World J Surg DOI 10.1007/s00268-014-2932-1
ORIGINAL SCIENTIFIC REPORT
Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection After Thyroid and Parathyroid Surgery: A Prospective Randomized Trial Takashi Uruno • Chie Masaki • Akifumi Suzuki • Keiko Ohkuwa • Hiroshi Shibuya • Wataru Kitagawa Mitsuji Nagahama • Kiminori Sugino • Koichi Ito
•
Socie´te´ Internationale de Chirurgie 2015
Abstract Background and Objective The effectiveness of antimicrobial prophylaxis (AMP) in the prevention of surgical site infection (SSI) following thyroid and parathyroid surgery remains uncertain. The objective of this prospective randomized controlled trial (Ito-RCT1) was to assess the effectiveness of AMP in clean neck surgery performed to treat thyroid and parathyroid disease. Methods Participants comprised patients scheduled for clean neck surgery for thyroid and parathyroid disease at Ito Hospital. Patients whose surgery included sternotomy or resection of the trachea, larynx, pharynx, or esophagus were excluded. AMP consisted of 2 g of piperacillin (PIPC) (group A, n = 541) or 1 g of cefazolin (CEZ) (group B, n = 541) administered intravenously immediately after endotracheal intubation. Patients in the control group (Group C, n = 1,082) did not receive AMP. Results Statistical analysis was performed to compare the AMP group (Group A ? Group B) with the control group (Group C). Drug-induced acute reactions correlated to PIPC or CEZ did not occur in the AMP group. No significant differences in the postoperative incidence of liver or renal dysfunction were seen between the AMP and control groups. Postoperative incidence of urinary tract infection was significantly higher in the control group (p = 0.002). The incidence of SSI events was very low, with only 1 event (0.09 %) in the AMP group and 3 events (0.28 %) in the control group, and this difference between groups was not significant (p = 0.371). Conclusions AMP is not necessary to prevent SSI after clean thyroid or parathyroid surgery.
Introduction Surgical site infections (SSIs) are very uncommon complications after thyroidectomy or parathyroidectomy that does not include resection of the trachea, larynx, pharynx, or esophagus. The reported incidence of SSI after thyroid surgery is 0.09–2 % [1–8]. Dionigi et al. of Italy reported an incidence of 2 % after 241 thyroid surgeries and concluded that preoperative antibiotic administration did not T. Uruno (&) C. Masaki A. Suzuki K. Ohkuwa H. Shibuya W. Kitagawa M. Nagahama K. Sugino K. Ito Department of Surgery, Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan e-mail: [email protected]
affect the incidence of SSI [7]. A recent retrospective study from China reported an incidence of 0.09 % (1 of 1,030 cases) after thyroidectomy without AMP [8]. Given such findings, international guidelines have not recommended routine systemic antimicrobial prophylaxis (AMP). The therapeutic guidelines of the American Society of HealthSystem Pharmacists recommend no AMP for clean surgery of the head and neck in either adult or pediatric patients, but the strength of evidence is rated as B (level IV–VI) [9]. In fact, routine systemic AMP is still commonly performed for clean thyroid and parathyroid surgeries at most medical institutions in Japan and in many other countries [10, 11]. According to an international survey of 275 endocrine surgeons, 26.2 % of endocrine surgeons administered AMP
123
World J Surg
‘‘almost always’’, and surgeons in Asia were most likely to give AMP ‘‘almost always’’ (58.5 %) [11]. We therefore conducted a single-institution randomized controlled trial to confirm the safety of clean thyroid and parathyroid surgery without AMP.
