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With the advent of designer pathologic therapies based on an
individual's genetic code on the horizon, those who dismiss LB patients'
complaints would do well to consider the fact that all patients' immune
systems are not created equal. The answer is not in the Western Blot. It
is in the patient's already-existing autoimmune phenotype, which is based
on genotype + environment. For example, Patient A...
With the advent of designer pathologic therapies based on an
individual's genetic code on the horizon, those who dismiss LB patients'
complaints would do well to consider the fact that all patients' immune
systems are not created equal. The answer is not in the Western Blot. It
is in the patient's already-existing autoimmune phenotype, which is based
on genotype + environment. For example, Patient A's IgG meets LB criteria
but Patient B's IgM is elevated while his IgG is within normal range.
Patient B is not clinically diagnosed, because the guidelines for
diagnosis are one-size-fits-all. In fact, B is infected and A has had an
immune reaction to something else entirely. A gets antibiotic, which
resolves his non LB-related symptoms. B's complaints continue and worsen.
B seeks out other doctors, who can't help him either.
Therefore, if patient complaints do not resolve, with or without an
antibiotic regimen, it would appear that tissue damage is permanent in
these individuals, and they should be referred to an appropriate
specialist (i.e., neurologist or rheumatologist) for treatment of the
remnant LB pathology.
We read with interest the review by Adebayo and Bjarnason on non-
steroidal anti-inflammatory drug enteropathy. The article cites capsule
endoscopy (CE) as an important tool to diagnose intestinal damage caused
by NSAID (1). The diagnosis of NSAID induced enteropathy prior to CE was
limited, as visualization of the small bowel using other modalities was
often suboptimal (2). In addition, patient’s s...
We read with interest the review by Adebayo and Bjarnason on non-
steroidal anti-inflammatory drug enteropathy. The article cites capsule
endoscopy (CE) as an important tool to diagnose intestinal damage caused
by NSAID (1). The diagnosis of NSAID induced enteropathy prior to CE was
limited, as visualization of the small bowel using other modalities was
often suboptimal (2). In addition, patient’s symptoms may be mild, non
specific or absent. However, presently there is a paucity of international
data evaluating the role of CE for the recognition of NSAID induced small
intestinal damage (2). A small number of studies (Table 1.0 (3-5)) and
case reports (6-7) have suggested that the prevalence of NSAID enteropathy
(including diaphragm disease) is between 55%-71%.
We would like to share our United Kingdom (UK) experience in the use of
capsule endoscopy to detect NSAID enteropathy. Our aim was to assess the
prevalence of small bowel (SB) injury in patients taking long term NSAID’s
and to evaluate the role of gastrointestinal (GI) symptoms in predicting
the presence of enteropathy. We conducted a pilot study on 22 patients
with arthritis (either osteoarthritis or rheumatoid) who had been on
conventional NSAID’s for a minimum of three months duration. Patients with
obstructive symptoms or previous gastrointestinal (GI) surgery were
excluded. The presence of other GI symptoms and all drug ingestions were
noted. 18 other patients who underwent CE for functional disorders/
diarrhoea in our unit were used as controls.
Nine patients were symptomatic with heartburn (n=6) and abdominal
pain (n=3). Evidence of intestinal injury throughout the small bowel was
seen in 50% of our patients: multiple erosions (n=9), ulcers (n=2) and red
spots (n=4) compared to 17% of controls (p<0.05).The presence of NSAID
induced enteropathy detected by CE was poorly correlated with GI symptoms;
36%, p<0.1). Intestinal damage was also independent of proton pump
inhibitor use.
We strongly agree with Adebayo & Bjarnason that CE is a useful
tool to detect the high prevalence of NSAID induced macroscopic small
bowel injury. Our study has shown that symptoms are poorly correlated with
the presence of enteropathy. The clinical relevance of the small bowel
findings in these patients have yet to be established. Larger studies are
needed to correlate and quantify small bowel injury detected by CE with
the presence of anaemia, obscure GI bleeding and small bowel perforations.
References
1. Adebayo D, Bjarnason I. Is non-steroidal anti-inflammaory drug
(NSAID) enteropathy clinically more important than NSAID gastropathy?
Postgrad Med J 2006;82:186-91.
2. Chutkan R, Toubia N. Effect of nonsteroidal anti-inflammatory drugs on
the gastrointestinal tract: diagnosis by wireless capsule endoscopy.
Gastrointest Endosc Clin N Am 2004;14:67-85.
3. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG. Video
capsule endoscopy to prospectively assess small bowel injury with
celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol
Hepatol 2005;3:133-41.
