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diisopropylphenol) is rare. We report a case of a 26-year-old male nurse in which autopsy showed unspecific signs of in- toxication. Criminological evidence pointed towards propofolabuse and/or overdose. Intravenously administered propofol is a fast as well as short acting narcotic agent. Therefore it seemed questionable whether the deceased was able to self- administer a lethal overdose before loosing consciousness.
The blood and brain concentrations corresponded to theconcentrations found 1-2min after bolus administration of a narcotic standard dose of 2.5mg propofol/kg body weight.
Extremely high propofol concentrations were found in urineindicating multiple abuse before death.
half-life of propofol the cumulative toxic effect of repeatedinjections should not be relevant for toxicity since this wouldresult in a blood level increase of only 1-2µg/ml.
detection and quantitation of propofol in three different hairsegments indicates a chronic propofol abuse of the deceased.
The results of the investigation suggest that death was notcaused by a propfol overdose but by respiratory depressionresulting from too fast an injection.
Chronic propofol abuse, Toxicology, Fatal propofol overdose,Hair analysis, Brain concentration ∗Institut of Legal Medicine, University of Hamburg, Butenfeld †Landeskriminalamt Schleswig-Holstein, M¨ day before his death when they made an appointment for thefollowing day.
Propofol is a new short-acting anaesthetic used for induct-ing and maintaining general anaestesia. It has no affinity to opiate-, benzodiazepin-, or NDMA-receptors and thus shouldhave no potential for abuse or addication—which are always Due to the findings of rigor mortis and livores at 8 a.m. death associated with the risk of overdosing like Fentanyl or Ke- was attributed to have occurred the previous evening. The tamine There are only two publications de- weight of the deceased was 91kg. Lung and brain were oede- scribing propofol abuse. In both cases propofol was used matous and congested. The heart, coronary vessels, aorta, for its sedative and relaxing property Other possible and kidney did not show any pathological changes. The organ motives for propofol abuse are sexual illusions and disinhibi- weights were: brain 1520g, heart 385g, lungs 1780g, kidneys tions during awakening from the narcotic-induced sleep 310g, liver 2170g, spleen 265g. The bladder contained ap- In a clinical trail 40% of patients (N=546) described plea- prox. 250ml urine. Needle marks were found on the forearm, surable feelings on awakening The risk of death due to a inside of his elbows, wrist, and back of the hand, they were self-administered propofol intoxication is very low, the main fresh or partially scarred. In the areas were the shin-bone reason being the low concentration found in commercial am- touched the ground skin vesicles were found. Furthermore poules (20ml containing 200mg propofol). This amounts to an aspiration of stomach contents was diagnosed during au- a standard dose of 2-2.5mg/kg body weight for the induc- topsy. Using the routine HE staining the only histopatholog- tion of a general anaesthesia within 1-2min after injection and an arousal after 5-10min. The fast acting narcotic ef-fect of propofol prevents the self-injection of more than one ampoule at a time. A cumulation of brain propofol levelsdue to repeated injection just after arousal, i.e. after 20- Pure propofol was kindly donated by Zeneca. Thymol used 30min, cannot be observed because of the fast redistribu- as internal standard was obtained from Fluka, all other chem- tion from the brain. The pharmacokinetic of propofol can icals and reagents were of analytical grade and were used as be described by a three compartment model with a t1/2 of purchased.
1.8-8.3min for distribution, t1/2β1 of 34-64min and t1/2β2 of184-382min. The last half-life corresponds to the eliminationfrom adipose tissue but being insignificant due to the rapid metabolism of propofol. Propofol is maily metabolised Urine samples were screened for drugs and drugs of abuse by two pathways: either direct glucronide conjugation or by immunoassays using the CEDIA, Hitachi 911-Analyser p-hydroxylation with subsequent glucuronidation (or sulpha- (Boehringer Mannheim Mannheim, Germany), Hitachi, and tion) where quinol glucuronide amounts to 20–50% of FPIA (ADx-System, Abbott, Wiesbaden, Germany) accord- the dose Only very small amounts are aliminated with- ing to the manufacturer’s instructions. Further “general un- known” screening for acid-neutral and basic drugs was per- We report on the death of a male nurse found dead in his flat formed after alkaline or acid liquid-liquid or SPE-extraction with several empty propofol ampoules littering the floor. His partner said he knew about a propofol abuse for several yearsthough non was abused during the last couple of months.
