ToxicologicalMyths and HALF-TruthsChris Nickson FACEMAlfred ICU Senior RegistrarA Talk by Chris Nickson FACEMSenior Regist...
Image	  from	  h+p://technicalinfodotnet.blogspot.com.au/2012/03/virtual-­‐execu@on-­‐and-­‐emperors-­‐new.html	  NO CONFL...
Photo	  by	  Cavin	  on	  Flickr	  
Glucagon	  	  Calcium,	  Digoxin	  &	  	  the	  Stone	  Heart	  Theory	  	  Paracetamol	  Toxicity	  &	  	  Liver	  Transp...
Glucagon	  	  Calcium,	  Digoxin	  &	  	  the	  Stone	  Heart	  Theory	  	  Paracetamol	  Toxicity	  &	  	  Liver	  Transp...
Glucagon	  	  Calcium,	  Digoxin	  &	  	  the	  Stone	  Heart	  Theory	  	  Paracetamol	  Toxicity	  &	  	  Liver	  Transp...
Glucagon
Glucagone?
Boyd	  R,	  Ghosh	  A.	  Towards	  evidence	  based	  emergency	  medicine:	  best	  BETs	  from	  the	  Manchester	  Roya...
[In toxicology an] evidence basis is oftenlacking and one therefore needs to rely on acombination of practical experience,...
Each of us has personal experience of thedramatic improvement in cardiovascularparameters that can occur following theadmi...
…Nobody would suggest that naloxone should notbe used for opiate overdose yet the evidencebase for its use is as flimsy as ...
Smith	  GC,	  Pell	  JP.	  Parachute	  use	  to	  prevent	  death	  and	  major	  trauma	  related	  to	  gravita@onal	  c...
Photo	  by	  JD	  Hancock	  on	  Flickr	  Or isglucagon oneof these?
Show me theevidence!Photo	  by	  Chris	  Nickson	  
Photo	  by	  zzpa	  on	  Flickr	  
Photo	  by	  zzpa	  on	  Flickr	  Before 1998 some	  vials	  of	  glucagon	  contained	  up	  to	  100	  units	  of	  insu...
Photo	  by	  Marianne	  Perdomo	  New dogma?Insulin 6versusGlucagon 4
Calcium,Digoxin and theStone HeartTheory
Photo	  by	  Peregrinari	  on	  Flickr	  
h+p://lifeinthefastlane.com/ecg-­‐library/basics/hyperkalaemia/	  
Calcium,Digoxin Toxicityand theStone HeartTheoryCalciumfor	  hyperkalaemia	  in	  digoxin	  toxicity?	  Photo	  by	  Gapto...
Photo	  by	  Melina	  from	  Flickr	  Beware the Stone Heart!
h+p://www.realmagick.com/digoxin-­‐mechanism-­‐of-­‐ac@on/	  
Whathappened tome?Photo	  by	  Peregrinari	  on	  Flickr	  
She	  gotbetter
doi:10.1016/j.jemermed.2008.09.027Selected Topics:ToxicologyTHE EFFECTS OF INTRAVENOUS CALCIUM IN PATIENTS WITHDIGOXIN TOX...
20%of	  pa@ents	  with	  	  digoxin	  toxicity	  died	  
No difference	  	  if	  IV	  calcium	  was	  given	  or	  not	  	  	  calcium	  given:	  5/23	  (22%)	  died	  not	  given...
No dysrhythmias 	  within	  4	  hours	  of	  IV	  calcium	  
Photo	  by	  Stefan	  onFlickr	  We need tokeep looking…
Only	  5 case reports of	  	  calcium	  linked	  to	  death	  in	  digoxin	  toxicity	  	  None	  are	  convincing	  Bower...
Original	  animal	  models	  	  were	  flawed…	  	  Only	  harmful	  if	  calcium	  	  >15 mmol/L	  
Photo	  by	  Nitot	  from	  Flickr	  
Pseudoaxioms	  false	  principles	  or	  rules	  handed	  down	  	  from	  	  genera@on	  to	  genera@on	  	  and	  accept...
