A prospective study between prophylactic antibiotic and placebo-controlled group of donor nephrectomy patients:  Are prophylactic antibiotics really necessary?

ERNESTO L. GERIAL, JR, JOSE BENITO A. ABRAHAM, REYNALDO C. DELA CRUZ
National Kidney and Transplant Institute Division of Urology, QC, Philippines

Keywords: Donor Nephrectomy, Prophylactic Antibiotics, Postoperative Infection in Living Kidney Donors

ABSTRACT

Objectives: To determine whether prophylactic antibiotics are necessary in preventing possible postoperative infectious complications in healthy living kidney donors.

Materials and Methods: 25 living kidney donors were divided into two groups: Group A – received intravenous normal saline solution (placebo) and Group B – received prophylactic broad-spectrum antibiotics. Both of these were administered one hour prior to donor nephrectomy and in two doses 24 hours postoperatively. Signs of postoperative infection were evaluated using fever, pyuria, wound changes and bacteriologic studies as clinical parameters. Data was analyzed using the chi-square test.

Results: Five patients (30.7%) in the placebo group and two patients (16%) in the prophylaxis group developed postoperative fever. The differences in this two groups was however not statistically significant.

"Significant pyuria" was noted in two patients belonging to group A while none was seen in group B. The presence of urinary tract infection was documented in both cases by culture studies. No patient in Group B developed urinary tract infection. This difference however, was not statistically significant.

No documented wound infection occurred in both placebo and prophylaxis groups. However, one patient in the placebo group developed serous wound discharge, which healed with intake of antibiotics, and daily wound care.

Conclusions: No statistically significant differences were observed in donor nephrectomies who received either placebo or broad-spectrum prophylaxis in terms of post-operative fever, significant pyuria and wound infection. The use of prophylactic antibiotics in these otherwise healthy individuals may not really be necessary in preventing postoperative infectious complications.

Key words: donor nephrectomy, prophylactic antibiotics, postoperative infection IN LIVING kidney donors


Introduction

Antibiotics play an integral role in the preparation of a patient for operation. The decision to use an antibiotic revolves around the interplay of the type of surgery, patient’s level of immunocompetence, presence or absence of co-morbidity, calculated operational time and physician’s prerogative. The dreaded sequelae of infectious complication can range from a simple wound infection to frank septicemia leading to death. Clearly, many physicians believe that the benefits that could be derived from the use of an antibiotic can far outweigh the anticipated morbidity and mortality.

Operative wounds are classified in relation to contamination and increasing risk of infection. The American College of Surgeons categorizes this into clean, clean-contaminated, contaminated and dirty and infected wounds. In terms of outcome, contaminated and dirty and infected wounds are at greater risk of infectious complications as compared to clean and clean-contaminated wounds. Because of this, administration of antibiotic as prophylaxis is absolutely indicated for contaminated and dirty and infected wounds.

Prophylactic antibiotics are indicated in clean operations only if the patient has risk factors, if the operation involves placement of prosthetic materials and if the operation is an open-heart procedure. Likewise, prophylaxis is required for clean-contaminated cases if the patients are at high risk: e.g. those whose common bile duct are likely to be explored, those with acute cholecystitis, those more than 70 years old and the majority of gynecological cases. On the other hand, no clinical guidelines exist when the genito-urinary tract is entered in the absence of infected urine.

Patients who are candidates for living related kidney donors fall under the classification of clean-contaminated cases. Prophylactic antibiotic has been used in this subset of patients and is the recommended pre-operative strategy in many studies. However, no randomized clinical trial involving the use of prophylactic antibiotic in living related kidney donors has been published.

Clinical studies have demonstrated that there are some situations in which chemoprophylaxis is highly effective and others in which it is totally without value and may in fact be deleterious. There are still numerous situations where an attempt to use antimicrobial compounds to prevent bacterial infection is controversial.

In clean and clean-contaminated surgical procedures, which account for approximately 75% of total major operations, the expected incidence of wound infection is less than 5% and antibiotics should then not be used routinely.