Doupts existed regarding the self-administration of such high doses of propofol knowing the pharmacological data. There- Solid tissue samples were minced and 1g was homogenized fore analyses were made to clarify this case.
with two parts of water and ultrasonicated for 30min, thencentrifuged.
Blood samples were only centrifuged.
was analyzed untreated and acidic hydrolyzed at 100◦C for 30min. The supernatants of the tissue samples, blood, and(neutralised) urine samples were spiked with thymol and A 26-year-old male nurse was found dead in his flat at 8am.
subsequently diluted with one volume of KH2P O4 buffer He was surrounded by several partly empty as well as unused (1.5mol/l, pH 6.8, one part saturated KH2P O4 solution, 3 ampoules of propofol and two syringes. Furthermore drug parts aqua dest.). The samples were extracted twice with 3ml packs of diphenhydramine, amitriptyline, amoxicilline, and cyclohexane. Ethanolic N aOH (100µl, 0.1mol/l in ethanol) ranitidine were found. His partner reported that the deceased was added to the organic phase and the extract was dried at had abused propofol for many years. He was also known to 40◦C under a slow stream of nitrogen. The samples were re- abuse other drugs available to him in the intensive care unit constituted with 50µl ethanol and 1µl was injected (splitless at work. He was said to have suffered an acute kidney failure mode) into a Hewlett Packard (HP) gas chromatograph 5890 3 years ago which was said to be due to his intravenous drug series II coupled to a HP 5972 mass selective detector. He- abuse. During the previous 6 months he was on sick-leave for lium was used as carrier gas with a flow rate of 1ml/min. A medical treatment of his depressive illness. To the knowledge (5% phenyl)-methylpolysiloxane capillary column (HP-5MS, of his friend he did not abuse propofol during therapy. Ten 30m × 0.25mm internal diameter, 0.25µm film thickness) days before his death he returned to work. There was no was used for separation. Operating temperatures for injector evidence that he intended to take his own life. The nurse and detector were 200◦C and 280◦C, respectively. The oven and his friend had a telephone conversation at 4 p.m. on the temperature was programmed from 100◦C (1min hold) to 240◦C at 20◦C/min (5min hold) and to 280◦C at 10◦C/min (20min hold). The mass spectrometer was operated in EI mode and in full-scan mode.
Since the amount of hair material was limited in this case no special method for propofol determination in hair was de- veloped. Instead, our routine method for general unknown hair analysis was used to screen for a broad spectrum ofsubstances. Hair samples were taken by cutting the hair as close to the scalp as possible. Starting at the scalp (0cm) they were cut into segments of 2cm, washed three times (aqua dest., acetone, CH2Cl2), and dried. Afterwards the segments were separately pulverized using a ball mill. 2mlmethanol and 200ng of the internal standard methaqualon were added to 50mg of the pulverized hair. This mixture was incubated in an ultrasonic bath for 4h. After centrifu- gation the supernatant was transferred to a clean vessel and 2ml methanol was added to the residue and again incubatedfor 4 hours. After centrifugation the two supernatants were combined, ethanolic N aOH (100µl) was added and evap- orated to dryness under a stream of nitrogen at 40◦C. The reconstituted samples were examined by GC/MS using the proven methods aused for the body fluids.
Table 1: Results of toxicological analysis compared withtwo other fatal cases of propofol overdose.
