Keywords PRIS - infusion syndrome - pregnancy - obstetrics
Propofol is a widely known drug used for sedation in the anesthesia and intensive
care unit (ICU) population. Approved by the Food and Drug Administration in 1989,
propofol has gained its popularity because of its rapid onset of action, quick recovery
profile, and favorable pharmacokinetic profile.[1 ] “Propofol infusion syndrome” was first termed by Bray in 1998 to describe a clinical
state associated with propofol infusion in children.[2 ]
[3 ] All these children exhibited a similar constellation of symptoms including metabolic
acidosis, lipemic serum, and refractory bradycardia progressing to asystole.[3 ] Also known as propofol-related infusion syndrome (PRIS), there have been many complications
and adverse reactions associated PRIS in both adults and children, but no reports
of women in the peripartum period. To our knowledge, this is the first reported case
of a patient who developed PRIS after an emergent cesarean delivery of a preterm infant.
Case Study
A 35-year-old, G11 P3439, African American woman with a medical history significant
for anxiety disorder, depression, and opiate abuse was well controlled on 110 mg of
methadone maintenance therapy as well as citalopram and quetiapine fumarate for 6
months before presentation. She presented to triage at 32 4/7 weeks gestation, by her estimated delivery date, complaining of leakage of fluid
per vagina and decreased fetal movement. Spontaneous rupture of the membrane was ruled
out immediately with negative pooling on speculum examination, negative nitrazine
test, negative ferning on microscopic evaluation of vaginal discharge, and a mean
vertical pocket of 4.47 cm on ultrasound. The fetal nonstress test was evaluated and
it was noted to have minimal variability with no accelerations and no decelerations.
The patient was consequently admitted for prolonged monitoring. Approximately, 4 hours
after admission there was a 7-minute fetal heart tone deceleration to 60 bpm. Despite
intrauterine resuscitative measures with the administration of oxygen by mask at 10
L/min, maternal repositioning to the left decubitus position, and knee-chest position,
the fetal heart rate would not recover. The decision was made to proceed with emergent
cesarean delivery under general anesthesia with intubation. The patient received 200 mg
intravenous (IV) push of propofol during the induction process. She gave birth to
a male infant weighing 2,040 g with Apgar score of 0, 2, 4, and 7 (at 1, 5, 10, and
20 minutes, respectively).
Her immediate postoperative course was benign except for suboptimal pain control secondary
to her significant narcotic tolerance. On postoperative day (POD) 3 however, the patient
complained of a productive cough with yellow sputum. She remained afebrile with no
clinical signs of respiratory distress. She underwent a chest X-ray that revealed
a right lower lobe consolidation and a differential diagnosis of hospital-acquired
pneumonia versus aspiration pneumonia, due to a recent intubation, was made. The patient
was started on IV vancomycin and pipercillin–tazobactam. Subsequently, the patient
complained of chest pain and was noted to be desaturating to 88% on room air. Oxygen
(O2 ) supplementation was administered as well as a nebulized β agonist, but the patient
continued to be tachypneic with no improvement in her oxygen saturation level. A spiral
computed tomography scan was performed to rule out pulmonary embolism. An electrocardiogram
(ECG) demonstrated sinus tachycardia. The patient was transferred later the same evening
to the Maternal Special Care Unit (MSCU) for closer monitoring. She was controlled
on 8 L of O2 supplementation on mask ventilation. In the MSCU, an arterial blood gas was performed
demonstrating continued hypoxia and tachypnea with the following values: pH, 7.37;
PO2 , 64 mm Hg; PCO2 , 45.6 mm Hg; and bicarbonate, 25.9 mEq/L. The patient was transferred to the medical
intensive care unit secondary to worsening respiratory status and the need for intubation
and sedation. Although the patient was given IV fentanyl at 1 μg/kg/h as well as IV
midazolam at 1 mg/h, the patient required extra sedation measures, perhaps secondary
to her history of opiate abuse. Propofol was given as a 50 mg intravenous bolus to
aid in sedation, and a continuous IV infusion at 50 μg/kg/min was subsequently started.
With her weight recorded at 72.4 kg, the rate of the propofol infusion was 3.6 mg/min.
We estimate that the patient received approximately 9,000 mg of propofol during her
intubation and sedation period of 4 days.
On POD 7, persistent acute kidney injury was noted. The patient had a rising serum
creatinine level from a baseline of 0.7 to 1.4 mg/dL, ECG changes, and creatinine
phosphokinase (CPK) was drawn and noted to be significantly elevated at 4,585 units/L.
