Effect of Surgical Blood Loss and Volume Replacement on Antibiotic Pharmacokinetics Doris Sue, PharmD, Theresa A. Salazar, PharmD, Kevin Turley, MD, and B. Joseph Guglielmo, PharmD Division of Clinical Pharmacy and Department of Surgery, University of California, San Francisco, California

Antibiotic prophylaxis is used widely to prevent postop- erative infection associated with cardiac operations. The influence of perioperative blood loss on antibiotic phar- macokinetics has not been well studied. Plasma cefazo- lin sodium samples from 8 patients undergoing a cardiac operation were collected postoperatively and analyzed.

ntibiotic prophylaxis significantly reduces the inci- A dence of infection after a cardiac operation [l]. Cefazolin sodium is often used as a prophylactic agent in these procedures because of its ability to achieve and maintain antibiotic levels exceeding minimum inhibitory concentrations for common pathogens including Staphy- lococcus aureus [2-4]. In addition, it has been shown that cefazolin penetrates well into myocardial tissue and peri- cardial fluid [5, 61.

Although it has been demonstrated that therapeutic concentrations of antibiotics must be present in the target tissue at the time of incision [7, 81, it is unknown whether therapeutic levels are necessary throughout the immedi- ate postoperative period. Substantial blood loss can take place postoperatively, resulting in large fluid-volume re- pletion. Massive blood loss and subsequent fluid replace- ment may result in subtherapeutic antibiotic levels. It is known that low serum antibiotic levels at the conclusion of a cardiac procedure are associated with an increased risk of infection [9]. Furthermore, patients with excessive postoperative bleeding often require emergent reopera- tion. It is possible that plasma antibiotic levels might be subtherapeutic before reoperation, thus resulting in an increased risk of infection. The effect of blood loss on the kinetics of antibiotics has not been well studied. We elected to determine the effect of perioperative blood loss and volume replacement on cefazolin pharmacokinetics in patients undergoing an elective cardiac operation.

Material and Methods Patients admitted to the University of California, San Francisco, and scheduled to undergo an elective cardiac procedure were eligible for this study. Patients were excluded from the study if they (1) had a known allergy or hypersensitivity to p-lactam antibiotics, (2) had concomi-

Accepted for publication Dec 9, 1988

Address reprint requests to Dr Guglielmo, Division of Clinical Pharmacy, University of California, San Francisco, C-152 Box 0622, San Francisco, CA 94143.

The results suggest that blood loss has a minimal effect on the elimination of cefazolin and that therapeutic concentrations are maintained without altering the dos- age regimen.

(Ann Thorac Surg 1989;47:857-9)

tant or previous antibiotic therapy within 1 week of initiation of cefazolin therapy, or (3) had received concom- itant probenecid or any other agent known to alter the active tubular secretion of cefazolin. The study was ap- proved by the committee on human research of the University of California, San Francisco. Written informed consent was obtained from all patients.

A single 1.0-g dose of cefazolin was administered intra- venously at the induction of anesthesia. The cardiopul- monary bypass machine also was primed with a 1.0-g dose of cefazolin. Patients were admitted directly to the intensive care unit after completion of the procedure. Five-milliliter blood samples were collected before the first postoperative cefazolin dose (eight hours after the initial dose), at the end of a 30-minute infusion, and 15, 30, 60, 120, 180, 240, 360, and 480 minutes after the end of the infusion. Blood samples were also collected from the chest tube drainage hourly up to 480 minutes after the dose. The exact volume of intravenous fluids, colloids, and blood administered during the postoperative sampling period, as well as the total blood loss, was recorded.