Standard 6-point calibration curves were obtained using0.01–10µg propofol/ml serum blank and for hair using0.01µg - 0.5µg propofol/50mg hair blank. The detection limit was determined according to DIN 32645 It was Hydrolysis of quinol conjugates in urine yielded 2,6- 0.04µg propofol/ml serum and 0.2µg propofol/g using 50mg diisopropyl-1,4-quinone due to the fast oxidation of the lib- hair. The calibration curves were found to be linear over the whole calibration range. The recovery for spiked serum amounts of the oxidized metabolites could be detected in all samples was determined to be 65% at 0.1µg/ml and 64% body fluids, tissues, and even in hair. Due to the absence of at 3µg/ml. Precision results showed an intraassay variance standards for the quinol and other unidentified metabolites a of propofol determination in serum (n = 6) of 4.7% (at quantification of the metabolites was not possible. According 0.1µg/ml) and 4.3% (at 3µg/ml). Inter-assay variance de- to Vree the quinol glucuronide amounts to 20-50% termined on 5 different days was 6.9% (at 0.1µg/ml) and Quantification of propofol in 3 different hair segments showed samples was determined to be 65% at 3µg/ml and 54% for an increase in the concentrations towards the scalp i.e. the The toxicological examination revealed the presence of propo- In order to assess the relevancy of the measured propofol blood concentrations of this case they were compared to two substances or alcohol were not detected. The blood con- fatal cases of propofol abuse reported in literature (Tab. centration of diphenhydramine was neglectable (0.09µg/ml).
The first case concerned a female radiographer who was said Analytical results of propofol determination in blood, urine, to have abused propofol for a prolonged period of time and various organs are summarised in Table 1.
The other case regards the suicide of a medical doctor who fol was mainly metabolized by two pathways: used two hypodermic needles in the back of his hand for rect glucuronide conjugation or p-hydroxylation with subse- an infusion of propofol The propofol blood concen- quent glucuronidation (or sulphation) Only very small trations in our case were higher by a factor of 24 and 2, amounts were eliminated without metabolization respectively. These concentrations as well as the high level Acidic urine hydrolysis increased the propofol concentration of propofol found in the brain tissue demonstrates how high from 5.4µg/ml to 8900µg/ml. Because the urine bladder the concentrations used by the male nurse really were. It is contained 250ml urine the eliminated propofol amounted commonly said that such high a concentration of propofol to 2225mg even without the other hydroxy metabolites for can not be self-administered, resulting—at the first glance— which the quantification was made impossible by the lack of in the conclusion that it had to be administered by a third standards. Therefore more than 11 ampoules of 20ml propo- party. However, taking all the facts of the case into account fol emulsion must have been administered during the last this conclusion can not be maintained.
After a bolus injection consciousness is lost in patients at propofol blood concentrations of 1.3-6.8µg/ml. Conscious-ness was regained after 8-10min at concentrations of 1- It is well known that the results of hair analysis have to be assessed with care By analysing hair segments centration of 5.3µg/ml measured in our case is well within we could prove that the propofol abuse of the male nurse was the range of the anaesthetically used concentrations during not an excessive one-off abuse but an increasing cronic one.
