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propofol infusion syndrome ( pris ) was initially described in 1992 as a syndrome with fatal outcome in critically ill children .
further investigation showed that critically ill adults suffer from identical symptoms after administration of propofol .
the syndrome was defined by bray in 1998 , describing a sudden onset of bradycardia , resistant to treatment and progression to asystole plus one of the following : hyperlipidemia , fatty infiltration of the liver , severe metabolic acidosis or muscle involvement with rhabdomyolysis and myoglobinuria .
the findings of a multicenter study with 1017 medical and neurosurgical adult patients was published in 2009 .
incidence slightly exceeded 1% , but the short exposure of a maximum 24 h in this study has to be taken into account .
a previous retrospective study of 55 patients receiving propofol for sedation during catheter radiofrequency ablation suggests a higher incidence : 24% ( 13 of 55 ) of the patients showed a metabolic acidosis ( base excess ( be ) 2 ) which was interpreted as the initial indicator of the syndrome .
an alert and well - oriented 7-year old boy presented after being involved in a road traffic accident .
the computed tomography ( ct ) scan of the brain showed a depression of the os parietale with small subcortical contusions , perifocal edema , little intracranial air , but no midline shift .
intracranial pressure ( icp ) monitoring was installed with a combined liquor drain . at the same time
elevated icp ( 25 mm hg ) called for a postoperative ct scan ; results were unchanged .
after surgery , the intubated patient was sedated with propofol ( 12 mg / kg / h ) and transferred to the intensive care unit .
ph and serum lactate levels were monitored several times daily , and creatine kinase levels once daily . during sedation with propofol , inotropic support with
low - dose norepinephrine was necessary to reach the goal of 60 mm hg cranial perfusion pressure .
propofol infusion was stopped after 39 h. eight hours later , the patient had a glasgow coma score of 10 , and his trachea was extubated . at that time , generalized muscle weakness and slow awakening were observed .
two hours after successful weaning and extubation , the patient was in respiratory distress with aggravating metabolic acidosis ( ph 7.19 , be 13.2 , lactate
sedation with propofol was reinstalled for another 11 h ( 7.3 mg / kg / h ) after which the regimen was changed to midazolam and nalbuphine . on the following day , blood tests showed decreasing metabolic acidosis ( ph 7.31 , be 6.6 , lactate 1.8 mmol / l ) but elevated creatine kinase ( 1023 u / l , reference range 38 - 157 u / l ) and mildly elevated liver enzymes ( asat 179 u / l , reference range 11 - 34 u / l , alat 174 u u / l , reference range 10 - 37
twenty hours after cessation of propofol , generalized seizure was observed under sedation with midazolam and nalbuphine , which was successfully treated with intravenous thiopentone .
no change was observed in another ct brain scan performed immediately afterwards . during the following 6 h , cardiac instability with supraventricular tachycardia up to 180 bpm and peracute renal failure developed .
after immediate mechanical and medical resuscitation , the patient presented with unreactive and bilateral dilated pupils and bradyarrhythmia that were resistant to therapy . a further ct brain scan ( 10 h after the previous scan ) showed a generalized edema of the brain with obliteration of the basal cisterns and transtentorial herniation .
nevertheless , renal replacement therapy was installed and cardiac performance improved , and metabolic acidosis could be normalized . due to persistent rhabdomyolisis ( creatine kinase > 100,000 u / l ) , an open muscle biopsy of the m. quadriceps followed by in vitro muscle contracture testing ( ivct ) and histological analysis were performed .
these investigations were carried out because the clinical signs involved skeletal muscle dysfunctions and because the patient was intubated using succinylcholine , a known trigger agent for malignant hyperthermia ( mh ) .
while histology revealed completely normal values , the muscle could not be stimulated electrically for ivct but presented with spontaneous muscle contracture ( figure 1 ) .
a blood sample was taken to isolate genomic dna and investigate for mutations in the gene encoding for the skeletal muscle type 1 ryanodine receptor ( ryr1 ) using molecular genetic investigations , but no ryr1 variant was identified . 

figure 1original recordings from freshly biopsied skeletal muscle were obtained from the vastus medialis of the quadriceps muscle .
muscle strips approximately 2.5 cm long and approximately 3 mm wide were mounted in a tissue bath and slowly stretched to a pre - load force of approximately 25 mn .
the tissue bath , containing krebs - ringer solution , was bubbled with carbogen at 37c .
muscle strips were stimulated electrically in order to produce repeated muscle contractions ( twitches ) .
( a ) a muscle strip of the patient showing a continuously increasing muscle contracture with absolutely no response to electrical stimulation , resulting from the loss of function of excitation - contraction coupling .
( b ) a muscle strip from a healthy subject . note the stabilization of the baseline as well as the muscle contractions upon electrical stimulation .
original recordings from freshly biopsied skeletal muscle were obtained from the vastus medialis of the quadriceps muscle .
muscle strips approximately 2.5 cm long and approximately 3 mm wide were mounted in a tissue bath and slowly stretched to a pre - load force of approximately 25 mn .
the tissue bath , containing krebs - ringer solution , was bubbled with carbogen at 37c .
muscle strips were stimulated electrically in order to produce repeated muscle contractions ( twitches ) .