After the samples were drawn, they were immediately placed on ice and centrifuged. The plasma was collected and stored at -20°C until it was assayed. The plasma cefazolin concentration of each sample was determined by a high-pressure liquid chromatography assay developed at the University of California, San Francisco. An Alltech C-8 column was used. The mobile phase consisted of 15% acetonitrile, 15% phosphoric acid, and 0.1% tetramethyl- ammonium chloride titrated to a pH of 7. Spectrophoto- metric determinations were made at 254 nm with a Waters 441 detector. Cefoxitin was used as the internal standard. The specificity of the assay was 0.5 pg/mL.

Results Eight male patients scheduled for coronary artery bypass grafting or cardiac valve replacement were enrolled in the study. Age ranged from 62 to 78 years with a mean of 67 years. Patients had estimated creatinine clearances [lo] ranging from 39.0 to 80.8 mL/min with an average of 54.7

0 1989 by The Society of Thoracic Surgeons 0003-4975/89/$3.50

858 S U E E T A L BLOOD LOSS AND ANTIBIOTIC PHARMACOKlNETlCS

Ann Thorac Surg 1989;47857-9

Table 1 . Effect of Blood Loss on Cefazolin Sodium Elimination

Estimated Creatinine Half-Life of Rate of Trough Weight Clearance Cefazolin Blood Loss Concentration

Patient No. (kg) (mL/min) (h) (mL/h)

1 96 59.1 2.7 75 7.7 2 72 39.0 9.5 52 59.0 3 68 41.9 16.3 248 153.1 4 81 59.0 2.7 31 17.3 5 48 45.0 4.3 186 22.2 6 106 53.2 2.8 56 20.2 7 96 80.8 2.8 125 12.9 8 79 59.7 3.2 113 8.4

Average 81 2 18 54.7 ? 13.4 5.5 2 4.9 111 2 74 37.6 2 49.4

f 13.4 mL/min (Table 1). Seven of the 8 patients under- went coronary artery bypass grafting, and 1 had aortic valve replacement. A variety of anesthetics were used including nitrous oxide, isoflurane, and fentanyl.

There was a large degree of variability in the amount of blood loss and fluid replacement (Table 2). The amount of blood lost through the chest tube over the sampling period ranged from 400 to 2,050 mL with a mean of 1,123 f 562 mL. The rate of blood loss was as high as 248 mL/ h. Concomitant fluid replacement reflected the variability in blood loss with an average of 3,180 ? 476 mL (range, 2,694 to 3,945 mL). Calculated cefazolin half-life resulted in a range of 2.7 to 16.3 hours with a mean of 5.5 f 4.9 hours. The absolute amount of cefazolin lost through the chest tube did not appear to be related to the volume of blood lost. The average amount of antibiotic lost through the chest tube was 139.4 & 85.3 mg (range, 28.3 to 287.3 mg). Of note, an autotransfuser device was used in 6 patients in this study. However, reinfusion of cefazolin- containing blood did not appear to substantially affect the plasma concentrations.

Cefazolin concentrations immediately before adminis- tration of the postoperative dose ranged from 24.0 to 144.7

Table 2. Blood Loss and Volume Replacement

mg/L with an average concentration of 65.4 f 38.6 mg/L. The average peak concentration immediately after the dose was 161 ? 91 mg/L (range, 88.8 to 354.4 mg/L). The mean trough concentration eight hours after the dose was measured as 37.6 f 49.4 mg/L, with the lowest level being 7.7 mg/L (see Table 1).

Comment All cefazolin concentrations were far in excess of the minimum inhibitory concentration of S aureus, a major pathogen in these patients undergoing coronary artery bypass grafting procedures. The minimum inhibitory con- centration of cefazolin for S aureus in our institution approximates 0.5 mg/L. The lowest observed concentra- tion of cefazolin, independent of blood loss and fluid replacement, was 7.7 mg/L, which is approximately 16 times greater than the minimum inhibitory concentration.

