Ann Thorac Surg 2007;84:1605-1610. doi:10.1016/j.athoracsur.2007.06.052
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
In Vivo Microdialysis to Measure Antibiotic Penetration Into Soft Tissue During Cardiac Surgery
Doris Hutschala, MDa,
Keso Skhirtladze, MDa,b,
Christian Kinstner, MDa,
Bernhard Mayer-Helm, PhDb,
Markus Müller, MDb,
Ernst Wolner, MDc,
Edda M. Tschernko, MDa,b,*
a Department of Cardiothoracic Anesthesia and Intensive Care Medicine, University of Vienna, General Hospital, Vienna, Austria
b Department of Clinical Pharmacology, University of Vienna, General Hospital, Vienna, Austria
c Department of Cardiothoracic Surgery, University of Vienna, General Hospital, Vienna, Austria
Accepted for publication June 19, 2007.
* Address correspondence to Dr Tschernko, Department of Cardiothoracic Anesthesia and Intensive Care Medicine, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria (Email: edda.tschernko{at}meduniwien.ac.at).
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Abstract
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Background: Wound infections remain an important problem after cardiac surgery despite antimicrobial prophylaxis, causing increased mortality, morbidity, and costs. Penetration properties of antibiotics are altered by extracorporeal circulation, fluid resuscitation, surgery, and postoperative treatment measures. So far, interstitial antibiotic concentration has not been measured continuously during surgery. It remains uncertain whether the concentration of the prophylactic antibiotic is sufficient in interstitial tissue. Therefore, we measured interstitial concentrations of cefazolin in vivo during cardiac surgery.
Methods: Seven patients undergoing aortic valve replacement were studied in this prospective, observational, pharmacokinetic study. Cefazolin, 4 g, was administered before skin incision and additionally 2 g during skin closure. Microdialysis, an in vivo approach, was used to measure unbound interstitial drug concentrations.
Results: Cefazolin plasma concentration rose to a peak of 443 µg/mL (range, 169 to 802 µg/mL) within 20 minutes (range, 20 to 40 minutes). The maximum of interstitial concentration of cefazolin was observed within 60 minutes after antibiotic administration. Cefazolin tissue levels exceeded minimum inhibitory concentration values for most potential wound pathogens for more than 600 minutes after infusion. The maximum drug concentration of cefazolin in subcutaneous interstitial fluid was 22.6% of maximum plasma levels, comparable with 19.4% in muscular tissue.
Conclusions: Cefazolin, administered in the high dose used at our institution, is effective for prevention against infection with the most prevalent pathogens during and immediately after cardiac surgery. Additionally, our data show that it is important to reevaluate clinical dosing schemas by means of direct in vivo measurements.
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Introduction
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Surgical site infections (SSIs) are a potentially devastating complication after cardiac surgery [1]. The term SSIs summarizes sternal infections (superficial and deep) and leg wound infections [2]. The incidence of infections at the surgical sites, chest and leg, ranges from less than 1% to greater than 10% [3–5]. Despite antimicrobial prophylaxis and improved surgical procedures that led to an appreciable decline of SSIs, wound infections remain an important problem [6]. Fortunately, the incidence of mediastinitis is rare with about 1% [1, 3–6]. However, mediastinitis after cardiac surgery is associated with a reported mortality between 17%–47% [7]. Furthermore, all SSIs create enormous health care costs [3, 7].
Surgical site infections are frequently caused by Staphylococcus epidermidis and S aureus [6]. Therefore, cephalosporins are frequently chosen for prophylaxis during and after cardiac surgery in North America and Europe [8]. The prophylactic use of cephalosporins is often claimed to attribute to ß-lactamase-resistant S epidermidis and methicillin-resistant S aureus (MRSA) infections, leading to the administration of vancomycin and teicoplanin for prophylactic therapy [9, 10]. However, large in vitro studies revealed that the isolated pathogens are frequently susceptible to cephalosporins [9]. Therefore, it seems likely that insufficient antibiotic tissue concentrations may play an important role in the development of SSIs. The evaluation of antibiotic concentrations in interstitial tissue, the target site of SSIs, has been attempted by means of tissue biopsies during cardiac surgery [11]. However, at least two methodologic problems hampered the correct interpretation of data derived from tissue biopsies: (1) longitudinal pharmacokinetic data cannot be evaluated because it is impossible to measure antimicrobial concentrations continuously, and (2) a tissue biopsy represents a mixture of different anatomic sites and is therefore not an equivalent for interstitial tissue concentrations.