4. Maiden L, Thjodleifsson B, Theodors A, Gonzalez J, Bjarnason I. A
quantitative analysis of NSAID-induced small bowel pathology by capsule
enteroscopy. Gastroenterology 2005;128:1172-8.
6. Yousfi MM, De Petris G, Leighton JA, Sharma VK, Pockaj BA, Jaroszewski
DE, Heigh RI, Ramzan NN, Fleischer DE. Diaphragm disease after use of
nonsteroidal anti-inflammatory agents: first report of diagnosis with
capsule endoscopy. J Clin Gastroenterol 2004;38:686-91.
7. Manetas M, O'Loughlin C, Kelemen K, Barkin JS. Multiple small-bowel
diaphragms: a cause of obscure GI bleeding diagnosed by capsule endoscopy.
Gastrointest Endosc 2004;60:848-51.
Table 1 Studies using capsule endoscopy to detect NSAID induced enteropathy.
The finding that most patients with type 2 diabetes are either obese
or overweight (1) is not surprising, but is nevertheless worrisome.
Recently published data (2) show that there has been a steady increase in
the prevalence of type 2 diabetes in England and Wales between 1994 and
2001. This study which evaluated a large number of individuals in several
primary care centres also found that prevale...
The finding that most patients with type 2 diabetes are either obese
or overweight (1) is not surprising, but is nevertheless worrisome.
Recently published data (2) show that there has been a steady increase in
the prevalence of type 2 diabetes in England and Wales between 1994 and
2001. This study which evaluated a large number of individuals in several
primary care centres also found that prevalence of obesity in the
population with diabetes was rising. Importantly, this happened despite
significant therapeutic advancements. Obesity has been directly linked to
the metabolic syndrome, type 2 diabetes and cardiovascular risk and this
underscores the urgent need to tackle this problem, more aggressively in
people.
This begs the question, do clinicians provide adequate information to
patients on weight reduction and physical activity during consultations
and in-hospital management? It can be argued that physicians compared to
other members of a multidisciplinary team, tend to have a greater impact
on patients. The National Institute for Health and Clinical Excellence is
due to publish formal guidance on prevention and treatment of obesity in
November this year (3). One has to wait and see whether it will improve
practices and alleviate the growing burden of ‘diabesity’ in the
community.
References
1. C Daousi, I F Casson, G V Gill, I A MacFarlane, J P H Wilding, and J H
Pinkney. Prevalence of obesity in type 2 diabetes in secondary care:
association with cardiovascular risk factors. Postgrad Med J 2006; 82: 280
-284.
2. Lusignan S, Sismanidis C, Carey IM, DeWilde S, Richards N, Cook DG.
Trends in the prevalence and management of diagnosed type 2 diabetes 1994-
2001 in England and Wales. BMC Fam Pract 2005 Mar 22;6(1):13.
The recommended T4 only treatment may be preferred, but if the
peripheral metabolism of T4 to T3 is deficient, the addition to or the
replacement of T4 therapy with a T3 therapy is indicated. One might liken
T4 to the crude oil that we extract from nature. In order to use it in
our vehicles we must refine it to make an active hydrocarbon fuel - like
T3. If we run out of fuel but not out of crude, w...
The recommended T4 only treatment may be preferred, but if the
peripheral metabolism of T4 to T3 is deficient, the addition to or the
replacement of T4 therapy with a T3 therapy is indicated. One might liken
T4 to the crude oil that we extract from nature. In order to use it in
our vehicles we must refine it to make an active hydrocarbon fuel - like
T3. If we run out of fuel but not out of crude, we don't dump crude in
our gas tanks, we get more refining capacity. Similarly when the
peripheral metabolism fails, we must travel down the well worn road of
hormone replacement and replace the deficient hormone - T3.
The only way that a T4 only therapy can be successful over all
hypothyroidism cases (broad, symptom based definition, not narrow thyroid
based definition) is to assume that the peripheral metabolism of T4 is
infallible. While the deficiency may be relatively rare, its low
occurance rate is no excuse for ignoring studies that show that peripheral
metabolism is fallible. It is no excuse for ignoring studies done by
Baisier, et al. -- the successful treatment of thyroxine-resistant victims
of hypothyroidism and the end of the "nonspecific" symptom myth.
If medicine actually did a careful logical analysis of the situation,
our out reach program would not have found with a minimalist effort over a
few weeks over 80 West Virginians that medicine has not treated -- has
failed to treat -- some for more than 30 years. While the media clammored
over dog leashes in Iraq, these people could claim cruel and unusual
punishment by medical turnkeys who keep them locked in their exhausted
bodies.