This raised concerns for PRIS. On POD 8, 4 days after initiation of intubation, other
laboratory studies were obtained including amylase, 134 units/L; lipase, 736 units/L;
triglycerides, 259 mg/dL; and another CPK, which was noted to be 2,626 units/L. These
laboratories were all significantly elevated further supporting the diagnosis of PRIS.
On POD 9, with antimicrobial therapy and corticosteroids in addition to the discontinuation
of propofol, her respiratory status had dramatically improved, and the patient was
successfully extubated. On POD 13, atorvastatin 20 mg daily was started for the significant
hypertriglyceridemia of greater than 600 mg/dL. On POD 15, her amylase was 90 units/L;
lipase, 219 units/L; triglycerides, 376 mg/dL; and CPK, 188 units/L. Eventually, all
of her laboratories trended down toward normal and the patient was discharged home
in stable condition with instructions for follow-up with all specialties of her multidisciplinary
team.
Discussion
Propofol infusion syndrome is a rare, often fatal, condition of unknown etiology.
Upon literature review, serious adverse reactions have occurred with patients including:
metabolic acidosis, rhabdomyolysis with or without myoglobinuria, cardiac collapse,
cardiac arrhythmias (most commonly bradyarrhythmias) myocardial failure, hypertriglyceridemia,
renal failure, hepatomegaly, hepatic steatosis, and death all occurring after the
initiation of propofol therapy.[1 ]
[2 ]
[3 ]
[4 ]
[5 ] However, there is no universal definition of PRIS. Our patient did not have metabolic
acidosis and only showed signs of lipemic serum (hypertriglyceridemia), acute renal
failure, and abnormal cardiac function, which eventually resolved after propofol was
discontinued.
The incidence of PRIS in the adult population is approximately 1.1 to 4.1% and the
mortality rate is 18 to 33%.[4 ]
[5 ] However, determining the incidence of PRIS is complicated because many of the PRIS-associated
clinical manifestations may reflect either pharmacological manifestations or critical
illness (e.g., metabolic acidosis).[6 ] In addition to the confusion regarding the true incidence of PRIS, there remains
no consensus on the management of PRIS other than early recognition and discontinuation
of propofol.[4 ] Within 5 days of the patient receiving the first propofol bolus, it was noted that
she developed sinus tachycardia with a productive cough. The differential diagnosis
was nosocomial versus aspiration pneumonia. Moreover, after the patient was intubated
for the second time, requiring a continuous infusion of propofol, the patient developed
acute kidney injury, however, the cause was attributed to use of contrast with the
computed tomography scan and furosemide.
Propofol infusion syndrome is defined clinically, and although definitions vary, metabolic
acidosis is a common factor.[7 ] In addition to clinical manifestations, abnormal laboratory values include, lactate,
creatine kinase, triglycerides, and ST-segment elevation in right precordial leads.[6 ] On POD 5 the patient was intubated for a second time due to worsening symptoms and
a continuous infusion of propofol was started thereafter. By POD 11 the medical team
noted her lipase was twice the normal limit as well as an increase in CPK and triglycerides
levels. During this time, the patient continued to have ECG changes including sinus
bradycardia with prolonged QT interval, anterior ischemia, and abnormal T-wave abnormality.
After discontinuation and by the time of discharge, all of the patients ECG abnormalities
resolved and she was scheduled to follow-up with cardiology. The most commonly reported
laboratory and clinical findings are metabolic acidosis (88.2%), rhabdomyolysis (64.7%),
cardiac arrhythmias (70.5%), and hypotension (52.9%). Less commonly described presentation
included renal failure (47%), hyperkalemia (44.1%), and hyperlipidemia (20.5%).[1 ]
It has been suggested that a minimum dose of propofol is required to develop this
syndrome. Many studies state that in cases of PRIS, patients who were on > 4 mg/kg/h
for > 48 hours, developed similar symptoms.[2 ]
[3 ]
[4 ]
[6 ] The recommended induction dose of propofol given as an infusion in adults requiring
sedation in an ICU is 0.3 mg/kg/h, which may be increased by 0.3 to 0.6 mg/kg/h until
the desired level of sedation is achieved.[1 ] Our patient was noted to have received over 9,000 mg of propofol during her hospital
stay, well over the recommended limit that can cause PRIS. We suspect this was due
to her profound opioid tolerance that caused her to require high doses of medication
to induce sedation.