( a ) a muscle strip of the patient showing a continuously increasing muscle contracture with absolutely no response to electrical stimulation , resulting from the loss of function of excitation - contraction coupling .
( b ) a muscle strip from a healthy subject . note the stabilization of the baseline as well as the muscle contractions upon electrical stimulation . despite high doses of inotropic support , the patient developed progressive cardiac and pulmonary failure .
u / l ) , rhabdomyolysis ( creatine kinase > 100,000 u / l ) , and coagulopathy ( thrombin time > 120 s , prothrombin time 48% ) .
the boy died of brain death and multiple organ failure four days and 6 h after discontinuation of the propofol infusion .
although millions of patients worldwide are sedated with propofol , there have been only a few reports of pris .
this implies a particular susceptibility of some patients and is , therefore , highly suggestive of a pharmacogenetic disease .
hypothesize that the key pathogenetic mechanism is an imbalance between energy demand and utilization through the impairment of free fatty acid utilization and mitochondrial activity , which is generated in the presence of propofol .
propofol seems to produce a cytochrome oxidase deficiency in muscle tissue , as observed in a child after prolonged high - dose infusion .
the link between free fatty acid metabolism and myocytolysis was found after plasma analysis of a 2-year old boy which showed raised concentrations of malonyl carnitine and c5 acylcarnitine ; these returned to normal after recovery .
state that these findings indicate that altered long - chain free fatty acid entry into the mitochondrion and uncoupling of beta - spiral oxidation and respiratory chain at complex ii are the critical events in pris .
bray and vasile et al . defined the triggering factors to be catecholamines , steroids , cytokine production , and metabolic stress ; all these are present or administered for conditions including polytrauma , multiple organ failure , and severe brain or burn injury .
showed a greater risk with high - dose propofol ( 5 mg / kg / h ) or prolonged sedation ( > 48 h ) .
the postulated risk factors in our patient are young age , brain injury , norepinephrine application , high - dose propofol and a total of 49 h of therapy .
the hypermetabolic state , rhabdomyolysis , and muscle weakness of our patient suggested some parallels to episodes of mh .
therefore , a muscle sample was taken after obtaining written informed consent from his parents .
this muscle sample did not twitch in vitro following supramaximal electrical stimulation , but showed spontaneous contracture ( figure 1 ) .
the enzyme - histochemical examination showed neither a structural congenital myopathy nor an abnormal accumulation of mitochondria . as the involved organs included the brain , heart , and skeletal muscle , and the main symptoms of our patient were metabolic acidosis , seizure , cardiac conduction abnormalities and rhabdomyolysis
, we postulate that the key mechanism for the observed dysfunctions in all three organs involves calcium regulation and , therefore , ryanodine receptors . as a different isoform of the ryanodine receptor ( ryr1 , ryr2 , and ryr3 )
is involved for each of the organs mentioned above ( brain , heart , and skeletal muscle ) , a common modulator of each of these subtypes of receptors could be the missing link .
this view is supported by the fact that ryr1 is present in all 3 organs and that all 3 isoforms of ryanodine receptors are very similar . whether the common final pathway of an altered intracellular calcium regulation via a dysfunction of ryanodine receptors is the result of a decreased energy supply due to impaired oxidation in the mitochondria or by alternative direct or indirect effect(s ) of propofol on the function of ryanodine receptors are factors in patients presenting with pris remains to be clarified .
the basis for this disorder is the triggering of a sustained rise in intracellular ca in skeletal muscle due to hyperactivation of mutated ryr1 channels .
the variability of the clinical presentation and the time differences between the first laboratory findings in published cases with pris , as well as the fact that only a small number of individuals in all age groups developed pris after anesthesia or sedation using propofol , support the view of pris being a pharmacogenetic disorder .
the involvement of an altered calcium regulation in pris may be an interesting and attractive approach for identifying potential genetic alterations in patients presenting with pris .
pris could well be an entity of disorders with an identical common pathway caused by a variety of causative genetic mutations .
we present the case of a 7-year old boy with traumatic brain injury who received propofol during 38 h. thirty - six hours after cessation of propofol infusion asystole occurred . 
 after immediate mechanical and medical resuscitation , unreactive dilated pupils were observed . the following computed tomography scan revealed a generalized brain edema with transtentorial herniation . 
 prolonged bradyarrhythmia , rhabdomyolysis , and peracute renal failure were observed . despite immediate craniectomy , barbiturate treatment , hemofiltration , and recovery of appropriate cardiac function , 
 the patient died four days after discontinuation of propofol . in this case , 
 metabolic acidosis , cardiac failure , rhabdomyolysis , and renal failure are in accordance with the symptoms of propofol infusion syndrome ( pris ) , while seizure , brain edema , and transtentorial herniation could be caused by traumatic brain injury . 
 however , it may be assumed that the entire clinical picture was caused by pris . 
 this view could be explained by a common loss of function of ryanodine receptors in patients presenting with pris .