If everything is so good, why

things might be so wrong ?!!

A new/old pathology in Critical Care:

P R I S

Gabriel M. Gurman, MD Professor of Anesthesiology and Critical Care

Ben Gurion University of the Negev, Israel

gurman@bgu.ac.il October 2016

A second title : Did I tell you

that I was sick ?!

Let’s discuss a patient a 28-year patient,

after a motor vehicle accident, head trauma and open fracture of left femur and tibia

He is ventilated and still

needs, after 7 days, sedation

by continuous infusion of

propofol, in increasing

dosage

(from 3 mg to 6.5 mg/Kg/hour)

*hemodynamic

instability because of

sepsis,

*supraventricular

tachycardia

*increasing dosage of

noradrenaline

Propofol in ICU

Used for continuous sedation since the 80’s, officially in USA from 1993

No need for loading dose and this reduces the hypotensive effect

Clearance time 3-5 times faster than midazolam

Rapid elimination from the central compartment, much slower from highly lipophilic and poorly perfused tissues (adipose)

Slower elimination in elderly

A question for the audience:

How many of you use

Propofol in continuous infusion,

either in OR or in ICU?

Bertolini et al. Minerva Anestesiologica 2000;67:97

Use of sedative and analgetics in ICU

2932 patients in Italy in 1994

22612 patient-days in ICU

(11221 analyzed)

% sedated patients

%days of sedation

Drug

40 32.5 Propofol

36 25 Fentanyl

35 21.5 Diazepam

22 15 Morphine

8 3.7 Droperidol

19 12.3 Midazolam

What are the main uses of

propofol in ICU ?

When short-term

sedation and rapid

awakening are

desired (for

checking patient’s

condition)

In prolonged

sedation, after

which one is

interested to

decrease the

time to

awakening

It is not so simple, because

continuous infusion of

propofol has some

drawbacks

Effects on lipids ?

Not so….

Crit Care Med

1997;25:1976

Propofol (mg)

T

R

I

G

L

E

R

I

D

E

S

2000 4000 6000 8000 10000

Hemodynamic effects ?

Yes and no !

Gurman, Karayev, Estis et al

Appl Cardiopulm Pathophysiol 1996;6:71

A much more evident hemodynamic stability when:

dosage adjusted according to SEF

(significantly less BP and HR deviations from the baseline)

Cost ?

Today Propofol is

not expensive

anymore!!!! AND A more rapid

awakening after

propofol and lack

of withdrawal

syndrome

It has a positive financial effect in comparison to

other sedation regimens in ICU

Now, back to our patient

On the 8th day

Anuria

Hypotension , needing large doses of noradrenaline and adrenaline

Dark urine

Fever 38.5

Metabolic acidosis

Creatinine kinase 2450 U/L

Potassium 6.1 mEq/L

And an interesting sign: RBBB simulating a

Brugada syndrome

Possible explanations

Septic shock

Subarachnoid hemmorhage

Compartment syndrome

Lung contusion

Something different ?

Select !!!

Yes, something completely

different happens to this patient

P R I S

Propofol infusion

syndrome !!!

•Severe metabolic

acidosis

•Rhabdomyolysis

•Acute renal failure

•Fatal cardiac failure

Clinical details…….

Severe cardiac failure due to severe bradicardia, refractory to treatment

Lipemia

Muscle damage resulting in rabdomyolysis

Fever, with no evident explantation

Everything happening in patients who got “too much, too long” propofol

The list of complications Orsini J et al 2009

% Feature 88 Lactic acidosis

64 Rhabdomyolisis

70 Cardiac arrhythmias

53 Hypotension

47 Renal failure

44 Hyperkalemia

20 Hyperlipidemia

So…….. PRIS is:

A syndrome characterized by occurrence of bradycardia resistant to treatment and progressing to asystole associated with propofol infusion

Roberts RJ et al, Crit

Care 2009;13:R169)

1017 patients, Prop

infusion > 24 hrs

1.1% PRIS

There is a long list of risk factors

Airway infections Severe head injury Poor oxygen delivery Sepsis Age < 18 yrs Vasopressor therapy Renal failure Prolonged hypotention Rabdomyolysis Dislipidemia

+ Propofol

continuous

infusion in

large doses

How come ?!