My theoretical analysis begins with a broad, symptom oriented
definition of hypothyroidism and finds that it is more related to the use
of triiodothyronine than to the availability of thyroxine. This gives the
care and treatment an extra step or two. Upon the failure of the standard
first step, the physician shifts gears and assumes that the an exo-
endocrine etiology is contributing to the patient's malady. This warrents
T3 as the operative replacement. Supra T3 can only then be considered
with the even rarer cases of increased peripheral cell hormone receptor
resistance.
The symptom re-assignment to "nonspecific" somatic conditions is
supported by Barsky, et al. Barsky, however does not claim to have
excluded subjects with hypothyroidism. Thus, the irrationale used a study
tainted by hypothyroidism to prove that these results are not related to
hypothyroidism. Basal temperature has the same problem...
The belief that T3 is so dangerous is quite overblown -- I know
someone who is now 80 was on it for 25 years. Only when the T3 was
replaced by T4 did the symptoms reappear. Now a combination therapy
produces clinical euthyroidism.
I think it is quite overdue for endocrinology to re-examine the
hippocratic oath and decide that it is time to treat these thyroxine-
resistant patients. The proper hormone replacements are approved safe,
effective, and available. All that stands between the sufferer of
thyroxine resistance and clinical euthyroidism is shear stupidity or
worse. Refrain from "every voluntary act of mischief and corruption."
There are some 80 West Virginians indicative of a hundred thousand
Americans who would tearfully appreciate that as it would give them their
lives back.
Bycroft et al provide a useful overview of autonomic dysreflexia.
However as a nurse with many years experience of managing episodes of AD
in Spinal Cord Injured patients, I would disagree with a couple of the
practical interventions suggested.The authors twice mention 'flushing'
blocked catheters, which is generally not recommended for two reasons: it
may be possible to force liquid through the cath...
Bycroft et al provide a useful overview of autonomic dysreflexia.
However as a nurse with many years experience of managing episodes of AD
in Spinal Cord Injured patients, I would disagree with a couple of the
practical interventions suggested.The authors twice mention 'flushing'
blocked catheters, which is generally not recommended for two reasons: it
may be possible to force liquid through the catheter which may not clear
the blockage and will then only increase the volume of fluid in the
bladder and thus add to the noxious stimulus triggering the AD; and it
wastes valuable time. The best thing to do with a blocked catheter in
these circumstances is to remove it quickly (which may of itself trigger
reflex emptying of the bladder and thus relieve the symptoms) and replace
it with a new one. The authors do not generally convey the speed with
which AD can develop or how important it is to act promptly.
The authors also recommend that the first thing that should be done is to
sit the patient up to couteract the rise in BP. Again, this wastes
valuable time (you are only going to have to lie the patient down again to
deal with the catheter) and is in my experience completely ineffective
anyway.
The reason why studies of rhythm vs rate control in atrial
fibrillation (AF) have failed to show an advantage to a rhythm control
policy is that, without stringent monitoring of rhythm control along the
lines of the Catheter Ablation for the Cure of Atrial Fibrillation
Study(1), investigators such as those in the AFFIRM Study were not in a
position to acertain which of their rhythm control patients h...
The reason why studies of rhythm vs rate control in atrial
fibrillation (AF) have failed to show an advantage to a rhythm control
policy is that, without stringent monitoring of rhythm control along the
lines of the Catheter Ablation for the Cure of Atrial Fibrillation
Study(1), investigators such as those in the AFFIRM Study were not in a
position to acertain which of their rhythm control patients had fully
converted to sinus rhythm (SR), entitling them to be compared with rate
controlled counterparts, and which of them had merely reached the halfway
house of paroxysmal AF, which, in the absence of anticoagulation, would
leave them at considerable risk of embolic complications(2). Instead of
relying on daily transtelephonic electrocardiograms(ECG's)for the first
three months, and also on Holter monitoring at 1,4,7,10, and 13 months as
Stabile et al had done(1), the AFFIRM investigators merely relied on
documenting heart rhythm (presumably only with standard (ECG's) at 2 months
and 4 months after randomisation, and every 4 months thereafter until the
patient died or was lost to follow up(3). Consequently, although the highly
efficacious antiarrhythmic, amoidarone(4), had been utilised by comparable
proportions of patients, namely, 62.3% and 62.6%, respectively, in the two
studies(1)(5), as many as 91.3% of the patients allocated solely to
antiarrhythmic drugs by Stabile et al had experienced at least one AF
recurrence at one year(1), whereas relapse into AF was documented as being
as low as 17.6% at one year in the AFFIRM study(the latter being
documented as an 82.4% prevalence of SR)(5).