Complications of antibiotic prophylaxis though few, are still relevant. Although the formal development of resistant strains has not yet been well proven, it remains a danger for any ecosystem in which prophylaxis is inappropriate. A rare but important complication of the antibiotic use is pseudomembranous enterocolitis, induced by clindamycin, cephalosporins, and ampicillin. Although no documented case of pseudomembranous enterocolitis in living related kidney donor has been reported, this remains to be a potential complication. The rate of toxicity and unnecessary expense are, of course, possible additional disadvantages.

Living related kidney donors are healthy individuals with no co-existent morbidity. These individuals also have high levels of immunocompetence. Thorough evaluation of these patients prior to renal transplantation requires that they be physically fit without factors that might place them at risk for developing surgical complications. The use of chemoprophylaxis in these groups of patient, therefore, may be debatable. This significant question concerning preoperative chemoprophylaxis remains to be answered.

The main objective of this study is to determine whether prophylactic antibiotics are necessary in preventing possible postoperative infectious complications in healthy living kidney donors. Specifically, the investigators would like to determine if prophylaxis could reduce the incidence of post-operative fever, significant pyuria and wound infection in this group of patients when compared with placebo.

Materials and Methods

Subjects

A total of 57 renal transplants employing healthy living kidney donors were performed at the National Kidney and Transplant Institute from February until November 1998. Thirty-one (31) were private cases and twenty-six (26) were service cases. All service cases were enrolled in the study after completion of the preliminary standard screening for qualified living related donors. Inclusion criteria are all healthy living donors who have no concomitant illnesses and are cleared for admission by both the Transplant and Urologic services. Patients were randomly assigned into two groups: Group A – placebo using an equal volume of 10 cc. normal saline solution and Group B – given prophylactic broad-spectrum antibiotic. These were instructed as to the possible consequences of the treatment employed and were assured that standard remedy for these complications will be promptly instituted once they arise. An informed consent was obtained from all patients.

GROUP A (Placebo) – Patients received an equal volume of placebo using normal saline administered intravenously one hour before surgery and another two doses within 24 postoperatively in a similar manner.

GROUP B (Prophylaxis) – Patients received the usual recommended dose of a broad-spectrum antibiotic (third generation cephalosporins) one-hour before surgery and another two doses given within 24 hours postoperatively.

Pre-operative Care

The patient is admitted two to three days prior to the planned renal transplant. An arteriogram and pyelography are obtained to provide clear anatomic definition of the renal vessels and collecting system. Normal hemoglobin and blood chemistry are prerequisites Intravenous fluids are given eight hours prior to the planned operation to ensure adequate intravascular volume prior to surgery.

Technique for Donor Nephrectomy

All nephrectomies are performed using the extraperitoneal flank approach, the level of incision depending on the position of the kidney and the preference of the surgeon, almost always with the 11th or 12th rib resection. Donor nephrectomy is then carried out applying the basic principles and techniques of donor nephrectomy that had been described and illustrated in detail elsewhere in literature. Copious irrigation of the wound and adequate hemostasis are ensured prior to wound closure. All wounds are closed in a similar fashion in layers using absorbable sutures without drains. The skin is closed in a subcuticular manner using polyglactin 4.0. Strict asepsis and antisepsis are observed in all procedures.

Postoperative Care

All patients are catheterized once using a straight catheter immediately post-op before transfer to the recovery room, observing the prescribed sterile technique. Early ambulation is encouraged. Intravenous fluids are continued until oral alimentation is established to ensure adequate hydration, generally, after 48 hours post-operatively.

Parameters for Clinical Assessment

The presence or absence of postoperative infection was evaluated using the following parameters:

    1. Presence or absence of fever
    2. Presence or absence of significant pyuria
    3. Gross evidence of wound infection
    4. Culture-positive bacteriologic studies

TEMPERATURE MONITORING. All nurses were informed regarding the ongoing study and were instructed to obtain regular temperature readings every 4 hours using the standard clinical thermometer via the axillary route. All readings were accurately plotted in the standard TPR sheet. Any elevation of the temperature above 37.5 was considered abnormal and this was promptly relayed to the investigator immediately upon recognition for assessment.

