Effects of short?term propofol administration on ... - Wiley Online Library

45 downloads 6135 Views 68KB Size Report
1 Senior House Officer, 3 Specialist Paediatricians, 5 Professor and Director, Department of Paediatric Haematology and. Oncology, 2 Specialist ... and smooth recovery profile. .... not normally distributed data (serum triglycerides), the.
Anaesthesia, 2005, 60, pages 660–663 .....................................................................................................................................................................................................................

Effects of short-term propofol administration on pancreatic enzymes and triglyceride levels in children S. Gottschling,1 S. Meyer,2 T. Krenn,3 S. Kleinschmidt,4 H. Reinhard,3 N. Graf5 and G. M. Shamdeen6 1 Senior House Officer, 3 Specialist Paediatricians, 5 Professor and Director, Department of Paediatric Haematology and Oncology, 2 Specialist Paediatrician, Paediatric Intensive Care Unit, 4 Professor and Specialist Anaesthetist, Department of Anaesthesiology and Intensive Care Medicine, 6 Specialist Paediatrician, Section of Paediatric Neurology, University Children’s Hospital, Kirrbergerstr, 66421 Homburg ⁄ Saar, Germany Summary

This prospective, clinical trial evaluated the effects of short-term propofol administration on triglyceride levels and serum pancreatic enzymes in children undergoing sedation for magnetic resonance imaging. Laboratory parameters of 40 children, mean age (SD; range) 67 (66; 4–178) months undergoing short-term sedation were assessed before and 4 h after having received propofol. Mean (SD) propofol loading dose was 2.2 (1.1) mg.kg)1 followed by continuous propofol infusion of 6.9 (0.9) mg.kg)1.h)1. Serum lipase levels (p = 0.035) and serum triglyceride levels (p = 0.003) were raised significantly after propofol administration but remained within normal limits. No significant changes in serum pancreatic-amylase levels were seen (p = 0.127). In two (5%) children, pancreatic enzymes and in four (10%) children triglyceride levels were raised above normal limits; however, no child showed clinical symptoms of pancreatitis. We conclude that even short-term propofol administration with standard doses of propofol may have a significant effect on serum triglyceride and pancreatic enzyme levels in children. . ......................................................................................................

Correspondence to: Dr Sven Gottschling E-mail: [email protected] Accepted: 27 March 2005

Little is known about drug-induced pancreatitis, although it is reported to have been caused by over 85 different drugs [1, 2]. Drug-induced pancreatitis is a relatively rare disorder, with a prevalence of 1.4% among patients presenting with acute pancreatitis from all causes [1]. Propofol, a sedative-hypnotic agent, is used for sedation as well as for induction of general anaesthesia in children and adults. Propofol is a lipid-based, global central nervous depressant which has a rapid onset of sedation with a dose-related hypnotic effect and a quick and smooth recovery profile. Dose dependent hypotension is the most common complication [3]. Hypertriglyceridaemia is another possible adverse effect [4–10]. Since its approval in 1989, there have been reports indicating a possible link between the use of propofol and the development of acute pancreatitis [11–19]. This was mostly in an intra- or postoperative setting and most of these patients received propofol continuously for several 660

days. Furthermore, in these cases, a number of different drugs were co-administered, thus preventing the establishment of a clear causal link between propofol and the occurrence of acute pancreatitis [12, 13, 15–20]. Recently, we reported a definite association between short-term propofol administration in an 11-year-old girl and the occurrence of acute pancreatitis [11]. The mechanism of propofol-induced pancreatitis remains unknown. Although induction of hypertriglyceridaemia has been described and is therefore a suspected mechanism, it seems unlikely that short-term administration of propofol could raise serum lipid levels as much as to induce pancreatitis. To our knowledge, only one clinical trial (n = 21), focusing on pancreatic function in adult patients under postoperative sedation with propofol, has been published so far and no elevated markers of altered pancreatic function were found [21]. Moreover, a recent experimental study by Donmez et al. [22] failed  2005 Blackwell Publishing Ltd

Æ

Anaesthesia, 2005, 60, pages 660–663 S. Gottschling et al. Propofol and pancreatitis in children . ....................................................................................................................................................................................................................

to confirm a statistically significant relationship between propofol administration and the higher incidence of acute pancreatitis in rats. However, up to now, no clinical trials have evaluated pancreatic function in children receiving short-term propofol sedation. Therefore, we conducted a clinical trial to investigate whether short-term propofol administration alters triglyceride levels and pancreatic enzymes in children.

standard deviations. Since serum amylase and lipase values were normally distributed, significances were verified using Student’s paired t-test. For statistical comparison of not normally distributed data (serum triglycerides), the Mann–Whitney U-test was employed. The p-value of < 0.05 was considered significant. Spearman’s correlation coefficient was applied to look for a correlation between propofol dose per kg body weight and a change in serum pancreatic amylase, lipase and triglycerides.