Everything started in 1992, in

children : BMJ 305:613-616

Metabolic acidosis and fatal

myocardial failure after

propofol continuous infusion

in FIVE children Only one year later

(Lactic acidosis associated

with propofol . Chest

1996;109:292) the first

case in adults

Possible explanations ?

Not only one but three!!!

And each one

completes the

others!!

A first one…. Propofol

infusion

Uncoupling the

respiratory chain in heart

and muscle cells

Free fatty

acids (FFA)

Cardiac

arrhythmias

Low

carbohydrates

supply

Energy

supplied

by

lipolysis

The negative effects of

catecholamines Intracerebral lesions

Hyperdynamic state

SIRS

High cathecolamines

Rapid propofol

metabolism

Need for more propofol!!!

But the dreadful aspect of this

story is the vicious circle

Propofol

continuous

infusion

Decrease in

cardiac

output

CC in high

dosage

Increase in cardiac

output

Decrease in

Propofol blood

concentration

(increase in propofol

clearance )

Need for more

propofol

And now an interesting

question :

What’s the connection to head

injury and other neurological

conditions ?

Very simple !

IF

So many

neurological

conditions

(subarachnoid

hemorrhage,

head trauma,

status

epilepticus,

stroke)

AND Are

accompanied

by

sympathetic

stimulation

and release of

large

amounts of

NA into the

myocardium

Use of propofol

demands

increasing

amounts of

exogenous CC

AND….

Some of these

neurological

conditions are also

treated by steroids

(cerebral edema,etc)

AND

CCs and steroids exert

profound effects on

immunity and inflammation

•Impaired

lymphocytes traffic

and proliferation

•Modulate cytokine

production

•Affect the activity of

lymphoid cells

All this produces a net

immunosupressive effect

in major injury and stress

IT MEANS THAT……

PRIS IS……. According to some authors, it is part of a

dreadful TRIGGERING triangle, with serious influence on the priming factor,

THE CRITICAL ILLNESS

PROPOFOL

CATHECOLAMINES STEROIDS

HEAD TRAUMA

What can be done ?

No high doses of propofol, especially in acute neurological conditions

Special care of glucose blood level

Oxygen delivery to be assessed and managed

No prolonged sedation with propofol in these cases (no longer than 48 hours)

The alternative :

*lorazepam 0.01 mg/Kg/hour

*midazolam 0.04-0.2 mg/Kg/hr

In any case, careful monitoring of plasmatic levels of CPK, troponin I and myoglobin

Any other idea?

Carbohydrate supply

Immediate removal of propofol from the blood circulation (Fudikar A et al. Curr Opin Anesth

2006;19:404): *Extracorporeal membrane oxygenation *Hemofiltration *Hemodyalisis Partial exchange blood transfusion (the

push-pull method) –Shonola S et al Pediatrics 2010;125:e 1493)

Can we prevent PRIS

development? Some authors propose the interdiction of

using propofol in continuous infusion IN CHILDREN

Monitoring of pH, serum lactate and creatine kinase when using high doses of propofol

A DOSE LIMIT of 4 mg/Kg/hour is recommended

Do not use propofol alone but IN COMBINATION with other sedative drugs

Be very careful in patients with head injury or any acute neurosurgical lesion

The impact !

These data imply that the use of

propofol in patients with acute

neuro (surgical)logical conditions

might be dangerous

If so, we might lose the main

advantage of using propofol in

Critical Care : the possibility of

rapid awakening !!

Crozier TA (Eur J Anaesth 2006;23:987)

“The available data is still insufficient to determine beyond reasonable doubt if this

rarely occurring event (PRIS) is caused by

administration of propofol , and some

authors contest the very existence of the

syndrome “

One cannot be too sure of

anything!!!!!

And this is the question: does PRIS

really exists as a clinical entity? (Allen K et al. Eur J Anaesth 2006;23:990)

Head trauma is accompanied by itself by cardiovascular instability, arrhythmias, hypekalemia

PRIS is not a syndrome, just a complication of propofol overdosage

Sepsis, used to be described as part of PRIS, is usually accompanied by hypotension, acidosis, multiple organ failure

Lipid component of propofol infusion is to blame for impairment of mythocondrial oxygen uptake

Steroids by themselves can produce rabdomyolysis