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•Toxic Withdrawals Jennifer Nicol PGY-1 Dr. Yael Moussadji May 27th, 2010 Outline • Will cover withdrawal from: – Alcohol – Opioids – Benzodiazepines – Cocaine The Facts: addiction and withdrawal • Emergency physicians must recognize and treat many phases of substance abuse • 80% Canadians drink alcohol – Majority moderation without harm – 17% high risk drinking • 2002: Cost of illicit drugs, tobacco, and alcohol – Canada $40 billion – Alberta $4.4 billion Principles of Withdrawal • Every withdrawal syndrome has two characteristics: – pre-existing adaptation to a drug, the continuous presence of which prevents withdrawal – decreasing concentrations of that drug Principles of Withdrawal • Withdrawal syndromes that fulfil both criteria are treated by re-administration followed by weaning of drug – Opiates, benzodiazepines, alcohol • Withdrawals that fulfil only first criteria are treated by supportive measures only – I.e. cocaine, marijuana DSM-IV: withdrawal • Withdrawal is manifested by either of the following: – a characteristic withdrawal syndrome for the substance – the same (or a closely related) substance is taken to relieve withdrawal symptoms. Case: • 56 yo F chronic alcoholic • Stopped drinking 3 days prior. Now feels tremulous, nauseous, disoriented, • Has had numerous falls in the past 3 days, can’t use her right hand • Thoughts? Case (con’t) • PMHx: – alcohol withdrawal seizures, DT – CAD, HTN, Afib, COPD – ICU admission 2 months ago for DTs • NSTEMI during admission • Meds: – ASA, tinzaparin, metoprolol, trazadone, advair, lipitor • Do you have any concerns? Alcohol Withdrawal Syndrome (AWS) • 15-20% inpatients and ED patients are alcohol dependant • Many present with unrelated problems – Trauma – Infections / sepsis – Pancreatitis, renal failure – ACS, stroke Historical Perspective Pathophysiology • Alcohol has depressant effect on CNS • Effects of alcohol dependency and tolerance mediated primarily through 2 receptor systems: – GABAα – NMDA • Withdrawal characterised by CNS excitation NMDA • EtOH inhibits excitatory neurotransmitter glutamate function at NMDA • chronic EtOH use – upregulation of NMDA receptors. • When EtOH withdrawn, increased NMDA receptor activity Clinical Presentation • “The patient is restless and agitated, requiring restraints… conversation being garbled and unintelligible. Autonomic over-activity is manifested by dilated pupils, tachycardia, and an elevated temperature, attributable occasionally to no other cause other than delirium.” – Victor and Adams 1953 I swear, I only had one drink 2 nights ago. Clinical Presentation • Three sets of symptoms: – Autonomic hyperactivity • Tremor, hypertension, hyperthermia, hyper-reflexia • Sleep disturbances, diaphoresis, nausea, vomiting, – Neuronal excitation • Alcohol withdrawal seizures – DT’s • Extreme end of AWS spectrum • Profound confusion, delirium, hallucinations • Hyperadrenergic state Clinical Presentation • Symptoms develop 6-12 hrs after reduction of EtOH intake. • Spectrum of withdrawal: – Mild – Moderate – Delirium tremens • Duration of withdrawal up to 7 days Clinical Presentation - Classification • Minor – Early onset 6hrs, peak 24-48 hrs – Mild autonomic hyperactivity: nausea, anorexia, coarse tremor, hypertension, tachycardia, sleep disturbance • Major – Later onset 24 hrs, peak 50hrs-5days – Tremor, fever, irritation, ++anxiety, insomnia, anorexia, hypertension, tachycardia – Decreased seizure threshold, hallucinations, hyperreflexia Clinical Presentation - Classification • Delirium Tremens – Serious complication of, not synonymous with AWD – 5-10% pts admitted for alcohol WD – Appears day 3-5 post abstinence (rarely before) – Lasts 5-10 days, up to 2 weeks – Main concern is recognition and early management – MEDICAL EMERGENCY!!! Delirium Tremens DeBellis et al. J Intens Care Med.2005;20:164 DT: Risk Factors • • • • • Tachycardia at admission WD signs with BAL >0.16 mmol/l (1g/L) Infectious process History of withdrawal seizures History of delirious episodes associated with withdrawal DeBellis et al. J Intens Care Med.2005;20:164 DT: Mortality • 5-15% mortality