Methods

Results

This study was conducted according to the principles established in the Declaration of Helsinki. The study was approved by the Saarland University ethics committee. Written, informed consent was obtained from the parents prior to the procedure. The study enrolled 40 children with cognitive and ⁄ or motor developmental delay, aged 4–178 months (mean (SD) age 67 (66) months) undergoing elective magnetic resonance imaging (MRI). All children presented with American Society of Anesthesiologists Physical Status ASA I or II. Children with haemodynamic instability, pre-existing hypotension, airway or respiratory failure, and prior hypersensitivity reactions to propofol were excluded from the study, as were children aged 3 months or younger. Patients with a history of seizures were also excluded. Prior to any sedation, every child received a peripheral venous catheter and a first blood sample was taken. Sedation was provided by the Department of Anaesthesia. Mean (SD; range) sedation time was 46 (29; 15–160) min, mean (SD) propofol loading dose administered was 2.2 (1.1) mg.kg)1, followed by a mean (SD; range) continuous propofol administration of 6.9 (0.9; 5–8) mg.kg)1.h)1. Four hours after stopping the propofol infusion, a second blood sample was drawn and analysed. Blood samples were centrifuged at room temperature (18–23 C) and measured within 2 h after sampling with a Hitachi Modular PPE automat (Roche Diagnostics GmbH, Mannheim, Germany). Serum pancreatic-amylase (normal value 13–53 IU.l)1) was measured by ethylidene G7PNP liquid 37 C test (Roche Diagnostics; variation coefficient: 1.39%; accuracy: 4.48%), serum lipase (normal value 13–60 IU.l)1) by photometric enzyme colour test (Roche Diagnostics; variation coefficient: 4.18%; accuracy: 0.46%) and serum triglycerides (normal value: < 200 mg.dl)1) by enzymatic colourimetric test GPO-PAP (Roche Diagnostics; variation coefficient: 3.04%; accuracy: 2.53%).

In this study, all elective sedations were completed without relevant complications. Patients, demographic data and data concerning sedation are presented in Table 1. Two patients experienced transient oxygen desaturation (SaO2 below 90%) for several seconds, which resolved on correction of the airway. No patient developed any clinical signs of pancreatitis within 24 h after stopping propofol infusion. There was no significant difference between serum pancreatic-amylase baseline values and values measured 4 h after stopping propofol infusion. Mean serum lipase levels were raised significantly, but remained within normal limits. Mean serum triglyceride levels were significantly higher after propofol infusion but also remained within normal limits. There was no correlation between triglyceride and lipase or amylase serum level elevations in individual patients. One patient developed an elevated serum amylase and another an elevated serum lipase outside the normal range. In three patients, triglyceride levels were pathologically elevated before propofol infusion, two of whom had further increases in triglyceride levels after propofol infusion, and the third patient showed a drop in serum triglyceride level. Another two patients’ values were outside the normal range for triglycerides after propofol infusion. There was no correlation between propofol dose per kg body weight and changes in measured parameters. Data concerning all patients are shown in

Statistical analysis Statistical analysis was performed using SPSS (SPSS 10.0, SPSS Inc., Chicago, IL). Data are presented as means and  2005 Blackwell Publishing Ltd

Table 1 Demographic

characteristics and data concerning sedation. Data are presented as mean (SD) and range. Propofol (n = 40)

Age; months Gender; male ⁄ female Weight; kg Duration of sedation; min Propofol loading dose; mg.kg)1 Propofol continuous infusion; mg.kg)1.h)1 Propofol total dose; mg.kg)1

67 (66) 24 ⁄ 16 26 (20) 46 (29) 2.2 (1.1) 6.9 (0.9) 7.5 (1.7)

Range 4–178 7–92 15–160 1.5–4.5 5–8 5–15.5

661

Æ

S. Gottschling et al. Propofol and pancreatitis in children Anaesthesia, 2005, 60, pages 660–663 . ....................................................................................................................................................................................................................

