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Previous Volume 333:147-154 July 20, 1995 Number 3 Next

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ABSTRACT

Background Between June 1990 and February 1993, the Centers for Disease Control and Prevention conducted investigations at seven hospitals because of unusual outbreaks of bloodstream infections, surgical-site infections, and acute febrile episodes after surgical procedures.

Methods We conducted case–control or cohort studies, or both, to identify risk factors. A case patient was defined as any patient who had an organism-specific infection or acute febrile episode after a surgical procedure during the study period in that hospital. The investigations also included reviews of procedures, cultures, and microbiologic studies of infecting, contaminating, and colonizing strains.

Results Sixty-two case patients were identified, 49 (79 percent) of whom underwent surgery during an epidemic period. Postoperative complications were more frequent during the epidemic period than before it. Only exposure to propofol, a lipid-based anesthetic agent, was significantly associated with the postoperative complications at all seven hospitals. In six of the outbreaks, an etiologic agent (Staphylococcus aureus, Candida albicans, Moraxella osloensis, Enterobacter agglomerans, or Serratia marcescens) was identified, and the same strains were isolated from the case patients. Although cultures of unopened containers of propofol were negative, at two hospitals cultures of propofol from syringes currently in use were positive. At one hospital, the recovered organism was identical to the organism isolated from the case patients. Interviews with and observation of anesthesiology personnel documented a wide variety of lapses in aseptic techniques.

Conclusions With the increasing use of lipid-based medications, which support rapid bacterial growth at room temperature, strict aseptic techniques are essential during the handling of these agents to prevent extrinsic contamination and dangerous infectious complications.

Methods

Definition and Ascertainment of Cases

We reviewed microbiologic, surgical, infection-control, and medical records to identify case patients. In each investigation, a case patient was defined as any patient with an organism-specific infectious complication or acute febrile episode after a surgical procedure during the hospital-specific study period (Table 1). Infections of the bloodstream, surgical sites, or other sites were defined according to CDC criteria.^2,3 An acute febrile episode was defined as the occurrence of fever (temperature, >39°C [101.5°F]) with no apparent cause after a surgical procedure and during the study period. For each hospital the study period encompassed the interval before the epidemic period and the epidemic period itself.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Epidemics, Attack Rates, and Type of Study Conducted at Each Hospital.

 
Comparative Studies

To determine whether an outbreak was occurring, we compared the rates of hospital-specific cases of postoperative infections meeting our definition that occurred before the epidemic period with those occurring during the epidemic. At each hospital, a case–control or cohort study was performed; in some instances, both kinds of studies were performed. In the case–control studies, the case patients were compared with randomly selected patients in the same hospital who underwent surgery during the epidemic period (Table 1). In the cohort studies, the case patients were compared with all other patients in the same hospital who underwent surgery during the epidemic period. Follow-up case–control or cohort studies were conducted to define exposures and associations further.

All medical records for the case patients and the control patients were reviewed to determine the patients' characteristics and potential preoperative, perioperative, and postoperative risk factors.

Procedural Review

To evaluate the role of procedural factors, we reviewed operating-room and anesthesia practices by interviewing personnel, observing surgical and anesthesia procedures, administering written questionnaires, and reviewing infection-control policies.

Microbiologic Studies

All available isolates from the case patients, the environment, and hospital personnel were sent to the CDC and were identified according to standard methods. All Staphylococcus aureus isolates were phage-typed.⁴ Strains of Candida albicans were compared by means of pulsed-field gel electrophoresis⁵ and DNA fingerprinting followed by Southern blot transfer and hybridization with the CARE-2 probe.⁶ All Enterobacter agglomerans isolates were examined by plasmid and restriction-endonuclease analysis.⁷ All Serratia marcescens isolates were serotyped with Edwards and Ewing's O antigen tests and Le Minor's H-immobilization tests.^8,9 Endotoxin assays were performed on selected serum and environmental samples with the turbidimetric limulus amebocyte lysate assay (LAL-5,000, Associates of Cape Cod, Woods Hole, Mass.)¹⁰ or gel clot assay.¹¹