rate – Secondary to complications • RF’s for Mortality – Khan et al. Acad emerg Med. 2008;15:787 – Risk factors: • Physical Restraints • Hyperthermia – Protective: • Use of clonidine • Diagnosis in ED DeBellis et al. J Intens Care Med.2005;20:164 Back to the case • VS: HR130, BP160/90, temp37.6, RR18, SaO2 96 2LNP • On exam: – Confused but oriented, agitated, PERL, tremulous – Large bruise right arm and face – Think she can’t extend right wrist but can’t be sure – she is so tremulous • What other conditions do you want to rule out? AWD – Differential Considerations Wren et al. Amer J Emerg Med. 1991;9(1):57 Differential Considerations • • • • CNS: encephalitis, meningitis, IC bleed Infectious: Numerous sources. GI: hepatic encephalopathy Tox: – Toxidromes: anticholinergic, stimulant – WD: Sedative hypnotics (opiates, benzos, barbituates) – Contemporary alcoholic often polydrug users • Metabolic: thyrotoxicosis, hypoglycemia • Psychiatric: drug induced psychosis, schizophrenia Physical Exam • • • • • Level of consciousness Signs hepatic failure Signs of focal infection Trauma Complete neuro exam – – – – Reflexes Deficits Pupils, occulomotor function Gait if possible, coordination Investigations • • • • • • CBC, lytes, LFT’s, lipase, coags, BUN, Cr, BG EtOH +/- toxic EtOH Blood Cultures Urinalysis, urine culture CXR ECG Investigations • Consider – LP, CT head, VBG, tox screen • Look at your anion & osmolar gaps Diagnosis of Alcohol Withdrawal DSM-IV A. B. Cessation or reduction of alcohol use that has been heavy and prolonged Two or more of the following, developing within several hours to a few days after criterion A: 1. 2. 3. 4. 5. 6. 7. 8. C. D. autonomic hyperactivity (sweating, HR>100/min) Increased hand tremor Nausea or vomiting Insomnia Transient visual, tactile, or auditory hallucinations or illusions Psychomotor agitation Anxiety grand mal seizures The symptoms in criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning The symptoms are not sue to a general medical condition and are not better accounted for by another mental disorder. Return to Case • • • • Hbg 107, WBC 7.4, plt 174 Na 113! K 2.6, Mg 0.47, PO4 0.5 Urinalysis: +nitrates, WBC, RBC CT head: nil acute Management Principles • 4 principles of treatment 1) Evaluate for concurrent illness 2) Restore inhibitory tone to CNS 3) Identify and correct electrolyte & fluid deficiencies 4) Allow pt to recover with the least amount of physical restraint to decrease the risk of hyperthermia and rhabdomyolysis EM Reports 26(16) July 25, 2005 Pharmacologic Intervention • Ideal drug profile for EtOH withdrawal: – Rapid onset – Wide margin safety – Minimal hepatic metabolism – Limited abuse potential – (Cost effective) • High doses, infusions Pharmacologic Intervention • >150 drugs have been used in the last 30 years to treat alcohol withdrawal • Benzodiazepines are the mainstay of current therapy – Potentiate the effects of GABA – Restore the inhibitory tone Mechanism of BZD in Alcohol WD • GABAα downregulated • Loss of chronic inhibition from EtOH • Benzos restores inhibitory tone provided by EtOH Pharmacotherapy - BZD • Numerous prospective trials demonstrating benzos more effective than placebo in decreasing signs and sx of WD – Bowman et al. Dis Nerv Syst. 1966;27:342 – Sellers et al. J Stud Alcohol. 1977;3:575 – Adinoff et al. Alcohol Clin Exp Res. 1995;18:873 • Also beneficial over placebo in decreasing incidence of Sz and delirium – Mayo-Smith, JAMA 1997 278(2):144 • meta analysis 5 pRCTs Choice of Benzo • When considering which benzo to initiate, need to consider: – Route of administration – Hepatic function – Half life – Formulary status – Regime • Symptom triggered vs. Fixed scheduled Benzo profiles Choice of Benzo • No significant difference has been shown between benzos in reducing Sx/signs of WD • Generally: – Long acting: • smoother WD course with fewer rebound and breakthrough WD. • Better seizure prevention – Rapid onset: • control agitation more quickly – Diazepam: long acting and rapid acting • Not on ED formulary Mayo-Smith. Arch int Med. 2004 164:1405 Choice of Benzo • No significant difference has been shown between benzos in reducing