The average half-life of cefazolin in patients with unim- paired renal function is approximately 1.5 hours. The observed half-life of cefazolin in all patients was longer (mean half-life, 5.5 hours) than expected. The observed elevated trough concentrations may be accounted for by

Through the Chest Tube Volume

Total Blood Lost Rate of Loss Cefazolin Lost Replacement Patient No. (mL) (mLih) 0%) (mL)

1 900 75 28.3 2,744 2 625 52 100.1 3,700

1,490 400

2,050 670

248’ 31

186 56

287.3 . . .

127.3 . . .

2,694 2,790 3,945 3,279

7 1,500 125 133.4 3,411

8 1,350 113 160.0 2,877

Average 1,123 2 562 111 -c 74 139.4 IT 85.3 3,180 2 476

Sampling period was interrupted because the patient had to be returned emergmtly to the operating room.

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S U E E T A L 859 BLOOD LOSS AND ANTIBIOTIC PHARMACOKINETICS

the increased half-life. Patient 3, who had the highest rate of blood loss, was noted to have a substantial decrease in his ability to eliminate the drug. His cefazolin half-life was calculated to be approximately 16.3 hours compared with two to three hours in patients who lost blood at lower rates.

More than 95% of cefazolin is eliminated unchanged by the kidneys [ll]. Therefore, creatinine clearance is a good estimation of cefazolin elimination. The estimated creati- nine clearance was determined through the application of a standard formula developed by Cockcroft and Gault [lo]. The estimated creatinine clearance in patient 3 was 42 mL/min; however, this decrease in renal function does not completely account for the marked increase in the cefazolin half-life. Patient 2 had an estimated creatinine clearance that was less than that of patient 3. As expected, his cefazolin half-life was extended, although not to the degree of patient 3 (9.5 hours versus 16.3 hours). If the decrease in elimination of cefazolin was entirely due to the patient's renal status, patient 2 should have demon- strated a longer half-life than patient 3. Patient 2 lost an average of 52 mL/h compared with 248 mL/h for patient 3. It may be that the accelerated blood loss in patient 3 contributed to the pharmacokinetic changes.

The increased cefazolin half-life associated with accel- erated blood loss may be explained by certain physiolog- ical compensatory mechanisms activated in response to hemorrhagic shock, including decreased renal blow flow. Because cefazolin is primarily eliminated through the kidneys, this acute decrease in blood flow to the kidneys might influence the elimination of the drug. The possibil- ity that the rate of blood loss can alter kidney function and subsequently the elimination of cefazolin appears to be supported by the data derived from the patients in this study.

Our data suggest that cefazolin is widely distributed into the tissues with only a small percentage of the total dose concentrated in the blood. As a result, the total amount of cefazolin in the body is not greatly affected by the loss of blood. This point was demonstrated in this study with the largest amount of cefazolin lost through the blood being 287.3 mg in the patient with the most substantial blood loss. The lowest cefazolin concentration in this patient was 152.1 mg/L. On average, only 14% of the cefazolin dose was eliminated through blood loss in our patients. Therefore, blood loss appears to have a minimal effect on the elimination of cefazolin from pa- tients. It may be that the cefazolin dose added to the heart-lung machine, along with the distribution character- istics and extended half-life of the drug, accounts for this phenomenon.

Autotransfusion of the cefazolin-containing blood did not appear to affect antibiotic concentrations. However, it

is important to keep in mind that other drugs, such as heparin sodium, anesthetics, narcotics, and sedatives, will be collected as blood is drained into the autotrans- fuser device. As a result, when this blood is reinfused into patients, these drugs may result in major pharmacological effects. Drugs that are highly plasma-protein bound or hydrophilic may be important in this regard.

In summary, blood loss after a cardiac operation does not result in a clinically significant loss of cefazolin. Prolongation of plasma half-life was noted in this patient population, which may account for the elevated trough antibiotic concentrations. In addition, although autotrans- fusion did not result in appreciable increases in plasma cefazolin concentrations, inadvertent administration of other agents, such as heparin, may be taking place. Future studies are necessary to further characterize the pharmacokinetic disposition of antibiotics and other agents in this setting.

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