Material for culture was obtained from products and personnel thought to be involved in the epidemics as well as from selected products and personnel not implicated in the epidemics. Cultures of the hands of personnel were obtained with use of a previously described method.¹² In some instances, direct impressions of obvious hand lesions were made onto tryptic-soy-agar plates; other lesions were swabbed with premoistened cotton-tipped applicators that were then streaked on tryptic-soy-agar plates. Water, fluids, and medications were cultured on tryptic soy agar according to the membrane-filtration technique.¹³

Statistical Analysis

All data were collected with the use of standardized forms and analyzed with Epi Info version 5.¹⁴ Odds ratios, relative risks, and 95 percent confidence intervals were calculated. Fisher's exact test or the chi-square test was used to compare categorical variables, and Student's t-test or Wilcoxon's test was used to compare continuous variables.

Results

Comparative Studies

Sixty-two patients met the case definitions, 49 of whom underwent surgery during the hospital-specific epidemic periods. In all six hospitals in which it was evaluated, the attack rate was significantly greater during the epidemic period than in the period preceding it (Table 1). The epidemic periods lasted from 2 to 65 days (median, 11) (Figure 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. Distribution of Case Patients According to the Date of Surgery and Hospital.

 
Next, the investigation focused on the 49 case patients who became ill during an epidemic period. These patients ranged in age from 22 to 90 years. Forty-one (84 percent) had infectious complications in which an etiologic agent was isolated, and 8 (16 percent) had acute febrile episodes. Thirty-two (65 percent) were women. Twenty-two of the 49 case patients had undergone orthopedic surgery (45 percent), 10 gynecologic surgery (20 percent), 9 general surgery (18 percent), 2 urologic surgery (4 percent), 1 ophthalmologic surgery (2 percent), 3 biopsy (6 percent), and 2 other surgical procedures (4 percent) (Table 2). Of the 41 case patients from whom an etiologic agent was isolated, 12 (29 percent) had only bloodstream infections, 18 (44 percent) only surgical-site infections, and 6 (15 percent) both surgical-site and bloodstream infections. One case patient had a surgical-site infection and an endocardial infection. Four case patients had other infections (urinary tract infection or endophthalmitis). The interval from the time of surgery to the first positive culture ranged from less than 1 day to 51 days. Eight case patients had their hospitalization prolonged because of their infections, 20 required rehospitalization, and 11 required surgical intervention. Eighteen had infectious complications distant from the surgical site.

View this table: [in this window] [in a new window]   Table 2. Characteristics of the 49 Case Patients Who Became Ill during an Epidemic Period.

 
Two case patients (4 percent) who became ill during the epidemic period died. At hospital 5, three of the four case patients had signs of sepsis and required vasopressor support; disseminated intravascular coagulation, acute renal failure, and symptoms of the adult respiratory distress syndrome developed in all three. At hospital 7, all case patients had hypotension (systolic blood pressure, <90 mm Hg; mean systolic blood pressure, 82 mm Hg), required vasopressor support, had thrombocytopenia (platelet count, <100,000 per cubic millimeter; mean, 74,000 per cubic millimeter) within 48 hours after surgery, and had elevated concentrations of fibrin-split products (mean, >10 µg per milliliter) within 24 hours after surgery.

At each hospital, there were no significant differences between case patients and controls or unaffected surgical patients in sex, age, inpatient or outpatient status, preoperative American Society of Anesthesiologists score, preoperative skin preparation, surgical-wound class, receipt of prophylactic antimicrobial therapy, or duration of surgery.

Although a number of potential risk factors were identified, including the use of certain intravenous anesthetic agents or other intravenous agents, only the receipt of propofol was significantly associated with postoperative infectious complications at all hospitals (Table 3). At six hospitals, exposure to a single anesthesiologist or nurse-anesthetist was a risk factor. At the seventh facility, the preparation of a propofol-infusion pump by a specific nurse-anesthetist was found to be a risk factor.

