Propofol.. white lightning

[ffpm41]

Interesting u mentioned propofol.... i would be interested to know if any agencies carry this medication for pre-hospital use. From what I understand the medication is not routinely carried because it requires great temperature control and constant refrigeration.

I think Grays County in Washington State carries it.

Like all other meds I guess it's risk vs. benefit. I think it would be more of a hassle than it's worth in pre-hospital, for inter-facilities it might make more sense.

[chbare]

Good points on the prehospital application of propofol. It is pretty easy for me to monitor somebody on a nice still bed with equipment plugged in to a central monitor and a more static environment. However, in the back of a bouncing, swerving, rocking ambulance, monitoring the patients hemodynamic status is difficult at best. I would not want to use propofol routinely in the field because you really need instant feed back on these patients. Perhaps with a service specialized in transports and a patient with an art line so I can have instant hemodynamic feed back. Just my opinion however.

Take care,

chbare.

[Spock]

Boy there is quite a bit to discuss here and great post. This is a very difficult patient that really needed a helicopter. What was her outcome? Some thoughts:

1. Propofol does not need refrigerated. It must be used within 6 hours of opening of the vial and must be administered under strict aseptic conditions because it is a good medium for bacteria. Cost has dropped considerably since it came off patent a number of years ago.

2. My experience with ICU sedation of patients with propofol is that they never give enough. You get adequate sedation at 75-100mcg/kg/min and I rarely see this dose used outside of the OR. Propofol has no analgesic properties. It will drop the BP at these dosages and vasopressor support is usually needed. I use neosynephrine.

3. Pennsylvania does not allow a medic to transport with propofol so an RN from the hospital would have been necessary. Since there was such a long transport time it seems that giving ativan up front and supplementing it with versed and fentanyl for the trip might have worked. Also, the pt needs redosing of the paralytic agent (either rocuronium or vecuronium).

4. Hypotension is the worst possible thing for this patient since she needs a cerebral perfusion pressure of 80-90 to maintain perfusion of the unaffected brain. CPP= MAP - ICP (or CVP). A normal CVP is 10 so you need a mean pressure of 90 or better. Vasopressors are usually needed. I just did a case in neuroradiology for an acute stroke pt and was running her BP in the 160/110 range for the case. Again I was using neosynephrine. Other pressors that are possible are dopamine, epinephrine or norepinephrine.

5. A pt on nipride without an arterial line generates an incident report in my hospital. Are you able to monitor an ATL in the ambulance?

6. This would be an excellent educational opportunity through a case study discussion. Get the community DEM involved and learn of her outcome at the Level 1 center. It would be a very beneficial session.

Live long and prosper.

Spock

[Ace844]

(Survival of propofol infusion syndrome in a head-injured patient

Stephanie Mallow Corbett @ PharmD; Jesse Moore, MD; Jill A. Rebuck, PharmD, BCPS;

Frederick B. Rogers, MD, FACS; Christopher M. Greene, MD)

From the Department of Surgery, Division of Trauma/ Critical Care, University of Vermont College of Medicine (SMC, JM, JAR, FBR); and Department of Pharmacotherapy (SMC, JAR) and Department of Anesthesiology (CMG), Fletcher Allen Health Care, Burlington, VT. The authors have not disclosed any potential conflicts of interest. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000230238.72846.B3

Objective: To describe the clinical progression of an adult patient with traumatic brain injury who survived propofol infusion

syndrome. Design: Case report.

Setting: Tertiary care surgical intensive care unit.

