
remodelling with left ventricular dilatation and hypertrophy as well as
apoptosis, or programmed cell death, leading to worsening of myocardial
contractility. Furthermore, left ventricular dilatation causes increased
wall tension and may provoke myocardial ischaemia in patients with
coronary
artery disease. If we consider heart failure as a state of imbalance
between systemic perfusion and metabolic demands of the body as a result
of impaired myocardial contractility, I may postulate that improving
systemic perfusion and /or reducing metabolic demands can suppress the
detrimental neurohormonal systems. Mechanical ventilation and sedation -
with or without muscle paralysis- can minimise the whole-body oxygen
consumption and reduce the burden on the failing heart that no longer
needs to pump too much blood to meet the increased metabolic demands.
Consequently, I may speculate that neurohormonal systems may be more
suppressed in ventilated, sedated and paralysed patients with heart
failure. It may be appropriate to measure B-type natriuretic peptide,
endothelin 1 and other parameters of neurohormonal activation before and
after assisted ventilation. In patients with severe dyspnoea, positive-
pressure ventilation can significantly reduce the work of breathing and
allow the distribution of cardiac output away from the overacting
muscles
of respiration into more vital organs such as the heart, brain, and
kidneys. This may lead to improved coronary perfusion, myocardial oxygen
supply and enhanced contractility in patients with ischaemic
cardiomyopathy. Preload reduction - as a result of reduced venous return
-
will decrease left ventricular end-diastolic diameter, wall tension,
myocardial oxygen demand and ischaemia. In addition to improving
arterial
oxygenation, assisted ventilation can also increase myocardial oxygen
supply, reduce demand and thus improve myocardial ischaemia and enhance
contractility of the failing heart. In ventilated patients with severe
heart failure, the dose of diuretics can be decreased or temporarily
discontinued to reduce the risk of hypotension or renal impairment as a
result of ACE inhibitor therapy. It is to be remembered that ventilator
-
induced hypotension is a potential complication in volume - depleted
patients and is not considered a significant risk in heart failure
patients who are often fluid overloaded. As a result, ventilated
patients
with severe heart failure may be more tolerant to initially low,
gradually
increasing doses of ACE inhibitors and B-blockers, particularly when
using
lower levels of PEEP and tidal volume. Invasive haemodynamic monitoring
with a Swan-Ganz catheter may be important in selected patients to
optimise
cardiac filling pressures (central venous pressure and pulmonary
capillary
wedge pressure) and to monitor cardiac output in order to avoid
significant hypotension or renal dysfunction, as a result of ACE
inhibitor
or B-blocker therapy. ACE inhibitors may be initiated under an umbrella
of
inotropic support with dobutamine or milrinone in order to increase
cardiac output and compensate for peripheral vasodilatation and
decreased
systemic vascular resistance. After ACE inhibitor therapy had been
maximised, continuous inotrope infusion can be gradually weaned off. It
may be wise to accept some degree of hypotension (without necessarily
discontinuing ACE inhibitors) as long as adequate systemic perfusion and
tissue oxygenation are maintained, keeping in mind that oxygen
consumption
had been significantly reduced because of ventilation, sedation and
muscle
paralysis. It must be emphasised that hypotension is not synonymous with
shock. Patients with low blood pressure may have normal tissue perfusion
if systemic vascular resistance is also decreased. On the other hand,
tissue perfusion may be impaired despite normal blood pressure in the
presence of low cardiac output and severe systemic vasoconstriction. As
long as coronary, cerebral and renal perfusions are maintained, cardiac
output may be allowed to increase progressively during the period of so-
called "permissive hypotension" as a result of afterload reduction and
gradually improving left ventricular function. Ultimately, blood
pressure
can be mainly supported by cardiac output rather than intense peripheral
vasoconstriction that often occur at the expense of left ventricular
performance and systemic perfusion. Tissue oxygenation can be monitored
directly by measuring whole-body oxygen uptake - using calorimetry- or
indirectly by calculating oxygen extraction ratio (O2 ER = SaO2 - SvO2 /
SaO2) where SaO2 is arterial O2 saturation and SvO2 is mixed venous O2
saturation (of blood taken from pulmonary artery with right-sided
cardiac
catheter). Other parameters of tissue oxygenation include arterial blood
lactate and gastric mucosal pH. In selected patients with relatively low
blood pressure, assessment of cerebral perfusion can be done by
calculating cerebral O2 extraction ratio (cerebral O2 ER = SaO2 - SvjO2
/
SaO2) where SvjO2 is O2 saturation of blood taken from internal jugular
vein. Similarly, myocardial oxygenation can be directly evaluated by
measuring myocardial blood lactate, oxygen extraction ratio, regional pH
and base deficit during transvenous catheterisation of the coronary
sinus
(that drains most of the cardiac veins and opens into the right atrium).
