The slides for my talk on 'Toxicological Myths and Half-Truths' that was given at the CICM ASM 2013 in Wellington, New Zealand. The theme of the conference was "Down with Dogma: Challenging the Fundamentals of Critical Care"
9. Boyd
R,
Ghosh
A.
Towards
evidence
based
emergency
medicine:
best
BETs
from
the
Manchester
Royal
Infirmary.
Glucagon
for
the
treatment
of
symptoma@c
beta
blocker
overdose.
Emerg
Med
J.
2003
May;20(3):266-‐7.
O'Connor
N,
Greene
S,
Dargan
P,
Jones
A.
Glucagon
use
in
beta
blocker
overdose.
Emerg
Med
J.
2005
May;22(5):391.
PubMed
PMID:
15843722;
PubMed
Central
PMCID:
PMC1726782.
10. [In toxicology an] evidence basis is often
lacking and one therefore needs to rely on a
combination of practical experience, case
reports and assessment of biological
plausibility. There is a sound theoretical basis
for the use of glucagon in the cardiovascularly
compromised patient who has taken a beta
blocker overdose. Glucagon activates adenyl
cyclase and exerts an inotropic and
chronotropic effect by a pathway that bypasses
the beta receptors.
…
11. Each of us has personal experience of the
dramatic improvement in cardiovascular
parameters that can occur following the
administration of glucagon in this clinical
situation.
…
12. …
Nobody would suggest that naloxone should not
be used for opiate overdose yet the evidence
base for its use is as flimsy as that of glucagon
in beta blocker overdose. We suggest that to
attempt to undertake a randomised clinical
trial of the use of glucagon in the compromised
beta blocker overdosed patient would be
unethical.
…
13. Smith
GC,
Pell
JP.
Parachute
use
to
prevent
death
and
major
trauma
related
to
gravita@onal
challenge:
systema@c
review
of
randomised
controlled
trials.
BMJ.
2003
Dec
20;327(7429):1459-‐61.
Is glucagon
really a
parachute?
14. Photo
by
JD
Hancock
on
Flickr
Or is
glucagon one
of these?
32. Only
5 case reports of
calcium
linked
to
death
in
digoxin
toxicity
None
are
convincing
Bower
JO
,Mengle
HAK.
The
addi@ve
effect
of
calcium
and
digitalis.
JAMA
1936
;106(14):1151–1153
35. Pseudoaxioms
false
principles
or
rules
handed
down
from
genera@on
to
genera@on
and
accepted
without
serious
challenge
or
inves@ga@on
Newman
DH:
Truth,
and
epinephrine,
at
our
finger@ps:
unveiling
the
pseudoaxiom.
Ann
Emerg
Med
2007;
50:476–477.
39. Photo
by
dno1967b
on
Flickr
Select early
Risks of surgery
Immunosuppression
$$$$$
Opportunity cost
40. King’s College
Criteria
for
paracetamol-‐induced
hepatoxicity
Grady
JG,
Alexander
GJ,
Hayllar
KM,
Williams
R.
Early
indicators
of
prognosis
in
fulminant
hepa@c
failure.
Gastroenterology.
1989
Aug;97(2):439-‐45.
41. pH < 7.3
or,
in
a
24h
period,
all
3
of:
INR > 6 (PT > 100s)
Cr > 300 mmol/L
grade III or IV encephalopathy
recent
modifica@on:
lactate >3.5 mM
44. Evidence and consequences of spectrum bias in studies of
criteria for liver transplant in paracetamol hepatotoxicity
G.K.A. DING1,2,3
and N.A. BUCKLEY1,4
From the 1
Australian National University Medical School, ACT, 2
Department of Intensive Care,
The Canberra Hospital, 3
Department of Intensive Care, The Calvary Hospital, Canberra and
4
Faculty of Medicine, University of NSW, Australia
Received 31 October 2007 and in revised form 7 April 2008
Summary
Objective: In severe paracetamol hepatotoxicity,
orthotopic liver transplant (OLT) is a standard
treatment in patients judged to have a hopeless
prognosis. The most commonly used criteria to
make this decision are the King’s College Criteria
Survival was worse in studies originating in the
King’s unit (13.8 vs. 30.0%). It was apparent that this
may be due to spectrum bias occurring in this much
larger unit. There was clear evidence that those with
the best prognosis were preferentially transplanted
Q J Med 2008; 101:723–729
doi:10.1093/qjmed/hcn077 Advance Access published on 7 July 2008
45. 0 10 20 30 40 50 60
0
50
100
Transplanted
Not transplanted
extrapolation
QALY (transplanted)
extrapolation
Years after transplant
Survival%
46. Survival benefit
for
a
20-‐year-‐old
who
meets
King’s
College
Criteria
13.4
years
without
transplant
13.5
years
with
transplant
(8.4
QALYs)
56. Eddleston
M,
et
al.