surgery, and participants were allocated by simple randomization of group rotation. The order of the group rotation was as follows: groupA-C–B-C-A-C–B-C…, to achieve equal the numbers patients in group A ? B (AMP group) and group C (without AMP, control). Exclusion criteria
Methods Exclusion criteria comprised Design A randomized, controlled, equivalence trial at a single institute (Ito Hospital) in Tokyo, Japan. Participant recruitment and randomization All study protocols were approved by the Human Research Ethics Committees at Ito Hospital, and written informed consent was obtained from all participants prior to enrolment. The trial has been registered with Clinical Trials. gov (NCT01805856). Between November 2010 and April 2012, the 2,164 consecutive patients who consented to participate in this randomized control trial were enrolled. All participants underwent clean neck surgery for thyroid or parathyroid disease at Ito Hospital and had been randomized into three groups; a group that received piperacillin sodium (PIPC) as AMP (Group A, n = 541), a group that received cefazolin sodium (CEZ) as AMP (Group B, n = 541), and a control group that did not receive AMP (Group C, n = 1,082) (Fig. 1). Group allocations were based on the date of
Fig. 1 Trial profile and number of patients identified between 3 groups in the randomized controlled study
123
• • •
•
Absence of consent to participate in the randomized controlled trial; Patients who underwent an operation that included sternotomy; Patients who underwent an operation that included resection of the trachea, larynx, pharynx, or esophagus; or Known allergy to cephems or penicillin.
Protocols Patients in the AMP group received either 2 g of PIPC (Group A) or 1 g of CEZ (Group B) intravenously immediately after endotracheal intubation. If the operation time was more than 3 h, the same dose of PIPC or CEZ was administered again. After the patient had been returned to their room, the same dose of the same drug was administered again. Operating room and operation Ito Hospital specializes in the diagnosis and treatment of thyroid and parathyroid disease. All patients in the present study underwent surgery for thyroid or parathyroid disease. The operating room is surveyed for cleanliness annually by a third party. The survey includes measurements of air velocity, volume, pressure, temperature, humidity, suspended particulate matter, and bacterial surface colonization, and a high-efficiency particulate air filter leak test. The airborne particulate cleanliness of our operating room was evaluated as class 5 according to ISO 14644-1 and class 10 according to FED-STD-209E. All patients underwent surgery under general anesthesia and urinary catheterization was performed in cases when the operation time was expected to last more than 1.5 h, because postoperative bed rest is maintained for 3 h in our hospital. The All Silicone Foley Tray Kit (CREATE MEDIC Co., Ltd., Yokohama, Japan), a closed catheter system that includes a catheter made of 100 % silicone rubber, was used to catheterize almost all patients who required urinary catheterization. Catheterization was performed by an experienced, trained nurse in a disinfected field. The urinary catheter was usually removed 3 h after
World J Surg
the patient was returned to their own room. Surgeons used 3 MTM AvagardTM (chlorhexidine gluconate 1 % Solution and ethyl alcohol 61 % w/w) for the surgical scrub and wore disposable surgical gloves and gowns as usual. A 0.5 % w/v chlorhexidine gluconate solution or 0.025 % w/v germitol water (for patients who were allergic to alcohol) was used to disinfect the operating field immediately prior to making the incision. With the exception of the synthetic, monofilament, non-absorbable polypropylene sutures (Prolene; Ethicon, New Jersy, USA) used to repair injured large blood vessels, all sutures used at surgical sites were absorbable, synthetic, braided sutures (Vicryl; Ethicon). Measurements and other observations The primary outcome in this study was the frequency of SSI, based on the definition published by the Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee [12]. The secondary outcomes were frequencies of medical side effects and other complications such as drug allergy reactions and other infections, including urinary tract infection (UTI). Patients usually stayed in the hospital until postoperative day 4. The length of postoperative hospitalization was relatively short in comparison with other hospitals in Japan. Patients were examined for manifestations of drug allergic reactions (skin rash and anaphylactic shock) in the operating room. Prospective observations for the development of SSI and UTI were continued until postoperative day (POD) 4 and then performed again at 1 month, when the patient made the first postoperative visit to the outpatient clinic. If a patient showed any symptom of UTI, additional blood and urine tests were performed to reach or exclude the diagnosis. Blood tests for liver and renal dysfunction were performed on POD 3. Liver and renal dysfunction were diagnosed clinically by the patient’s own physician and the author, and included cases in which function deteriorated compared to preoperative laboratory data. An infection at a surgical site was diagnosed as an SSI if treatments such as surgical drainage or antibiotic therapy were considered necessary. Whenever surgical drainage was performed, microbial cultures were also taken. Sample size calculation The sample size calculation was based on the primary outcome of differences in the frequency of SSI. The frequency of SSI after thyroid surgery is reportedly 0.09–2 %. We hypothesized SSI frequencies of 0.1 % in the AMP group and 1 % in the control group, so 1,101 participants per group would be required to provide a significance level of 0.05 and a power of 80 %. We expected 20 % attrition from the
study. The total number of patients to be included in the study was therefore 2,700, to allow for potential dropouts. Statistical analysis The Mann–Whitney U test and Fisher’s exact test were used to analyze differences between two groups, and values of p \ 0.05 were considered statistically significant.
