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Propofol EDTA and reduced incidence of infection.

SUMMARY

Propofol formulated in a lipid vehicle supports the growth of microorganisms. There have been worldwide reports of extrinsic microbial contamination of propofol leading to outbreaks of serious postoperative nosocomial infections. Therefore it is essential that medical professionals follow strict aseptic precautions when handling propofol, as recommended by manufacturers of propofol and the Centers for Disease Control and Prevention. Non-adherence to these recommendations increases the risk of nosocomial postoperative infections, which impose a heavy burden of morbidity and mortality and have serious economic consequences.

It has also been recommended that the use of EDTA-containing formulations of propofol be considered. In vitro studies have confirmed that EDTA added to propofol retards microbial growth. Data on the incidence of nosocomial infections before and after the introduction of propofol with EDTA indicates that there have been no further cluster outbreaks and individual nosocomial infections appear to have been reduced. The addition of EDTA is an additional safety precaution to good aseptic practice.

Key Words: propofol; extrinsic contamination; nosocomial infection; postoperative infection; anaesthesia; sedation

Clinical trials with the emulsion formulation of propofol (Diprivan Diprivan[TM], AstraZeneca, Macclesfield, U.K.) began in 1983 with the first commercial launches occurring in New Zealand and the United Kingdom in 1986. In November 1989, propofol was introduced into the market in the United States of America. It was initially approved for the induction and maintenance of anaesthesia and its use in both inpatient and outpatient surgery is now widespread. Propofol has also become a valuable agent for sedation during minor procedures for patients in intensive care (1).

Propofol is water insoluble and formulated in a lipid vehicle (a soybean oil lipid emulsion). As with all intravenous agents, propofol must be handled in an aseptic manner and, since the lipid formulation supports the growth of microorganisms, the manufacturer's prescribing information recommends strict aseptic precautions to avoid the possibility of accidental extrinsic microbial contamination and subsequent microbial growth.

Despite these recommendations, within a year of propofol being available in the U.S.A., clusters of postoperative infection were documented, involving two or more reports of infection or fever at a single centre, involving a single anaesthetist, temporally associated with propofol use and involving a single microbial contaminant. Cases were also documented in a number of countries worldwide; rarely fatalities of generally healthy patients were reported. Extensive investigation of these cases both by the manufacturer and the Centres for Disease Control and Prevention (CDC) implicated external extrinsic microbial contamination of the emulsion due to improper handling and use, in contravention of the prescribing information. (2)

In order to reduce the risk of such bacterial contamination and following discussions with the Food and Drug Administration Agency (FDA) in USA, the manufacturers incorporated the anti-microbial additive EDTA (disodium edetate) into the propofol formulation. Hart (2) reviewed the selection of EDTA as a suitable antimicrobial additive and stated that the essential characteristics were an ability to suppress the growth of microorganisms without compromising clinical safety, efficacy or the stability of the emulsion. A number of other potential additives were investigated including benzyl alcohol, phenylmercuric nitrate, chlorobutanol, chlorocresol, phenol and phenylmercuric acetate, although these were rejected due to potential toxicity issues.

Sodium metabisulphite was investigated more fully but this was also rejected due to insufficient microbiological action at Diprivan's[TM] pH, destabilization of the emulsion at a microbiologically active pH (3) and triggering dimerization of the propofol molecule. The possible sensitivity and allergic reaction to sulphites has led the USA FDA to impose warnings on most pharmaceutical products containing sulphites, including sodium metabisulphite or sodium sulphite4. Sodium sulphite, sodium methyl and propyl hydroxybenzoate and sodium calcium edetate were found to be less able to fulfil the essential characteristics of a suitable antimicrobial additive. In 1996, the optimal additive that fulfilled the criteria agreed with the FDA was selected and propofol with 0.005% w/v EDTA was introduced (2,5).

As an additional safety measure, the manufacturer introduced the Diprivan[TM] Pre-Filled Syringe (PFS), which is produced under strict aseptic conditions and avoids the risk of contamination of the anaesthetic while drawing up from a vial into a syringe in the clinical situation. The PFS is designed for single use in an individual patient; following use, any unused propofol together with infusion equipment is discarded, thereby maintaining asepsis for the anaesthetic and the infusion equipment.

This review examines reports of extrinsic microbial contamination of propofol, postoperative infection following propofol use, and the likely causes of infection. Studies designed to investigate the ability of propofol to support microbial growth with and without the addition of EDTA to the formulation are reviewed. Data on the frequency of reports of 'clusters' of infection before and after the addition of EDTA to the propofol formulation are analysed. Finally, the potential economic and individual patient implications associated with the development and treatment of postoperative nosocomial infections are briefly considered.