Patient: A 21-yr-old male with traumatic brain injury was administered high doses of propofol for sedation and intracranial

pressure control combined with vasopressor therapy to maintain cerebral perfusion pressure >60 mmHg. He developed a significant

metabolic acidosis with a lactic acid level of 10.9 mmol/L. Interventions: Exploratory laparotomy, discontinuation of

propofol infusion. Measurements and Main Results: An exploratory abdominal laparotomy was negative for traumatic injury. During the procedure, the propofol infusion was considered a possible cause and was discontinued. On review, it became apparent that a combination of

high-dose propofol and catecholamines were responsible for the lactic acidosis. An echocardiogram revealed severe left ventricular

dysfunction and cardiomyopathy, which resolved within 19 days. Conclusions: High-dose propofol should be avoided and alternative agents should be instituted for sedation and intracranial pressure management. The use of catecholamine infusions to maintain cerebral perfusion pressure in the setting of a high-dose propofol infusion may be pharmacologically unsound and may be a triggering factor for propofol infusion syndrome. Identification of the syndrome and discontinuation of propofol resulted in complete reversal of symptoms in the case described. (Crit Care Med

2006; 34:●●●–●●●)

KEY WORDS: propofol; acidosis; brain injuries; intracranial pressure;

catecholamines

Crit Care Med 2006 Vol. 34, No. 9 1

Propofol infusion syndrome (PRIS) has been described as a rare, often fatal syndrome, particularly in the head-injured population (1– 6). Development of this syndrome may result in severe metabolic acidosis, rhabdomyolysis, cardiac dysrhythmias, cardiovascular collapse, and death (1– 6). The risk is increased when propofol infusion is combined with catecholamine administration (1– 6). Although PRIS was first described in children (1–2, 6–11), a total of 15 adult cases have now been reported in the English language literature. Nine of these cases

occurred in patients sustaining traumatic brain injury, none of whom survived the syndrome (2– 4). The current report is

the first description of an adult head injured patient to survive PRIS, due to timely recognition of the syndrome and discontinuation of propofol. Per institutional review board instruction, written informed consent was obtained from the patient for this case report.

CASE PRESENTATION

A 21-yr-old, 79-kg male was an unrestrained rear seat passenger admitted to the emergency department of a nearby hospital after a motor vehicle crash. His Glasgow Coma Scale score was 6, blood pressure was 140/80 mm Hg, and heart rate was 76 beats/min. He sustained a

laceration on the right side of his forehead and an open depressed skull fracture. He was intubated for airway protection and transferred to our institution. At admission at 0245 to our emergency department, his Glasgow Coma Scale score was 7. Computed tomography scan of the head revealed a comminuted depressed skull fracture of the right frontal bone, with a subdural hematoma and interventricular hemorrhage. The remainder of his trauma work-up was negative, including plain films of the chest and pelvis and computed tomography of the abdomen and pelvis. Laboratory tests were remarkable for potassium, 3.3 mEq/L; serum bicarbonate, 23 mEq/L; phosphorous, 1.3 mg/dL; chloride, 111 mEq/L; white blood cell count, 25.5 K/cm2; and blood alcohol level, 108 mg/dL. Serum creatinine, liver function tests, and cardiac enzymes were

within normal limits. Arterial blood gas at admission revealed a combined respiratory and metabolic acidosis (Table 1). He was transferred to the intensive care unit at 0410 where an intermittent propofol infusion was administered at a rate of 32–105 g/kg/min (1.9–6.3 mg/kg/hr). At 0530 he was taken to the operating room for emergent right frontal craniotomy and removal of fragmented bone, evacuation of subdural hematoma,

and placement of an intracerebral pressure monitor. Intraoperatively he received isoflurane, fentanyl, vecuronium, esmolol, cefazolin, and phenytoin; his propofol infusion was continued at a rate of 105 g/kg/min (6.3 mg/kg/hr). Phenylephrine boluses were administered for decreased cerebral perfusion pressure (CPP) but he was otherwise hemodynamically stable throughout the operation, with intracranial pressures (ICP) ranging from 5 to 9 mm Hg. On return to the surgical intensive care unit at 0930, the propofol infusion was continued at a rate of 105 g/kg/min (6.3 mg/kg/hr) for sedation (Fig. 1). Two hours postoperatively the propofol infusion was discontinued for 1 hr to assess