Therefore, we used the approach of in vivo microdialysis to continuously measure cefazolin levels in interstitial tissue during elective cardiac surgery. Microdialysis is an innovative technique that allows on-line measurements of unbound, microbiologically active drug concentrations in the interstitial space fluid [12]. The time versus concentration profiles of these pharmacokinetic data should lead to improve timing and dosing of prophylactic antibiotic therapy during cardiac surgery.
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Material and Methods
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The protocol was approved by the local Ethics Committee. All patients were given a detailed description of the study and their written informed consent was obtained. The study was performed in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines of the European Commission.
Patients
Seven patients scheduled for cardiac surgery on cardiopulmonary bypass (CPB) were included in this study. Inclusion criteria for the study were as follows: (1) patient is scheduled for elective aortic valve replacement; (2) left ventricular ejection fraction greater than 40%; (3) absence of coexisting renal, hepatic, or cerebrovascular disease, or insulin-dependent diabetes mellitus; and (4) a body mass index between 20 and 30. Patients undergoing coronary artery bypass grafting were excluded from the study in order not to interfere with venous graft harvesting. Patient data are given in Table 1.
Anesthesia and Cardiopulmonary Bypass
The following procedures routinely took place before study administration. For maintenance of fluid balance, 10 mL/kg body weight Ringer’s lactate solution was administered through a peripheral venous line before induction of anesthesia. After placement of routine monitoring (electrocardiogram, pulsoxymetry, and invasive blood pressure monitoring), general anesthesia was induced through a peripheral vein. A median sternotomy was performed in all 7 patients. All patients underwent cardiac surgery on CPB. Heparin sodium (300 IU/kg) was administered, and the activated clotting time was kept above 400 s (Hemochrom 400; International Technidyne, Edison, New Jersey). The extracorporeal circuit consisted of a membrane oxygenator (Monolyth, Sorin Biomedica Cardio, Saluggia, Italy), an open venous reservoir system (Monolyth, Sorin Biomedica Cardio), and polyvinyl chloride tubing. Ringer’s lactate solution (1,700 mL), mannitol 20% (100 mL), and heparin sodium (5,000 IU) were used to prime the circuit. During extracorporeal circulation, body core temperature was maintained at 36°C (normothermic CPB). After termination of CPB, the heparin effect was reversed with protamine (1 mg protamine for each 100 IU heparin used). Further details on the surgical procedure, time of surgery, aortic cross-clamp time, duration of CPB, and volume administration are given in Table 1.
Measurements of Interstitial Cefazolin Concentrations
In vivo microdialysis was employed to measure unbound interstitial concentrations of cefazolin. This technique is based on sampling of analytes from the interstitial space fluid by means of a semipermeable membrane at the tip of a microdialysis probe (Fig 1). The probe was perfused constantly with a physiologic solution with a flow rate of 1.5 µL/min. Once the probe was implanted into the tissue, substances present in the interstitial fluid at a concentration (Ctissue) are filtered, by diffusion, out of the interstitial fluid into the probe, resulting in a concentration (Cdialysat) in the perfusion medium. For most analytes, equilibrium between interstitial space fluid and the perfusion medium is incomplete; therefore, Ctissue greater than Cdialysate. The factor by which the concentrations are interrelated is termed relative recovery. For determination of the relative recovery the microdialysis probes were calibrated in vivo in each experiment according to the retrodialysis method [12]. The principle of this method is based on the fact that the diffusion process is quantitatively equal in both directions through the semipermeable membrane. Therefore, cefazolin was included in the perfusion medium for probe calibration, and the disappearance rate (delivery) through the membrane was calculated subsequently. The in vivo recovery value was calculated as follows:
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In vivo recovery was assessed for each experiment by dialyzing the tissue (muscle and subcutaneous adipose tissue) with a perfusion medium containing 20 µg/mL cefazolin for 30 minutes.