CLINICAL STUDIES OF PROPOFOL CONTAMINATION DURING USE

Several studies have examined contamination of propofol without EDTA during clinical use (6-8).

Webb et al retrospectively analysed data in a quality assurance database to determine the incidence and clinical significance of administering potentially contaminated propofol to patients in the Intensive Care Unit (ICU) (8). Eighteen of three hundred and two syringes of propofol without EDTA that had been used only once were positive for bacterial contamination when samples were cultured. Organisms identified included Bacillus spp, Micrococcus kristinae, Gemella spp and Streptococcus salivarius. The incidence of possible propofol contamination was 5.9%. The authors concluded that the rate of contamination of propofol syringes was low, but the study demonstrates that propofol can become contaminated during normal clinical use.

Soong studied the incidence of bacterial contamination of propofol without EDTA during usual practice in the operating theatres of a single large hospital group and investigated whether there was any relationship between contamination and the practice of multi-dosing (6). One hundred samples of propofol were collected from the remnants of syringes and ampoules immediately after propofol administration. The samples produced three positive bacterial cultures of Staphylococcus epidermidis, Pseudomonas aeruginosa and a mixed growth of organisms. The contaminated samples were all from multiple patient doses drawn up from a single ampoule. The authors noted that this technique is most frequently used in paediatric anaesthesia where small doses are required and as such does not comply with the manufacturer's recommendations. The authors warned that the practice of repeated drawing up of doses from an open ampoule may be particularly associated with accidental bacterial contamination of propofol. They recommended that propofol should be handled in an aseptic fashion and drawn up into a syringe immediately after opening. They observed that propofol infusions contained no preservative or antimicrobial agent (6). The contamination incidence in this study (6) was 4.9%, in accord with a previous study, which found a 6.3% incidence of bacterial contamination of propofol (7).

It is clear from these studies that accidental extrinsic microbial contamination of propofol or equipment can occur in the operating theatre or ICU, even during normal clinical use, especially when practice deviates from the manufacturer's recommendations. To minimize the risk of contamination during use, all formulations of propofol should be used for a single patient only, used as soon as possible after drawing up from the vial and handled in an aseptic fashion.

PROPOFOL ASSOCIATED POSTOPERATIvE AND NOSOCOMIAL INFECTIONS

Clusters of postoperative and nosocomial infections linked with propofol use have been reported (9-11). Henry et al conducted a case-control study in 1999 at a community hospital in Ontario, Canada, to determine the risk factors associated with infection (9). Five of the patients with infections had bacteraemia and two of these patients died due to infection with Serratia marcescens. All the patients with infections were exposed to the same anaesthesiologist who administered propofol. The anaesthesiologist associated with the infections prepared multiple syringes of propofol and did not wear gloves when drawing up or administering propofol or when intubating patients. The authors proposed that the hands of the anaesthesiologist had become colonized with Serratia marcescens and that, because he did not wear gloves for filling the syringes, the propofol syringe became contaminated. Without the addition of preservatives, propofol supports rapid microbial growth at room temperature. The authors suggested that manufacturers should be required to develop single-dose vials or to formulate the medication to prevent bacterial growth. From a health economics point of view, a US study has estimated that the extra costs of a single case of bacterial nosocomial infection exceeds US$40,000 (12).

In a cluster of cases of hepatitis C infection following surgery investigated by Massari et al (10), the infection of four patients linked to the administration of propofol and with one potential source patient demonstrates the potential for cross-infection via extrinsically contaminated non-EDTA containing propofol.

Prior to the introduction of the propofol formulation containing EDTA, seven unusual outbreaks of postoperative infection involving a variety of microorganisms were observed in the U.S.A. during the period June 1990 to February 1993. In an outbreak investigated by McNeil et al (11), 1% (4 out of 364) patients developed Candida albicans fungaemia or endophthalmitis after surgery in one hospital, clustered over two days. The anaesthesiologist associated with the infection routinely opened ampoules with ungloved hands and stored filled syringes before use. The syringe in the infusion pump was reused for the duration of the procedure and refilled repeatedly from a second syringe. The authors concluded that this unusual cluster of postoperative Candida albicans infections was due to extrinsic microbial contamination of the propofol and the likely mechanism for contamination was via the hands of one of the anaesthesiologists during manipulation of propofol. Like other investigators, the authors of this study advised that strict aseptic techniques should be followed when handling propofol, in accordance with the manufacturer's recommendations. The authors also noted that the subsequent addition of preservative to the formulation may have reduced the ability of propofol to support microbial growth. This is supported by evidence that propofol with EDTA inhibits the growth of Candida albicans (5).