Given the suboptimal
monitoring of AF relapse in the AFFIRM study, the recorded proportion of
patients remaining in SR at each of the stated time intervals must have
been an overstimate, and, in reality, this was a study comparing, in the
main, the fate of patients with paroxysaml AF who were on antiarrhythmic
drugs with the fate of rate controlled patients who were either in
permanent AF or in paroxysmal AF. The rhythm controlled patients with
persisting paroxysmal AF did not have the benefit of a protocol mandating
anticoagulants, and, therefore, remained exposed to the risks, not only of
drug side effects, but also of embolic complications, whilst their rate
controlled conterparts, at the very least, enjoyed the benefit of strict
anticoagulation.
The shortcomings of AFFIRM should not be allowed to obscure the fact that
sinus rhythm (SR) is superior either to permanent AF or to paroxysmal AF,
regardless of the excellence of rate control. What diminishes the value of
SR is its attainment at the cost of intolerable drug side effects. There
must also be a continuing search for prophylactic strategies against AF
itself, exemplified by the use of angiotensin receptor blockade in high
risk groups such as those with hypertension(6)
Oscar M P Jolobe
References
(1) Stabile G., Bertaglia E., Senatore G., et al
Catheter ablation tretment inn patients with drug-refractory atrial
fibrillation: a prospective multi-centre, randomised, controlled
study(Catheter Ablation For The Cure Of Atrial Fibrillation Study)
European Heart Journal 2006:27:216-21
(2) Glotzer TV., Hellkamp AS., Zimmerman J et al
MOST Investigators
Atrial high rate epsodes detected by pacemaker diagnostics predict death
and stroke
Circulation 2003:107:1614-19
(3) The AFFIRM Investigators
Relationship betweensinus rhythm, treatment, and survival in the Atrial
Fibrillation Follow-Up Investigation of Rhythm management(AFFIRM) Study
Circulation 2004:109:1509-13.
(4) Roy D., Talajic M., Dorian P., et al
Amiodarone to prevent recurrence of atrial fibrillation
New England Journal of Medicine 2000:342:913-20.
(5) The Atrial Fibrillation Follow-up Investigation of Rhythm
management(AFFIRM) Investigators
A comparison of Rate Control and Rhythm Control in patients with atrial
fibrillation
New England Journal of Medicine 2002:347:1825-33.
(6) The Losartan Intervention for End Point Reduction in
Hypertension(LIFE) Study
Angiotensin II receptor blockade reduces new-onset atrial fibrillation and
subsequent stroke compared to atenolol
Journal of the American College of Cardiology 2005:45:712-9.
I read with interest the case reported by Dr De associating
acquired neuromyotonia (NMT) and sinoatrial block.1 He correctly pointed
out there was no previous literature describing the association between it
and any kind of heart block. However, there was one case subsequently by
Dr Liguori et al. suggesting between Morvan's syndrome and cardiac
arrhythmia with antibodies to voltage-gated potassium ch...
I read with interest the case reported by Dr De associating
acquired neuromyotonia (NMT) and sinoatrial block.1 He correctly pointed
out there was no previous literature describing the association between it
and any kind of heart block. However, there was one case subsequently by
Dr Liguori et al. suggesting between Morvan's syndrome and cardiac
arrhythmia with antibodies to voltage-gated potassium channels (VGKC).2
Morvan’s syndrome is characterised by NMT, hyperhydrosis, encephalopathy
with insomnia, confusion and hallucinations. The electrocardiographic
abnormality in the latter case was frequent supraventricular extrasystoles
and NMT discharges which were abolished with plasma exchange, therefore
reinforcing the notion of an immune-mediated mechanism.
NMT is a syndrome of spontaneously occurring muscle activity of
peripheral nerve origin, which can be triggered by voluntary or induced
muscle contraction. VGKC antibodies have been shown to induced
hyperexcitability. Acquired NMT is thought to be autoimmune in a high
proportion of cases, in which VGKC antibodies have been detected and other
presumed antibodies which are not VGKC related.
Autoantibodies induced heart block is not novel because of the known
anti-Lo/Ra related congenital heart block in Sjögren's syndrome.3
Therefore, it is possible other antibodies still to be defined (rather
than VGKC) to be associated with NMT and heart block.
References
1. De P. Neuromyotonia and sinoatrial block. Postgrad Med J. 2000
Jul;76(897):453.