Results Since the number of events, including side effects of PIPC and CEZ, was quite low, and specific differences between Groups A and B were not found, statistical analyses were performed to compare the AMP and control groups. Table 1 shows the clinical characteristics of each group. No significant differences were evident between groups in terms of age, gender, disease, surgical procedure, operation time, intraoperative blood loss, or incidence of diabetes. Table 2 shows the intra- and postoperative complications encountered. Skin rash developed in 2 patients in the control group, probably as a side effect of the anesthetic agents, but both rashes proved completely self-limiting without any treatment. No acute drug reactions, diarrhea or development of a Clostridium difficile infections related to PIPC or CEZ were seen in the AMP group despite careful prospective observation. No significant differences in the development of liver or renal dysfunction were identified between groups. All cases of liver and renal dysfunction recovered in response to conservative treatment. Unexpectedly, the incidence of UTI was significantly higher in the control group than in the AMP group (p = 0.002). All patients with UTI had been catheterized intraoperatively and had remained catheterized until at least 3 h after returning to their own room. The 20 patients with UTI consisted of 13 women and 7 men (median age, 51 years; range, 22–75 years), with a median operation time of 104 min (range, 40–135 min). All patients with UTI received medical treatment for the UTI and were quickly cured. The frequency of SSI was very low, at only 0.09 % (1 case) in the AMP group and 0.28 % (3 cases) in the control group, and no significant difference was apparent between groups (p = 0.371). Characteristics of the 4 patients with postoperative SSIs are shown in Table 3. One of the 4 patients with SSI was found during the hospital stay (POD 3), while the other 3 patients were diagnosed after discharge (POD 11–16). Only 1 patient was obese, and none of the 4 patients had diabetes. None of the 4 patients showed any other risk factors for SSI, such as cirrhosis, weight loss, malnutrition, or history of blood transfusions, systemic steroid therapy, chemotherapy, or radiation therapy.
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World J Surg Table 1 Clinical characteristics of the 2,164 patients randomized into 3 groups
Antimicrobial prophylaxis
AMP group (n = 1,082)
Control group (n = 1,082)
(Group A/Group B) Yes (PIPC/CEZ)
(Group C) No
p value
Mean ± SD
52 ± 15.1
52 ± 14.7
0.67
Median
53 (55/52)
53
0.95
Range
12–85 (12–85/12–83)
18–88
169 (87/82) 913 (454/459)
161 921
Age (years) (52 ± 15.0/51.1 ± 15.2)
Gender Male Female
0.63
Disease* Nodular goiter
362 (180/182)
316
Thyroid cancer
570 (284/286)
629
0.012
Graves’ disease
97 (46/51)
84
0.35
Hyperparathyroidism
42 (23/19)
46
0.74 0.32
Thyroidectomya Total/Near total
419 (205/214)
397
Subtotal/Lobectomy
590 (297/293)
616
None
73 (39/34)
69
CND
430 (216/214)
501
MND (ipsilateral)
79 (38/41)
85
MND (bilateral)
19 (12/7)
10
Partial None
21 (13/8) 533 (262/271)
8 478
0.020
42 (23/19)
45
0.74
74.7 ± 38.1
76.1 ± 34.0
0.37 0.030
0.79
Lymph node dissectionb
Parathyroidectomy
0.88
Operation time (min) Mean ± SD CND central node dissection, MND modified neck dissection * Statistical significance was evaluated by Fisher’s exact test. w/wo cancer (p = 0.012), w/wo Graves’ disease (p = 0.35), w/wo Hyperparathyroidism (p = 0.74) a
Statistical significance was evaluated by Fisher’s exact test. Total/near total versus others (p = 0.32), none versus others (p = 0.79)