Paracetamol OverdoseandLiver Transplantation
A dilemmaPhoto	  by	  dno1967b	  on	  Flickr	  
Select earlyPhoto	  by	  dno1967b	  on	  Flickr	  
Photo	  by	  dno1967b	  on	  Flickr	  Select earlyRisks of surgeryImmunosuppression$$$$$Opportunity cost
King’s CollegeCriteriafor	  paracetamol-­‐induced	  hepatoxicityGrady	  JG,	  Alexander	  GJ,	  Hayllar	  KM,	  Williams	 ...
pH < 7.3or,	  in	  a	  24h	  period,	  all	  3	  of:	  INR > 6 (PT > 100s)Cr > 300 mmol/Lgrade III or IV encephalopathyrec...
King’s	  College	  Criteria	  	  is	  specific	  	  80-­‐90%	  	  but	  not	  sensi@ve	  60-­‐70%	  
King’sCollegeCriteriaPhoto	  by	  	  The	  PIX-­‐JOCKEY	  on	  Flickr	  What couldpossibly bewrong withthe King’sCriteria?
Evidence and consequences of spectrum bias in studies ofcriteria for liver transplant in paracetamol hepatotoxicityG.K.A. ...
0 10 20 30 40 50 60050100TransplantedNot transplantedextrapolationQALY (transplanted)extrapolationYears after transplantSu...
Survival benefitfor	  a	  20-­‐year-­‐old	  who	  meets	  	  King’s	  College	  Criteria	  	  13.4	  years	  without	  tra...
Photo	  by	  shenamt	  on	  Flickr	  
Why so muchdogma?
Flawed	  understanding	  of	  physiology	  	  Poor	  quality	  or	  invalid	  studies	  	  ‘Chinese	  whispers’	  	  Surro...
Flawed	  understanding	  of	  physiology	  	  Poor	  quality	  or	  invalid	  studies	  	  ‘Chinese	  whispers’	  	  Surro...
Flawed	  understanding	  of	  physiology	  	  Poor	  quality	  or	  invalid	  studies	  	  ‘Chinese	  whispers’	  	  Surro...
Flawed	  understanding	  of	  physiology	  	  Poor	  quality	  or	  invalid	  studies	  	  ‘Chinese	  whispers’	  	  Surro...
Flawed	  understanding	  of	  physiology	  	  Poor	  quality	  or	  invalid	  studies	  	  ‘Chinese	  whispers’	  	  Surro...
Flawed	  understanding	  of	  physiology	  	  Poor	  quality	  or	  invalid	  studies	  	  ‘Chinese	  whispers’	  	  Surro...
Which way now?
Eddleston	  M,	  et	  al.	  The	  hazards	  of	  gastric	  lavage	  for	  inten@onal	  self-­‐poisoning	  in	  a	  resourc...
“It	  is	  	  everyone’s responsibility 	  to	  find	  out	  how	  to	  ask	  ques@ons	  systema@cally,	  find	  answers	  f...
Photo	  by	  Incurable_hippie	  on	  Flickr	  The EndTalk	  resources	  at	  h+p://liDl.org/11p0o81	  
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Toxicological Myths and Half-Truths

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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"

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  • 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 -&gt; impairs sodium-dependent calcium transport out of the myocyte -&gt; increase in intracellular calcium concentration -&gt; increased inotropy and automaticityThis also leads to decreased transport of K into cells by the Na/K ATPase pump -&gt; 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 &gt;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. &gt;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&apos; &quot;exhausting pump&quot; and Bush&apos;s &quot;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
  • Toxicological Myths and Half-Truths

    1. 1. ToxicologicalMyths and HALF-TruthsChris Nickson FACEMAlfred ICU Senior RegistrarA Talk by Chris Nickson FACEMSenior Registrar at the Alfred ICU
    2. 2. Image  from  h+p://technicalinfodotnet.blogspot.com.au/2012/03/virtual-­‐execu@on-­‐and-­‐emperors-­‐new.html  NO CONFLICTS OF INTERESTTalk  resources  at  h+p://liDl.org/11p0o81  
    3. 3. Photo  by  Cavin  on  Flickr  
    4. 4. Glucagon    Calcium,  Digoxin  &    the  Stone  Heart  Theory    Paracetamol  Toxicity  &    Liver  Transplanta>on  
    5. 5. Glucagon    Calcium,  Digoxin  &    the  Stone  Heart  Theory    Paracetamol  Toxicity  &    Liver  Transplanta>on  
    6. 6. Glucagon    Calcium,  Digoxin  &    the  Stone  Heart  Theory    Paracetamol  Toxicity  &    Liver  Transplanta>on  
    7. 7. Glucagon
    8. 8. Glucagone?