Sx/signs of WD • However, long acting can result in increased sedation – Elderly, hepatic failure – Lorazepam: no active metabolites, shorter t½ Benzo Dosing • • • • Diazepam 5-10mg IV q5-10 min Lorazepam 2-4 mg IV q15-20min May require massive doses - >2000mg/48hrs Titrate to desired balance between agitation/withdrawal and level of consciousness (don’t want to intubate the patient!) – “light somnolence” Benzos – Dosing regime • Fixed dose regime – Give set amount of medication at regular intervals – Breakthrough doses for WD symptoms – Taper at end of therapy (ie day7) • Loading Dose – Give initial large dose of long acting medication, which is decreased through metabolism – Not commonly used • Symptom Triggered dosing – Quantify symptoms of WD and dose accordingly Symptom Triggered • Monitored by a structured assessment scale • Given medication only when crosses threshold of severity • Dappen Arch Int Med. 2002;162:1117 – N=117, comparing Sx triggered to fixed dosing – Six fold decrease in amount benzo required (37.5mg vs. 231.4mg) – Shorter duration of therapy (20 vs. 62.7 hrs) • Jaegger et al. Mayo Clinic Proceedings 2001;76 – No change in duration of stay – Decreased DT Kosten et al. NEJM 348;18: 1786 Pharmacotherapy • Doctor, your patient has received 250 mg IV benzos, and now has significant abrasions from his 4 point restraints • Failure of benzo to control symptoms and signs of WD? • What are you going to do now? Resistant Alcohol Withdrawal • Subgroup who require very large doses of benzos to achieve sedation • ICU admission for close monitoring, +/intubation – Symptom triggered vs. fixed dosing vs. benzo infusion – Spies CD et al. Intensive Care Med. 2003;29:2230 • Second line GABAergic drug • Barbituates • Propofol Barbituates • Good alternative for WD resistant to BZD • Directly open GABA ion channels – Usually do not fail to manage AW symptoms • PRO: – Low abuse potential – Long acting – IV/PO/IM • CON – Increased respiratory depression – Lower safety profile in larger doses Young et al. Ann Emerg Med.1987;16:847-850 Yeh et al. J Gen Intern Med. 1992;7:123 Barbituates • Phenobarbital – – – – Long acting (t½ 80-100hrs) Difficult to titrate to sedation vs loss of consciousness 260mg IV over 5min Repeat at 30 min 130mg over 3min until desired effect • Pentobarbital – Short acting – 3-5mg/kg IV bolus followed by 100mg/hr infusion Propofol • GABAα agonist & NMDA antagonist • Rapid onset, short t½ • S/E: hypotension, bradycardia, respiratory depression – More rigorous monitoring than BZD • ICU setting for refractory WD or DT – McCowan et la. Crit Care Med. 2000;28:17811784 • Dose 0.3-1.25mg/kg Adjuncts to Alcohol Withdrawal • To be used IN CONJUNCTION with BZD • Neuroleptics • Adrenergic blockade – Beta blockers – Alpha-1 blockade • Carbamazepine • Magic Vitamins! Adjuncts - Neuroleptics • Increase seizure compared to placebo – 4 pRCTs – Lower seizure threshold – Impair temperature regulation • Sedative hypnotics better at preventing seizures and decreasing mortality • Useful in agitated / hallucinating patient in concert with BZD • Not safe or useful as monotherapy Mayo-Smith. Arch int Med. 2004 164:1405 Adjuncts – Adrenergic blockade • Beta blockers – Decrease WD symptoms – No evidence for an increase, decrease or no effect on WD seizures – Precipitate delirium – Use only in persistent hypertension, tachycardia • Alpha adrenergic blockers – Clonidine decreases WD symptoms – No evidence on seizure effect Adjuncts – Carbamazepine • Used widely in Europe • Antikindling, GABA agonist • Superior to placebo, equal to oxazepam and barbital in mild to moderate WD – Bjorkquist et al. Acta Psychiatr Scanf. 1976;53:333 – Malcom et al. Am J Psychiatry. 1989;146:617 • Limited evidence for treating seizures or delirium • Not recommended for routine use in AW Adjuncts – The Vits! • Thiamine and glucose – Alcoholics are malnourished with deplete thiamine stores – WD pts often left NPO in ED for airway concerns • Hepatic failure – low glycogen stores • Hypoglycemia as ddx for seizure • Wernicke-Korsokoff syndrome Wernicke-Korsokoff syndrome • WE: Acute life threatening neurologic disorder – Encephalopathy – Occulomotor dysfunction – Gait ataxia • Korsokoff: Chronic neuropsychiatric manifestation of WE – Anterograde and retrograde amnesia – Confabulate, long term memory intact Wernicke-Korsokoff syndrome • The real deal on thiamine & glucose – Case reports showing WE after glucose infusions • Koguchi et al. Neurology. 