2. Liguori R, Vincent A, Clover L, Avoni P, Plazzi G, Cortelli P,
Baruzzi A, Carey T, Gambetti P, Lugaresi E, Montagna P. Morvan's syndrome:
peripheral and central nervous system and cardiac involvement with
antibodies to voltage-gated potassium channels. Brain. 2001 Dec;124(Pt
12):2417-26.
3. Scott JS, Maddison PJ, Taylor PV, Esscher E, Scott O, Skinner RP.
Connective-tissue disease, antibodies to ribonucleoprotein, and congenital
heart block. N Engl J Med 1983; 309:209-12.
Ranged against the impressive array of endogenous appetite
suppresants described by the author there is, not only ghrelin(1), but
also the endogenous cannabinoid system, the orexigenic effects of the
latter being purportedly mediated by cannabinoid receptors located in the
hypothalamus(2). Just as ghrelin has been utilised for the purpose of
stimulating appetite in anorexic cancer patients(3), and also in cachectic
patie...
Ranged against the impressive array of endogenous appetite
suppresants described by the author there is, not only ghrelin(1), but
also the endogenous cannabinoid system, the orexigenic effects of the
latter being purportedly mediated by cannabinoid receptors located in the
hypothalamus(2). Just as ghrelin has been utilised for the purpose of
stimulating appetite in anorexic cancer patients(3), and also in cachectic
patients with chronic obstructive pulmonary disease(4), so might the
cannabinoids be called upon to fulfil the same role, at least in carefully
selected cases, given the demonstration, in the animal model, that
cannabinoids stimulate appetite and increase food intake(5). Indeed,
dronabinol, an oral form of delta 9-tetrahydrocannabinol, has been used in
the treatment of anorexia and cachexia in HIV infection(6), and in the the
control of nausea and vomiting complicating cancer chemotherapy(7).
Although mental confusion, emotional lability and hallucinations may
complicate therepy with the cannabinoids(5), a placebo-controlled cross-over trial of dronabinolon in 15 patients with Alzheimer's disease
resulted in an increase in body weight with euphoria and somnolescence as
only occasional side effects(8). Assuming that the side effects might be
dose-related, there might be room for pursuing the proposition by Berry
and Marcus that treatment with the cannabinoids might be extended to the
major problem of anorexia in the elderly(9)
References
(1) Hickson M
Malnutrition and ageing
Postgrad. Med. J. 2006:82:2-8.
(2) Cota D, Marsicano G, Tscip M, et al
The endogenous cannabinoid system affects energy balance via central
orexigenic drive and peripheral lipogenesis
J. Clin. Invest. 2003:112:423-31.
(3) Neary NM, Small CJ, Wren CJ, et al
Ghrelin increases energy intake in cancer patients with impaired appetite:
acute, randomised placebo-controlled trial
J. Clin. Endocrinol Metab. 2004;89:2832-6.
(4) NagayaN, Itoh T, Murakami S, et al
Treatment of cachexia with ghrelin in patients with COPD
Chest 2005;128:1187-93.
(5) Berry EM and Mechoulam R
Tetrahydrocannabinoids in feeding and appetite
Pharmacol and Therap 2002;95:185-90.
(6) Balog DS, Epstein ME, Amodio-Groton MI
HIV wasting syndrome
Ann Pharmacother 1998;32:446-58.
(7) Gonzalez-Rosales F and Walsh D
Intractable nausea and vomiting due to gastrountestinal metastases
releived by tetrahydrocannabinol(dronabinol)
J Pain Symtom Manage 1997;14:311-4.
(8) Volicer L, Stelly M, Morris J, McLauglin CL and Volicer BJ
Effects of dronabinol on anorexia and disturbed behaviour in patients with
Alzheimer's disease
Int J Geriatr Psychiatry 1997;12:913-19.
(9) Berry EM and Marcus EL
Disorders of eating in the elderly
J Adult Dev 2000;7:97-99.
We read with interest the concise review on Acute glomerulonephritis by
Vinen et al.[1] The mechanisms involved in the pathogenesis of IgA
nephropathy or Henoch-Schonlein glomerulonephritis (HSP-GN) are still
poorly understood, but mesangial IgA and C3 deposition play an important
role in the renal damage. Although the Japanese Society Nephrology
reported that serum IgA of more than 350 mg/dl in adult...
