Propofol Infusion Syndrome
The Good, the Bad, and the Ugly
Lynelle Scullard BSN CCRN CNRN
Clinical Care Supervisor SICU
Hennepin County Medical Center
Objectives
Discuss the benefits and adverse drug effects
of Propofol.
 Describe the patients at risk of developing
Propofol Infusion Syndrome.
 Identify the clinical manifestations of Propofol
Infusion Syndrome.

Sedation
Purpose safe and comfortable environment
 5 million lives campaign, high alert meds
 Most critically ill with vent require at least 2 different
analgesic and sedative agents, avg of 3 days


SCCM 2002
– Recommend given to pain free and arousable state
Sedation

Non-pharmacologic
–
–
–
–
–
–
Establish non-verbal communication
Calm voice and touch
Freq repositioning
Distraction
Make environmental change
Complementary tx
Ideal sedative
Fast acting
 Anxiolysis
 Sedation and amnesia
 Quick emergence
 Easy administration and dose adjust
 No active metabolites or adverse effects
 Cheap

Inadequate sedation
Unsafe
 Unpleasant recall
 Increased pain
 Increased oxygen consumption and demand
 Change in vital signs
 Interfere with medical management

Excessive sedation
Increased ventilator days, risk of VAP
 Decreased GI motility
 Drug accumulation
 Cost
 Neuro exam
 Propofol Infusion Syndrome

Society of Critical Care Medicine
American Society of Health-System
Pharmacists
SCCM how to sedate

Titrate to a defined endpoint (grade A)
– Systematic tapering or daily interuptions

Withdrawal prevention of high dose 7+day opioid,
benzo and propofol (grade B)
– Taper systematically
– Neuroadaptation

Use guideline or protocol (grade B)
– Daily wake up
– Restart at ½ then titrate
Step 1…. assessment
Goals:
 RN

– Thinks MD wants less to wean from vent

MD
– Thinks RN ensure comfort and make care easier
Scales and monitoring

Sedation scales
– GCS, Ramsay, SAS, MAAS, Richmond ASS

BIS
– Value represents measure of cerebral cortical activity
– 1hr after initiation Propofol
• 3 increased
• 7 no change
• 35 decreased
– Goal 60-70 = Ramsay level 4
Benzodiazepines
Sedation and retrograde amnesia
 Most widely used

Versed (midazolam)
Rapid sedation of acute agitation 2-5 min
(grade C)
 For short term use only (grade A)

– Unpredictable awakening and time to extub > 4872h
– <24h if obese or renal
Ativan (lorazepam)
Intermittent IV or continuous if sedation
needed > 24h (grade B)
 Indep risk factor in ICU for development of
delirium

Adverse effects of benzo’s
Cardiac and respiratory depression
 Hypotension
 Tolerance and dependence
 Paradoxical agitation
 Unpredictable awakening from accumulation
and active metabolites

Precedex (dexmedetomidine

Alpha 2 adrenergic receptor agonist
– Inhibits norepi and epi centrally and peripherally






Rapid onset 5min
No respiratory depression
Activates a sleep promoting pathway, easily
aroused
Less delirium after cardiac surgery
Adverse: hypotension and brady
FDA: short term <24h
Propofol
Sedative hypnotic for anesthesia and
sedation
 Preferred for rapid awakening (grade B)
 Onset 1-2 minutes
 Decrease ICP, cerebral blood flow and
metabolism

Adverse effects
Dose dependent hypotension
 Respiratory depression
 Pain at site
 Lipid emulsion… triglyceride
 Diprivan brand preservative chelator trace
minerals- zinc (5d)
 Sodium metabisulfate allergy, esp if asthma

Nursing management of propofol
Strict aseptic technique
 Dedicated IV line
 Tubing and bottle change q12 h
 Transfer to another container 6h


http://www.fda.gov/downloads/Drugs/DrugSaf
ety/PostmarketDrugSafetyInformationforPatie
ntsandProviders/ucm125815.pdf
Propofol
Label advocates optimization of
hemodynamic and oxygen delivery
parameters
 DC if metabolic acidosis, rhabdo,
hyperkalemia, and/or progressive cardiac
failure

Propofol
Oil in water emulsion
 100mg/ml soybean oil (10%)
 Egg phosphatide (1.2%)
 Glycerol (2.25%)
 Preservative (required by FDA)

–
–
–
–
AstraZeneca EDTA pH 7-8.5
Baxter pH 4.5-6.4
Bedford pH 7-8.5
Hospira pH 7-8.5
Propofol withdrawal
13-33% adults, 17-57% kids
 Peaks in 6h
 Higher dose… longer w/d
 Guidelines;

– Reduce 5-10% qd
– Reduce 40%, then 10% qd
– ? precedex
Fospropofol
Approved 2008
 Water soluble
 Converts to propofol, formaldehyde,
phosphate
 Adverse effects

– Puritis
– Parasthesias
– HTN
Delirium
An acute change in the course of a patients
mental status plus inattention and either
disorganized thinking or an altered level of
consciousness
 22-87% prevalence
 Risks: age, comorbidities, pre-existing
cognitive impairment, excess sedation,
psychoactive meds, benzo’s
 Tx: Haldol 86%

Haldol
Preferred for delirium (grade C)
 Monitor QT (grade B)

No studies show antipsychotics effectively
treat anxiety, agitation, or even delirium
 Considered off label use for delirium

PIS: Propofol Infusion Syndrome
 PRIS: Propofol infusion Syndrome
 Propofol on the market 1989
 First case report 1992
 1992-2008 38 case reports with assoc
mortality >80%