View this table: [in this window] [in a new window]   Table 3. Comparison of Potential Risk Factors among Case Patients and Controls or Other Surgical Patients without Postoperative Infections.

 
Procedural Review

In general, the practices of anesthesia personnel who were implicated in the outbreaks did not differ from those of other personnel. However, they were found to have done at least one of the following: prepare multiple syringes of propofol at one time for use throughout the day; reuse syringes or infusion-pump lines, or both, on different patients; use syringes of propofol that had been prepared up to 24 hours beforehand; transfer prepared syringes of propofol between operating rooms or facilities; sometimes fail to wear gloves during the insertion of intravenous catheters; and sometimes fail to wear gloves during procedures that involved touching mucous membranes or preparing or administering propofol. At hospital 7, anesthesia personnel were also found not to disinfect the rubber stoppers of 50-ml propofol vials before use.

Microbiologic Studies

At five of seven hospitals, an etiologic agent was isolated from the case patients (Table 4). In four of those five hospitals, all available isolates from the case patients were found to be identical by phage-typing (hospitals 1 and 3), plasmid analysis (hospital 5), or serotyping (hospital 6). At the remaining hospital (hospital 2), pulsed-field gel electrophoresis, DNA fingerprinting, and CARE-2 hybridization patterns of C. albicans isolates revealed two distinct karyotypic patterns, each of which was isolated from two case patients.

View this table: [in this window] [in a new window]   Table 4. Results of Cultures of Samples from Hospital Personnel and Propofol and Results of Typing of the Isolates Obtained from Case Patients, Personnel, and Propofol.

 
At hospital 1, the same strain of S. aureus was recovered from the case patients and from a lesion on the scalp of the anesthesiologist implicated in the outbreak. At hospital 3, the same strain of S. aureus was recovered from the case patients and the hands of the nurse-anesthetist implicated in the outbreak. At hospital 2, C. albicans was the infecting strain and a variety of candida species were isolated from the hands of a number of anesthesiology personnel. Candida species were not commonly recovered from the handwashings of anesthesia personnel at other hospitals. Only one anesthesiologist was colonized with C. albicans; this anesthesiologist was not implicated in the epidemic, and the isolate was not typed. At hospital 5, E. agglomerans was isolated from the hands of a nurse-anesthetist who was not implicated in the epidemic; this isolate had a plasmid banding pattern that was different from the pattern of the isolates from the case patients and the propofol samples.

Cultures of unopened ampules of propofol from lots in use at hospitals 1 through 5 were negative. Ampules of propofol in use at the time of the outbreaks were not available for analysis at most hospitals. At two hospitals, syringes of propofol in use at the time of the outbreaks were available for analysis. At hospital 4, cultures of propofol from the syringes were positive for endotoxin and grew Moraxella osloensis; only the case patients had received propofol from these syringes. At hospital 5, cultures of propofol from the syringes grew the same organism as that isolated from the case patients (E. agglomerans).

Discussion

Between June 1990 and February 1993, we investigated seven outbreaks of perioperative or postoperative infectious complications in which epidemiologic and laboratory evidence documented extrinsically contaminated propofol as the cause. Extrinsic contamination, contamination that occurs during the handling of propofol after its manufacture, was suggested because different lots of propofol were used in each outbreak; cultures of unopened vials of propofol from the same lots as the implicated vials were negative; the presence of specific nurse-anesthetists and anesthesiologists and the receipt of propofol, particularly by infusion, were epidemiologically associated with postoperative infectious complications; and lapses in aseptic technique by anesthesia personnel were observed or reported.

Viruses and bacteria have been associated with extrinsic contamination of intravenous agents.^15,16,17 Extrinsically contaminated infusates have also been associated with pyrogenic reactions without bacteremia.^18,19 However, no other single intravenous agent has been associated with such widespread outbreaks of extrinsic contamination or has been contaminated by such a wide variety of organisms.