Non-invasive assessment of myocardial ischaemia can be performed with
electrocardiography to detect ST segment - T wave changes and
echocardiography to evaluate LV function and regional wall motion. Renal
function should be closely monitored with urine output, BUN and
creatinine, in addition to serum potassium.
In conclusion, patients with NYHA class 4 heart failure, who are poorly
tolerant to ACE inhibitors or B-blockers can be electively intubated,
ventilated and sedated in order to minimise oxygen consumption and
metabolic demands of the body and to improve arterial oxygenation,
myocardial contractility and systemic perfusion. ACE inhibitors can then
be gradually introduced (with or without inotropic support) and
continued
in spite of relatively low blood pressure as long as systemic perfusion
and tissue oxygenation are maintained. After maximising the dose of ACE
inhibitor and B-blocker, patients can be awaken from "hibernation" and
gradually weaned off ventilatory and inotropic support.
References
1 American Heart Association. 2001 Heart and Stroke Update.
American Heart Association.
2 ACC/AHA Guidelines for the Evaluation and Management of Chronic
Heart Failure in the Adult.
2001 by the American College of Cardiology and the American Heart
Association.
3- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone
on morbidity and mortality in patients with severe heart failure.
Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;
341: 709-717
4- Pitt B, Cohn JN et al. Effect of enalapril on survival in
patients
with reduced left ventricular ejection fractions and congestive heart
failure (SOLVD) N Engl J Med. 1991;325:293-302.
5- packer M, Coats AJ, Fowler MB et al. Effect of carvedilol on
survival in severe chronic heart failure. N Engl J Med.2001;
344:1651-1658
We read with interest the educative review by Drs English and Williams,[1] and would like to congratulate the authors for their effort.
The authors have raised a question- namely why ketoacidosis does not occur in HHS. Accumulation of ketone bodies in the blood in DKA stems from a greatly accelerated hepatic production rate, such that the capacity of non-hepatic tissues to use them, is exceeded....
We read with interest the educative review by Drs English and Williams,[1] and would like to congratulate the authors for their effort.
The authors have raised a question- namely why ketoacidosis does not occur in HHS. Accumulation of ketone bodies in the blood in DKA stems from a greatly accelerated hepatic production rate, such that the capacity of non-hepatic tissues to use them, is exceeded. A part of the answer may be that the non-hepatic tissues can utilize acetoacetic acid and 3-hydroxybutyric acid at an appreciable rate.That is why ketoacidosis may not manifest in HHS. Formation of acetone by spontaneous decarboxylation of acetoacetic acid may represent a compensatory mechanism to combat the acidosis. That is because the strong acid viz, acetoacetic acid is spontaneously converted into the metabolically inert acetone, which is predominantly excreted by the kidney. The odour of nail varnish remover in breath emphasizes the fact that the lungs efficiently can get rid of acetone. The reaction is :
CH3-CO-CH2-COOH (Acetoacetic acid) → CH3-CO-CH3 (Acetone) + CO2 (Carbon dioxide).
Why did the liver make the ketone bodies in the first place? In biochemical terms, in the liver, there is a depletion of oxaloacetate (OAA), the catalyst of the citrate cycle. OAA is a key gluconeogenic substrate in the liver (and the kidney) and, glucagon -stimulated gluconeogenic mechanisms are enhanced in diabetes mellitus.
Also, for the operation of the urea cycle in the liver, aspartate has to be regenerated by transamination of OAA. Hence, due to lack of OAA, the citrate cycle remains impaired in insulin deficiency. However, in non-hepatic tissues, there does not seem to be any such depletion of OAA. In hypercatabolic states prevailing in the poorly controlled diabetic, protein catabolism is inevitable. This would provide free amino acids in increasing quantities for transamination reactions.
The non-hepatic tissues can utilize enormous quantities of acetoacetate. This requires succinyl CoA. The reaction is catalyzed by aceto acetate: succinyl CoA, CoA transferase.