neurologic function. The infusion was then restarted with doses ranging from 53 to 105 g/kg/min (3.1– 6.3 mg/kg/hr) and ICPs ranging from 5 to 16 mm Hg. The patient’s acidosis resolved and electrolytes normalized within 5 hrs. Approximately 7 hrs postoperatively, the patient’s ICP became elevated. The propofol infusion was increased to 158 g/kg/min (9.5 mg/kg/hr) and subsequently to 200 g/kg/min (12 mg/kg/hr) in an attempt to decrease the patient’s ICP. The patient’s ICP ranged from 18 to 43 mm Hg, despite therapy that included mannitol, morphine, and vecuronium. The patient remained on 158–200 g/kg/min (9.5–12mg/kg/hr) of propofol for approximately 7 hrs until the infusion was stopped for approximately 15 mins for neurologic assessmenton hospital day 2. ICP at this time was 22 mm Hg but increased to 28–31 mm Hg, for which 25 g of mannitol was administered. Following the neurologic exam, propofol was reinstituted at doses ranging from 74 to 105 g/kg/min. Vasopressor therapy consisting of dopamine and norepinephrine was required to provide a satisfactory CPP (60 mm Hg).

Within several hours of adding high-dose vasopressor therapy, the patient developed sinus tachycardia (heart rate 99–128 beats/min). He continued to receive a total of 125 g of mannitol, 34 mg of morphine, 30 mg of vecuronium, and high-dose propofol during the following 24 hrs. A blood gas obtained after approximately 42 hrs of high-dose propofol infusion, with an overall average dose of 112.8 g/kg/min (6.8 mg/kg/hr), showed a metabolic acidosis with a base excess of 6. At this time the patient was receiving propofol at 105 g/kg/min, dopamine at 30.4 g/kg/min, and norepinephrine at 8g/min. His overall fluid balance was positive for 2.5 L with a continuous infusion of normal saline at a rate of 100–125 mL/hr and urine output exceeding 190mL/hr. At 1040 on hospital day 2 the patient returned to the operating room for a right hemicraniectomy to treat refractory ICP elevation. During this procedure the patient continued on propofol at 105 g/kg/min in addition to receiving norepinephrine, dopamine, phenylephrine, mannitol, vecuronium, and isoflurane.

Following the hemicraniectomy, the ICP was 8 mm Hg. The arterial blood gas obtained immediately

postoperatively (0028, hospital day 3) indicated an increasing metabolic acidosis with a base excess 13.4 and an elevated lactate level of 10.9 mmol/L. The acidosis persisted despite vigorous fluid administration with normal saline. Vasopressor support to maintain CPP was continued with maximum infusion rates of dopamine and norepinephrine at 30.4g/kg/min and 8 g/min, respectively. Propofol was continued for sedation at a rate of 52.7 g/kg/min. ICP during this time ranged from 8 to 18 mm Hg. Blood, urine, sputum, and cerebral spinal fluid cultures were obtained, and empirical antibiotics(piperacillin-tazobactam and vancomycin) were initiated; the patient

remained afebrile during this episode. A serum cortisol level was 23 g/dL. An abdominal computed tomography was obtained to evaluate the possibility of a missed injury and was remarkable for

Table 1. Time point characteristics related to arterial blood gas measurements and corresponding propofol administration rates

Day 1 Day 2 Day 3

Admit 1441 0520 1927 0028 0231 0613 0802 1806 2204

Propofol dose,

g/kg/mina

— 94.9 84.4 105.5 52.7 52.7 52.7 31.6 D/C:

1420

—

Dopamine,

g/kg/min

— — 6.8 30.4 30.4 30.4 16.9 3.4 D/C:

1000

—

Norepinephrine,

g/min

— — — 8.0 2.0 2.0 2.0 8.0 8.0 8.0

NaCl w/20

mEq KCl,

mL/hrb

— — 100 125 125 125 125 125 125 125

Chloride,

mEq/L

111 108 113 114 117 121 — 123 120 —

PO4, mg/dL 1.3 2.5 1.1 — 1.6 2.2 — — — —

BUN, mg/dL 8 8 8 — — 4 — 6 10 11

Creatinine,

mg/dL

0.9 0.9 0.9 — — 1.0 — 1.1 1.2 1.3

Urine output,

mL/hr

— 545 190 400 750 210 80 50 50 80

pH 7.30 7.46 7.42 7.30 7.24 7.21 7.18 7.19 7.28 7.31

PCO2, mm Hg 42 35 36 42 31 28 29 29 25 26

tCO2, mEq/L 22 25 24 21 14 12 11 12 12 14

Base excess,

mEq/L

5.0 0.9 1.6 6.0 13.4 13.7 16.2 15.5 13.8 11.4

HCO3, mEq/L 23 27 26 22 16 13 — 13 12 —

Lactate,

mmol/L

— — — — 10.9 10.2 — 8.3 7.5 5.3 Anion gap,mEq/L 13.3 10.6 6.8 13.1 16.3 15.0 — 13.0 14.9 —

D/C, discontinued; PO4, phosphorus; BUN, blood urea nitrogen; tCO2, total carbon dioxide; HCO3, serum bicarbonate; anion gap, (sodium

potassium) (chloride serum bicarbonate).

aPropofol infusion rates listed in table are not inclusive but reflect time points at which arterial blood gases were obtained; bNaCl w/ 20 mEq KCl, normal saline with 20 milliequivalents of potassium chloride.

2 Crit Care Med 2006 Vol. 34, No. 9

mesenteric edema surrounding the second portion of the duodenum and possible thumb-printing of the right colon. Due to the patient’s persisting metabolic acidosis, he was returned to the operating room at 1420 on hospital day 3 for an exploratory laparotomy, which was negative for traumatic injury. During this procedure the anesthesiologist considered the possibility of propofol as a cause of the patient’s acidosis and discontinued administration of the agent. The patient returned to the intensive care unit at 1600. His elevated lactic acid level began to decrease following reduction and subsequent discontinuation of the propofol infusion. However, he remained acidotic with a hyperchloremic component. His urine output decreased to 50 mL/hr and his creatinine increased to 1.2 mg/dL. During the next 24 hrs the patient’s lactic acidosis resolved, his sinus tachycardia slowed to a normal sinus rhythm, his CPP stabilized, and he was weaned off his vasopressor drips. Tube feeds were initiated on day 5; before this the patient had received no nutrition. By hospital day 5, all cultures were negative with the exception of a sputum culture, which revealed Haemophilus influenzae, and antibiotics were tailored to treat a suspected pneumonia with ceftriaxone. However, the patient continued to be oliguric, with his creatinine increasing to 1.3 mg/dL. As part of a work-up for renal insufficiency, an echocardiogram was obtained. This revealed moderate to severe global left ventricular (LV) dysfunction with an ejection fraction of 25–30% and moderate global dysfunction of the right ventricle. The patient’s creatinine kinase (CK) was elevated (3076 /L), and he had a normal MB fraction and troponin-I.

Based on these findings, therapy with metoprolol and captopril was initiated. A repeat echocardiogram 2 days later (hospital day 7) showed improved LV dysfunction. By hospital day 19, a final echocardiogram revealed resolution of the cardiomyopathy with normal LV systolic function and an ejection fraction of 50–55%. On hospital day 26 he was transferred to inpatient rehabilitation, where he progressed to a full neurologic recovery and was subsequently discharged home.

DISCUSSION

Nine adult cases of PRIS have been

previously reported in patients sustaining

traumatic brain injury, and all cases have

resulted in death (2– 4). Myocardial dysrhythmias

and catecholamine therapy

were features of every case. In addition,

all but one patient presented with metabolic

acidosis (1–3). Increased serum potassium,

rhabdomyolysis with elevated

creatinine kinase levels, and lipemia

were among additional presenting factors

(1– 4). All nine patients died before

diagnosis; thus, all factors were determined

retrospectively. We report the first

case of an adult head-injured patient to

survive PRIS, after receiving a prolonged

propofol infusion, with complete resolution

of symptoms.