    9. 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.      OConnor  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. 10. [In toxicology an] evidence basis is oftenlacking and one therefore needs to rely on acombination of practical experience, casereports and assessment of biologicalplausibility. There is a sound theoretical basisfor the use of glucagon in the cardiovascularlycompromised patient who has taken a betablocker overdose. Glucagon activates adenylcyclase and exerts an inotropic andchronotropic effect by a pathway that bypassesthe beta receptors.…
    11. 11. Each of us has personal experience of thedramatic improvement in cardiovascularparameters that can occur following theadministration of glucagon in this clinicalsituation.…
    12. 12. …Nobody would suggest that naloxone should notbe used for opiate overdose yet the evidencebase for its use is as flimsy as that of glucagonin beta blocker overdose. We suggest that toattempt to undertake a randomised clinicaltrial of the use of glucagon in the compromisedbeta blocker overdosed patient would beunethical.…
    13. 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 glucagonreally aparachute?
    14. 14. Photo  by  JD  Hancock  on  Flickr  Or isglucagon oneof these?
    15. 15. Show me theevidence!Photo  by  Chris  Nickson  
    16. 16. Photo  by  zzpa  on  Flickr  
    17. 17. Photo  by  zzpa  on  Flickr  Before 1998 some  vials  of  glucagon  contained  up  to  100  units  of  insulin
    18. 18. Photo  by  Marianne  Perdomo  New dogma?Insulin 6versusGlucagon 4
    19. 19. Calcium,Digoxin and theStone HeartTheory
    20. 20. Photo  by  Peregrinari  on  Flickr  
    21. 21. h+p://lifeinthefastlane.com/ecg-­‐library/basics/hyperkalaemia/  
    22. 22. Calcium,Digoxin Toxicityand theStone HeartTheoryCalciumfor  hyperkalaemia  in  digoxin  toxicity?  Photo  by  Gaptone  on  Flickr  
    23. 23. Photo  by  Melina  from  Flickr  Beware the Stone Heart!
    24. 24. h+p://www.realmagick.com/digoxin-­‐mechanism-­‐of-­‐ac@on/  
    25. 25. Whathappened tome?Photo  by  Peregrinari  on  Flickr  
    26. 26. She  gotbetter
    27. 27. doi:10.1016/j.jemermed.2008.09.027Selected Topics:ToxicologyTHE EFFECTS OF INTRAVENOUS CALCIUM IN PATIENTS WITHDIGOXIN TOXICITYMichael Levine, MD,* Heikki Nikkanen, MD,†‡ and Daniel J. Pallin, MD†*Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, Arizona, †Department of Emergency Medicine,Brigham and Women’s Hospital, Boston, Massachusetts, and ‡Division of Medical Toxicology, Division of Emergency Medicine,Children’s Hospital, Boston, MassachusettsReprint Address: Michael Levine, MD, Department of Medical Toxicology, Banner Good Samaritan Medical Center,925 East McDowell Road, 2ndfloor, Phoenix, AZ 85006e Abstract—Background: Digoxin is an inhibitor of the mortality. We found no support for the historical beliefThe Journal of Emergency Medicine, Vol. 40, No. 1, pp. 41–46, 2011Copyright © 2011 Elsevier Inc.Printed in the USA. All rights reserved0736-4679/$–see front matter
    28. 28. 20%of  pa@ents  with    digoxin  toxicity  died  
    29. 29. No difference    if  IV  calcium  was  given  or  not      calcium  given:  5/23  (22%)  died  not  given:  27/136  (20%)  died  
    30. 30. No dysrhythmias  within  4  hours  of  IV  calcium  
    31. 31. Photo  by  Stefan  onFlickr  We need tokeep looking…
    32. 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  
    33. 33. Original  animal  models    were  flawed…    Only  harmful  if  calcium    >15 mmol/L  
    34. 34. Photo  by  Nitot  from  Flickr  
    35. 35. Pseudoaxioms  false  principles  or  rules  handed  down    from    genera@on  to  genera@on    and  accepted  without  serious  challenge  or  inves@ga@onNewman  DH:  Truth,  and  epinephrine,  at  our  finger@ps:  unveiling  the  pseudoaxiom.  Ann  Emerg  Med  2007;  50:476–477.  