The
hazards
of
gastric
lavage
for
inten@onal
self-‐poisoning
in
a
resource
poor
loca@on.
Clin
Toxicol
(Phila).
2007;45(2):136-‐43.
57. “It
is
everyone’s responsibility
to
find
out
how
to
ask
ques@ons
systema@cally,
find
answers
from
searching
the
literature,
cri@cally
appraise
the
literature
and
apply
the
results
to
prac@ce”
Bellomo
R.
The
dangers
of
dogma
in
medicine.
Med
J
Aust.
2011
Oct;195(7):372-‐3.
Thank you for the introduction Paul. I am speaking to you today about Toxicological myths and half-truths.
Toxicology represents something of a paradox. There should be no more scientific a dicipline than toxicology. Science has given us the ability to characterise and describe poisons and venoms at the molecular level, we can study how they interact with receptors in a laboratory, and we can see what they do to animals. Yet going from the bench to the bedside remains a serious problem. Not many patients are lining up to take part in DB-RCTs on poisons,.Most of what we do for critically ill poisoned and envenomed patients we do, not because we know it works but because we think it might work or there is nothing else we can do. As such I see critical care toxicology as a microcosm, or even an amplification, of the problems facing intensive care medicine as a whole.
I will look at just a few examples, namely the use of glucagon as an antidote, the remarkable ‘stone heart theory’ in digoxin toxicity, the role of liver transplantation in paracetamol-induced hepatotoxity and whether antivenoms actually work.
The cynic might look at the history of toxicology as a repetition of the mistakes of Mithradates — a lack of correctly performed studies, mixed with myths and mis-truths about which substances are truly hazardous and which treatments actually work. I will look at just a few examples, namely the use of glucagon as an antidote, the remarkable ‘stone heart theory’ in digoxin toxicity, the role of liver transplantation in paracetamol-induced hepatotoxity and whether antivenoms actually work.
The cynic might look at the history of toxicology as a repetition of the mistakes of Mithradates — a lack of correctly performed studies, mixed with myths and mis-truths about which substances are truly hazardous and which treatments actually work. I will look at just a few examples, namely the use of glucagon as an antidote, the remarkable ‘stone heart theory’ in digoxin toxicity, the role of liver transplantation in paracetamol-induced hepatotoxity and whether antivenoms actually work.
First up is glucagon
Or perhaps that should be glucaGONE
In 2003, Boyd and Ghosh published a Best BETs “short cut” review in the EMJ that concluded that clinical studies did not support the use of glucagon in BB OD. This stimulated a few responses, including a letter by O’Connor and colleagues. They argued the following:
This stimulated a few responses, including a letter by O’Connor and colleagues. They argued the following:[In toxicology an] evidence basis is often lacking and one therefore needs to rely on a combination of practical experience, case reports and assessment of biological plausibility. There is a sound theoretical basis for the use of glucagon in the cardiovascularly compromised patient who has taken a b blocker overdose. Glucagon activates adenylcyclase and exerts an inotropic and chronotropic effect by a pathway that bypasses the b receptors. Their first point is thus biological plauability. This is how we practice medicine in the ICU all the time when we stray into the grey zones where RCTs can’t help us. It makes sense that glucagon should work – skip out the blocked adrenergic receptor – and go straight onto the second messenger, cAMP.
The authors go on: Each of us has personal experience of the dramatic improvement in cardiovascular parameters that can occur following the administration of glucagon in this clinical situation.As clinicians we can all empathise. But we all know the dangers of anecdote — and as for ‘cardiovascular parameters’, are they pateint orientated outcomes that matter?
Finally they argue:Patients seldom take an overdose solely of a b blocker and the purist evidence base sought by Boyd is unlikely to be achievable. There is a wealth of clinical experience in support of administration of glucagon. Nobody would suggest that naloxone should not be used for opiate overdose yet the evidence base for its use is as flimsy as that of glucagon in b blocker overdose. We suggest that to attempt to undertake a randomised clinical trial of the use of glucagon in the compromised b blocker overdosed patient would be unethical.