Acetoacetate + succinyl CoA → Acetoacetyl CoA + succinate
The following "anaplerotic" reactions are known to take place in the non-hepatic tissues, as otherwise, the availability of the citrate cycle intermediates would become a limiting factor.
1. Conversion of pyruvate to malate by the "malic enzyme".
Malate can be converted into succinyl CoA through the citrate cycle.
2. Conversion of glutamate to keto glutarate by glutamate dehydrogenase.
Glutamate + NAD+ → alpha-keto glutarate + NH4 + NADH + H+
The alpha-ketoglutarate is converted into succinyl CoA by alpha-ketoglutarate dehydrogenase complex as shown.
2a.
alpha-ketoglutarate + NAD+ + CoASH → Succinyl CoA + CO2 + NADPH + H+
3. Conversion of propionyl CoA (formed from valine and isoleucine) to succinyl CoA.
Propionyl CoA + HCO3- + ATP → D-Methyl malonyl CoA ® L-Methyl malonyl CoA → Succinyl CoA.
The non-hepatic tissues are able to utilize the acetoacetate because of the availability of succinyl CoA and that should be one of the reasons for not finding ketoacidosis in HHS. Atleast a part of the citrate cycle viz, from alpha-ketoglutarate onwards should be operational for utilization of any of the aforementioned metabolites.
Another important mechanism which the authors have overlooked is, in chronic metabolic acidosis, the kidneys excrete ammonium 2 rather than NaH2PO4. After three days of the onset of acidosis, enormous amount of ammonium is excreted by the kidneys. Excretion of NaH2PO4 would drain the body of Na+ in no time and also would require the pH of the urine to be low. In acidosis, it is well known that activation of the enzyme glutaminase and glutamate dehydrogenase occurs- both of which form ammonium. The main advantage of excretion of protons as ammonium is that, it can be excreted without any decrease in urinary pH ( pK of NH4 is 9.3). Excretion of ammonium spares the body of Na+ and K+. At the onset of acidosis, the excretion of H2PO4 requires Na+, but as the body's Na+ stores become depleted, K+ excretion rises. If NH4 were not available, even moderate acidosis could quickly become fatal 3.
References
1.English P, Williams G. Hyperglyaemic crises and lacti acidosis in diabetes mellitus. Postgrad Med J 2004; 80:253-261.
2.The citric acid cycle. In: Nelson DL and Cox MM. Lehninger Principles of Biochemistry. 3rd ed, Worth, New York, 3rd ed, 2000, pp 567-592.
3. Baggott J. Gas transport and pH regulation. In Textbook of Biochemistry with Clinical Correlations. Devlin TM, ed. Wiley-Liss, New York, 4th ed, 1997, pp 1026-1054.
In their recent review English and Williams state "The primary
mechanism for the development of ketoacidosis (DKA) and hyperglycaemic
hyperosmolar state (HHS) is ... insulin deficiency per se ... together
with a concomitant elevation of the counter-regulatory hormones" but "why
ketoacidosis does not occur in HHS is unknown".[1]
However, the pure existence of HHS is strong evidence against the
sta...
In their recent review English and Williams state "The primary
mechanism for the development of ketoacidosis (DKA) and hyperglycaemic
hyperosmolar state (HHS) is ... insulin deficiency per se ... together
with a concomitant elevation of the counter-regulatory hormones" but "why
ketoacidosis does not occur in HHS is unknown".[1]
However, the pure existence of HHS is strong evidence against the
statement that "The primary mechanism for the development of DKA is
insulin deficiency per se". There are several other observation to support this evidence:
1. Schade and Eaton measured insulin concentration in the
blood of 106 patients with DKA: they found sufficient amounts of insulin.[2]
2. DKA occurs also in diabetic patients with normal values of blood
glucose.[3]
3. "Hepatic mitochondria oxidise free fatty acids to the ketone
bodies acetoacetate and 3-hydroxybutyrate".[1] According to Niwa there are increased amounts of 36 organic acids in DKA.[4] Acetoacetic and 3-hydroxybutyric acids usually show the highest increase.
However, some patients have increased
amounts of the remaining 34 organic acids, resulting in life threatening
acidosis with pH of 6.85 and negative acetoacetate and 3-hydroxybutyrate.[5] The influence of insulin on these 34 acids has not been
reported.
It seems that re-evaluation of the role of insulin in the
pathogenesis of DKA is necessary.