We read with interest the concise review on Acute glomerulonephritis by
Vinen et al.[1] The mechanisms involved in the pathogenesis of IgA
nephropathy or Henoch-Schonlein glomerulonephritis (HSP-GN) are still
poorly understood, but mesangial IgA and C3 deposition play an important
role in the renal damage. Although the Japanese Society Nephrology
reported that serum IgA of more than 350 mg/dl in adults is a frequent
finding and and a diagnostic criterion for IgA nephropathy,[2] a textbook
of paediatrics still describes that serum IgA levels have no diagnostic
value in patients with IgA nephropathy because they are elevated in only
15% of patients.[3] Also, the levels of serum C3 tend to decrease in the
active stage of chronic glomerulonephritis, but those are not generally
decreased in IgA nephropathy or HSP-GN.
Recently, however, Tomino et al. reported that the ratio of serum IgA to
C3 is a good marker to distinguish patients with IgA nephropathy from non-
IgA nephropathy and may predict prognostic grading in adult patients with
IgA nephropathy.[4,5] Also, we demonstrated that the serum IgA/C3 ratio
could be a useful marker to predict disease activity in children with
severe HSP-GN.[6]
Therefore, serum IgA/C3 ratio should be studied in a large cohort
including children and adolescents and according to the stage of
glomerulonephritis to elucidate the clinical usefulness of this parameter
in IgA nephropathy, HSP-GN, and other forms of glomerulonephritis.
2. Tomino Y, Sakai H. Special Study Group (IgA Nephropathy) on Progressive
Glomerular Disease. Clinical guidelines for immunoglobulin A (IgA)
nephropathy in Japan, second version. Clin Exp Nephrol 2003;7:93-7.
3. Davis ID, Avner ED. Conditions particularly associated with hematuria.
In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson Textbook of
Pediatrics, 17th edn. WB Saunders, Philadelphia, 2004;1735-8.
4. Ishiguro C, Yaguchi Y, Funabiki K, Horikoshi S, Shirato I, Tomino Y.
Serum IgA/C3 ratio may predict diagnosis and prognostic grading in
patients with IgA nephropathy. Nephron 2002;91:755-8.
5. Maeda A, Gohda T, Funabiki K, Horikoshi S, Shirato I, Tomino Y.
Significance of serum IgA levels and serum IgA/C3 ratio in diagnostic
analysis of patients with IgA nephropathy. J Clin Lab Anal 2003;17:73-6.
6. Shin JI, Park JM, Shin YH, Lee JS, Jeong HJ, Kim HS. Serum IgA/C3 ratio
may be a useful marker of disease activity in severe Henoch-Schonlein
nephritis. Nephron Clin Pract 2005;101:72-8.
I read with great interest the article by Gompels, et al. (1) which
highlights the confusion regarding the correct dose, concentration, and
route of administration for adrenaline recommended in the treatment of
anaphylaxis. Although the authors rightly point out that improved
training in this area is required, further clarification of some points is
warranted, especially with regard to the proper...
I read with great interest the article by Gompels, et al. (1) which
highlights the confusion regarding the correct dose, concentration, and
route of administration for adrenaline recommended in the treatment of
anaphylaxis. Although the authors rightly point out that improved
training in this area is required, further clarification of some points is
warranted, especially with regard to the proper route of administering
adrenaline. Indeed, in the past few years, there have been recurrent
debates on the indications for and optimal route of administrating
adrenaline. Commentaries emphasise the need to re-evaluate current
recommendations with regards to prevailing clinical conditions, clinical
urgency, degree of circulatory compromise, availability of vascular
access, and the level of care available.(2,3,4)
In the beginning, it is worth mentioning the most important results
of the Gompels, et al. study. In this interview study, senior house
officers, at the start of their accident and emergency post, were given an
anonymous five case history questionnaire containing one case of true
anaphylaxis and asked to complete the medication they would prescribe.
The results showed that 45% of the group elected to use intramuscular
adrenaline and 42% would administer adrenaline by the intravenous route.
Moreover, out of the total group of 78 respondents, only 5% were able to
indicate the correct route and dose of adrenaline according to current
guidelines for the management of anaphylaxis in adults. Surprisingly,
only a few respondents elected to use subcutaneous adrenaline. On the
other hand, some respondents would administer intravenous adrenaline to
patients who do not have the potentially life threatening features.
Based on these results, Gompels et al. concluded that “there was a
tendency to over-diagnose anaphylaxis, resulting in the over use of
adrenaline.” Although this cohort had not received formal teaching on
anaphylaxis, these results are apparently alarming in view of the fact
that over 100 000 epinephrine syringes have been prescribed throughout the
UK for community use in the year 2001 (5) and that there was a 300%
increase of EpiPen prescriptions in Australia over the 1998-2002 years
(6). Paradoxically, undertreatment is also a problem not mentioned by the
authors. In fact, as pointed out by Ellis and Day (7) in their timely
review, many cases of anaphylaxis are undertreated, with potentially life-
threatening consequences. For illustration, an Epipen device was only used
in 29% of cases in children with recurrent episodes of anaphylaxis (8) and
only 7% of children with peanut and tree nut allergy had a self-injection
epinephrine device available (9).