These studies have demonstrated that clusters of postoperative infection have been associated with a lack of appropriate asepsis when using propofol. In all the cases described, there was no antimicrobial agent in the propofol formulation. There is evidence of association between infections and deviations from aseptic practice such as ungloved hands, reuse of , syringes, use of vials as multidose vials, and significant delay between drawing up propofol into syringes and use.

EFFECT OF EDTA ON BACTERIAL GROWTH IN PROPOFOL IN vITRO

The effect of addition of EDTA on the ability of propofol to support microbial growth has been investigated in vitro (13,14). Noriega et al conducted a prospective study to compare saline with three commercially available preparations of propofol: Propocam[R] (propofol, ABBOTT Laboratories), Recofol[R] (propofol, PISA Laboratories), and Diprivan[TM] (propofol+ 0.005% EDTA, AstraZeneca) (13). Ten microorganisms (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicans, Enterococcus faecalis, Serratia marcescens, Acinetobacter calcoaceticus and Enterobacter aerogenes) commonly associated with postoperative infection were chosen for the study and cultured. Following incubation at room temperature (18-25[degrees]C), bacterial growth was assessed at 3, 6, 12 and 24 hours. All propofol solutions showed bacterial growth compared with the saline control. However for the majority of microorganisms tested, growth was less in the propofol with EDTA formulation. As early as three hours after inoculation, growth of Serratia marcescens and Acinetobacter calcoaceticus in propofol with EDTA was lower than in Propocam[R] (P<0.05). Differences were also seen at the later sampling times.

Fukada et al (14) recently demonstrated that propofol supports the growth of a variety of microorganisms in vitro and this is significantly inhibited by the addition of EDTA (Figure 1). Methicillin resistant and susceptible Staphylococcus aureus (MRSA and MSSA), Pseudomonas aeruginosa and Escherichia coli were cultured at room temperature (22.5[degrees]C) in the two anaesthetic formulations and a control solution of saline. The authors noted that in propofol with EDTA, growth of all four strains was suppressed compared with the growth in propofol without EDTA. For example, after 12 hours: E.coli was reduced 40 fold; MSSA was reduced 8 fold; MRSA and P. aeruginosa were reduced 11 fold.

[FIGURE 1 OMITTED]

The authors concluded that where propofol is used over several hours, propofol with EDTA offers less risk of bacterial growth following extrinsic microbial contamination and should reduce the incidence of postoperative infections (14).

These in vitro comparative studies have demonstrated that the addition of an appropriate concentration of EDTA to propofol retards the growth of microorganisms commonly associated with nosocomial infections, even when the cultures are incubated at temperatures commonly found in the ICU and operating rooms, for up to 48 hours.

EFFECT OF THE ADDITION OF EDTA ON THE REPORTED INCIDENCE OF NOSOCOMIAL INFECTIONS ASSOCIATED WITH PROPOFOL USE

Estimates of the incidence of nosocomial infections following propofol use vary. Bach and Motsch surveyed the literature from 1971 to 1995 using the Medline database and evaluated the incidence of infection associated with intravenous anaesthetic agents1. They reported that the risk of infection is minimal and often caused by failure to adhere to aseptic techniques.

An incidence of 0.34% nosocomial infections following anaesthesia was reported by Hajjar and Girard in France (15). Infections were significantly more frequent in patients who had received general anaesthesia and in those who were anaesthetized for more than two hours.

An AstraZeneca database holds reports of postoperative infections or fever following propofol use. (16) Inspection of the data for USA showed 271 cases in these categories from November 1989 to June 1996 (prior to the introduction of propofol with EDTA), an average of 39 per year. The introduction of the EDTA formulation was phased over two years following June 1996. During the period from June 1996 until November 2004, there were 74 such case reports, an average of nine per year. This reduction in the incidence of postoperative infection or fever occurred despite a marked increase in the use of propofol (Figure 2). Review of data from the U.K. and France, where the EDTA containing formulation of propofol has not been approved, shows a smaller reduction in the incidence of reports of fever and postoperative infection. An average of eight cases per year were reported during the period November 1986 to June 1996, whereas during the period July 1996 to November 2004 there was an average of four cases per year (16). These data point towards a reduced incidence of postoperative infection or fever following the introduction of propofol with EDTA, although it should be noted that adverse event reporting is subject to many variables and overall there has been a decreasing number of adverse events reported from these regions.