b
Statistical significance was evaluated by Fisher’s exact test. MND versus less than CND (p = 0.88), none versus others (p = 0.02)
(74.5 ± 38.6/75 ± 37.5) Median
66 (66/67)
68
Range
15–400 (15–400/23–312)
16–310
70 ± 98.9
60.9 ± 85.9
0.024 0.027
Blood loss (ml) Mean ± SD
(67.7 ± 96.4/72.1 ± 101.3) Median
38 (36/41)
35
Range
1–1033 (1–870/1–1033)
1–1228
Diabetes Yes
48 (28/20)
31
No
1,034 (513/521)
1,051
911
900
171
182
Urinary catheterization Yes No
Discussion Although guidelines for AMP to prevent SSI exist, clinical evidence supporting these guidelines for thyroid surgeries is insufficient. Most reports on the incidence of SSI after thyroid surgery are old, and no reports of
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0.051 0.52
randomized clinical trials for methods to prevent SSI after thyroid surgery are available. The recent incidence of SSI after clean thyroid surgery thus needs to be investigated, because great advances have been made in surgical instruments such as absorbable sutures and vessel-sealing devices.
World J Surg Table 2 Intraoperative and postoperative complications
Statistical significance was evaluated by Fisher’s exact test
Antimicrobial prophylaxis
AMP group (Group A/Group B) Yes (PIPC/CEZ) n = 1,082 (541/541)
Control group (Group C) No n = 1,082
p value
Skin rash (allergic)
0 (0/0)
2
1
Anaphylactic shock
0 (0/0)
0
1
Liver dysfunction Renal dysfunction
7 (2/5) 1 (1/0)
8 2
1 1
Urinary tract infection
3 (2/1)
17
0.002
Surgical site infection
1 (0/1)
3
0.37
Table 3 Characteristics of the patients with postoperative surgical site infections AMP No
Age Gender
Disease
Diabetes
BMI
Surgical procedure
Duration (min)
Blood loss (ml)
Surgical drainage
Onset (POD)
Microorganisms isolated
51 y/o
PTC
No
29.0
LO CND
57
101
Yes
3
Staphylococcus aureus
PTC Recurrence
No
19.2
PND
49
15
Yes
16
Klebsiella pneumoniae Streptococcus sp.
PTC Graves
No
19.4
LO CND
66
17
Yes
11
Staphylococcus aureus
AG
No
22.3
LO
61
97
Yes
11
Streptococcus sp.
Female Yes
55 y/o Female
No
51 y/o Female
No
28 y/o Female
PTC papillary thyroid cancer, AG adenomatous (nodular) goiter, LO thyroid lobectomy, TT total thyroidectomy, PND partial neck dissection, CND central node dissection
The first research endpoint of the present study was whether AMP prevents SSI after thyroid surgery. The results showed no significant difference in the frequency of SSI according to AMP use. One probable reason for this result is that our hospital has an almost ideal clean operating room. Another reason is that absorbable sutures contribute to a decreased incidence of SSI in comparison with non-absorbable silk sutures [13, 14]. In addition, new surgical devices and vessel-sealing systems were used in some of our cases, and contribute to decreasing the frequency of ligation, intraoperative blood loss, and operation times [15, 16]. As a result, SSI was only in 4 of 2,164 patients (0.18 %) in the present trial. Because of the small number of SSI events, the statistical power achieved with 2,164 participants may have been inadequate to demonstrate a statistically significant difference. If an ideal clean surgical environment is not available, because of the equipment in the hospital, regional situation or other socioeconomic reasons, the incidence of SSI will unfortunately be higher. Under such conditions, AMP may be useful to decrease the relatively higher risk of SSI even after clean surgery. PIPC and CEZ infusions to prevent SSI are very safe and entail low risks of complications and side effects. The present results confirmed the safety of these drugs as a secondary endpoint.
