The romance begins…

2. The romance begins… • Ms Juliet, 32 yrs old • Good past health, came from Shanghai • Found dull-looking and sitting in street, with 2 empty bottles of 葡萄糖酸鈣片 • E1V1M5 in AED • Intubated for airway protection

3. Haemodynamically stable • Physical exam unremarkable • Dx: suspected drug overdose ?nature • Admitted ICU, put on mechanical ventilation • CBP, L/RFT, ABG unremarkable

4. Remained comatose without sedation, E1VTM1 • Bilateral pupils fixed and dilated, absent gag and cough reflexes, absent doll’s eye reflex • No limb/facial movement to painful stimuli, generalized hyporeflexia, absent plantar response

5. Urgent CT brain & MRI unremarkable • LP result not suggestive of CNS infection • …deep coma with total loss of all cerebral and brainstem function…?cause

6. Causes for suppressed GCS

7. Serum toxicology result came back on D5 >1000 (non-toxic range: 43-172 μmol/L)

8. Treatment • Multiple dose activated charcoal • Activated charcoal 50gm q8h x 4doses • Stopped due to intestinal obstruction • Forced alkaline diuresis • 2LH20+300ml 8.4%NaHCO3 iv 100ml/hr • Charcoal haemoperfusion x 2 session • Complicated by thrombocytopenia • High flux intermittent haemodialysis x 4 sessions

9. Progress • Pupils reactive on D7 • Noticed biting ETT on D8 • Gradual neurological recovery, E4VTM4 on D9 and extubated • IO resolved with conservative mx, platelet count returned to normal • Full neurological recovery and transferred to medical ward on D11

10. Phenobarbital was brought to market in 1912 by Bayer using the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1950s. The young doctor Alfred Hauptmann gave it to his epilepsy patients as a tranquiliser and discovered that their epileptic attacks were susceptible to the drug… In 1940, Winthrop Chemical produced sulfathiazole tablets that were contaminated with phenobarbital. Each antibacterial tablet contained more than twice the required dose of phenobarbital necessary to induce sleep. Hundreds of patients died or were injured as a result… History

11. Clinical effects • Neurological • Ataxia, lethargy, coma • Cardiovascular • Hypotension, cardiovascular collapse, cardiac arrest • Respiratory • Respiratory arrest, pulmonary edema • Hepatic • Hepatotoxicity • Genitourinary • Crystalluria, ARF secondary to hypotension or rhabdomyolysis • Haematological • Thrombophlebosis • Dermatological • bullae

12. EEG • isoelectric, to the point of mimicking brain death.

13. Pharmacokinetics • T1/2=5 days • Clearance=4ml/kg/hr • pKa=7.24 • Vd=0.54-0.7L/kg • Plasma protein binding=50% • Excreted unchanged in urine

14. Multiple doses of activated charcoal

15. NEJM Vol. 307, no.11, P.642-4 • 6 healthy men were given 200mg phenobarbital sodium iv per 70kg of BW over 75mins on 2 occasions separated by 1 week • At each occasion, the subjects were randomized to either: • 40g activated charcoal at time 0 and 20g at 6,12,18,24,30,42,and 66hours • No charcoal

16. Serum levels of phenobarbital were measured up to 90 hours after the infusion

17. Charcoal decreased serum half-life of phenobarbital from 110+/-8 to 45+/-6 hours • Increase total body clearance from 4.4+/-2 to 12.0+/-1.6ml per kg per hour

18. JAMA, Vol 251, No 23, P3104-8 10 patients with (1) serum phenobarbital >60mg/L and (2) comatous and require mechanical ventilation 50g activated charcoal 5 patients received repeated dose of 17g activated charcoal q4h until extubation 5 patients receive no further charcoal

19. A T-piece trial was performed if the patient was • Conscious • maximal inspiratory negative pressure >20cmH20 • Vital capacity>10ml/kg • PaO2>60mmHg with inspired O2 concentration=21% • T-piece connected for 30mins. • If the arterial blood gases remained stable, extubation was performed.