These findings are supported by a review of propofol with EDTA by Ovechkin and Gagarina in Russia17. The rate of propofol contamination during handling is considered to be 6.3% despite an intensive education campaign undertaken by the manufacturer that focused on drug handling and compliance with aseptic technique. The authors suggest that the actual number of cases is likely to be much higher as cases were included only where a definite causal link can be established between propofol use and contamination. They observed that, since 1996 in the USA, the EDTA formulation of propofol has been used in more than thirty million patients, 15% receiving it for long-term sedation. Over this period, there has not been a single case of infection proven to be due to extrinsically contaminated Diprivan[TM], while such reports continue for areas where the formulation without EDTA is licensed. (15)

These data suggest that the incidence of nosocomial infection associated with propofol use is low when recommended procedures are followed. However, an incidence of accidental extrinsic microbial contamination of about 6% has been reported and appears predominantly associated with deviations from recommended aseptic protocol during use. The available data on the incidence of infections and/or fever before and after the addition of EDTA to the formulation indicates an absence of clusters of infection and a marked reduction in individual occurrences of infection without a clear association with propofol following the addition of EDTA.

DISCUSSION

Postoperative nosocomial infection presents a serious medical problem, having a significant impact on patient morbidity and mortality, increasing health care costs and reducing hospital management efficiency. Accidental extrinsic microbial contamination of anaesthetic agents has been identified as a risk factor for nosocomial infection. This review has examined factors involved in nosocomial infection following propofol use.

It is clear that contamination of propofol can occur in the operating theatre or ICU, particularly when practice deviates from the manufacturer's recommendations. To minimize the risk of contamination, a two-pronged approach has been shown to be effective:

* The manufacturer's and CDC recommendations and protocols for good aseptic practice should be strictly followed.

* Use of an EDTA containing formulation should be considered as in vitro comparative studies have demonstrated that the addition of EDTA to propofol retards the growth of microorganisms commonly associated with nosocomial infections, and the available data on the incidence of infections before and after the addition of EDTA to a propo- propofol formulation shows both an absence of clusters of infection and suggests a reduction incidence of individual infections following its addition.

The in vitro study reported by Fukada et al (14) indicated that the growth of a range of microorganisms, particularly Pseudomonas aeruginosa, could increase markedly after 24 hours incubation in a propofol emulsion, both with and without an antimicrobial additive. This increase in growth may be a reflection of the development of resistance mechanisms such as reduced outer membrane permeability and the over-expression of one or more efflux systems. The manufacturer's prescribing information for propofol currently recommends that the emulsion and any syringe or infusion line must be discarded at the end of a procedure or at 12 hours, whichever is the sooner, and be replaced as appropriate; a precaution against infections associated with microbial growth in infusion lines.

The medical economic implications of nosocomial infections have been noted by a number of authors (18-20). Rebollo et al observed that nosocomial infections significantly prolong hospital stay and are associated with substantial morbidity, mortality and economic burden (18). Kimura refers to a survey in 1976 by the Study of the Efficacy of Nosocomial Infection Control (SENIC) in the U.S.A., which found that nosocomial infections prolonged hospital stay by an average of 3.6 days per case. According to data for 1995, nosocomial infection occurred in 5% of patients admitted to hospital and prolonged stay by five to seven days (20).

In Japan, the extended costs of hospital infections associated with post-surgical and nosocomial infection in a hospital with about 1,000 beds were reviewed by Kimura (20). In gastrointestinal tract operations, infections of the surgical site prolonged hospital stay by an average of 35.1 days per case and they extended costs by approximately US$12,000 per case, based on exchange rates at the time of publication. Nosocomial infections attributed to MRSA prolonged hospital stay by an average of 66 days per case and extended costs by approximately US$22,000 per case. The current extended costs of treatment and hospital stay due to nosocomial medical and post-surgical site infections are more than US$11,000,000 per year. It is estimated that improvements in anti-infection measures in hospitals could prevent 30% of such cases (20). The use of propofol with EDTA could represent a significant anti-infection measure.

The evidence presented suggests that the use of a propofol formulation containing EDTA together with strict adherence to good aseptic practice will reduce the risk of nosocomial infections, thereby reducing the considerable expense and suffering associated with nosocomial infections originating from accidental extrinsic contamination of propofol formulations.

ACKNOWLEDGEMENTS

The authors would like to thank Ms Evelyn Frearson, medical writing consultant, for assistance with the writing of this review. Financial support for preparing this manuscript was provided by AstraZeneca. Propofol with EDTA (Diprivan[TM]) is manufactured and marketed by AstraZeneca.

REFERENCES

(1.) Bach A, Motsch J. Infectious risks associated with the use of propofol. Acta Anaesthesiol Scand 1996; 40:1189-1196.

(2.) Hart B. 'Diprivan': a change in formulation. Eur J Anaesthesiol 2000; 17:71-73.