There is general agreement that the correct diagnosis and treatment
of anaphylaxis can be life saving. However, no evidence exists that the
more liberal community prescribing EpiPen has saved lives significantly.
Furthermore, as pointed out by Unsworth (5) "Death following anaphylaxis
is most feared but fortunately remains a very rare event, currently
estimated at less than one case per year per million of the UK population
(10)" Likewise, a large child population based study of fatal and
severe reactions to food from UK yielded only 0,006 fatal events per 100
000 children per year over the period 1990-2000.(11) It should be
remembered that adrenaline carries some risk of cardiac arrhythmia, even
when given in recommended doses. (12) This danger is relatively high,
because therapeutic and toxic doses are rather similar and the risk
increases in patients with cardiovascular co-morbidity or who are taking
an interacting medications. (13) It is therefore possible that the risk
associated with improper administration of adrenaline or incorrect
diagnosis might be higher than that when adrenaline is not administered at
all.
As Gomples et al. rightly point out, the potential for misdiagnosis
was recognised by the authors of Resuscitation Council guidelines.(14) For
this reason, the guidelines emphasize the importance that the first line
treatment should be safe, even in inexperienced hands. In this regard they
unequivocally recommend non-intravenous adrenaline administration in
initial pharmacologic management of anaphylaxis in a setting without
monitoring and intensive care facilities. Furthermore, intramuscular
administration is favoured because of faster absorption in comparison with
a subcutaneous route. However, more disputable is the notion that
adrenaline should be given only if the life threatening features such as
hypotension and respiratory difficulty are present. (14,15). Accordingly,
generalised urticaria, flushing, itching, and even angio-oedema, unless
affecting the larynx, are not an indication for use of adrenaline. It is
assumed that to label such benign reactions as anaphylaxis may render the
subject vulnerable to being over-treated. However, such opinion neglects
the fact that more than half of the patients may have mild symptoms for
one hour or more before severe respiratory compromise develop.(16) This
may increase the risk of late administration of adrenaline which is
generally associated with a poor outcome.
Indeed, there is now good clinical and experimental evidence
indicating that delay of administration of adrenaline is associated with
both increased risk and decreased benefit. (17,18) Thus, it appears that
underestimation of the milder reactions may be a double edge sword. I
have, therefore, suggested a compromise solution; that in such situations,
it would be reasonable to administer adrenaline subcutaneously instead of
intramuscularly.(2) The potential for harm following subcutaneous
adrenaline administration is extremely small,(19) and its efficacy for
prevention of anaphylaxis has been documented.(20) It is important to note
that the use of adrenaline with milder symptoms will depend on the
patient´s history. A history of severe reaction is probably the most
important criterion in the algorithm for identifying patients who may
benefit from adrenaline. It should be noted however, that many
anaphylactic reactions, especially those associated with insect stings,
may occur without a documented prior exposure. Furthermore, a number of
other factors may lower the threshold for when to administer adrenaline
e.g., if the reaction is provoked by peanut, tree nuts, seafood, a
personal history of atopy and/or asthma, adolescence (especially late
teens), failure to identify the responsible allergen in the meal and lack
of access to emergency medical care.
Finally, it is important to mention the most controversial issue, the
role of intravenous adrenaline in the treatment of anaphylaxis. According
to current guidelines, this route of adrenaline administration should be
reserved for patients with immediate life threatening profound shock where
appropriate monitoring facilities exist. The reluctance to use intravenous
adrenaline is mainly based on reports of rare cases of fatal overdose of
adrenaline.(10) However, the opponents of the intravenous route ignore
the fact that intravenous administration of adrenaline ensures rapid
delivery to its site of action and avoids the problem of erratic and
variable absorption. Notably, it is the time of maximum plasma adrenaline
concentrations that affects the outcome. Recent, first prospective study
significantly contribute reliable clinical evidence supporting the use of
carefully titrated intravenous adrenaline with volume resuscitation for
treating significant insect sting anaphylaxis.(21) It is of interest that
safety of intravenous adrenaline has also been documented in a small
series of younger adults with acute life-threatening asthma (22) Thus, it
seems, that the expert use of high dilution intravenous adrenaline in
hospitals with appropriate monitoring may be the most optimal care for a
patient with severe anaphylaxis.