In 1996, Merinella was the first author to suggest that propofol reaction should be
included in the differential diagnosis of metabolic acidosis developing in adult patients
during long-term sedation with propofol.[4 ]
[5 ] PRIS remains a complex and multifaceted clinical syndrome, and the overwhelming
majority of patients diagnosed with PRIS have significant preexisting and overlapping
comorbidities.[4 ] In our case, the patient first showed signs of hypoxia, likely due to the developing
pneumonia that was diagnosed and lead to her intubation. Usual sedation practices
include midazolam and fentanyl as in our patient, however, propofol was added because
the patient remained combative and attempted self-extubation several times. We believe
that her history of opiate abuse and a high dose of methadone could have contributed
to this.
The mechanism responsible for PRIS remains controversial. The leading hypothesis ([Fig. 1 ]) is that propofol causes metabolic derangements by affecting β-oxidation of free
fatty acids (FFAs).[4 ] Cardiac muscle uses FFAs in preference to glucose. FFAs are also the main source
of energy for skeletal muscles during sustained exercise. During critical illness
and in states of carbohydrate deprivation, catecholamines induce lipolysis to release
FFAs from the adipose tissue, so these can be used to derive energy and spare glucose
for the brain. The FFAs undergo β-oxidation in the mitochondria to generate adenosine
triphosphates (ATPs) by passing electrons to the electron transport chain. Acetyl-CoA
is also released which is oxidized in the Krebs cycle, or is used to generate ketone
bodies in the liver. Propofol inhibits the electron transport chain causing uncoupling
of oxidative phosphorylation. This decreases the mitochondrial transmembrane potential
and thus affects transportation of FFAs into the mitochondria. Loss of ATP production
leads to widespread cell death resulting in hepatic dysfunction, multiorgan failure,
and metabolic collapse. Lactic acidemia results from inhibitory effects of acylcarnitine
metabolites on various steps of pyruvate metabolism, contributing to metabolic acidosis.
Due to an imbalance in energy demand and supply, there is cardiac dysfunction ultimately
leading to cardiovascular collapse. Accumulating metabolites are also proarrhythmogenic,
and thus, the electrocardiographic changes. Skeletal muscle necrosis leads to rhabdomyolysis.
Myoglobin release leads to acute renal failure and hyperkalemia. Infusion of catecholamines
and corticosteroids in the setting of critical illness also contribute to myopathy.
In patients with PRIS, lipemia experienced results from the lipid emulsion in the
solvent and from accumulating FFAs. Despite the widespread use of propofol, PRIS has
been rarely reported. Genetic susceptibility to develop this condition has therefore
been postulated. However, the genetic predisposition has not been identified. Thus,
we suggest that a toxic effect on mitochondria occurring only in genetically susceptible
individuals could account for the sporadic nature of propofol-related metabolic acidosis.[2 ]
[7 ] In some cases, PRIS is associated with the genetically proven mitochondrial disease.[8 ]
[9 ] It is unknown whether the patient had this underlying comorbidity. Maintaining adequate
carbohydrate intake in critically ill patients may prevent the switch to fat metabolism
and thus prevent the onset of PRIS.[4 ]
Fig. 1 Pathophysiology of propofol-related infusion syndrome. ATP, adenosine triphosphate;
FFA, free fatty acids.
Risk factors for PRIS include critical illness, propofol dosage > 4 mg/kg/h, duration
of therapy > 48 hours, exogenous catecholamines and corticosteroids, poor carbohydrate
intake, severe head injury, airway infection, young age, large total cumulative dose,
low carbohydrate intake/high fat intake, or inborn errors of fatty acid oxidation.[3 ]
[6 ] Our patient had many risk factors that contributed to her clinical outcome. She
received propofol over a 5-day period, she had an airway infection with a diagnosis
of aspiration pneumonia with possible bacterial infection, her calculated total dose
of propofol was approximately 9,000 mg, and she did not have any carbohydrate intake
during her ICU admission. The increased metabolic demand in the peripartum period,
the relative tissue hypoxia secondary to the postoperative state and sepsis may have
impacted the development of this condition in our patient.
In conclusion, propofol should not be used for sedation for more than 3 days if possible.
During propofol infusions, clinicians should monitor arterial blood gases, serum triglycerides,
creatine kinase, all electrolytes (particularly potassium), serum lactate levels,
liver function tests, blood urea nitrogen, and creatinine.[4 ] Prevention of PRIS should include the use of the lowest dose of propofol with the
shortest duration, minimal lipid load (concentrating propofol drip and adjusting parenteral
nutrition), and provide an adequate amount of carbohydrate. A propofol infusion should
be stopped at the earliest sign of abnormal laboratory results or ECG changes.[3 ]
[6 ]