Propofol’s association with metabolic

acidosis is well documented, appearing

after both relatively short (4 hrs) (12–

15) and prolonged (24 hrs) (16) infusions.

Our patient exhibited a complex

metabolic acidosis consisting of both a

hyperchloremic acidosis (anion gap 12)

and an elevated anion gap acidosis (due to

lactate and other unmeasured anions). A

significant metabolic acidosis was first

noted in this patient after approximately

42 hrs of high-dose propofol infusion,

with a marked lactic acidosis within 5 hrs

of concomitant therapy of dopamine and

norepinephrine. It may be important to

note that two previous blood gases obtained

during the first 24 hrs of his

Table 1. (Cont’d )

Day 4 Day 5 Day 6 Day 7 Day 8 Day 9

0034 0457 2035 0322 0345 0408 0625 0806

— — — — — — — —

— — — — — — — —

7.3 6.0 D/C: 1400 — — — — —

125 125 40 40 40 40 — —

123 122 120 123 123 120 116 114

— 2.4 — 3.5 3.6 2.7 2.6 3.3

— 13 — 18 32 37 32 30

— 1.3 — 1.3 1.7 1.3 1.0 0.9

60 40 60 60 34 260 270 330

7.34 7.36 7.40 7.41 7.43 7.44 7.51 7.46

27 28 27 27 23 27 30 34

15 17 17 18 15 19 24 25

10.0 8.5 7.9 7.1 8.6 — 0.6 0.3

17 17 19 18 17 21 25 27

3.7 2.2 1.2 1.1 1.3 0.9 — 0.7

8.6 8.4 8.5 7.4 8.9 10.1 8.1 6.7

Crit Care Med 2006 Vol. 34, No. 9 3

propofol infusion without concomitant

vasopressor administration showed no

evidence of a metabolic acidosis. Lactate,

which accounted for most of the base

deficit before the discontinuation of

propofol, progressively decreased after a

halving of the rate of the propofol infusion,

from 105.5 to 52.7 g/kg/min. Following

discontinuation of propofol, a

rapid resolution of his elevated gap acidosis

was apparent, whereas a nongap

hyperchloremic acidosis persisted for 2

more days.

Other possible etiologies for our patient’s

lactic acidosis include cardiogenic

and hypovolemic shock as well as cytopathic

hypoxia. The high doses of dopamine

and norepinephrine administered

to our patient may have caused myocardial

dysfunction as well as a metabolic

acidosis (1, 17, 18). However, lactate levels

declined on hospital day 3 despite

continued high-dose catecholamine infusions.

As proposed by Vasile et al. (1),

catecholamine infusions may be a permissive

factor for the infusion syndrome

caused by high-dose propofol. It also

seems unlikely that our patient had a

possible cardiogenic shock that resolved

during hospital day 3. Our patient had no

signs of cardiac trauma at admission, as

demonstrated by normal cardiac enzymes

and unremarkable chest radiography. A

sinus tachycardia may have been the first

sign of cardiac toxicity; this resolved with

propofol discontinuation. The diagnosis

of cardiomyopathy with moderate to severe

global LV dysfunction by echocardiogram

occurred approximately 48 hrs after

discontinuation of propofol.

Ventricular dysfunction has been previously

described in patients who developed

PRIS (1–3). In the nine adult patients

who reportedly died as a result of

PRIS, five had an echocardiogram (1–3).

Two of the five patients had documentation

of LV dysfunction (3) and one had

global hypokinesis (2). Severe biventricular

dysfunction was also noted in a pediatric

head-injured patient recently reported

to have survived this syndrome

(8). Echocardiographic resolution of ventricular

dysfunction was observed in both

the pediatric survival case (8) and in our

patient several days following discontinuation

of propofol. However, it is not

possible to definitively ascribe this patient’s

ventricular dysfunction to PRIS, as

cardiac dysfunction has been reported in

association with subarachnoid hemorrhage

and traumatic brain injury (19).

