Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital AHA Evidence Based Guidelines How to proceed with scant evidence

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Levels of Evidence 1

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Levels of Recommendation

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital AHA Guidelines  Cocaine-Induced Ventricular Dysrhythmias l Recommended Therapies, Ordered By Preference: –Sodium Bicarbonate (IIB), Lidocaine (IIB), Alpha Adrenergic Blockers (IIB) l Inappropriate Therapies: –Non-Selective Beta Blockers, Epinephrine (Both III)  Cocaine-Induced Acute Coronary Syndrome (ACS) l Recommended Therapies, Ordered by Preference: –Benzodiazepines (IIB), Nitrates (IIB), Alpha- Adrenergic Antagonists (IIB) l Inappropriate Therapies: –Non-Selective Beta-Blockers (III)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital AHA Guidelines  Calcium Channel Blocker Poisoning or Overdose l Recommended Therapies, Ordered By Preference: –Pacemaker, Vasopressors, High-Dose If Necessary(IIB), Calcium (IIB)  Beta-Blocker Poisoning or Overdose l Recommended Therapies, Ordered By Preference: –Pacemaker, Vasopressors, High-Dose If Necessary (IIB), Glucagon (IIB)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital AHA Guidelines  Tricyclic Antidepressant Poisonings l Recommended Therapies, Ordered By Preference: –Sodium Bicarbonate (IIB), Lidocaine l Inappropriate Therapies: –Procainamide (III)  Refractory Drug-Induced Shock l High-Dose Vasopressors (IIB), Circulatory Assist Devices (IIB), Vasopressin (Indeterminate)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Opiate Poisoning: Ventilation before Naloxone? Dr Andrew Dawson Director Hunter Area Toxicology Service Newcastle, Australia

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Opiate Poisoning: Ventilation before Naloxone?  “Evidence supports the correction of respiratory failure with bag valve mask techniques followed by administration of naloxone in any patient suspected of opioid induced respiratory failure.”

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Are all clinical situations the same?  24 year male recreational heroin OD  75 year male IHD post operative narcosis  24 year old post heroin OD respiratory arrest being ventilated

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Naloxone & Ventilation Grid

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Naloxone: Efficacy  Animal –Good controlled studies  Clinical data –Anaesthetic l Good controlled studies –Clinical Toxicology l Case series –indirectly address the issues

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Naloxone: Risk  Incidence of possible ADR <1%  Seizure & cardiac arrest –Extremely rare –Probably catecholamine mediated  ? Pulmonary Oedema  Behavioural 7%

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Naloxone & Catecholamines  Increases catecholamine release –especially in the presence of hypercapnoea –The correction of of hypercapnoea reduces haemodynamic effects. l Mills CA (1988)  There is no clinical evidence to support hypercapnoea correction prior to administration of naloxone.

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Mills et al

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Mills et al

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Naloxone Dose  0.12 mg endpoint ETCO 2 < 6.5% Tigerstedt  Out of Hospital: Protocol Driven

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Respiratory Arrest/Depression  Detectable pulse & BP  >90% response to naloxone  IV=IM –Sporer et al  IV=SC –Wanger et al

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Opioids: Asystolic arrest  Prehospital physician & paramedic medical team survival (4/7) –all IV naloxone l Bertini G et al  Prehospital paramedic (0/16) –50% received naloxone IV l Sporer KA et al 1996

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Is Naloxone Neurotoxic?  Glutamate mediated neuroexcito-toxicity  Modulating effect of endorphines & morphine  Direct effects of Naloxone

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Excitatory amino acids, glutamate Increased intracellular calcium and sodium Protein kinases C, II Proteases Phosphatases Excitotoxicity Ca 2+ Phospholipases Xanthine oxidase Nitric oxide synthase (NO) Heme oxygenase (CO) Endonucleases

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Glutamate accumulation Astrocyte Presynaptic Postsynaptic Astrocyte

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital NMDA Sodium and Calcium NMDA or glutamate Glycine Poly- amine H+H+ Phencyclidine Zinc Magnesium SH NO-S

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital AMPA, Kainate Sodium or Calcium AMPA Kainic acid or glutamate 2,3-benzo- diazepines

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Drug modification  Decreased glutamate release –Adenosine derivatives, catecholamines –Sodium channel blockers l Phenytoin l Lamotrigine –Ca 2+ -channel blockers (L-type) l Nimodipine –Platelet activating factor antagonists

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Drug modification  Glutamate receptor antagonism –Glutamate binding site –2,3-benzodiazepine site l GYKI 52466, ? very high dose diazepam –Glycine binding site l Felbamate –Receptor associated ion channel l Magnesium, ketamine, memantine –Redox modulatory site l Nitroglycerine, nitroprusside

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Opioids: Ventilation before Naloxone  “Evidence supports efforts to correct respiratory acidosis and hypoxia followed by naloxone administration in patients suspected of opioid induced respiratory failure.”  Class IIb

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Naloxone Dose  IMI: 0.8mg –If systolic BP >100 mmHg  IV: 0.4 mg –Cardiac arrest –If an IV line is in situ  Repeated & titrated against response  Rate of non-behavioural adverse reactions does not appear to be related to dose