2004;62:512 • Watson et al. Ir J Med Sci. 1981;150:301-303. • Drenick EJ et al. NEJM. 1966;274:937-939. – Signs WE present before administration of glucose – Prolonged parenteral dextrose • “The evidence supports neither the need to precede glucose administration with thiamine. The established biochemical link between the 2 substances reminds clinicians that their contemporaneous administration is desirable. It is our experience that if the first provider fails to give parenteral thiamine at the time of glucose administration, thiamine is often forgotten. We cannot advocate any delay in glucose delivery while awaiting thiamine administration.” 1998; Hack & Hoffman New York City Poison Control Center Adjuncts – The Vits! • Magnesium – Alcoholics are magnesium deplete • Normal on admission, decreased during WD, spontaneously revert to normal after WD – No difference in severity or duration of WD symptoms • Wilson et al. Alcohol Clin Exp Res. 1984;8:452 – No evidence to support use, but if really low replace it Adjuncts – just get drunk again • Ethyl Alcohol – Medicine used by alcoholics everywhere to prevent and treat their withdrawals at home – Toxicity, increased monitoring – Conflicting evidence – No role for ED management of AWS IV vodka STAT!! Case Conclusion • Your patient is admitted to Teams. Becomes very delirious during admission, but is managed with +++ lorazepam and some haldol, on CIWA. • Lytes and UTI are treated. • When delirium clears she is diagnosed with Erb’s palsey • Referred to Foothills addiction program, motivated for change. Case • 64 year old first nations man arrived by EMS following a witnessed ground level fall. – ? Shaking activity ? – homeless alcoholic, new in town from Hobbema • Brought to ER by EMS • Confused, disoriented, can’t tell you what happened • Unkept, malodorous, incontinent of urine. Case • 2 cm lac above L eye, GCS 12, not much else on exam • STAT labs: hbg 120, WBC 15, EtOH 12 • He is given ativan 2mg IV, thiamine, glucose • You send your medical student to suture his lac before his CT head. – Just as she is finishing, pt defecates, rubs it all over his body, and seizes. Alcohol Related Seizures • 8% AW complicated by seizures • One third seizure related admissions are secondary to alcohol • Alcohol causative factor in 11-24% pts with status epilepticus • 90% occur within 48hrs of abstinence • Recurrence risk during same WD episode is 12-24% Differential Considerations... Again • Large DDx to think about: – – – – – – – – – Withdrawal Exacerbation idiopathic/post traumatic seizure Acute intoxication – you name it, it does it Metabolic: hypo-glc,Na,Ca; hyperNa, severe encephalopathy CNS infections Trauma CVA Sleep deprivation Non-compliance with anticonvulsants Rosens 7th Ed. AW Seizures EFNS task force. European Journal of Neurology 2005;12:575–581 AWSz: Classification • Alcohol withdrawal syndrome and: – No seizure history – Positive seizure history – not alcohol related • May be on an antiepileptic for reason pt does not remember or know! – History of withdrawal seizures – Other possible etiologies of seizure (infection, trauma, etc) – Alcohol related status epilepticus ASAM Clinical Practice Guideline Dilantin Dilemma • Placebo controlled trials • No difference in seizure rates between placebo and phenytoin • N=90 Alldredge et al. AM J Med 1989;87:645-8 • N=55 Chance. Ann Emerg Med 1991;20:520-2 • N=100 Rathlev et al. Ann Emerg Med 1994;23:513-8 • Comparison study • No seizures in either arm • N=200 Rothstein. Am J Psychiatry. 