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Fig 1. Schematic diagram of a microdialysis probe. The semipermeable membrane at the tip of the probe allows exchange of soluble molecules between the probe and the surrounding tissue. The probe with a pore cutoff of 20,000 Dalton is implanted into the interstitial tissue. When the probe is implanted into interstitial tissue, molecules continuously diffuse out of the interstitial space fluid into the perfusion medium until equilibrium is reached. The amount of cefazolin molecules in the dialysate correlates with the interstitial concentration of the drug. Dialysate samples are continuously collected and analyzed by standard chemical analytical techniques.
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Experimental Design
In this study, we used a flexible microdialysis probe (CMA 70; Microdialysis AB, Stockholm, Sweden) with a membrane length of 20 mm and a cut-off level of 20,000 Dalton. All probes were inserted and calibrated after induction of anesthesia. The insertion of the probes was performed under sterile conditions. One microdialysis probe was inserted into the skeletal muscle and a second probe into the subcutaneous adipose layer of the thigh. The surface of the skin was punctured using a 20G intravenous plastic cannula. The steel mandrin was removed, the appropriate placing of the probe was checked by aspiration, and the dialysis probe was inserted into the plastic cannula. The plastic cannula was removed, leaving the probe under the surface of the skin (Fig 2). The microdialysis system was connected and perfused with Ringer’s solution with a flow rate of 1.5 µL/min. This was performed by a microinfusion pump (Predicor; Infors-AG, Basel, Switzerland). After a 30-minute baseline perfusion period, in vivo probe calibration was performed as described previously for a period of 30 minutes followed by a 30-minute washout period. Thereafter, 4 g cefazolin (Zolizef, intravenously, 2 x 2 g; Bristol-Myers Squibb GesmbH, Vienna, Austria) were administered within 15 minutes. This initial bolus dose was administered at the ward but at least 60 minutes before skin incision. Because of the short half life of cefazolin, 2 g of this antibiotic drug was administered once more during closure of the skin. This dosing scheme is regularly used for prophylaxis of wound infections during elective cardiac surgery at our institution.
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Fig 2. Microdialysis probes. One probe is already implanted, whereas the other is just inserted through an intravenous plastic cannula.
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Blood samples for determination of antibiotic concentration were taken first in 20 minutes intervals after drug administration for 2 hours. Two hours after the start of drug administration, the sampling periods were prolonged, because a steady state can be expected at that time. Thereafter, blood and simultaneously microdialysis samples were collected every 60 minutes for about 10 hours. Simultaneously with blood sampling, microdialysis samples were collected. Additionally, blood samples were collected immediately after start of CPB from the inlet port and outlet port of the oxygenator to determine whether cefazolin is adherent to the oxygenator membrane of the extracorporeal circuit. The whole study period was 12 hours.
Analysis of Plasma and Microdialysis Samples
All measurements were performed with capillary zone electrophoresis on a Hewlett Packard 3DCE instrument with a diode array detector (Agilent Technologies, Waldbronn, Germany). The detection wavelengths were 270 nm, the absorption maximum of cefazolin, and 214 nm as a control wavelength. Detailed information about the quantitative determination technique is given by Mayer and coworkers [13].
Calculation and Data Analysis
For microdialysis experiments, interstitial concentrations were calculated by the following equation:
Data are presented as means and standard deviations. The median value and range were used when data were not normally distributed. The time-versus-concentration profiles of cefazolin for plasma and interstitial fluid (subcutaneous and muscular) were measured, and the following key pharmacokinetic parameters were determined: area under the concentration curve (AUC), AUCplasma/AUCtissue ratio, maximum drug concentration (Cmax), time to maximum drug concentration (Tmax), and half-life time of the ß-phase (T1/2ß).
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Results
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All patients underwent uncomplicated aortic valve replacement. None of the patients suffered from SSIs during the initial 30 days after cardiac surgery. Additionally, no complications associated with the microdialysis procedure were observed. Demographic data, surgical data, and intraoperative treatment data are given in Table 1.