Several properties inherent to propofol contribute to its extrinsic contamination. The active ingredient, 2,6-diisopropylphenol, is formulated in an emulsion of soybean oil, glycerol, and egg lecithin. Lipid emulsions, lipid-based anesthetic agents, and propofol support rapid microbial growth at room temperatures,^{20,21,22,23,24} whereas most intravenously administered anesthetic or sedative agents are not lipid-based and do not support rapid microbial growth.^24,25,26 Unlike most other intravenous anesthetics, propofol contains no preservatives or antimicrobial agents to retard bacterial growth, and refrigeration is not recommended by the manufacturer.²⁷

Before 1991, propofol was available only in 20-ml glass ampules, and anesthesia personnel drew up the contents of several ampules into a single syringe for use in an infusion pump. In 1991, propofol became available in 50-ml and 100-ml rubber-topped vials. Use of the larger vials was intended to decrease the risk of extrinsic contamination by obviating the need to use multiple ampules of propofol during the assembly of an infusion pump. However, the larger vials look like multidose vials, and our investigations revealed that the vials are sometimes being used for an extended period of time, for more than one patient or procedure, and to refill syringes meant to be used only once.

Our investigations revealed a number of anesthesia practices that could contribute to the extrinsic contamination of propofol. Despite the written recommendations of professional associations, such as the American Society of Anesthesiologists²⁸ and the American Association of Nurse Anesthetists,²⁹ which specifically advocate the use of aseptic techniques during the handling of medications, several authors have reported poor compliance with aseptic techniques and infection-control practices by anesthesia personnel.^{30,31,32,33,34,35,36} Contamination of multidose vials,^15,37,38 use of a single syringe to administer medication to different patients,³⁹ assembling infusion equipment far in advance of use,⁴⁰ and contamination of syringes and catheters³⁸ have all been implicated in other outbreaks. Studies show that reuse of multidose vials can cause contamination of the medication in the vial¹⁵ and that contamination can occur during the opening of a glass vial whose surface has not been disinfected.⁴¹ Injecting medications into intravenous catheters can cause syringes to become contaminated even if the needle is changed,^{42,43,44,45,46} so that using common syringes to administer medication to different patients can transmit infectious agents. In other outbreaks unrelated to the use of propofol, anesthesia personnel have been identified as the carriers or source of the outbreak.^47,48,49

The contamination of intravenous agents as a result of the anesthesia practices noted above may not always result in the appearance of clinical disease because many intravenous agents do not support bacterial growth. With propofol, however, and potentially other lipid-based intravenous agents, contamination of the agent with even very small numbers of organisms may result in clinical disease. Therefore, the manufacturer's recommendations for the use of propofol must be carefully followed, including appropriate disinfection of the surface of the neck of the ampule or the rubber stopper in a vial before use, preparation of propofol just before use, use of aseptic handling procedures, and restriction of the use of an ampule or vial to a single patient.²⁷

After the first report in 1990 of four CDC investigations demonstrating the risks of propofol use and the necessity for strict aseptic techniques in the handling of this anesthetic,¹ the manufacturer sent letters to all registered anesthesiologists, nurse-anesthetists, and chief pharmacists in the United States informing them of these outbreaks and the risks of extrinsic contamination of propofol. The manufacturer also revised the product label and package insert to stress the importance of the use of aseptic techniques and to warn users that propofol can support rapid microbial growth.²⁷ It also broadly advertised the requirement for aseptic techniques in promotional and instructional materials. Despite these efforts, in June 1993 we were informed of another outbreak in which two deaths occurred. This outbreak was linked to the use of propofol from the recently introduced 50-ml rubber-topped vial. In March 1994, we were informed of two more propofol-associated outbreaks in different states.

We continue to receive reports of sporadic episodes of fever, infection, or sepsis thought to be associated with extrinsically contaminated propofol. Between July 1989 and May 1994, the FDA received reports of 38 clusters of fever or infection (or both) involving 155 patients in 20 states that were thought to be associated with propofol use (FDA: unpublished data). At least four patients who received propofol have died.