Yet, as I said before, glucagon is out of favour with many clinical toxicologists. We all know that some RCTs cannot be done – the famous BMJ parachute paperby Smith and Pell that failed to find any RCTs supporting their use attests to that.
But in comparing glucagon to naloxone I think we may be comparing a parasol a true parachute – and in clinical practice it is not always easy to tell the difference.
The best evidence we have from animal studies is that glucagon increases heart rate, but not MAP in BB OD. It has also been studied in CCB overdose, where again it was found to increase heart rate, cardiac output and reverse AV blocks in animal models (at least transiently), but again there was no change in MAP. Apart from being small, unblinded studies using varying doses of glucagon – the most alarming feature of those studies is that there are no controlled studies showing that poisoned animals receiving glucagon are more likely to live.Since the early 1970s a number of case reports of glucagon therapy, implying benefit, have been published for both BB and CCB overdose. But there has never been satisfactory studies of efficacy or clinical effectiveness in humans.
Interestingly, there may be another spanner in the glucagon works. Through the wonders of the Internet, I was able to listen to a lecture by clinical toxicologist Dr. Kerns at the Carolinas Medical Center where he commented that: “Nearly all studies examining glucagon… were conducted prior to the availability of recombinant glucagon and used Eli Lilly’s standard glucagon preparations instead… The standard preparation of glucagon, made from mammalian pancreatic extract, contained insulin (also from pancreatic cells) until recombinant glucagon was available in 1998. Some vials of glucagon, when analyzed by this study group at Carolinas Medical Center, contained 100 units of insulin. This even if there was any benefit from adminstering glucagon in those old case studies, they may have been inadvertently testing the effects of insulin!
Interestingly, there may be another spanner in the glucagon works. Through the wonders of the Internet, I was able to listen to a lecture by clinical toxicologist Dr. Kerns at the Carolinas Medical Center where he commented that: “Nearly all studies examining glucagon… were conducted prior to the availability of recombinant glucagon and used Eli Lilly’s standard glucagon preparations instead… The standard preparation of glucagon, made from mammalian pancreatic extract, contained insulin (also from pancreatic cells) until recombinant glucagon was available in 1998. Some vials of glucagon, when analyzed by this study group at Carolinas Medical Center, contained 100 units of insulin. This even if there was any benefit from adminstering glucagon in those old case studies, they may have been inadvertently testing the effects of insulin!
So if glucagon is gone, what are we using?The standard approach these days is initial fluid resusucation, temporising treatemnt with atropine and (in the case of CCBs) calcium, followed by the early administration of catecholamine infusions and high dose insulin euglycemic therapy or HIET.HIET has only gone head to head to with glucagon in one study I’m aware of – 6/6 pigs with propanololtoxicty survived with insulin, only 4 with glucagon. Meanwhile on the order of 100 cases of HIET for BB and CCB overdose have been published, and clinical toxicologists are finding that they can sleep more peacefully on call.Is there equipoise for an RCT on HIET?Recent TPR paper suggesting that catecholamines work well and are safehttp://www.thepoisonreview.com/2013/05/17/are-vasopressors-effective-therapy-in-calcium-channel-blocker-overdose/That’s a story for another day…
We will now shift focus to calcium, digoxin and the stone heart theory.
I first became interested in this when I saw an elderly woman in the ED with an ECG that looked a bit like this.
Her gas showed she had a K of 6, in the context of acute renal impairment, so I gave her calcium gluconate for it’s cardioprotective effects – given that she had a junctinoal rhythm and peaked T wavesThen I found out she was on digoxin – and sure enough her digoxin level was high
This made me uncomfortable, because all the best toxicology textbooks warn against giving calcium in the setting of hyperkalemia.
But in digoxin toxicity, the prevailing dogma for some time has been that calcium administration runs the ‘risk of creating a stone heart’, as suggested by studies in animal models in the first half of last century.The stone heart refers to an irreversible non-contractile state, due to impaired diastolic relaxation from calcium-troponin C binding.