Table 2 Changes in serum pancreatic-amylase, lipase and tri-

It is known that propofol, a lipid-based formula, can cause hypertriglyceridaemia, a phenomenon that was also demonstrated by this study. A proposed mechanism of hypertriglyceridaemia-induced pancreatitis is as follows. Hydrolysis of triglycerides in the pancreas leads to unbound fatty acids in high concentrations. These are toxic and can cause acinar cell and capillary injury. Furthermore, pancreatic capillaries are plugged by chylomicrons leading to ischaemia. The combination of an acidotic environment and free fatty acids causes activation of trypsinogen and initiates acute pancreatitis. Whether transiently elevated triglyceride levels, as reported in this study, can lead to acute pancreatitis is an important question. However, it is widely accepted that long-term triglyceride levels between 1000 and 2000 mg.dl)1 are necessary to cause hyperlipidaemic pancreatitis [4, 5]. Therefore, mild, transient hypertriglyceridaemia, as demonstrated in both this study and in a study of adult patients by Piper et al. [21] is highly unlikely to be the cause of propofol-induced pancreatitis. Moreover, pancreatic enzyme elevations in our patients occurred independently from triglyceride levels and vice versa. This clinical study demonstrated that serum amylase and lipase levels in two (5%) children were elevated above the normal range after short-term propofol administration (Table 3). A conceivable explanation for these results is that propofol might have a direct damaging effect on pancreatic cells. A possible reason why elevated serum lipase levels were found in our study population, in contrast to the data of Piper et al. [21], could be that pancreatic cells in children might be more sensitive to propofol exposure. Although the mechanism for propofolassociated pancreatitis remains unclear, we conclude that even short-term propofol administration using standard doses can have a significant effect on triglycerides and pancreatic enzyme levels in children.

glycerides before sedation and 4 h after stopping propofol infusion. Data are presented as mean and standard deviation (SD). Exact p-values are given.

Variables (normal range) Pancreatic-amylase; (13–53 IU.l)1) Lipase; (13–60 IU.l)1) Triglycerides (< 200 mg.dl)1)

Baseline (n = 40)

4 h after propofol infusion (n = 40)

p-values

21.2 (14)

23.8 (17.6)

p = 0.127

23.8 (7.7)

27.3 (13.1)

p = 0.035*

141.9 (111.7)

p = 0.003*

106 (83.2)

*Indicates a significant change.

Table 2. Data concerning individual patients with elevated levels of serum amylase, lipase or triglycerides are shown in Table 3. None of the patients with alterations in either serum pancreatic-amylase, lipase or triglyceride levels received concomitant drug medication. Discussion

Propofol is an extensively used sedative hypnotic agent with unique pharmacodynamic and pharmacokinetic properties. It offers a very rapid onset of sedation and a quick and smooth recovery profile [3]. Known adverse effects of propofol administration include cardiovascular depression and transient oxygen desaturation, often due to hypoventilation. The propofol–infusion syndrome, a rare but frequently fatal combination of acidosis, renal and cardiac failure, seems to occur only in patients who receive long-term propofol administration (> 48 h) [23]. Recently, a number of cases of presumed propofolassociated acute pancreatitis have been reported [12–20].

Table 3 Changes in serum pancreatic-amylase, lipase and triglycerides before sedation and 4 h after stopping propofol infusion in

individual patients. Values outside normal range are in bold. Mean (SD) total propofol dose for all patients was 7.5 (1.7) mg.kg)1.

Amylase; IU.l)1 normal range (13–53 IU.l)1)

Lipase; IU.l)1 normal range (13–60 IU.l)1)

Triglycerides; mg.dl)1 normal range (< 200 mg.dl)1)

Propofol infusion

Propofol infusion

Propofol infusion

Patients age, gender, body weight

Before

After

Before

After

Before

After

Total propofol; mg.kg)1

1. 2. 3. 4. 5. 6.

52 20 18 43 17 20

91 44 18 46 18 20

17 29 29 40 19 23

46 76 30 42 25 21

102 62 455 365 70 212

217 147 635 428 349 82

10.1 8.3 14.2 6 6 11.2

49 months, female, 16 kg 33 months, male, 20 kg 14 months, male, 13 kg 172 months, male, 92 kg 34 months, male, 12 kg 39 months, female, 14 kg

662

 2005 Blackwell Publishing Ltd

Æ

Anaesthesia, 2005, 60, pages 660–663 S. Gottschling et al. Propofol and pancreatitis in children . ....................................................................................................................................................................................................................