    36. 36. Paracetamol OverdoseandLiver Transplantation
    37. 37. A dilemmaPhoto  by  dno1967b  on  Flickr  
    38. 38. Select earlyPhoto  by  dno1967b  on  Flickr  
    39. 39. Photo  by  dno1967b  on  Flickr  Select earlyRisks of surgeryImmunosuppression$$$$$Opportunity cost
    40. 40. King’s CollegeCriteriafor  paracetamol-­‐induced  hepatoxicityGrady  JG,  Alexander  GJ,  Hayllar  KM,  Williams  R.  Early  indicators  of  prognosis  in  fulminant  hepa@c  failure.  Gastroenterology.  1989  Aug;97(2):439-­‐45.
    41. 41. pH < 7.3or,  in  a  24h  period,  all  3  of:  INR > 6 (PT > 100s)Cr > 300 mmol/Lgrade III or IV encephalopathyrecent  modifica@on:    lactate >3.5 mM
    42. 42. King’s  College  Criteria    is  specific    80-­‐90%    but  not  sensi@ve  60-­‐70%  
    43. 43. King’sCollegeCriteriaPhoto  by    The  PIX-­‐JOCKEY  on  Flickr  What couldpossibly bewrong withthe King’sCriteria?
    44. 44. Evidence and consequences of spectrum bias in studies ofcriteria for liver transplant in paracetamol hepatotoxicityG.K.A. DING1,2,3and N.A. BUCKLEY1,4From the 1Australian National University Medical School, ACT, 2Department of Intensive Care,The Canberra Hospital, 3Department of Intensive Care, The Calvary Hospital, Canberra and4Faculty of Medicine, University of NSW, AustraliaReceived 31 October 2007 and in revised form 7 April 2008SummaryObjective: In severe paracetamol hepatotoxicity,orthotopic liver transplant (OLT) is a standardtreatment in patients judged to have a hopelessprognosis. The most commonly used criteria tomake this decision are the King’s College CriteriaSurvival was worse in studies originating in theKing’s unit (13.8 vs. 30.0%). It was apparent that thismay be due to spectrum bias occurring in this muchlarger unit. There was clear evidence that those withthe best prognosis were preferentially transplantedQ J Med 2008; 101:723–729doi:10.1093/qjmed/hcn077 Advance Access published on 7 July 2008
    45. 45. 0 10 20 30 40 50 60050100TransplantedNot transplantedextrapolationQALY (transplanted)extrapolationYears after transplantSurvival%
    46. 46. Survival benefitfor  a  20-­‐year-­‐old  who  meets    King’s  College  Criteria    13.4  years  without  transplant  13.5  years  with  transplant  (8.4  QALYs)  
    47. 47. Photo  by  shenamt  on  Flickr  
    48. 48. Why so muchdogma?
    49. 49. Flawed  understanding  of  physiology    Poor  quality  or  invalid  studies    ‘Chinese  whispers’    Surrogate  outcomes    Publica>on  prac>ce  distorts  science    Difficulty  learning  to  unlearn  
    50. 50. Flawed  understanding  of  physiology    Poor  quality  or  invalid  studies    ‘Chinese  whispers’    Surrogate  outcomes    Publica>on  prac>ce  distorts  science    Difficulty  learning  to  unlearn  
    51. 51. Flawed  understanding  of  physiology    Poor  quality  or  invalid  studies    ‘Chinese  whispers’    Surrogate  outcomes    Publica>on  prac>ce  distorts  science    Difficulty  learning  to  unlearn  
    52. 52. Flawed  understanding  of  physiology    Poor  quality  or  invalid  studies    ‘Chinese  whispers’    Surrogate  outcomes    Publica>on  prac>ce  distorts  science    Difficulty  learning  to  unlearn  
    53. 53. Flawed  understanding  of  physiology    Poor  quality  or  invalid  studies    ‘Chinese  whispers’    Surrogate  outcomes    Publica>on  prac>ce  distorts  science    Difficulty  learning  to  unlearn  
    54. 54. Flawed  understanding  of  physiology    Poor  quality  or  invalid  studies    ‘Chinese  whispers’    Surrogate  outcomes    Publica>on  prac>ce  distorts  science    Difficulty  learning  to  unlearn  
    55. 55. Which way now?
    56. 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. 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.  
    58. 58. Photo  by  Incurable_hippie  on  Flickr  The EndTalk  resources  at  h+p://liDl.org/11p0o81  

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