After the end of bolus-infusion of cefazolin concentration rose rapidly in plasma with a peak of 443 µg/mL (range, 169 to 802 µg/mL) within 20 minutes (range, 20 to 40 minutes; Fig 3,
Table 2). Mean concentrations of cefazolin in the subcutaneous interstitial tissue and in muscular interstitial tissue rose rapidly over 60 minutes (Fig 3). Thereafter, interstitial tissue concentrations fell at a slower rate than the plasma concentrations. Interstitial fluid concentrations in the subcutaneous and muscular tissue remained on a high level over the entire observation period of 720 minutes (Fig 3).
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Fig 3. Time to concentration profile of cefazolin in plasma, subcutaneous, and muscular interstitial tissue. Cefazolin concentration (µg/mL) in plasma (squares), subcutaneous interstitial tissue (circles), and muscular interstitial tissue (triangles) is shown on the y-axis. On the x-axis, the observation time is plotted, zero indicating the end of administration of the initial cefazolin bolus. Additionally, the minimal inhibitory concentration (MIC90) values for the most prevalent pathogens are shown. (Dashed line = MIC90 for Staphylococcus aureus; dotted line = MIC90 for Staphylococcus epidermidis; dashed/dotted line = MIC90 for Enterobacter sp.) Values are shown as the mean ± SEM.
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Table 2 Key Pharmacokinetic Indicators of Cefazolin in Plasma and Interstitial Tissue During and After Cardiopulmonary Bypass
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The interindividual variability of maximum drug concentration in interstitial tissue was associated with a factor 2.4 for subcutaneous tissue and with a factor 5 for muscular tissue.
Cefazolin levels exceeded minimum inhibitory concentration (MIC90) values for the most potential wound infection pathogens in subcutaneous and muscular tissue for at least 600 minutes. Key pharmacokinetic characteristics are shown in Table 2.
The median AUC in subcutaneous interstitial fluid was 39.6%, and in the muscular interstitial fluid 48.3% of that in plasma. The maximum drug concentration of cefazolin in subcutaneous interstitial fluid was 22.6% of maximum plasma levels compared with 19.4% in muscular tissue. Penetration of cefazolin into muscular interstitial tissue was comparable with penetration into subcutaneous interstitial tissue. Data plotted as plasma/interstitial tissue antibiotic concentrations are shown in Figure 4.
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Fig 4. Ratio of plasma to interstitial tissue concentration (µg/mL). Circles represent plasma/muscular tissue concentration and squares represent plasma/subcutaneous tissue concentration. On the x-axis, the time after administration of the initial cefazolin bolus is given in min. Values are shown as the mean ± SEM (standard error of the mean).
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The plasma samples of cefazolin taken from the inlet port and outlet port of the oxygenator were comparable, indicating that the antibiotic has no adherence to the oxygenator membrane.
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Comment
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In the present study, microdialysis was successfully performed during cardiac surgery for the determination of antibiotic concentrations in muscular and subcutaneous interstitial fluid in vivo. We measured concentrations of cefazolin in interstitial tissue fluid and in plasma of elective heart valve replacement patients, thus successfully performing on-line antibiotic tissue concentration measurements in patients undergoing open heart surgery.
Prophylactic antibiotic therapy does not exert the primary effects within the plasma compartment but in defined target tissues into which drugs have to distribute from the central compartment. Unfortunately, a complete and lasting equilibrium between blood and tissue cannot always be taken for granted [14]. Appropriate dosing of antibiotic agents should result in antibiotic concentrations exceeding the minimal inhibitory concentration (MIC90) of the causative pathogens at the target site, the interstitial space fluid in case of nonsepticemic infections [15]. The distribution process to the interstitium is highly variable [16] and has been shown to be altered by iatrogenic procedures such as surgery, extracorporeal circulation, and intensive care therapy [17, 18].