20. Mean serum phenobarbital concentration on admission was 121+/-31mg/L in the single-dose group and 132+/-36mg/L in the repeated-dose group • At the time of extubation, serum phenobarbital concentration in the single-dose group was 83+/-13mg/L, which was significantly higher than in the repeated-dose group (49+/-16mg/L)

21. The length of time that patients require mechanical ventilation, 39+/-24 hours (single-dose group) and 48+/-8 hours (repeated-dose group), did not differ significantly; nor did the time spent in hospital.

22. Haemoperfusion/haemodialysis • Most patients with phenobarbital overdose can be adequately treated with supportive care, cathartics, activated charcoal and forced alkaline diuresis. • In severely compromised patients, both haemodialysis and haemoperfusion have been used to enhance elimination of the drug. • Haemoperfusion is generally considered to be more effective because phenobarbital has significant protein binding.

23. Therapeutic Drug Monitoring 23:209-216 30 patients with blood phenobarbital 80-120μg/ml Forced alkaline diuresis Iv NaHCO3 infusion 2mg/kg mixed with NS 15ml/kg at an infusion rate of 5ml/min urine pH mainteined 7.5-8; u/o=6-8ml/kg/h MDAC 75g activated charcoal50g q4h Combined group Blood x phenobarbital level collected at 6,12,18,24,30,36,42, 48hrs after admission

25. American Journal of Kidney Diseases, Vol 36, No 3, P640-3 • A 33-yr-old woman was found comatose. Urine toxicology in AED was +ve for barbiturates.The patients was admitted to ICU and treated with MDAC. Phenobarbital level 18 hrs after admission was 147mcg/ml. Forced alkaline diuresis was initiated.

26. Haemodialysis was started 23hrs after admission. • High-flux, high-efficiency polysulfone haemodialysis membrane (F80, Fresenius) • Blood flow=400ml/min • Dialysate flow rate=500ml/min • Duration=4hrs

27. Patient began to show spontaneous movement and was able to say her name 2hrs after start of the procedure. By the end of the treatment, she was able to respond to verbal commands.

28. During the dialysis, phenobarbital level decreased from 130 to 53mcg/ml

30. Intermittent haemodialysis • Blood flow=150-250ml/min • Dialysate flow=400ml/hr • Duration=7hr • Dialyser=APS650 • MachineAK200US

31. 2nd charcoal haemoperfusion 1st charcoal haemoperfusion 1st HD 2nd HD 3rd HD

32. Pitfalls in charcoal haemoperfusion • Drugs must have the following characteristics for there to be a significant increase in clearance from haemoperfusion • Volume of distribution less than 3 L/kg • Affinity for charcoal (or resin, if used instead) • Commoner examples of eligible drugs carbamazepine, theophylline, paraquat • Set-up more complicated

33. Take home message • Barbiturate coma can mimick brain death. • MDAC is better than single-dose activated charcoal but it is often limited by intestinal obstruction. • Although administration of MDAC to patients with phenobarbital overdose significantly increased the elimination of phenobarbital, it had no clear effects on the patients’ clinical course. • Charcoal haemoperfusion/haemodialysis is more efficient in removing phenobarbital compared with MDAC and reserved to use in severe case. MDAC is in turns more efficient than FAD. • Both haemoperfusion and IHD can remove phenobarbital. However, IHD is not associated with thrombocytopenia and require less nursing manpower.

34. Our story continues… • Ms Juliet engaged with Mr Romeo years ago in Shanghai although she knew that he had a wife. Recently, Mr Romeo asked for separation. Therefore, Ms Juliet came to HK alone to find Mr Romeo.

35. She prepared 2 bottles of phenobarbital and called Mr Romeo outside his office. He rejected her and she impulsively took all the drug… • Mr Juliet was transferred to psychiatry ward on D17…She decided to separate with Mr Romeo. She was discharged on D 20 and continued follow up in Shanghai.

37. References: • Wikipedia, the free encyclopedia • Acceleration of the body clearance of phenobarbital by oral activated charcoal. NEJM 1982;307:642-4 • Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA, June 15, 1984, vol 251, no, 23 • Effectiveness of haemodialysis in the extracorporeal therapy of phenobarbital overdose. American Journal of Kidney Diseases, vol 36, no. 3, Sep 2000: p640-3 • Therapeutic Drug Monitoring 23:209-216

38. The end