In closing, I would like to summarize that the intramuscular
adrenaline recommended in current guidelines may not be the only correct
route of application. Both intradermal and intravenous routes may be more
appropriate in certain situations. The decision which route is the most
appropriate in a particular situation will depend on several factors
discussed above. Nevertheless, the early use of intramuscular adrenaline,
particularly in pre hospital or in the unmonitored setting, still warrants
direct comparison with intravenous adrenaline to examine their relative
efficacies compared with complication rates. Similarly, the benefits and
risk of subcutaneous adrenaline in patients with milder reactions or
increased cardiovascular risk warrants further investigation.
References
1. Gompels LL, Bethune C, Johnston SL, et al. Proposed use of
adrenaline (epinephrine) in anaphylaxis and related conditions: a study of
senior house officers starting accident and emergency posts. Postgrad Med
J 2002;78:416–18.
2. Pijak MR. Subcutaneous adrenaline for anaphylaxis: compromise in
high risk patient with mild symptoms.
http://bmj.com/cgi/eletters/327/7427/1332#44125, 19 Dec 2003
3. Fisher M. Treatment of acute anaphylaxis. Letters contained errors
of logic.
BMJ 1996;312: 637c - 638.
4. Brown AF. Anaphylaxis: quintessence, quarrels, and quandaries.
Emerg Med J 2001;18:328.
5. Unsworth DJ. Adrenaline syringes are vastly over prescribed. Arch
Dis Child 2001;84:410-1.
6. Kemp AS. EpiPen epidemic: suggestions for rational prescribing in
childhood food allergy. J Paediatr Child Health 2003;39:372.
7. Ellis AK, Day JH. Diagnosis and management of anaphylaxis. CMAJ
2003;169:307.
8. Gold MS, Sainsbury R. First aid anaphylaxis management in children
who were prescribed an epinephrine autoinjector device (EpiPen). J Allergy
Clin Immunol 2000;106:171-6.
9. Sicherer SH, Munoz-Furlong A, Burks AW, et al. Prevalence of
peanut and tree nut allergy in the US determined by a random digit dial
telephone survey. J Allergy Clin Immunol 1999;103:559-62.
10. Pumphrey RSH. Lessons for management of anaphylaxis from a study
of fatal reactions. Clin Exp Allergy 2000;30:1144-50.
11. Macdougall CF, Cant AJ, Colver AF. How dangerous is food allergy
in childhood? The incidence of severe and fatal allergic reactions across
the UK and Ireland. Arch Dis Child 2002;86:236-9.
12. van der Linden PW, Hack CE, Struyvenberg A, et al. Intentional
diagnostic sting challenges: an important medical issue. J Allergy Clin
Immunol 1994;94:563-4.
13. Johnston SL, Unsworth J, Gompels MM. Adrenaline given outside the
context of life threatening allergic reactions. BMJ 2003;326:589-90.
14. Project team of the Resuscitation Council (UK). Update on the
emergency medical treatment of anaphylactic reactions for first medical
responders and community nurses. Emerg Med J 2001;18:393-5.
15. Hourihane JO'B, Warner JO. Benign allergic reactions should not
be treated with adrenaline. BMJ 1995;311:1434.
16. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal
anaphylactic reactions to food in children and adolescents. N Engl J Med
1992;327:380-4.
17. Pumphrey RSH. Lessons for management of anaphylaxis from a study
of fatal reactions. Clin Exp Allergy 2000;30:1144-50.
18. Bautista E, Simons FE, Simons KJ, et al. Epinephrine fails to
hasten hemodynamic recovery in fully developed canine anaphylactic shock.
Int Arch Allergy Immunol 2002;128:151-64.
19. Cone DC; National Association of EMS Physicians Standards and
Clinical Practice Committee. Subcutaneous epinephrine for out-of-hospital
treatment of anaphylaxis. National Association of EMS Physicians Standards
and Clinical Practice Committee. Prehosp Emerg Care 2002;6:67-8.
20. Premawardhena AP, de Silva CE, Fonseka MM, et al. Low dose
subcutaneous adrenaline to prevent acute adverse reactions to antivenom
serum in people bitten by snakes: randomised, placebo controlled trial.
BMJ 1999;318:1041-3.
21. Brown SG, Blackman KE, Stenlake V, et al. Insect sting
anaphylaxis; prospective evaluation of treatment with intravenous
adrenaline and volume resuscitation. Emerg Med J 2004; 21: 149–154.
22. Smith D, Riel J, Tilles I, et al. Intravenous epinephrine in
life-threatening asthma. Ann Emerg Med 2003;41:706-11.
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