Unexpectedly, omission of AMP was associated with a higher incidence of UTI (p = 0.002). All patients with a UTI had been catheterized intraoperatively and had remained catheterized until at least 3 h after returning to their own room. Despite the relatively short duration of catheterization of low-risk patients, the incidence of UTI after catheter removal was too high. One reason for the relatively high incidence of UTI in the control group (without AMP) may have been the long interval between the time of catheter removal and first urination, because of the reductions in both fluid intake and activities of daily life after the operation and general anesthesia. The Infectious Diseases Society of America does not recommend routine systemic AMP at the time of catheter removal or replacement [17]. In-and-out catheterization of the patient at the end of the procedure might thus have been preferable to leaving in an indwelling catheter, with the inherent increase in the risk of UTI. Otherwise, patients who do not receive AMP may have to adhere more strictly to water intake, or the volume of the drip infusion may need to be increased as a means of maintaining adequate urinary volume to reducing the risk of UTI after urinary catheter removal. In conclusion, AMP is not necessary to prevent SSI after clean thyroid or parathyroid surgery.
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World J Surg Acknowledgments The authors are grateful to the medical staff and members of the Division of Health Information Management of Ito Hospital, with particular thanks to Ms. Mayumi Tanaka for her precise data managements.
References 1. Zambudio AR, Rodriguez J, Riquelme J et al (2004) Prospective study of postoperative complications after total thyroidectomy for multinodular goiters by surgeons with experience in endocrine surgery. Ann Surg 240:18–25 2. Johnson JT, Wagner RL (1987) nfection following uncontaminated head and neck surgery. Arch Otolaryngol Head Neck Surg 113:368–369 3. Flynn MB, Lyons KJ, Tarter JW et al (1994) Local complications after surgical resection for thyroid carcinoma. Am J Surg 168:404–407 4. Moulton-Barrett R, Crumley R, Jalilie S et al (1997) Complications of thyroid surgery Int Surg 82:63–66 5. Brown BM, Johnson JT, Wagner RL (1987) Etiologic factors in head and neck wound infections. Laryngoscope 97:587–590 6. Tabet JC, Johnson JT (1990) Wound infection in head and neck surgery: prophylaxis, etiology and management. J Otolaryngol 19:197–200 7. Dionigi G, Rovera F, Boni L et al (2006) Surgical site infections after thyroidectomy. Surg Infect (Larchmt) 7(Suppl 2):S117– S120 8. Qin Q, Li H, Wang LB et al (2014) Thyroid surgery without antibiotic prophylaxis: experiences with 1,030 patients from a teaching hospital in China. World J Surg 38:878–881
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9. ASHP (1999) Therapeutic guidelines on antimicrobial prophylaxis in surgery. American Society of Health-System Pharmacists. Am J Health Syst Pharm 56:1839–1888 10. Gentile I, Rosato L, Avenia N et al (2012) Do Italian surgeons use antibiotic prophylaxis in thyroid surgery? Results from a national study (UEC—Italian Endocrine Surgery Units Association) Ann Ital Chir 11. Moalem J, Ruan DT, Farkas RL et al (2010) Patterns of antibiotic prophylaxis use for thyroidectomy and parathyroidectomy: results of an international survey of endocrine surgeons. J Am Coll Surg 210:949–956 12. Mangram AJ, Horan TC, Pearson ML et al (1999) Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 27:97–132; quiz 133–134; discussion 196 13. Watanabe A, Kohnoe S, Sonoda H et al (2012) Effect of intraabdominal absorbable sutures on surgical site infection. Surg Today 42:529–559 14. Togo S, Kubota T, Takahashi T et al (2008) Usefulness of absorbable sutures in preventing surgical site infection in hepatectomy. J Gastrointest Surg 12:1041–1046 15. Kuboki A, Nakayama T, Konno W et al (2013) New technique using an energy-based device versus conventional technique in open thyroidectomy Auris Nasus Larynx 40:558–562 16. Ruggiero R, Gubitosi A, Conzo G et al (2014) Sutureless thyroidectomy Int J Surg 12(Suppl 1):S189–S193 17. Hooton TM, Bradley SF, Cardenas DD et al (2010) Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 50:625–663