1973;130:1381 Dilantin – when to use • Yes, go ahead – Alcohol withdrawal syndrome and a known history of seizure disorder unrelated to EtOH • Grade C recommendation Kasser, CC. ASAM Clinical Practice Guidelines Dilantin – when to use • Have a think about it – Acute AW syndrome + history alcohol WD seizures – AW syndrome other possible causative factors for seizure (meningitis, CNS bleed) • Grade C Recommendation Kasser, CC. ASAM Clinical Practice Guidelines Dilantin – when to use • Nope, don’t do it! – AW and no AW Seizure Hx (Prophylaxis for AW seizures) • Grade A recommendation – Isolated AW seizures • Grade C recommendation Kasser, CC. ASAM Clinical Practice Guidelines Dilantin Dilemma • In context of alcohol withdrawal, best strategy is seizure prevention with benzos • Administer in context of known seizure disorder What if... In context of Alcohol WD • • • • Seizure is focal New onset alcohol related seizure Abnormal neurological deficits Pt is obtunded • These patients warrant a workup Alcohol Withdrawal – Disposition Alcohol Withdrawal – Disposition • Minor withdrawal: – Usually safe to discharge home – “follow up” and referral • Major withdrawal: – admit, usually to MTU, hospitalist • Delirium Tremens, resistant withdrawal – Consider ICU for monitoring, sedation Disposition – Minor WD • Inpatient Detox: – Supervised WD, brief length of stay – Free standing treatment centre vs hospital • Outpatient – Hayashida et al. NEJM 1989;320:358-65. – Safe, efficacious method of detox – Significantly less expensive, no difference at six months of follow up – Don’t have this option in Calgary • Other resources: ADAC Disposition – Alcohol Related Seizures • Return to baseline LOC, no focal neurological deficits, imaging and other cause for Sz ruled out: – d/c home after 4-6 hours observation – “appropriate” follow up • Persistently altered LOC, focal neurological concerns, co-morbid medical – Admit for observation and further workup Calgary Resources • Alpha house – Shelter, detox, outreach (DOAP team, CUPS) • Renfrew House – Detox 40 bed unit. – Intake daily at 8:45, first come first serve basis • AADAC Youth Services – Inpatient detox, family counselling, 3 month residential treatment program – Drop in counselling sessions • Shelters: – DI, Mustard Seed, YWCA, Mary Dover Questions? Case • 32 yo male presents in crisis • 2 days ago stole his dealers car in East Van then crashed it. • Took a bus out West back home. • No family or friends will take him in. • Last heroin the night before. He is tremulous, diaphoretic, and threatening to defecate on the bed in front of you. Opiate withdrawal “The anal clenching misadventure” Terminology • Opioid: natural, synthetic, semi synthetic materials with morphine like action. • Opiate: Natural agents only • Opium: Greek for poppy juice • Narcotic: any agent that induces sleep • Endorphins: endogenous opioids – Enkephalins, beta-endorphins, dynorphins Pathophysiology • 3 main types of endorphin receptors – Mu, kappa, delta – CNS: pain pathways, areas associated with pain perception – Systemic: sensory nerve cell endings, mast cells, GI tract • Effect is inhibitory Goldfrank’s 8th ed. Symptomatology • Early (4-6 hrs) – Restlessness, yawning – insomnia, • Delayed (36-72 hrs) – nausea/vomiting, diarrhea, abdominal cramps • Second stage: – Persistent weakness, insomnia, anxiousness – Can last up to 6 months Signs • Lacrimation, rhinorrhea, perspiration • Piloerection, mydriasis • +/- hypertension, hyperthermia, tachypnea, tachycardia • No seizures • Normal mental status throughout – Offensive +/- violent behaviour Kosten et al. NEJM 348;18: 1786 Management • • • • Control nausea and vomiting Correct volume status Electrolytes Rule out other causes accounting for symptoms • Look for pathology associated with IVDU – IE, abscesses, HCV/HIV and their complications α2 adrenergic agonist • Inhibitory in CNS: • decreases sympathetic activity • Overall effect: depression CNS function, sedation, bradycardia, general sedation • Side Effects: – Hypotension – Dry mouth, lethargy, sedation – Worse with EtOH The Cochrane Library 2009;3 Freitas et al. Amer J Emerg Med. 1985;3:456 Kosten et al. NEJM 348;18: 1786 α2 adrenergic adrenergic agonist • Inhibitory in CNS: • decreases sympathetic activity • Overall effect: depression CNS function, sedation, bradycardia, general sedation • Caution in patients with severe CAD, CVD, chronic renal failure, concurrent alcoholics. The Cochrane Library 2009;3 Freitas et al. Amer J Emerg Med. 