urinalysis. Daily urinalysis was obtained starting on the 1st postoperative day using the first morning specimen. Significant pyuria was defined as 5 or more leukocytes per high power field on two successive specimen analyses. This is based on the recommended cut-off level for significant pyuria (Brunsfitt, 1965; Kurumi, 1981; Stansfield, 1962). All patients who were noted to have significant pyuria were further evaluated by sending urine specimens for culture and sensitivity studies. Patients who had positive culture studies were treated accordingly with antibiotics based on sensitivity results. At the time of discharge, a repeat urinalysis was requested on all patients and they were advised to come back after one week for follow-up.

wound infection. The presence or absence of wound infection was assessed using a clinical score, which is summarized as follows:

Clinical Grade

Gross appearance

1

Dry and well-coaptated

2

Hyperemic wound edges

3

Serous discharge

4

Purulent discharge

5

Dehiscence

Ocular inspection was done daily by an independent evaluator who had no knowledge of the patient’s grouping using the aforementioned clinical score. There were plotted on the patients’ data sheet and returned to the primary investigators for analysis and interpretation.

The presence of wound discharge was interpreted as a potentially infected wound and culture studies were likewise carried out to confirm this. Patients who had positive cultures were treated accordingly with antibiotics based on sensitivity results. Daily wound care was done using povidone iodine.

Statistical analysis

The clinical parameters of postoperative fever and pyuria were analyzed using the Chi-square test with Yates’ correction. Wound characteristics are compared and summarized.

Results

A total of twenty-six (26) patients were initially enrolled in the study. One patient was excluded because of an episode of urinary tract infection one week prior to admission. A total of twenty-five (25) were available for analysis. Thirteen (13) patients belonged to Group A (Prophylaxis) and twelve (12) patients belonged to Group B (Placebo).

There are more female donors (14) than males (11). Age ranges from 20-52 among males and 15-55 among females. The greater majority is between 30-39-age bracket in both groups. Age distribution is comparable between the two groups as shown in Table 1.

All donor nephrectomies were performed through the extraperitoneal flank approach mostly with resection of the 11th rib. The right kidney was taken more often in both groups. No inadvertent entry into the pleura was committed in both groups.

The operative time range from 230" to 620" with a mean operative time of 4.05 hours. One patient in the placebo group required the longest operating time due to difficult dissection of multiple vessels. Incidentally, this same patient developed urinary tract infection postoperatively.

No patient suffered from intraoperative bleeding and subsequently, no blood transfusion was required in all patients. In all cases, kidneys removed were successfully used for transplantation with immediate urine production.

Clinical Outcome

There was no mortality in this study. Infectious complications are summarized in tables 4-6.

Five patients (30.7%) in the placebo group developed post-operative fever. Four of these were noted within 48, while the other was noted on the third postoperative day. The latter is a 34 year old male donor who also manifested throat irritation and productive cough. He was diagnosed to have upper respiratory tract infection and given appropriate antibiotics. Fever lysed promptly thereafter. Two patients (16%) in the prophylaxis group developed postoperative fever within 48. This resolved spontaneously with frequent ambulation and deep breathing exercises. All patients who had fever within 48 improved without active intervention. Thus, the investigators attributed these temperature elevations to pulmonary atelectasis. This difference in incidence of post-operative fever were however, not statistically significant.

"Significant pyuria" was noted in two patients (15.38%) belonging to group A and none (0%) belonging to Group B. In both patients, this was noted upon urinalysis on the 4th postoperative day. Subsequent culture studies were positive for both patients as evidenced by bacteriologic growth of Enterococci and Staphylococci sp. of > 1 x 105 colonies/cc., respectively. Appropriate antibiotics were administered accordingly to both patients. The difference in these findings is likewise, not statistically significant.

An independent evaluator, throughout the hospital stay and upon follow-up, performed daily ocular inspection. Wound characteristics are summarized in Table 6.