ORIGINAL SCIENTIFIC REPORT
Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection After Thyroid and Parathyroid Surgery: A Prospective Randomized Trial Takashi Uruno • Chie Masaki • Akifumi Suzuki • Keiko Ohkuwa • Hiroshi Shibuya • Wataru Kitagawa Mitsuji Nagahama • Kiminori Sugino • Koichi Ito
•
Socie´te´ Internationale de Chirurgie 2015
Abstract Background and Objective The effectiveness of antimicrobial prophylaxis (AMP) in the prevention of surgical site infection (SSI) following thyroid and parathyroid surgery remains uncertain. The objective of this prospective randomized controlled trial (Ito-RCT1) was to assess the effectiveness of AMP in clean neck surgery performed to treat thyroid and parathyroid disease. Methods Participants comprised patients scheduled for clean neck surgery for thyroid and parathyroid disease at Ito Hospital. Patients whose surgery included sternotomy or resection of the trachea, larynx, pharynx, or esophagus were excluded. AMP consisted of 2 g of piperacillin (PIPC) (group A, n = 541) or 1 g of cefazolin (CEZ) (group B, n = 541) administered intravenously immediately after endotracheal intubation. Patients in the control group (Group C, n = 1,082) did not receive AMP. Results Statistical analysis was performed to compare the AMP group (Group A ? Group B) with the control group (Group C). Drug-induced acute reactions correlated to PIPC or CEZ did not occur in the AMP group. No significant differences in the postoperative incidence of liver or renal dysfunction were seen between the AMP and control groups. Postoperative incidence of urinary tract infection was significantly higher in the control group (p = 0.002). The incidence of SSI events was very low, with only 1 event (0.09 %) in the AMP group and 3 events (0.28 %) in the control group, and this difference between groups was not significant (p = 0.371). Conclusions AMP is not necessary to prevent SSI after clean thyroid or parathyroid surgery.
Introduction Surgical site infections (SSIs) are very uncommon complications after thyroidectomy or parathyroidectomy that does not include resection of the trachea, larynx, pharynx, or esophagus. The reported incidence of SSI after thyroid surgery is 0.09–2 % [1–8]. Dionigi et al. of Italy reported an incidence of 2 % after 241 thyroid surgeries and concluded that preoperative antibiotic administration did not T. Uruno (&) C. Masaki A. Suzuki K. Ohkuwa H. Shibuya W. Kitagawa M. Nagahama K. Sugino K. Ito Department of Surgery, Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan e-mail: [email protected]
affect the incidence of SSI [7]. A recent retrospective study from China reported an incidence of 0.09 % (1 of 1,030 cases) after thyroidectomy without AMP [8]. Given such findings, international guidelines have not recommended routine systemic antimicrobial prophylaxis (AMP). The therapeutic guidelines of the American Society of HealthSystem Pharmacists recommend no AMP for clean surgery of the head and neck in either adult or pediatric patients, but the strength of evidence is rated as B (level IV–VI) [9]. In fact, routine systemic AMP is still commonly performed for clean thyroid and parathyroid surgeries at most medical institutions in Japan and in many other countries [10, 11]. According to an international survey of 275 endocrine surgeons, 26.2 % of endocrine surgeons administered AMP
123
World J Surg
‘‘almost always’’, and surgeons in Asia were most likely to give AMP ‘‘almost always’’ (58.5 %) [11]. We therefore conducted a single-institution randomized controlled trial to confirm the safety of clean thyroid and parathyroid surgery without AMP.