References
(1) English P, Williams G. Hyperglycaemic crises and lactic acidosis
in diabetes mellitus. Postgrad Med J 2004;80:253-61.
(2) Schade DS, Eaton RP. Prevention of diabetic ketoacidosis. J Am Med
Ass 1979;242:2455-8.
(3) Jenkins D, Close CF, Krentz AJ, Nattrass M, Wright AD. Euglycaemic
diabetic ketoacidosis: does it exist? Acta Diabetol 1993;30: 251-3.
(4) Niwa T. Mass spectrometry in diabetes mellitus. Clin Chim Acta
1995;241-242:190-220.
(6) Vernon DD, Postellon DC. Nonketotic hyperosmolal diabetic coma in
a child: management with low-dose insulin infusion and intracranial
pressure monitoring. Pediatrics 1986;77:770-2.
Persaud is quite right when he says that the medical profession
will pay the price for its poor public relations skills.[1]
Already there have been a number of investigations into the practice
of GPs in the UK who had higher than average mortality rates. So far all
of the investigations proved to be unfounded - the GPs simply had a lot of
patients in nursing homes.
Persaud is quite right when he says that the medical profession
will pay the price for its poor public relations skills.[1]
Already there have been a number of investigations into the practice
of GPs in the UK who had higher than average mortality rates. So far all
of the investigations proved to be unfounded - the GPs simply had a lot of
patients in nursing homes.
References
(1) Persaud R. Commentary on: Implications of Harold Shipman for general practice. Postgrad Med J 2004;80:308.
We think Gordon has been rather selective with his citation of the
literature.[1] The issue here is whether serum C reactive protein estimation
has acceptable sensitivity in undiagnosed patients presenting for the
first time with symptomatic Crohn’s disease. It was first reported for
this purpose by Shine et al who found that 19 of
19 newly presenting symptomatic Crohn’s disease patients had...
We think Gordon has been rather selective with his citation of the
literature.[1] The issue here is whether serum C reactive protein estimation
has acceptable sensitivity in undiagnosed patients presenting for the
first time with symptomatic Crohn’s disease. It was first reported for
this purpose by Shine et al who found that 19 of
19 newly presenting symptomatic Crohn’s disease patients had elevated
serum C reactive protein.[2] Beattie et al confirmed these
findings in a paediatric population with 26 of 26 children with
symptomatic Crohn’s disease having an elevated serum C reactive protein.[3] The 95% sensitivity we quoted was the result of an unpublished study
done by one of us (JMR) some years ago in an adult population at the Royal
Free Hospital.
The three papers cited by Gordon do not really address the same
issue. Boirivant et al describe a longitudinal study of patients
with
established Crohn's disease during follow-up.[4] Cellier et al again
studied patients with established Crohn’s disease and present data for
correlations between CRP measurement and disease activity that do not
allow extrapolation of a value for sensitivity.[5] Tibble et al focus on
faecal calprotectin. They provide data for serum CRP in 263 patients with
various organic diseases of whom only 84 had Crohn’s disease and do not
provide separate CRP data for the Crohn’s disease patients.[6]
We accept that serum C reactive protein is not always elevated in
symptomatic Crohn’s disease but 11.5% of the adult European population
have irritable bowel syndrome [7] and it is not appropriate to investigate
all such individuals by “appropriate endoscopic and radiological
investigations” particularly if the patient is young, has no alarm
symptoms or relevant family history and normal physical examination. In
that setting, normal results for serum C reactive protein, coeliac disease
antibodies and full blood count are very useful in helping to identify
patients in whom a primary diagnosis of irritable bowel syndrome can
safely be made. A recent study suggests that highly sensitive assay for
serum C reactive protein, using a cut-off value of 2.3 mg/l, has a
sensitivity of 100% in differentiating functional bowel disorders from new
cases of inflammatory bowel disease [8].
(2) Shine B, Berghouse L, Jones LE, Landon J. C-reactive protein as an
aid in the differentiation of functional and inflammatory bowel disorders.
Clin Chim Acta 1985;148:105-9.
(3) Beattie RM, Walker-Smith JA, Murch SH. Indications for
investigation of chronic gastrointestinal symptoms. Arch Dis Child
1995;73:354-5.
(4) Boirivant M, Leoni M, Tariciotti D, Fais S, Squarcia O, Pallone F.
The clinical significance of serum C reactive protein levels in Crohn’s
disease. Results of a prospective longitudinal study. J Clin Gastroenterol
1988;10:401-5.