1985;3:456 Kosten et al. NEJM 348;18: 1786 Clonidine • 0.1-0.2mg q4h x 10 days – Taper 0.2 mg/day starting at day 3 – Abrupt cessation: • rebound WD, headache • No rebound hypertension • Can be initiated in ED Kosten et al. NEJM 348;18: 1786 Opiate regimes • • • • Not initiated in the ED Methadone Buprenorphine Outpatient detox and addiction services Case • 36 yo M found down in industrial park. • Brought in by EMS after call from unidentified female. • PMHx: (SCM) – Known seizure disorder, takes dilantin – Last ED visit one month earlier for seizure. – Chronic back pain • Netcare: recently filled Rx for oxycodone Case: On exam • • • • • GCS 8 (E2 V2 M4) Protecting airway, hypoventilating Pinpoint pupils Nothing else of note He receives 0.5mg naloxone A few minutes later... • He turns into gorilla man!! • Becomes nauseous, with gooseflesh, pupils 4mm. • Still confused, agitated. • Quick! Get that man some morphine!! Later on that day • He rouses enough to tell you that he had a seizure. • His back was also really sore that day so he took extra “pain killers” • Dilantin level undetectable. Naloxone • • • • Opioid antagonist Rapid onset: 1-2min Half life 1.1 hours Overshoot dosing can precipitate acute withdrawal – Manage conservatively – Do not administer additional opioids – will outlast effect of naloxone Questions? Case • 32 yo F brought in by CPS. Found lying passed out on a park bench • You try to take a history but she keeps falling asleep half way through her sentences. • She does manage to tell you something about a “wild few days...” Cocaine • Plant derived alkaloid – Coca plant used for centuries in South America for medicinal purposes – Cocaine used for over 100 years as recreational drug by in North America and Europe Cocaine • Acute cocaine use causes release of and inhibits reuptake of: – Dopamine – Seratonin – Norepinephrine – Epinephrine • Sodium channel blocker How to cook yourself on Coke • Snort, smash, eat, shoot, muscle, smoke, “Cocaine Crash: The Washout” • Hx: – Hypoactivity: Lethargy, exhaustion, decreased LOC. – Increased appetite, vivid, unpleasant dreams • Px: – Vital signs usually relatively normal. No hypotension, bradycardia, depressed respiration – Psychomotor retardation – Again, look for signs of IVDU and sequelae Complications • Underlying pathology – Diagnosis of exclusion if presenting with ALOC – High index of suspicion for infection, metabolic abnormalities. • Myocardial ischemia Myocardial ischemia • Koonlowee N et al Annals int med. 1989;111;976 – N = 21 consecutive male patients admitted to outpatient treatment facility – All received 24 hr holter and treadmill soon after admission – Holter monitor: 38% spontaneous episodes ischemia (2% control) – 1 had ischemia on stress test Back to Case • Px: HR90, BP100/60, RR12 T37.7, SaO2 98RA – Grimaces during abdo exam – Tender legs and arms to palpation – PERL 3mm, no neuro deficits • WBC 13, nil else • Want a urine sample, but she won’t pee. Con’t • Near the end of your shift, tidying up for handover. – Finally get fed up, do in&out. – ++nitrates, WBC, RBC • She starts to rouse, tells you her right back hurts – Temp 38, HR 100(after tot 2L NS) – Right CVA tenderness – Ando us: shows obstructing right sided nephrolithiasis. Transfer to RGH for management of infected stone. Cocaine WD: Management • Mainly supportive – Most regain normal LOC and are safe for d/c several hours after admission. • Symptoms resolve spontaneously – Washout: 25-40 hrs – All within 1-2 weeks • Anxiety – Short Rx benzo • Rarely need admit, unless underlying condition identified. • Refer to treatment program Questions? Case • 65 yo M presents with SOB, cough, edema • Been feeling unwell for past 2 weeks • 10 lbs weight gain, increasing exertional dyspnea, cough • Feeling very anxious, had several panic attacks in the past few days Case • PMHx: – CHF: last ECHO 2009 EF<30% – HTN, obesity, DMII, OSA, EtOH use – CAD: ACS x 2 2008, 2009 with cath – Generalised Anxiety Disorder • Lorazepam 6 mg q4h on most days. Netcare: multiple Rx lorazepam filled by many MD’s • Not taken in 3 days • How are you going to approach this patient? Benzodiazepines • • • • First