In Group A, 6 patients had dry and well-coaptated wounds from the 1st postop day until the time of discharge. 2 patients had hyperemia of wound edges on the 1st postop day but was dry and well coaptated on the 2nd postop day. 5 patients manifested hyperemia of wound edges up to the 2nd postop day but was dry and well-coaptated on the 3rd postop day. One of these patients, a 48-year old male donor developed clear serous discharge from the wound edge upon follow-up at the outpatient on the 7th postoperative day. Specimen was taken for bacteriologic study but this was negative for growth. Nevertheless, antibiotic was given and the wound eventually healed with daily wound care. On further investigation, this patient had poor personal hygiene and refrained from a daily bath until the time of follow-up. No patient manifested with purulent discharge or dehiscence.

In Group B, 3 patients manifested dry and well coaptated wounds from the 1st postop day up to the time of discharge. 3 patients manifested hyperemia of the wound edges on the 1st postop day but was dry and well coaptated on the 2nd postop day. 5 patients manifested hyperemia of wound edges up to the 2nd postop day but were dry and well coaptated on the 3rd postop day. 1 patient manifested hyperemia of wound edges up to the 3rd postop day but was dry and well coaptated on the 4th postop day. No patient developed seroma, wound discharge or dehiscence. No statistically significant difference was observed in the incidence of wound infection in both groups.

Discussion

Despite the increasing availability of cadaver kidneys in the local setting, the living related donor (LRD) continues to be a major source of organs in kidney transplantation because of superior graft survival. In our institute, we perform an average of 100 cases of donor nephrectomies per year. In 1997 alone, our LRD’s totaled 136 cases. This increase in cases could be attributed to the widespread campaign for renal transplantation, which is the optimum treatment for patients with end stage renal disease.

Although the foremost consideration for donor nephrectomy procedures is a successful renal transplant, we firmly believe that the welfare of the volunteer healthy donor is of equal and vital importance. Efforts are being made to keep morbidity to a minimum and one of these strategies is the administration of prophylactic antibiotics to prevent infectious complications.

Long term outcome and complication rates in 300 donor nephrectomies were studied by Feraren et al in two separate reports in 1987 and 1988. All patients received prophylactic antibiotics. Complications were categorized into various organs system involvement, inclusive of the pulmonary, urinary tract, operative wounds, gastrointestinal tract and others. Majority of complications was non-infectious (44%). Infectious complications comprise a minority: pneumonia (3%), urinary tract infection (9%) and wound infection/abscess (4%). The recommended approach to this problem is routine use of chemoprophylaxis and this has been observed in this institution ever since. We undertook this study to determine its actual clinical applicability.

Many authors have ratified the need for antimicrobial prophylaxis. Bernard and Cole in their study of over 300 cases have shown an increased incidence of infection in potentially contaminated wounds in the absence of antibiotic prophylaxis. Eykyn (1988) also stated similar findings. This forms the rationale behind the attitude of many surgeons in giving routine prophylaxis liberally.

Haley (1985) however, suggested selection criteria for patients who would require prophylactic antibiotics:

    1. Prophylaxis may be utilized to protect healthy persons from acquisition of or invasion by specific microorganisms to which they are exposed.
    2. To prevent secondary bacterial infection in patients who are ill with other disease.
    3. To prevent endocarditis in patients with valvular and other structural lesions of the heart who are undergoing surgical procedures.

Any patient who meets any of these two criteria is highly likely to benefit from prophylaxis.

Clearly , our living kidney donors do not fall under the subset of patients in the last two groups.

The use of these criteria sets the guidelines for the judicious use of antibiotics. In addition, when a single effective drug is used to prevent infection by a specific microorganism or to eradicate it immediately or soon after it has been established, chemoprophylaxis is warranted and is frequently successful.

In contrast to the advocates of chemoprophylaxis, recent reports showed mounting evidence that imprudent use of chemoprophylaxis is unwarranted. There is also no data to suggest that the incidence of wound infection is lower if antimicrobial treatment is given preoperatively or continued after the day of surgery in low risk healthy patients. Prolonged use even lead to the development of a more resistant flora and of wound infection caused by antibiotic-resistant strains.

Fever that begins within the first 24 hours after operation usually suggests atelectasis. This is caused by certain factors such as decreased mobility, poor inspiratory effort, and splinting due to pain, which is not uncommon. When it extends beyond that period, the clinician should suspect an ongoing infection, which may arise from the respiratory, genito-urinary, and operative sites.