(5) Cellier C, Sahmoud T, Froguel E, Adenis A, Belaiche J, Bretagne
JF, Florent C, Bouvry M, Mary JY, Modigliani R. Correlations between
clinical activity, endoscopic severity, and biological parameters in
colonic or ileo-colonic Crohn’s disease. A prospective multicentre study
of 121 cases. The Groupe d’Etudes Therapeutiques des Affections
Inflammatoires Digestives. Gut 1994;35:231-5.
(6) Tibble JA, Sigthorsson G, Foster R, Forgacs I, Bjarnason I. Use of
surrogate markers of inflammation and Rome criteria to distinguish organic
from non-organic intestinal disease. Gastroenterology 2002;123:450-60.
(7) Hungin AP, Whorwell PJ, Tack J, Mearin F. The prevalence, patterns
and impact of irritable bowel syndrome: an international survey of 40,000
subjects. Aliment Pharmacol Ther 2003;17:643-50.
(8) Poullis AP, Zar S, Sundaram KK, Moodie SJ, Risley P, Theodossi A,
Mendall MA. A new, highly sensitive assay for C-reactive protein can aid
the differentiation of inflammatory bowel disorders from constipation- and
diarrhoea-predominant functional bowel disorders. Eur J Gastroenterol
Hepatol 2002;14:409-12.
This is a most complex subject. It is difficult to make adequate
and
constructive comment about this case without going into lengthy details
concerning the latest research on serotonin syndrome, which letter space
will
not allow. [1,2]
It
will be
helpful for your readers to appreciate that this report cannot
reasonably
be
upheld to represent serotonin syndrome (better referred to as serot...
This is a most complex subject. It is difficult to make adequate
and
constructive comment about this case without going into lengthy details
concerning the latest research on serotonin syndrome, which letter space
will
not allow. [1,2]
It
will be
helpful for your readers to appreciate that this report cannot
reasonably
be
upheld to represent serotonin syndrome (better referred to as serotonin
toxicity), nor to instruct anyone usefully about serotonin toxicity or
what
combinations of drugs cause it. It is a reminder of the pitfalls of
case
reports
and the difficulties involved in brief reviews of complex topics. I
have
commented on similar reports previously and noted that they reflect, at
least in part, the demands that editors and referees face in discharging
their
role as guardians of publishing standards.[3-5]
Box 2 contains several drugs (nefazodone, trazodone and
amitriptyline) that
decades of intensive use demonstrate to do not provoke serotonin
toxicity,
either by themselves, or if combined with monoamine oxidase inhibitors.[6]
The inclusion of these drugs perpetuates myths and inaccuracies that are
common in this field and are repeated in supposedly authoritative
publications, including the British National formulary.[1]
Professor Whyte's studies of large numbers of patients with
serotonin
toxicity
have now elucidated the typical symptoms clearly; I refer readers to his
seminal papers.[7-9] A more recent summary of most aspects of serotonin
toxicity is contained in a recent book chapter 1 and more detailed and
comprehensive data, that is more up-to-date, is contained in my web
based
summary document.[2] That covers all aspects of these complex
interactions
that
may lead to serotonergic toxicity.
The simple and important concept that is likely to be useful for
general
physicians is an appreciation that there is a spectrum, going from
serotonergic side effects and progressing to toxicity. Toxicity can be
life
threatening, but that only occurs with co-administration of MAOIs with
SRIs.
Serotonergic side effects occurring with monotherapy do not cause life-
threatening reactions. It therefore seems to us that using the term
serotonin
syndrome for cases such as this is unhelpful and suggests the potential
for a
fatal outcome. In reality all that is being described is exaggerated
side
effects.
References
1. Gillman P, Whyte I. Serotonin syndrome. In: Haddad P, Dursun S,
Deakin B,
editors. Adverse Syndromes and Psychiatric drugs. Oxford: Oxford
University
Press, 2004.
2. Gillman PK. Serotonin toxicity (serotonin syndrome): A current
analysis.
Psychopharmacology Update Notes [Online]: Available at:
www.psychotropical.com/SerotoninToxicity.doc, 2003.
3. Gillman PK. Mirtazapine: unable to induce serotonin toxicity?
Clinical
Neuropharmacology 2003;26:288-289.
4. Gillman P. The spectrum concept of serotonin toxicity. Pain Medicine
2004;
5:[in press].
