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

Indications for sedation

Children

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%)

PROPOFOL INFUSION SYNDROME

1. SUDDEN ONSET OF MARKED BRADYCARDIA, -RESITANT TO TREATMENT, -PROGRESSING TO COMPLETE HEART BLOCK
2. LIPEMIC PLASMA
3. CLINICALLY ENLARGED LIVER
4. METABOLIC ACIDOSIS WITH A BASE DEFICIT OF > 10 MMOL/L ON AT LEAST ONE OCCASION
5. RHABDOMYOLYSIS OR MYOGLOBINURIA 1

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

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

Deaths reported to the FDA

PRIS


                                                           CHILDREN                                 ADULT

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

PROPOFOL INFUSION SYNDROME

• Propofol= Ideal PICU/ICU sedative
• Hemodynamic stability
• Lack of accumulation
• Lack of withdrawal

Cardiovascular - failure, arrhythmia, bradycardia, CV collapse and arrest	18(86%)
Metabolic acidosis	15(71%)
Hypotension	13(62%)
Rhabdomyolysis	11(52%)

 
PRIS

• Common factors
• Higher doses
• Higher concentrations
• Longer duration

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.”
• 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.

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

Time Line

• 10 yr experience:
• 79 pt admitted to PICU for croup and long term ventilation
• NO DEATHS OR SERIOUS ILLNESSES

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.

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.

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.

Unpublished FDA multicenter randomized controlled trial #0859IL-0068.

• 327 pediatric ICU patients
• Comparing 3 regimens:
• 1% Propofol
• 2% Propofol
• “Standard sedative drugs”

Unpublished FDA multicenter randomized controlled trial

	MORTALITY
1% Propofol	8%
2% Propofol	11%
Standard sedatives	4%

PRIS

• Common factors
• Higher doses
• Higher concentrations
• Longer duration
• “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.

• Group P-
• 2% propofol infusion
• Group S
• - Sevoflurane
• Group S+IL-
• Sevoflurane + Intralipid

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

 
ANIMAL MODEL FOR PRIS

	Frothy Pulm edema	Sp02<90%	Pa02<90 @ Fi02=1.0	Bronchitis (eosinophils)
2% Propofol	+	+	+	_
Sevoflurane	_	_	_	Low grade,mainly around bronchi
Sevo + IL	_	_	_

ANIMAL MODEL FOR PRIS

	Liver	Gallbladder
2% Propofol	No lesion
Sevoflurane	No lesion,few inflammatory cells	No lesion
Sevo + IL	Slightly milky tincture, Low grade fatty changes-steatosis, Low grade active hepatitis Inflammatory cells around portal tracts and hepatocytes	Few inflammatory cells-submucosa

 
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	Few inflammatory cells-submucosa

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.

What should we do

• High index of suspicion
• > 48h propofol sedation
• Turn off the propofol
• Labs:
• ABG
• Triglycerides
• Lactate level

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 for Non-procedural sedation

• Mitochondrial disease
• Neuromuscular disease

Who should not receive Propofol for Non-procedural sedation

• Mitochondrial disease
• Neuromuscular disease

download lecture presentation  The Upper ExtremityPropofol Infusion Syndrome