In the presented study, we used the novel approach of in vivo microdialysis to measure continuously cefazolin levels in interstitial tissue during elective cardiac surgery. No complications associated with the microdialysis procedure occurred, indicating that the method is safe. However, owing to calibration and preparation time of the intraoperative measurements, it seems unlikely that microdialysis will become a standard procedure during cardiac surgery in the near future. Nevertheless, it seems well worth to use it in patients with an increased risk, namely, morbidly obese patients or patients suffering from diabetes mellitus.
Cefazolin is regularly used in many centers for antibiotic prophylaxis during cardiac surgery [1, 4, 8–10]. However, it has to be noted that an extremely high dosage of the substance is used at our institution. We used 4 g cefazolin bolus intravenously before skin incision, whereas Harbarth and colleagues [8], Slaughter and associates [8], and many others describe a preventive bolus of cefazolin in the range of 1 to 2 g before skin incision. The high initial dose of cefazolin was suggested by infection control and specialists of the Department of Infectious Disease after an outbreak of mediastinitis caused by susceptible pathogens in our institution. Owing to the 4 g cefazolin bolus, peak tissue concentrations in interstitial subcutaneous tissue (median, 100 µg/mL) and in muscular interstitial tissue (median, 86 µg/mL) exceeded the MIC90 of the pathogens most likely causing postoperative SSIs [19]. Even the patient with the lowest peak cefazolin value could expect to have good coverage against the most prevalent pathogens (Table 2).
Recently, Fellinger and colleagues [20] published cefazolin plasma levels in patients undergoing cardiac surgery on CPB with 1 g preoperative cefazolin bolus and 1 g bolus immediately after onset of CPB. They observed peak levels of cefazolin (36 µg/mL) that were substantially lower than expected in comparison with peak plasma levels of 443 µg/mL observed in our study. The substantially lower plasma concentrations of Fellinger and coworkers [20] can be attributed to their dosing schema and to the timing of their sample collection with long time intervals between plasma sampling. Owing to the long sampling intervals, Fellinger and coworkers [20] could have missed their "real" plasma peak. However, it cannot be extrapolated from our data whether an initial bolus of 1 g or 2 g cefazolin is associated with sufficient interstitial tissue concentrations. Prolonged antibiotic prophylaxis (longer than 48 hours), according to the suggestions of Harbarth and colleagues [8], was not used at our institution.
The mean of maximum interstitial drug concentration was reached in interstitial and muscular tissue respectively within 60 minutes after administration of 4 g cefazolin (Table 2), and thereafter remained on a high level for 720 minutes. Cefazolin should be administered at least 60 minutes before skin incision to guarantee for optimal tissue concentration at the beginning of surgery. Vast interindividual differences of factor 3 (shown in Table 2) were observed for the time required to reach maximum interstitial concentrations. So it seems reasonable to administer the prophylactic antibiotic as early as possible before skin incision. In some institutions, the prophylactic antibiotic is administered on the ward [20], whereas other centers recommend antibiotic administration about 30 minutes before operation [21]. The practice of early administration of the prophylactic antibiotic is supported by our data showing a very variable rise in tissue concentration after administration of the antibiotic drug (Tmax 1 in Table 2). Furthermore, administration at least 60 minutes before starting the operation seems safe, because once the maximum tissue concentration is reached, it decreases at a slow rate guaranteeing for sufficient concentrations during surgery (Fig 3).
The most common organisms causing postoperative infection in cardiac surgery are S epidermidis (27% to 40%), S aureus (17% to 32%), and gram-negative organisms, including Enterobacter (4% to 26%), Enterococcus (1% to 7%), and Serratia sp (9%) [22]. Except for the MIC90 of Serratia, the MIC90 of all species listed above was lower than maximum tissue concentrations observed in our study (Fig 3). Therefore, cefazolin administered in the described manner seems suitable to prevent SSIs, with the most common pathogens in patients not exhibiting increased risk for infection after cardiac surgery.
The technique of in vivo microdialysis can be applied successfully for measurement of antibiotic tissue concentrations during cardiac surgery. We can conclude that the prophylactic antibiotic should be administered timely before skin incision, and that a high dose of the initial bolus guarantees for sufficient tissue levels against the most common pathogens causing postoperative wound infections after cardiac surgery.
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Abstract
Introduction