In our study, postoperative fever occurred in both groups, majority of which occurred in less than 48 hours. Only one patient developed respiratory tract infection, which was treated adequately. No statistical difference was noted between these two groups. These were easily remedied and reversed without sequelae by the time of discharge from the hospital. The occurrence of atelectasis in living related donor is not uncommon. It ranks first in the non-infectious complications enumerated by Feraren in her study of 300 living donors.

The onset of postoperative urinary tract infection usually occurs as a result of catheterization, especially when indwelling catheters are used. In our protocol for donor nephrectomies, we have decided to sway from using indwelling catheters and instead, apply a single straight catheterization immediately post-op. Another catheterization is avoided whenever possible except in cases of urinary retention. As much as possible, patients are encouraged to void spontaneously. In our experience, this has significantly reduced postoperative urinary tract infections.

The presence of pyuria initially alarms the clinician of the presence of urinary tract infection. Pyuria, in the absence of bacteriological evidence of growth, is however, not synonymous to infection and may just be a result of urethral irritation secondary to instrumentation.

In our study, two patients were diagnosed to have urinary tract infection based on the conclusive evidence of significant pyuria and culture studies. Both of these came from Group A but this was however not statistically significant. One of these patients incidentally has the longest operative time. Whether this has contributed because of prolonged bladder distention from mannitol-diuresis intraoperatively cannot be extrapolated based on our results. No identifiable factor is present on the other patient.

Certain gross appearances of operative wounds suggest wound infection. Hyperemia in a wound is part of the normal healing process and is not synonymous with infection unless it persists beyond the 4th to 5th postoperative day. Serous discharge results from the accumulation of inflammatory fluid within a dead space in subcutaneous tissue. This results primarily from factor of inadequate closure of this layer.

In our study, various surgeons performed the operation. All of them were informed of the ongoing study and were advised to follow a similar standard technique. However, the variability in terms of skill cannot be controlled in a training institution such as ours. The use of a single surgeon in a randomized prospective clinical trial such as this is ideal but is not feasible because it will compromise the training of other residents.

Pus, abscess, wound dehiscence are, needless to say, frank evidence of active wound infection. In our study, 16 patients developed hyperemia, which did not progress during the rest of the hospital stay. One of these however, developed serous discharge on out patient follow-up. As previously mentioned, this may be attributable to poor personal hygiene. Bacteriologic studies negated the presence of wound infection.

Foreign literatures are scarce in reporting overt wound infections in living donors. The calculated incidence rate is less than 10% as reported by Weinstein, Ringden, Smith and Mcloughlin. The focus of studies in this group of patients is primarily on innovations of surgical techniques, optimal longevity in a solitary renal status, and outcome of renal transplantation. Feraren reported an incidence of 4% even in the presence of preoperative chemoprophylaxis.

Our data seems to suggest that there is no statistically significant difference in postoperative infectious complications in living kidney donors given placebo or prophylactic antibiotics. This is true for respiratory, genitourinary and wound complications.

A follow-up study using a similar design with a large sample size is useful to ascertain the validity of these findings. A cost-analysis comparative research of both approaches may also benefit both the patient and the clinicians as to the choice of treatment protocols. These may eventually help in deciding whether to modify the currently accepted notion that prophylactic antibiotic therapy is mandatory. Nevertheless the experience of various surgeons in creating a guideline for patient selection can not be taken for granted.

The use of prophylactic antibiotics in these otherwise healthy individuals may not really be necessary in preventing postoperative infectious complications.

Tables

Table 1. Age distribution of living kidney donors

 

Group A
(Placebo)

Group B
(Prophylaxis)

TOTAL

Statistical significance

 

< 20

1

1

 

NS

20-29

4

3

7

NS

30-39

6

4

10

NS

40-49

2

3

5

NS

> 50

0

1

1

NS

TOTAL

13 12 23  

Table 2. Sex distribution of living kidney donors

 

Group A
(Placebo)

Group B
(Prophylaxis)

TOTAL

M

6

5

11

F

7

7

14

TOTAL

13

12

25

 

 

Table 3. Wound incisions and laterality of kidneys in living kidney donors

Incision

Group A
(Placebo)