(3.) Han J, Davis S, Washington C. Comparative stability of propofol with disodium edetate versus Sulfite-containing propofol. Am J Anesthesiology 2000; 27 (6S) suppl:16-18.

(4.) Code of Federal Regulations Title 21, volume 4 Revised as of April 1, 2005. CITE: 21CFR201.22.

(5.) Bobey DG, Russell AD, Jones CB. Selection of disodium edetate as the optimal antimicrobial additive for use in propofol emulsion. Pharmacol Ther 2000; 25:589-603.

(6.) Soong WAL. Bacterial contamination of propofol in the operating theatre. Anaesth Intensive Care 1999; 27:493-496.

(7.) McHugh GJ, Roper GM. Propofol emulsion and bacterial contamination. Can J Anaesth 1995; 42:801-804.

(8.) Webb SAR, Roberts B, Breheny FX, Golledge CL, Cameron PD, van Heerden Pv. Contamination of propofol infusions in the intensive care unit: incidence and clinical significance. Anaesth Intensive Care 1998; 26:162-164.

(9.) Henry B, Plante-Jenkins C, Ostrowska K. An outbreak of Serratia marcescens associated with the anesthetic agent propofol. Am J Infect Control 2001; 29:312-315.

(10.) Massari M, Petrosillo N, Ippolito G et al. Transmission of hepatitis C virus in a gynecological surgery setting. J Clin Microbiol 2001; 39:2860-2863.

(11.) McNeil MM, Lasker BA, Lott TJ, Jarvis WR. Postsurgical Candida albicans infections associated with an extrinsically contaminated intravenous anesthetic agent. J Clin Microbiol 1999; 37:1398-1403.

(12.) Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs and attributable mortality. JAMA 1994; 271:1598-1601.

(13.) Noriega RL, Angulo GB, Alalorre MAM, Molina LR, Torres NPC. Extrinsic bacterial contamination of propofol. (Spanish). Rev Mex Anest 1999; 22:59-67.

(14.) Fukada T, Ozaki M. Bacterial growth in two propofol formulations recently used in Japan. Life Support and Anesthesia (LISA) 2004:11:1174-1175.

(15.) Hajjar J, Girard R. Surveillance of nosocomial infections associated with anaesthesia. A multicentre study. (French). Ann Fr Anesth Reanim 2000; 19:47-53.

(16.) AstraZeneca data on file (AstraZeneca, Macclesfield, U.K.).

(17.) Ovechkin AM, Gagarina Iuv. Diprivan EDTA--the choice in favour of patient's safety. (Russian). Anesteziol i Reanimatol 2002; 3:52-56.

(18.) Rebollo MH, Bernal JM, Llorca J, Rabasa JM, Revuelta JM. Nosocomial infections in patients having cardiovascular operations: A multivariate analysis of risk factors. J Thorac Cardiovasc Surg 1996; 112:908-913.

(19.) Christiansen B, Kirchhefer R, Gundermann KO. Hygienic monitoring of environmental surroundings in office-based ambulatory surgery units--an instrument for infection control. Zbl Hyg Umweltmed 1999; 202:363-375.

(20.) Kimura S. Prevention of nosocomial infection and cost benefits. (Japanese). The Japanese Journal of Clinical and Experimental Medicine 2004; 81:1086-1089.

J-R. JANSSON *, T. FUKADA [dagger], M. OZAKI [double dagger], S. KIMURA [section] Medical Neuroscience, AstraZeneca R&D, Sodertalje, Sweden and Tokyo Women's Medical University and AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan

* B.Sc., M.D., Principal Physician, Medical Neuroscience, AstraZeneca R&D, Sodertalje, Sweden.

([dagger]) M.D., Ph.D., Assistant Professor, Department of Anesthesiology, Tokyo Women's Medical University, Tokyo, Japan.

([double dagger]) M.D., Ph.D., Professor and Chairman, Department of Anesthesiology, Tokyo Women's Medical University, Tokyo, Japan.

([section]) M.D., Ph.D., Director General, AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan.

Address for reprints: Dr J-R. Jansson, AstraZeneca R&D, Clinical Science, SE-151 85 Sodertalje, Sweden.
Figure 2: Reports of postoperative infections or fever in the U.S.A.
and sales of propofol EDTA in the U.S.A.

 Number of reports Sales per year
 per year ($ US M)

1989-1996 39 130
1996-2004 0 267

Note: Table made from bar graph.
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Author:Jansson, J.-R.; Fukada, T.; Ozaki, M.; Kimura, S.
Publication:Anaesthesia and Intensive Care
Date:Jun 1, 2006
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