Considering the apparent rarity of acute pancreatitis, despite the large number of patients exposed to propofol, it is unlikely that any study would be large enough to identify prospectively specific patient-related risk factors for the development of propofol-induced acute pancreatitis. We would therefore propose that patients with a previously sensitised pancreas should not receive propofol (e.g. patients with a history of pancreatitis, biliary tract disease, cystic fibrosis). Pancreatitis as a possible complication of propofol administration should be kept in mind and a thorough evaluation of abdominal pain, even after a short-term and otherwise uneventful sedation with propofol, is indicated. The results of our study may hint at a direct damaging effect of propofol on pancreatic cells.

9

10

11

12

13 Acknowledgements

We are indebted to the nurses and doctors of ward KK05 and KK04, University Children’s Hospital Homburg, Germany. Without their co-operation this study would not have been possible. We thank Susanne Clearman for linguistic help. References 1 Lankisch PG, Droge M, Gottesleben F. Drug induced acute pancreatitis: incidence and severity. Gut 1995; 37: 565–7. 2 Steinberg W, Tenner S. Acute pancreatitis. New England Journal of Medicine 1994; 330: 1198–210. 3 Marik PE. Propofol: therapeutic indications and side-effects. Current Pharmaceutical Design 2004; 10: 3639–49. 4 Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. Journal of Clinical Gastroenterology 2003; 36: 54–62. 5 Barrachina F, Mateu-de Antonio J. Propofol and hypertriglyceridemia: no problem? Critical Care Medicine 1999; 27: 224–5. 6 McLeod G, Dick J, Wallis C, Patterson A, Cox C, Colvin J. Propofol 2% in critically ill patients: effect on lipids. Critical Care Medicine 1997; 25: 1976–81. 7 Kunst G, Bohrer H. Serum triglyceride levels and propofol infusion. Anaesthesia 1995; 50: 1101. 8 Eddleston JM, Shelly MP. The effect on serum lipid concentrations of a prolonged infusion of propofol-hypertri-

 2005 Blackwell Publishing Ltd

14

15

16 17

18 19 20 21

22

23

glyceridaemia associated with propofol administration. Intensive Care Medicine 1991; 17: 424–6. De Sommer MR, Driessen JH, Willems CM, Lust PC. A comparative study on the effects of propofol in emulsion and Intralipid on fat metabolism. Acta Anaesthesiologica Belgica 1990; 41: 133–8. Gottardis M, Khunl-Brady KS, Koller W, Sigl G, Hackl JM. Effect of prolonged sedation with propofol on serum triglyceride and cholesterol concentrations. British Journal of Anaesthesia 1989; 62: 393–6. Gottschling S, Larsen R, Meyer S, Graf N, Reinhard H. Acute pancreatitis induced by a short-term propofol administration. Paediatric Anaesthesia, in press. Kumar AN, Schwartz DE, Lim KG. Propofol-induced pancreatitis: recurrence of pancreatitis after rechallenge. Chest 1999; 115: 1198–9. Wingfield TW. Pancreatitis after propofol administration: is there a relationship? Anesthesiology 1996; 84: 236–7. Jawaid Q, Presti ME, Neuschwander-Tetri BA, Burton FR. Acute pancreatitis after single-dose exposure to propofol: a case report and review of literature. Digestive Diseases and Sciences 2002; 47: 614–8. Betrosian AP, Balla M, Papanikolaou M, Kofinas G, Georgiadis G. Post-operative pancreatitis after propofol administration. Acta Anaesthesiologica Scandinavica 2001; 45: 1052. Bird H, Brim V. Propofol and postoperative pancreatitis. Anaesthesia 2000; 55: 506–7. Possidente CJ, Rogers FB, Osler TM, Smith TA. Elevated pancreatic enzymes after extended propofol therapy. Pharmacotherapy 1998; 18: 653–5. Metkus AP, Trabulsy PP, Schlobohm RS, Hickey MS. A firefighter with pancreatitis. Lancet 1996; 348: 1702. Leisure GS, O’Flaherty J, Green L, Jones DR. Propofol and postoperative pancreatitis. Anesthesiology 1996; 84: 224–7. Donmez A, Sener M, Candan S, Arslan G. Can we blame propofol for pancreatitis? Pharmacotherapy 1999; 19: 1181–2. Piper SN, Kumle B, Maleck WH, Suttner SW, Fent MT, Boldt J. Effects of postoperative sedation with propofol and midazolam on pancreatic function assessed by pancreatitisassociated protein. Anaesthesia 2001; 56: 836–40. Donmez A, Arslan G, Pirat A, Demirhan B. Is pancreatitis a complication of propofol infusion? European Journal of Anaesthesiology 1999; 16: 367–70. Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Medicine 2003; 29: 1417–25.

663