Let’s look more closely at digoxin’s effects on cardiac myocytes:Like all cardiac glycosides, digoxin causes inhibition of Na/K ATPase pump on the surface of cardiac myocytesThis leads to increased intracellular Na -> impairs sodium-dependent calcium transport out of the myocyte -> increase in intracellular calcium concentration -> increased inotropy and automaticityThis also leads to decreased transport of K into cells by the Na/K ATPase pump -> hyperkalemiaCardiac glycosides also inhibits activity at the sinoatrial and atrioventricular nodes causing bradycardia and heart blocks.The basis for the stone heart theory comes from the biological plausability of an increase in intracellular calcium caused by digoxin, that is was found to worsen digoxin toxicty in some animal models and there are case reports highlighting the temporal relationship between calcium adminstration and death in digoxin toxic patients.
So given this theory – what happened to my patient?
She got better of courseSo, what exactly is the story behind the stone heart theory?
It turns out that my experience — the worthless anecdote that it is — is backed up by the meagre evidence out there.A retrospective case series by Levine et al, 2011. They found 2020 patients with serum digoxin concentration >2.0 ng/dl at a single center from 1989 to 2005Of which 161 were deemed digoxin toxic based on clinical criteria
20% of digoxin toxic patients died (from whatever reason) – digoxin toxicity is often a marker of intercurrent illness, such as worsening renal failure
and secondly, it didn’t matter if they received calcium or not.5/23 patients given IV calcium died (22%) compared with 27/136 (20%) of those who did not receive calcium (OR for death 1.1, 95%CI 0.38 – 3.3)
No patients had a dysrhythmia within 4 hours of giving calcium
Obviously we won’t get too carried away the findings of a humble chart review, a small study that is unlikely to detect rare cardiac events and the aptients overwhelmingly suffered from chroinc digoxin toxicty, leaving open the question in acute digoxin toxicity.But where is the evidence for the stone heart in humans?
Although there are multiple case reports of calcium use in patients with digoxin toxicty without any ill effects, it turns out there are only 5 case reports suggesting a temporal relationship between calcium administration and death in the setting of digoxin toxicity (primarily from the 1930s and 1950s). These cases are poorly detailed, no symptoms of digoxin toxicity are not described, no digoxin levels were taken and only 2 cases had a strong temporal relationship (which does not imply causation). Given that gigoxin toxicity is often a marker of severe comorbidities, it is highly likely that deaths may be unrelated to digoxin toxicity or its treatment.
Furthermore the original animal models were flawed animals were made severely hypercalcaemic (e.g. >15 mM/L) prior to digoxin administration and subsequent animal models mimicking digoxin toxicty have failed to demonstrate adverse effects
Now that all pieces are in place…
I think it is clear that the contra-indication of calcium for hyperkalemia in the setting of digoxin toxicity is a pseudoaxiomThe term, comes from emergency physician David Newman, who states that whereas Axioms are universally accepted principles or rules, Pseudoaxioms, like pseudoscience, are false principles or rules often handed down from generation to generation of medical providers and accepted without serious challenge or investigation.
Our next candidate for toxicological myth or mis-truth is liver transplantation for paracetamol
We know that a minority of paractamol overdoses devleop severe hepatoxicty that can be lethal.Ultimately such patients typically die from cerebral edema and or multi organ failure days after ingestionIt makes sense that if we can identify these patients, that we try to save them by providing them with a liver transplant.This presents with a dilemma – who should receive a transpalnt?