Definition

Bray; sudden onset of marked refractory
bradycardia… asystole, with one of the
following:
– Hyperlipidemia, enlarged fatty liver, severe
metabolic acidosis, rhabdo, ARF

Occurrence of acute bradycardia resistant to
treatment and progressing to asystole
associated with propofol infusion.
Criteria

Bradycardia combined with
–
–
–
–

Lipaemic plasma
Fatty liver enlargement
Metabolic acidosis with base excess <10
Rhabdomyolysis or myoglobinuria
Leads to cardiac and/or renal failure
Incidence

1989-2005
– 21 kids died girls (62%)> boys (38%)
• Mean peak dose 13.7mg/kg/hr, 2.4 days
– 68 adults died
• Mean peak dose 7.2mg/kg/hr, 7.3 days
– 90 suspected PRIS
– 89 “concerned”
– Increased mortality if propofol is used
FDA medwatch

3168 cases- 1139 included
– 30% fatal
– Dose >83mcg/kg/min 68%
– More likely to die if:
•
•
•
•
•
Younger
Male
Outside US
Longer than 48h
On a catecholamine
Risk factors
Long term, high dose
 5mg/kg/hr (83mcg/kg/min) x 48h
 4mg/kg/hr (66mcg/kg/min)
 Peds: 0.5-127 days

Risk factors
Head injury
 Sepsis/SIRS
 Pulmonary infection
 Poor oxygen delivery
 Critical illness myopathy, neuropathy

Risk factors

Age
Risk factors
Increased catecholamine level
 Vasopressor support
 Increased glucocorticoid level

Risk factors
Nutrition
 Low energy supply

Pathophysiology
Uncouples respiratory chain in mitochondria
 Defect first occurs in high energy cells
(myocytosis)

– Cardiac
– Skeletal

Enzyme deficiency?
Pathophysiology
Cardiac depressive effects
 Propofol inhibits cardiac beta-adrenoceptor
binding and Ca channel protein function

– Suppresses activity of sympathetic nerves and
baroreceptor reflex
– Concomitant use of catecholamine decreases
propofol serum level
Pathophysiology

Fat metabolism
– Impaired liver metabolism and delayed clearance
Free fatty acids pro-arrhythmogenic risk
 Propofol inhibits beta oxidation increases fatty
acids
 Lipaemic plasma may prevent diffusion to it’s
sites of action

Pathophysiology
Low carbohydrate supply
 Demand is supplied by lipolysis
 If supply low, favors free fatty acids
 Need 6-8mg/kg/min carbo to suppress

– 4mg/66mcg= 2-3g/kg/min lipid intake
Triggering factors

Catecholamines and SIRS= increase
clearance propofol
– Poor sedation and higher doses

Catecholamines lead to stress
cardiomyopathy
– Asthma, trauma, sepsis, intracerebral lesions
Symptoms
Cardiac 43%*
 Hypotension 34%*
 Rhabdo 27%*
 Renal 23.5%*
 Liver 24%
 Metabolic acidosis 20%*
 Hypoxia 17.5%
 Hyperthermia 11.6%

Cardiac

Arrhythmias
– Bradycardia
– Asystole
Hypotension
 Failure
 ECG
 SIRS/septic VS

Cardiac

Hypotension
–
–
–
–
Decreased stimulation
Decreased vascular tone
Vasodilatation
Worse if hypovolemic or unstable
Renal
Oliguria
 CK, urea, K
 Urine color
 Ketonuria
 Rhabdomyolysis

Rhabdomyolysis
Rhabdo: striated (skeletal)
 Myo: muscle
 Lysis: breakdown


The clinical and laboratory syndrome resulting from
release of potentially toxic substances into the
circulation.
Breakdown of Myoglobin
Pigment induced nephropathy
 Sloughing of tubular endothelium
 Exfoliate (casts) and myoglobin obstructs
renal tubules
 Low urine pH (<5.6)

– Facilitates cast formation
– Promotes dissociation of myoglobin molecules
into cytotoxic components
***If myoglobin unchanged, it’s harmless***
Liver
Enlargement
 Liver enzymes
 Coagulopathy?

GI

Drug induced pancreatitis
– Lipid… hypertriglyceridemia (18%)…. Risk of
pancreatitis
– 1.1kcal/ml lipid
Metabolic

Lacticacidosis
– Perfusion
– Propofol agglutination can cause microvascular
emboli
– Rhabdo
Other

Immune response
– Reduces microphage chemotaxis and
phagocytosis
– Limits production of interfuron, TNF, IL6,
neutrophil function
– High dose impairs bacterial clearance
Treatment
Stop propofol, alternative sedation
 Hemodynamic stability

–
–
–
–
Fluids
Vasopressor, catecholamines
Potassium level?
Acidosis?
Treatment

Carbohydrate substitution
Treatment

Bradycardia resistant to catecholamines and
pacing
– ECMO extra corporeal membrane oxygenation
Treatment

Renal
–
–
–
–
Fluids to flush myoglobin
Mannitol, bicarb
CRRT
CRRT and ECMO
Prophylaxis
Sedation guidelines
 Optimize hemodynamics and oxygen delivery
 Monitor:

– pH, serum lactate, CK, triglycerides
– FDA: BP, ECG, ABG

ACCCM
– DC if escalating vasopressor or inotropic support,
or cardiac failure
Look a likes, no rhythm change
Precursor to PRIS
 Lacticacidosis an early marker?
 Rhabdo early warning?
 Pre-op fasting and pneumonia enhances
development

Patient examples
Questions

[email protected]