the institution of a narcosis, leading to the conclusion that A similar pattern of excessive abuse was evident in the case death could have occured immediatly following the propofol of an anaesthesiologist who first abused and then was ad- injection. In the case of the radiographer a longer survival dicted to propofol for about a year. He did not increase the time has to be assumed whereas in the case of the medi- amount per injection (always 100mg) but the frequency (up cal doctor the possibility of different pharmacokinetics due to 15 times per day) A different pattern of abuse was to the absence of a bolus injection has to be taken into ac- found in a sober alcoholic who abused propofol 3 times a day count. Thus the high brain concentration with regard to the plasma concentration would represent the equilibrium distri- Due to the short duration of the narcotic effect propofol abuse bution between brain and blood. There is a sharp decline in is especially easy to hide. This very rare case of a documented propofol brain concentrations due to the redistribution from chronic propofol abuse in combination with the excessive fre- the central compartment (which includes the CNS) into pe- quency of administration just before death demonstrates that ripheral compartments, resulting in an awakening of the pa- hospital personnel may show patterns of misuse different from tient from the anaesthetic. Even during the disposition phase the rapid breakdown of propofol results in a steep decline ofthe propofol blood concentration. The extremely high urineconcentration (hydrolysed urine: 8900µg propofol/ml) in ourcase has to be taken as a sign of this elimination. At autopsythe bladder contained approx. 250ml. Assuming a urine pro-duction of 40-50ml/h the bladder contents would have beenproduced within 6 h and therefore there would have been atleast 12 injections of one ampoule each within this time pe-riod. Using a t1/2 of 30min, a distribution volume of 2l/kgand the assumption of being able to inject one ampoule every30min there would have been a blood propofol concentrationof 1-2µg/ml at the time of the last injection. Such a high fre-quency of injections within the last 6h makes it necessary totake cumulative effects of the propofol blood concentrationinto account. Due to the fast redistribution this accumu-lation is of no significance for CNS effects. Therefore theblood concentration resulting from the last injection has tobe reduced by 1-2µg/ml.
In our case the cause of death would not be a multiple over-dose but an accidental complication caused e.g. by apnoeor a drop in blood-pressure Complications due todysfunction of the kidneys as a result of the anuric state of3 years ago has been ruled out by histological examinationas well as the fact that propofol is eliminated by hepaticmetabolism.
Hypotension and apnoea are relevant side effects whichalso occur with other anaesthetic agents and are prob-ably dependent on the dose and speed of propofol adminis-tration. Apnoea during anaesthesia induction occurs morefrequently with propofol than with other anaesthetics. Theapnoea duration is usually short but it can persist for up to3 minutes Several fatalities were reported after contin-uous propofol infusion or sedation in children Someauthors link propofol to malignant hyperthermia induction inchildren. Other fatalities after anaesthesiological propofol in-duction were reported from high risk patients who sufferedcardiovascular collapse Taking this evidence as well as the normal redistributionphase propofol blood levels into account, it is more prob-able that the death was caused by to fast an injection of anormal propofol dose than by a propofol overdose.
[20] Guitton J, Desage M, Lepape A, Degoute CS, Manchon M, Btazier JL (1995) Quantitation of propofol in whole blood [1] Poklis A (1995) Fentanyl: a review for clinical and analytical by gas chromatography - mass spectrometry. J Chromatogr toxicologists. Clin Toxicol 33(5):429–447 [2] Hendersson GL (1991) Fentanyl-related deaths: demograph- [21] Maitre PO (1994) Diprivan: efficient concentrations in rela- ics, circumstances, and toxicology of 112 cases. J Forensic tion to physiological parameters and associated drugs. Ann [3] Sachs H, Uhl M, Hege-Scheuing G, Schneider E (1996) Anal- uttler J, Stoeckel H, Schwilden H (1985) Pharmacoki- ysis of fentanyl and sufentanil in hair by GC/MS/MS. Int J netic and pharmacodynamic modelling of propofol (‘Dipri- van‘) in volunteers and surgical patients. Postgrad Med J 61 [4] Peyton SH, Couch AT, Bost RO (1988) Tissue distribution of ketamine: two case reports. J Anal Toxicol 12:268–269 [23] Reed MD, Yamashita TS, Marx CM, Myers CM, Blumer JL [5] Licata M, Pierini G, Popoli G (1994) A fatal ketamine poi- (1996) A pharmacokinetically based propofol dosing strat- egy for sedation of the critically ill, mechanically ventilatedpediatric patient. Crit Care Med 24(9):1473–1481 [6] Follette JW, Farley WJ (1992) Anaesthesiologist addicted to [24] Langley MS, Heel RC (1988) Propofol. A review of its phar- macodynamic and pharmacokinetic properties and use as in- undel H, Kuhs H (1992) Kasuistische Mitteilung ¨ travenous anaesthetic. Drugs 35(4):334–72.
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