BZD chlordiazepoxide 1955 Diazepam 1963 Flumazenil 1987 Net effect is inhibitory – Increase inhibitory GABA – Suppress excitatory NMDA • Tolerance – ↑NMDA; ↓GABAα • Sound familiar?? Withdrawal • First description of BZD withdrawal – Hollister LE et alPsychopharmacologica;1961:63 – Single blinded study of inpatient psychiatric patients – Again, sound familiar? BDZ Withdrawal • Course of BZD WD depends on: – Half life • Short half life early onset, shorter duration – Baseline dose: • Higher dose more profound WD – Duration of therapy / abuse • Case reports >6 weeks high dose BZD use • Most studies conclude >4 months required – Underlying medical / psychiatric illness BZD Withdrawal • Short acting (lorazepam, oxazepam) – Onset Sx 1-2 days – Last up to 7 days • Long acting (diazepam) – Onset Sx 7-10 days – Can last for weeks • Instant withdrawal with flumazenil – Withdrawal in a bottle!! Symptoms • Very similar to EtOH WD • Anxiety, nausea, vomiting, insomnia, tremor • Autonomic hyperactivity: – HTN, tachycardia, hyperthermia, diaphoresis • In severe cases: – Delirium, seizures, hallucinations Back to Case • On Exam: – 37.6, 24, 110, 115/70, 90% NRB – Appears to be in heart failure, ↑JVP, grossly edematous, crackles to lung bases – Decreased a/e to right lung base – Slight tremor, looks anxious • Ix: – CBC 130, WBC 18, – CXR: c/w CHF ?consolidation RLL – TTE: EF <30% Case • Several hours later... – Diuresis, NTG, BIPAP (fails, pulls mask off) – Sa02 90 NRB, looking exhausted – Now so tremulous can’t hold cup ice chips to face – HR 120, BP 130/90, temp 38.5 • What do you want to do? Concerns? • ICU called, they take him for observation, BZD +/- intubation if needed. Management • Acute management similar to EtOH WD: – Manage ABCs, r/o other causes – Use long acting benzodiazepines to prevent and manage signs and symptoms of withdrawal – 20mg diazepam loading / hr po – 5-10mg diazepam IV prn – titrate to effect • Admission if refractory or severe WD, poor follow up Sellers. 1988. CMAJ;139:113 Management • Start on long acting BZD at equivalent dose to patients pre-existing dose • Initiate taper of 5-10% per day. Goal is to taper off BZD in: – 8 weeks if WD from long acting – 4-6 weeks if WD from short acting • Must have reliable supervision and follow up for outpatient withdrawal Sellers. 1988. CMAJ;139:113 BDZ equivalents • Diazepam 5mg equal to: – Oxazepam 30 mg – Lorazepam 1mg – Alprazolam 0.25 mg – Chlordiazepoxide 25mg Case • 17 yo F in resuscitation bay to the PLC with decrease LOC • Mother called 911 after finding her daughter unconscious with mom’s empty bottle of diazepam and a suicide note beside her – Mom is sure her little girl never takes pills or drugs, she is a “good girl” • Mom knows best! • Shortly after flumazenil IV pt seizes Flumazenil • • • • Imidazobenzodiazepine Peak Effect 6-10 min Half life 60 min, Competitive inhibitor at GABAa – No role in EtOH intoxication Flumazenil • Useful for solely BDZ OD for the BDZ naive • Not useful and DANGEROUS for: – Chronic BZD user – Mixed OD • Reverses effects of CNS depression but not reliably effects on respiratory depression Flumazenil adverse effects • Seizures – Secondary to severe WD and reversal of antiepileptic properties • • • • • Withdrawal Cardiac dysrhythmias Dangerous in co-ingestions Increases ICP Risks far outweigh benefits of use QUESTIONS? • “I was pulling needles out of my mom and dad’s arms by the time I was 3. I always told myself I would never end up there. I was 10 the first time my dad gave me meth” • “I came here because if I didn’t I would be dead in a month” • “I woke up in the hospital one morning with no pants, and no idea how I got there” • “There is no drug of choice. When you are an addict they are all drugs of choice” • “I needed the oxy’s to function. Ever since the accident my back has been unbearable. My doctor, he kept prescribing these oxy’s then he stopped and I needed them because I kept getting sick. I didn’t know these could do that to you. My husband is off work and I have 2 babies to feed. I need to work, and they need me. I’m not a junkie like these people, and can’t believe I’m here” Hooper detox patients QUESTIONS?