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PROPOFOL INFUSION SYNDROME

PROPOFOL INFUSION SYNDROME. Scott E. Benzuly, MD. PROPOFOL INFUSION SYNDROME. WHAT IS IT WHO IS AT RISK WHAT CIRCUMSTANCES ARE NECESSARY WHEN IS THE DIAGNOSIS MADE WHEN SHOULD WE BE CONCERNED WHY HAS IT TAKEN SO LONG TO FIGURE THIS OUT. PROPOFOL INFUSION SYNDROME.

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PROPOFOL INFUSION SYNDROME

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  1. PROPOFOL INFUSION SYNDROME Scott E. Benzuly, MD

  2. PROPOFOL INFUSION SYNDROME • WHAT IS IT • WHO IS AT RISK • WHAT CIRCUMSTANCES ARE NECESSARY • WHEN IS THE DIAGNOSIS MADE • WHEN SHOULD WE BE CONCERNED • WHY HAS IT TAKEN SO LONG TO FIGURE THIS OUT

  3. PROPOFOL INFUSION SYNDROME • SUDDEN ONSET OF MARKED BRADYCARDIA, -RESITANT TO TREATMENT, -PROGRESSING TO COMPLETE HEART BLOCK • LIPEMIC PLASMA • CLINICALLY ENLARGED LIVER • METABOLIC ACIDOSIS WITH A BASE DEFICIT OF > 10 MMOL/L ON AT LEAST ONE OCCASION • RHABDOMYOLYSIS OR MYOGLOBINURIA 1 1 Holzki,J, Aring,C, Gillor,A. Pediatric Anesth 2004.14:265-270.

  4. PRIS • Propofol marketed in the USA since 11/1989. • PRIS has been described in both children and adult patients sedated with propofol. • FIRST CASE REPORTS- 1992 2Wysowski,D,Pollock,M. Anesth 2006: 105:1047-51.

  5. FDA Investigation of Deaths associated with Propofol • Reviewed reports of death with propofol as the suspect drug: pediatric pt(≤ 16y) and adults(>16y) for non-procedural sedation. • Time period= Nov 1989-Apr 2005. • Strict definition: • Metabolic acidosis and/or rhabdomyolysis with progressive cardiac failure US deaths for Nonprocedural sedation reported to the FDA • 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51.

  6. Deaths reported to the FDA • 21 deaths ≤ 16yo (1993-2004) • 68 deaths ≥ 16yo (1989-2004) • Exclusions: • 7 children receiving propofol for indications other than sedation • 90 adult reports excluded: 89 were during anesthesia and 1 medical error/overdose 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51.

  7. PRIS Children Adults 2 Wysowski DK,Pollock ML. Anesth 2006; 105:1047-51.

  8. Indications for sedation Children Adults 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51.

  9. PROPOFOL INFUSION SYNDROME • Propofol= Ideal PICU/ICU sedative • Hemodynamic stability • Lack of accumulation • Lack of withdrawal

  10. PRIS Most Prominent Features Children • 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51.

  11. PRIS Most Prominent Features Adults • 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51.

  12. PRIS • Common factors • Higher doses • Higher concentrations • Longer duration

  13. PRIS • US Product labeling(PDR) • “Diprivan is not indicated for use in pediatric intensive care unit sedation because the safety of this regimen has not been established.” 3 Wysowski, DK, Pollack,ML. Anesth 2007; 107: 176.(US FDA)

  14. PRIS • Syndrome • Recognized in a retrospective cohort study of discharge diagnoses and medical records of 227 head injured adult patients age 16-55y admitted to INCU in The Netherlands between 1996-1999. • 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51.

  15. Time Line • 1989- Propofol released in US 11/1989 • 1990- Danish Side Effect Committee- issued a warning after 2 yo girl developed hypotension, hepatomegaly and multiorgan failure associated with propofol infusion 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508.

  16. Time Line • 1992 - Parke et al. Reported death in 5 children receiving propofol. (3 were disputed). • Similarities: • Increasing acidosis associated with bradycardia and progressive cardiac failure unresponsive to resuscitation • All had lipemic blood • No evidence of viral myocarditis at autopsy(3/5) 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508. 6 Park TJ, Stevens JE, Rice AS,et al. BMJ 1992; 305: 613-616.

  17. Time Line • 10 yr experience: • 79 pt admitted to PICU for croup and long term ventilation • NO DEATHS OR SERIOUS ILLNESSES 6 Park TJ, Stevens JE, Rice AS,et al. BMJ 1992; 305: 613-616.

  18. Time Line • The Committee on Safety and Medicines (UK) and Astra-Zeneca issued serious adverse warnings about the use in PICU for sedation. • 1992- FDA Advisory Committee (Anesthetic and Life Support Drugs) - no direct link between these deaths and propofol. 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508.

  19. Time Line • Since this time there have been at least 10 more reported cases in children with acidosis and arrhythmias( 7/10 died, 2/3 survivors treated with hemodialysis. 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508.

  20. Time line • 2001 FDA, Canadian Health Protection Board issued a notice- strict adherence to approved indications for propofol. • Included was a letter from Astra-Zeneca informing users of the FDA findings that there may be serious safety concerns regarding the use of propofol for sedation in critically ill children. 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508.

  21. Unpublished FDA multicenter randomized controlled trial #0859IL-0068. • 327 pediatric ICU patients • Comparing 3 regimens: • 1% Propofol • 2% Propofol • “Standard sedative drugs” 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508.

  22. Unpublished FDA multicenter randomized controlled trial 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508.

  23. PRIS • Common factors • Higher doses • Higher concentrations • Longer duration

  24. “Organ toxicity and Mortality in Propofol-Sedated Rabbits under Prolonged Mechanical Ventilation” 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166.

  25. ANIMAL MODEL FOR PRIS • Group P- • 2% propofol infusion • Group S • - Sevoflurane • Group S+IL- • Sevoflurane + Intralipid

  26. ANIMAL MODEL FOR PRIS 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166.

  27. ANIMAL MODEL FOR PRIS Lungs 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166.

  28. ANIMAL MODEL FOR PRIS 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166.

  29. ANIMAL MODEL FOR PRIS 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166.

  30. ANIMAL MODEL FOR PRIS 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166.

  31. Case Report • 2yo boy PICU s/p shot in the head with an air gun pellet. • Intubated and ventilated for right sided cerebral edema and rim of subdural blood. • Sedated with propofol rate of 4-5.4 mg/kg/h. over 72 h. • Day 4 • oliguria, increase in K+,BUN, Cr and then sudden, persistent bradycardia(HR= 28). • Propofol stopped, trans-venous pacer placed, restored HR but had persistent acidosis. • Diagnosis: PRIS- started dialysis. Complete recovery. 5 Wolf A,Weir P, Segar P et al. Lancet 2001; 357: 606.

  32. 5 Wolf A,Weir P, Segar P et al. Lancet 2001; 357: 606

  33. What should we do • High index of suspicion • > 48h propofol sedation • Turn off the propofol • Labs: • ABG • Triglycerides • Lactate level

  34. What to do • Hemodynamic maintenance • Pressors • Transvenous pacing • Adequate oxygenation • Increasing Lipemia should not be considered benign • Add sugar to IV fluids • Hemodialysis

  35. Who should not receive Propofol for Non-procedural sedation • Mitochondrial disease • Neuromuscular disease

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