We need to find transplant candidates early, so that they do do not become so sichk that they cannot survive the transplant procedure
But we need to be picky – we need to be able to choose the right patients – There are the risks to life, and quality of life, from major surgery and subsequent immunospuppressionIt requires big bucksAnd there is the opportunity cost – organs are precious, someone has to miss out
Which is why O’Grady and colleagues developed the King’s college Criteria to select which paracetamol poisoned patients should receive liver transplantsThis is the most commonly used prediction model for this pupose and is the basis for ELT registration in many countries
These are the criteria –They are based on data on a retrospective study on 588 patients with ALF managed medically during 1973–1985 that was subsequently validated in an independent cohort of 175 ALF patients treated between 1986 and 1987
Case series and meta-analyses suggest that KCC has a specificity of ~80-90%Sensitivity of KCC has been reported to be as low as ~60-70%indicating that KCC may fail to detect patients facing a fatal outcome without ELT – lactate has been added to try to improve this
Now my Skepticism may be prompted by a lack ofmarcharchistfervour — indded I would be far more concerned if these were the King Charles Criteria, we’d be making decisions based on the feelings of plants and patient’s shaqras…But I think this is well worth looking intoI think there are problems with the KCC
One of the most interesting analyses of the King’s College Criter for paracetamol hepatotoxicity is this paperby Ding and Buckley in 2008They performed a systematic review of papers published from January 1989 to January 2007They included studies included if data was available on survival rates of patients who met KCC but were not transplanted This allowed them to determine chance of survival in these patientsthere were 15 studies (an additional 10 had temporal overlap resulting in the same data being published twice)To determine survival of patients who received liver transplants as a comparisonThey then used the United Kingdom Transplant Support Service Authority, Liver Transplant Audit 1985–95 data
And from all of this they modeled outcome of decision to transplant a 20-year-old on their survival over the next 60 yearsAnd they assumed that the quality of life for a transplanted person estimated to be 0.6 compared to a healthy personThis is what they found:386 patients met KCC but were not transplantedof these 96 (24.9%) survived (95% Confidence interval 20.8–29.4) at 10 yearsliver transplant recipients after acute liver failure by comparison have survival at 10 years of 44% (95% CI 38–50)however, the survival advantage becomes increasingly unfavourable with extrapolation beyond 10 years, and even more so when using QALY
the expected survival benefit calculated as area under curve (AUC) for a 20-year-old with the KCC was similar without a transplant (13.4 years) as with a transplant (13.5 years), and the latter was only 8.1 QALYs.however, the survival advantage becomes increasingly unfavourable with extrapolation beyond 10 years, and even more so when using QALY
I think the KCC are a house of cards waiting to fallThe validty of the KCC is doubt because of spectrum biasThe overall survival benefit appears to marginal at best for liver transplantation (likely higher for older patients), even without considering quality of life and cost-effectiveness, given available dataFurthermore, the overall prognosis of paracetamol overdose is improving – with better use of NAC and better ICU care.
I highlighted these as case studies of how dogma in toxicology occurs, and indeed how it perpetuates throughout critical care and medicine.So let’s reflect on why there is so much dogma out there…
At the core is often a flawed understanding of physiology or expectation of biological plausability, to quote David Newman again, “a logical theory often trumps reality”.
Sometimes this comes from extrapolating from animal studies – or may or may not behave as humans do — but more importantly such studies are more geared towards proof of concept, and are far less rigourous clinical studies performed in humans.Many pseudoaxioms are based on case reports and anecdotes – and the toxicology literature is fraught with them.
We also see root literature get misinterpretated after it is referenced by secondary literatire, which is then compounded by a lack of awareness of the original data and neglect to examine all the available evidence.Conjecture becomes fact
Dogma also persists when we favourimmediate physiological gain (surrogate outcomes) that may not translate into patient-orientated clinically significant outcomes, or even benefit to society.
Other factors inlude the way current publication practices distort science – positive trials are more liekly to be published, and there is the malign influence of Big Pharma and other toxic facotrs
– and finally we need certainty to practice. Functioning in a state of constant flux is difficult, and we are not good an unlearning things.
So what is the way forward?Knowledge translation and disseminationBattle of ideas – hospital ,streets on the internetAccessible dataRegistriesProperly performed trialsAppropriate analysis of uncontrolled data
Before we embrace the cynival view that the history of toxicology as a repetition of the mistakes of Mithradates — a lack of correctly performed studies, mixed with myths and mis-truths about which substances are truly hazardous and which treatments actually work.But toxicology has not been without it’s advances.Take the barbaric practice of gastric lavage for instnce.First used on opium eaters in London in 1822, where it was known as Jukes' "exhausting pump" and Bush's "gastric exhauster”GL ultimately had its heyday with the rise of barbiturate overdoses in the 1950s and 1960sSincen then major toxicology organisations have recommended that it be all but abandoned, including the most recent position statements from the AACT and theirEuropean counterparts in Yet – in some settings – such as the developing world, this sometimes lethal procedure is still widely performedThe reasons included higher case fatality rates for poisonings (10-20% versus 0.5% in the West)The lack of other therapeutic optionsAnd becaue of entrenched dogma
Finally, the onus is on us. I’d like to finish with a quote from an article written by the speaker who follows me, RinaldoBellomo “It is everyone’s responsibility to find out how to ask questions systematically, find answers from searching the literature, critically appraise the literature and apply he results to practice” That is how I think we can bring down fight and identify the myths and mis-truths not just in toxicology, but in the wider spheres of critical care and medicine.Insert reference