Group B
(Prophylaxis)

 

N

R/L

N

R/L

11th rib

12

7/5

6

2/4

12th rib

0

0/0

1

0/1

Between 11th and 12th

1

1/0

5

5/0

TOTAL

 

8/5

 

7/5

 

Table 4. Incidence of postoperative fever in donor nephrectomy patients receiving placebo (Group A) and prophylactic antibiotics (Group B)

 

Group A
(Placebo)
n(%)

Group B
(Prophylaxis)
n(%)

TOTAL

Statistical significance

With Fever

       

<48

4(31)

2(16.7)

6(24)

NS

>48

1(7)

0(0)

1(4)

NS

No Fever

8(62)

10(83.3)

18(72)

NS

TOTAL

13

12

25

 

Chi-square (with Yates’ correction), p=0.44

Table 5. Incidence of post-operative "significant pyuria" in donor nephrectomy patients receiving placebo (Group A) and antibiotic (Group B)

 

Group A
(Placebo)
n (%)

Group B
(Prophylaxis)
n (%)

Total

Statistical
significance

Pyuria

2(15.3)

0(0)

(8)

NS

Without Pyuria

11(84.6)

12(100)

3(92)

NS

TOTAL

       

Chi-square test (with Yates’ correction), p=0.49

Table 6. Summary of wound characteristics in donor nephrectomy patients who received placebo (Group A) and prophylaxis (Group B)

Clin
Score

Characteristics

Group A (Placebo)

Group B (Prophylaxis)

Post-Operative Day

Total

Post-Operative Day

Total

1 2 3 4 5 1 2 3 4 5
1 Dry, well-coaptated 6         6 3         3
2 Hyperemic edges 2 5       7 3   5   1 9
3 Seroma                        
4 Purulent Discharge                        
5 Dehiscence                        
  TOTAL 8 5       13 6   5   1 12

References

  1. Bernard H.R. Cole W.R. The prophylaxis of surgical infection: the effect of prophylactic antimicrobial drugs on incidence of infection following potentially contaminated wounds. Surgery 56: 151, 1964
  2. Cosimi, A.B., The donor and donor nephrectomy. In Morris, T.J. (Ed.) Kidney Transplantation. Grune & Stratton, 1984, p.83.
  3. Eykyn S., The prophylactic use of antibiotics in surgery. Surgery 1304-1307, 1988
  4. Feraren R.E. et al. Living related donor nephrectomy: appraisal of early complications in 300 cases. (Unpublished). File copy.
  5. Feraren R.E. Prodigalidad A. Alano F. Living related donor nephroureterectomy: analysis of 150 donors. Phil. J. Surg. Specialties 43:38, 1988.
  6. Haley, R.W. et al. Identifying patients at high risk of surgical wound infection: a simple multivariate index of patient susceptibility and wound contamination. Am. J. of Epidemiology 121: 206, 1985.
  7. Mcloughlin, M.G., Related living donor nephrectomy. J. Urol. 116:304, 1976
  8. Meahem J. Prophylactic antibiotics. In ACS care of the surgical patient. Vol. 2. VI-3: 1-9, 1989.
  9. Ringden, O., Friman, L., Lundgren, G. Living related kidney donors: complications and long-term renal function. Transplantation, 25:221, 1978.
  10. Smith, M.J., Living kidney donors. J. Urol. 110:158, 1973.
  11. Streena, S.B. Novick, A.C., Steinmuller, D.R., Granet, D. Flank Donor Nephrectomy: Efficacy in the Donor and Recipient. J.Urology, 141:1099, 1989.
  12. Weinstein, S., Navarre, R., Loening, S., Experience with live donor nephrectomy. J. Urol. 124:321, 1980.

 

ERNESTO L. GERIAL JR, M.D.   JOSE BENITO A. ABRAHAM, M.D. REYNALDO C. DELA CRUZ, M.D.

Division of Urology, National Kidney and Transplant Institute, East Avenue, Quezon City, Philippines 1100

Back to Publications

Copyright 1999 National Kidney and Transplant Division of Urology, Philippines
All Rights Reserved.