5. Gillman PK. Comments on "Serotonin syndrome during treatment with
paroxetine and risperidone". Journal of Clinical Psychopharmacology
2001;
21(3):344-5.
6. Gillman PK. Serotonin Syndrome: History and Risk. Fundamental and
Clinical Pharmacology 1998;12(5):482-491.
7. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and
selective serotonin reuptake inhibitors in overdose compared to
tricyclic
antidepressants. Quarterly Journal of Medicine 2003;96(5):369-74.
8. Isbister G, Hackett L, Dawson A, Whyte I, Smith A. Moclobemide
poisoning:
toxicokinetics and occurrence of serotonin toxicity. British Journal of
Clinical
Pharmacology 2003;56:441-450.
9. Dunkley E, Isbister G, Sibbritt D, Dawson A, Whyte I. Hunter
Serotonin
Toxicity Criteria: a simple and accurate diagnostic decision rule for
serotonin
toxicity. Quarterly Journal of Medicine 2003;96:635-642.
I read with interest the review of the management of inflammatory
bowel disease by Nayar et al, in which the authors elegantly highlight
the
major points for the general physician. However I was concerned by the
potentially seriously misleading statement that serum C-reactive protein
(CRP) concentration is raised in over 95% of patients with symptomatic
Crohn's disease, and is useful in distingu...
I read with interest the review of the management of inflammatory
bowel disease by Nayar et al, in which the authors elegantly highlight
the
major points for the general physician. However I was concerned by the
potentially seriously misleading statement that serum C-reactive protein
(CRP) concentration is raised in over 95% of patients with symptomatic
Crohn's disease, and is useful in distinguishing it from irritable bowel
syndrome. This is not the case.
Crohn's disease can be difficult to diagnose and the non-specific
symptoms mean that in many patients diagnosis is delayed with
potentially
hazardous consequences. Literature from the past fifteen years has
clearly
shown that inflammatory markers are neither sensitive nor specific in
identifying patients with Crohn's disease and distinguishing them from
those with irritable bowel syndrome. In a prospective longitudinal study
of 101 patients by Boirivant et al, one-third of patients with
clinically
active Crohn's disease had normal CRP levels.[1] More recently Cellier
et
al. assessed the correlation between clinical activity, endoscopic
severity, and biological parameters in 121 consecutive patients with
Crohn's disease. They concluded that Crohn's disease clinical activity
seems to be virtually independent of the severity of the mucosal lesions
and biological activity.[2] Finally in a recent study by Tibble et al
investigating the use of surrogate markers and Rome criteria to
distinguish non-organic from organic disease CRP was shown to have a
sensitivity of 50% and specificity of 68% for the presence of organic
disease.[3] Thus, it should be emphasised that a normal CRP does not
preclude the diagnosis of Crohn's disease, and that until better non-
invasive tests emerge physicians will have to continue to rely on
clinical
judgment in conjunction with appropriate endoscopic and radiological
investigations to distinguish inflammatory bowel disease from irritable
bowel syndrome.
References
1. Boirivant M, Leoni M, Tariciotti D, Fais S, Squarcia O, Pallone
F.
The clinical significance of serum C reactive protein levels in Crohn's
disease. Results of a prospective longitudinal study. J Clin
Gastroenterol. 1988;10:401-5.
2. Cellier C, Sahmoud T, Froguel E, Adenis A, Belaiche J, Bretagne
JF, Florent C, Bouvry M, Mary JY, Modigliani R. Correlations between
clinical activity, endoscopic severity, and biological parameters in
colonic or ileocolonic Crohn's disease. A prospective multicentre study
of
121 cases. The Groupe d'Etudes Therapeutiques des Affections
Inflammatoires Digestives. Gut. 1994;35:231-5
3. Tibble JA, Sigthorsson G, Foster R, Forgacs I, Bjarnason I. Use
of
surrogate markers of inflammation and Rome criteria to distinguish
organic
from nonorganic intestinal disease. Gastroenterology. 2002;123:450-60
Dear Editor
I read with interest the review article by Thanvi and Lo on the long term motor complications of levodopa.[1] The authors describe the role of pulsatile stimulation of the post-synaptic dopamine receptors as a possible mechanism for these complications and describe the various strategies currently in use to prevent them. They however fail to acknowledge the role of a multidisciplinary team in the ma...
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Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac abnormality that impairs the ability of the left ventricle to fill with or pump blood.
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References...
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