PropofolInfusion

PropofolInfusion - PROPOFOL PROPOFOL INFUSION SYNDROME...

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Unformatted text preview: PROPOFOL PROPOFOL INFUSION SYNDROME Scott E. Benzuly, MD PROPOFOL INFUSION 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 PROPOFOL INFUSION SYNDROME 1. 2. 3. 4. 5. 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. PRIS 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 Wysowski,D,Pollock,M. Anesth 2006: 105:1047-51. 2 FDA Investigation of Deaths FDA Investigation of Deaths associated with Propofol Reviewed reports of death with propofol as the suspect drug: pediatric pt(≤ 16y) and adults(>16y) for non­procedural sedation. Time period= Nov 1989­Apr 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. Deaths reported to the FDA Deaths reported to the FDA 21 deaths ≤ 16yo (1993­2004) 68 deaths ≥ 16yo (1989­2004) 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. PRIS PRIS Children Adults Male 8(38%) 45(66%) Female 13(62%) 22(33%) Age range <16y 19-86y Peak dose (mean) 13.7 mg/kg/h 7.2 mg/kg/h Median dose 9.5 mg/kg/h 5.4 mg/kg/h Range 2.2-54mg/kg/h 0.6-25 mg/kg/h 2 Wysowski DK,Pollock ML. Anesth 2006; 105:1047-51. Indications for sedation Indications for sedation Children Adults Respiratory disorders 1(5%) 21(31%) Seizures 5(24%) 9(13%) Head trauma/ICP control 5(24%) 9(13%) Unspecified 10(47%) 4(6%) Post surgical sedation 7(10%) Agitation 5(7%) Delirium Tremens 1(2%) 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51. PROPOFOL INFUSION PROPOFOL INFUSION SYNDROME Propofol= Ideal PICU/ICU sedative Hemodynamic stability Lack of accumulation Lack of withdrawal PRIS Most Prominent Features Children Cardiovascular failure, arrhythmia, bradycardia, CV collapse and arrest 18(86%) Metabolic acidosis 15(71%) Hypotension 13(62%) Rhabdomyolysis 11(52%) 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51. PRIS Most Prominent Features Adults Cardiovascular failure, arrhythmia, bradycardia, CV collapse and arrest 31 Metabolic acidosis 21(38%) Hypotension 20 Rhabdomyolysis 13 Renal Failure/ARDS 16 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51. PRIS PRIS Common factors Higher doses Higher concentrations Longer duration PRIS 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) PRIS PRIS Syndrome Recognized in a retrospective cohort study of discharge diagnoses and medical records of 227 head injured adult patients age 16­55y admitted to INCU in The Netherlands between 1996­1999. 2 Wysowski,DK, Pollock,ML. Anesth 2006; 105: 1047-51 . Time Line 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. Time Line 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 6 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508. Park TJ, Stevens JE, Rice AS,et al. BMJ 1992; 305: 613-616. Time Line 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. Time Line Time Line The Committee on Safety and Medicines (UK) and Astra­Zeneca 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. Time Line 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. Time line Time line 2001 FDA, Canadian Health Protection Board issued a notice­ strict adherence to approved indications for propofol. Included was a letter from Astra­Zeneca 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. Unpublished FDA multicenter Unpublished FDA multicenter randomized controlled trial #0859IL­0068. 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. Unpublished FDA multicenter Unpublished FDA multicenter randomized controlled trial MORTALITY 1% Propofol 8% 2% Propofol 11% Standard sedatives 4% 4 Withington DE, Decell MK, AL Ayed, T. Pediat Anesth 2004;14:505-508. PRIS PRIS Common factors Higher doses Higher concentrations Longer duration “Organ toxicity and Mortality in PropofolSedated Rabbits under Prolonged Mechanical Ventilation” 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166. ANIMAL MODEL FOR PRIS ANIMAL MODEL FOR PRIS Group P­ Group S 2% propofol infusion ­ Sevoflurane Group S+IL­ Sevoflurane + Intralipid ANIMAL MODEL FOR PRIS ANIMAL MODEL FOR PRIS Mortality Lab Findings 2% Propofol 100% ↓ Sp02,Pa02,→↓ C.O.↓ U. O.,ABP, ↑HR Sevoflurane 0% ↑HR,CK,TGL Sevo + IL 0% ↑CK.TGL 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166. ANIMAL MODEL FOR PRIS ANIMAL MODEL FOR PRIS Lungs Frothy Pulm edema Sp02<90% Pa02<90 @ Fi02=1.0 Bronchitis (eosinophils) 2% Propofol + + + _ Sevoflurane _ _ _ Low grade,mainly around bronchi Sevo + IL _ _ _ 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166. ANIMAL MODEL FOR PRIS ANIMAL MODEL FOR PRIS Heart Skeletal Muscle 2% Propofol No lesion No lesion Sevoflurane No lesion No lesion Sevo + IL No lesion No lesion 4 Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166. ANIMAL MODEL FOR PRIS ANIMAL MODEL FOR PRIS Liver Gallbladder 2% Propofol No lesion Sevoflurane No lesion,few inflammatory cells Sevo + IL Slightly milky tincture, Few inflammatory Low grade fatty changes-steatosis, cells-submucosa Low grade active hepatitis Inflammatory cells around portal tracts and hepatocytes 4 No lesion Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166. ANIMAL MODEL FOR PRIS ANIMAL MODEL FOR PRIS Kidney Bladder 2% Propofol Sevoflurane No lesions 3/6. Few scattered lymphocytes in parenchyma Sevo + IL Few scattered lymphocytes in renal parynchema 4 Few inflammatory cells-submucosa Ypsilantis P, Politou M, et al. Anesth and Anal 2007; 105: 155-166. Case Report Case Report 2yo boy PICU s/p shot in the head with an air gun pellet. Day 4 Intubated and ventilated for right sided cerebral edema and rim of subdural blood. Sedated with propofol rate of 4­5.4 mg/kg/h. over 72 h. oliguria, increase in K+,BUN, Cr and then sudden, persistent bradycardia(HR= 28). Propofol stopped, trans­venous 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. Total Carnitine 66 µmol/L 23-60 µmol/L C5-acylcarnitine 8.4 µmol/L <0.8 µmol/L Malonylcarnitine 3.3 µmol/L <0.2 µmol/L Creatine Kinase 879 IU <240 IU Myoglobinuria Positive Troponin T 0.04 µg/L <0.01µg/L Triglyceride(serum) 2.6 mmol/L 0.4-1.2 mmol/L Venous 02 before pacing after pacing 65-80% 55% 70% Maximum lactate 4.9 mmol/L Max base deficit 10 mmol/L 0.67-2.44mmol/L 5 Wolf A,Weir P, Segar P et al. Lancet 2001; 357: 606 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. What should we do What should we do High index of suspicion > 48h propofol sedation Turn off the propofol Labs: ABG Triglycerides Lactate level What to do What to do Hemodynamic maintenance Pressors Transvenous pacing Adequate oxygenation Increasing Lipemia should not be considered benign Add sugar to IV fluids Hemodialysis Who should not receive Propofol Who should not receive Propofol for Non­procedural sedation Mitochondrial disease Neuromuscular disease ...
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