The magnitude of the problem has probably been underestimated. Most infections in surgical patients are thought to be related to the surgeon, surgical procedure, or postoperative care. The association of infection with the use of an agent such as propofol or a procedure such as anesthesia may not be appreciated. Propofol-associated outbreaks may remain unidentified unless an unusual organism is isolated from one or more patients; the infections occur in unusual settings, such as among patients undergoing clean, uncomplicated surgical procedures; the infections are clustered among a group of patients; signs of infection occur during or soon after surgery; unusual endotoxin reactions occur perioperatively; or the index of suspicion is high. The receipt of smaller doses of infective organisms may lead to milder illness or a delayed onset of symptoms that go undetected. We suspect that only larger outbreaks or those associated with serious or life-threatening outcomes have been identified, whereas smaller or less severe outbreaks or single episodes of illness associated with contaminated propofol may not have been identified.

Despite the initial reports of propofol-associated outbreaks and the education efforts by the manufacturer, the number of clusters of infection or fever associated with propofol use reported to the FDA rose steadily from 1991 through 1993 (FDA: unpublished data). In 1993, propofol was approved for use as a sedative in intensive care units. The availability of propofol in larger vials and the approval of its use in the intensive care setting, coupled with continued outbreaks and the recurrent linkage of such outbreaks with the non-aseptic handling of propofol by anesthesia personnel, suggest that further efforts are required.

Studies suggest that attempts to educate anesthesia personnel and revise their infection-control practices have not always been successful.⁵⁰ However, we strongly recommend increased efforts to educate anesthesia personnel about the need for aseptic techniques and basic infection-control practices. With the introduction of propofol into busy inpatient and outpatient settings where aseptic practices may be less rigorous and multidrug-resistant organisms are common,^51,52 the risk of extrinsic contamination may be higher than in the operating room. Access to propofol in these settings should be restricted to those educated in its unique properties and handling requirements.

Infection-control practitioners, anesthesia personnel, and others must maintain a high index of suspicion for episodes of infection or fever in patients who receive propofol for general anesthesia or sedation. Infections or acute febrile episodes thought to be associated with propofol use should be reported through state health departments to the Hospital Infections Program of the CDC at (404) 639-6413 and to the FDA's MedWatch medical-products reporting program at 1-800-FDA-1088.

We are indebted to Sonia M. Aguero, Roger L. Anderson, Ph.D., Loretta A. Carson, Gary A. Hancock, Sigrid K. McAllister, Conradine Riddle, and Barbara A. Schable of the Hospital Infections Program, CDC; to Brent A. Lasker, Ph.D., and Timothy Lott, Ph.D., of the Division of Bacterial and Mycotic Diseases, CDC; to Diane M. Simpson, M.D., Ph.D., Texas Department of Health; to Byron J. Francis, M.D., Illinois Department of Public Health; to William N. Hall, M.D., M.P.H., James Altamirano, M.D., M.P.H., Barbara Robinson-Dunn, Ph.D., and Kenneth R. Wilcox, M.D., M.P.H., Michigan Department of Public Health; to Edward B. Hayes, M.D., and Kathleen F. Gensheimer, M.D., M.P.H., Maine Bureau of Health; to Charles H. Woernle, M.D., M.P.H., Alabama Department of Public Health; to Lawrence K. Sands, D.O., M.P.H., Arizona Department of Health Services; to Raymond J. Alderfer, M.D., M.P.H., FDA; and to the many persons at the seven hospitals who contributed to these investigations.

Source Information

From the Hospital Infections Program, National Center for Infectious Diseases (S.N.B., L.A.B., M.J.A., M.E.V., D.R.B., S.F.W., D.A.P., L.S., W.R.J.), the Division of Bacterial and mycotic Diseases (M.M.M.), and the Division of Field Epidemiology, Epidemiology Program Office (P.S.Z.), Centers for Disease Control and Prevention, Atlanta; and the Texas Department of Health, Austin (D.M.P.).

Address reprint requests to Dr. Jarvis at the Hospital Infections Program, MS E-69, Centers for Disease Control and Prevention, 1600 Clifton Rd., NE, Atlanta, GA 30333.

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Propofol and Postoperative Infections
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