The prevailing hypothesis is that neurologically

induced cardiac dysfunction is

secondary to elevated catecholamine levels,

a relevant consideration in this and

other reported cases of PRIS.

The patient’s renal function preceded

the development of his acidosis, arguing

against hypovolemia and hypoperfusion

as a cause of his acidosis. At the time he

was first diagnosed with a lactic acidosis,

his overall fluid balance was positive, his

blood urea nitrogen and creatinine levels

were low, his hourly urine output was

high, and he had received 125 g of mannitol.

However, after development of his

acidosis, his urine output markedly decreased

and his blood urea nitrogen and

creatinine began to rise, reaching maximum

values on hospital days 5 and 6 and

then returning to normal values during

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

7/21:0500

1200

1800

7/22:0000

600

800

1400

2000

200

800

1400

2000

200

800

1400

Propofol (mcg/kg/min) Dopamine (mcg/kg/min) Norepinephrine (mcg/min)

Drug dose administered

Time (hours)

Figure 1. Trends in dosage administration over time.

4 Crit Care Med 2006 Vol. 34, No. 9

the next several days. His transient renal

insufficiency was therefore most likely

due to his cardiac dysfunction. Unlike

other reported cases (3, 8–10, 16), our

patient never developed rhabomyolysis.

Cytopathic hypoxia due to disruption

of fatty acid oxidation and the mitochondrial

electron transport chain has also

been proposed as the mechanism underlying

PRIS (20). This may occur only in

genetically susceptible individuals or may

be related to impaired lipid metabolism

during starved states. Our patient was not

fed until hospital day 5, and it is therefore

not possible to rule out this mechanism

as a possible contributing factor. However,

resolution of his lactic acidosis well

before day 5 argues against starvation as a

primary cause of his acidosis.

The clinical strategy of lowering ICP

with propofol (21) while maintaining CPP

with catecholamines may be pharmacologically

unsound, as initial infusions of

these agents will be antagonistic. Exogenous

infusions of dopamine and norepinephrine

decreased the blood concentration

of propofol by 52.9% and 63%,

respectively, in sheep receiving continuous

infusions of propofol (22). Spontaneously

breathing patients undergoing

brain biopsy under propofol sedation (177

g/kg/min) showed no significant change

in ICP but significant decreases in mean

arterial pressure and CPP when compared

with unsedated patients (23). Kelly

and colleagues (21) compared propofol to

morphine for sedation in intubated,

head-injured patients and were only able

to demonstrate that ICP was significantly

lowered with propofol on just 1 of 4 days

of therapy; however, propofol-treated patients

required greater use of vasopressors.

Increasing rates of propofol and catecholamine

infusions thus create a

vicious cycle leading to myocardial depression

(1). Catecholamine -receptor

stimulation, mannitol-induced hypovolemia,

and shock would be expected to decrease

effective blood volume and further

increase the plasma concentration of

propofol (24 –27). Propofol clearance has

been shown to be reduced in critically ill

infants and children following cardiac

surgery (28) and is also dependent on

renal function (29). Although it is not

possible to intuit the plasma level of

propofol at any time in our patient, it is

nonetheless likely that it was significantly

higher than that predicted by equations

for short-term infusions in healthy patients.

CONCLUSIONS

This report is consistent with previously

reported cases describing the development

of lactic acidosis and myocardial

dysfunction in association with the continuous

infusion of high-dose propofol,

generally accepted to be 83 g/kg/min.

PRIS did not develop in our patient until

high-dose propofol was given in combination

with catecholamine infusions, a

finding consistent with the hypothesis of

Vasile et al. (1) that the syndrome requires

both priming and triggering factors.

Based on our findings, this syndrome

can be reversed if symptoms are

recognized and the propofol infusion is

discontinued promptly.

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