surgery, and participants were allocated by simple randomization of group rotation. The order of the group rotation was as follows: groupA-C–B-C-A-C–B-C…, to achieve equal the numbers patients in group A ? B (AMP group) and group C (without AMP, control). Exclusion criteria
Methods Exclusion criteria comprised Design A randomized, controlled, equivalence trial at a single institute (Ito Hospital) in Tokyo, Japan. Participant recruitment and randomization All study protocols were approved by the Human Research Ethics Committees at Ito Hospital, and written informed consent was obtained from all participants prior to enrolment. The trial has been registered with Clinical Trials. gov (NCT01805856). Between November 2010 and April 2012, the 2,164 consecutive patients who consented to participate in this randomized control trial were enrolled. All participants underwent clean neck surgery for thyroid or parathyroid disease at Ito Hospital and had been randomized into three groups; a group that received piperacillin sodium (PIPC) as AMP (Group A, n = 541), a group that received cefazolin sodium (CEZ) as AMP (Group B, n = 541), and a control group that did not receive AMP (Group C, n = 1,082) (Fig. 1). Group allocations were based on the date of
Fig. 1 Trial profile and number of patients identified between 3 groups in the randomized controlled study
123
• • •
•
Absence of consent to participate in the randomized controlled trial; Patients who underwent an operation that included sternotomy; Patients who underwent an operation that included resection of the trachea, larynx, pharynx, or esophagus; or Known allergy to cephems or penicillin.
Protocols Patients in the AMP group received either 2 g of PIPC (Group A) or 1 g of CEZ (Group B) intravenously immediately after endotracheal intubation. If the operation time was more than 3 h, the same dose of PIPC or CEZ was administered again. After the patient had been returned to their room, the same dose of the same drug was administered again. Operating room and operation Ito Hospital specializes in the diagnosis and treatment of thyroid and parathyroid disease. All patients in the present study underwent surgery for thyroid or parathyroid disease. The operating room is surveyed for cleanliness annually by a third party. The survey includes measurements of air velocity, volume, pressure, temperature, humidity, suspended particulate matter, and bacterial surface colonization, and a high-efficiency particulate air filter leak test. The airborne particulate cleanliness of our operating room was evaluated as class 5 according to ISO 14644-1 and class 10 according to FED-STD-209E. All patients underwent surgery under general anesthesia and urinary catheterization was performed in cases when the operation time was expected to last more than 1.5 h, because postoperative bed rest is maintained for 3 h in our hospital. The All Silicone Foley Tray Kit (CREATE MEDIC Co., Ltd., Yokohama, Japan), a closed catheter system that includes a catheter made of 100 % silicone rubber, was used to catheterize almost all patients who required urinary catheterization. Catheterization was performed by an experienced, trained nurse in a disinfected field. The urinary catheter was usually removed 3 h after
World J Surg
the patient was returned to their own room. Surgeons used 3 MTM AvagardTM (chlorhexidine gluconate 1 % Solution and ethyl alcohol 61 % w/w) for the surgical scrub and wore disposable surgical gloves and gowns as usual. A 0.5 % w/v chlorhexidine gluconate solution or 0.025 % w/v germitol water (for patients who were allergic to alcohol) was used to disinfect the operating field immediately prior to making the incision. With the exception of the synthetic, monofilament, non-absorbable polypropylene sutures (Prolene; Ethicon, New Jersy, USA) used to repair injured large blood vessels, all sutures used at surgical sites were absorbable, synthetic, braided sutures (Vicryl; Ethicon). Measurements and other observations The primary outcome in this study was the frequency of SSI, based on the definition published by the Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee [12]. The secondary outcomes were frequencies of medical side effects and other complications such as drug allergy reactions and other infections, including urinary tract infection (UTI). Patients usually stayed in the hospital until postoperative day 4. The length of postoperative hospitalization was relatively short in comparison with other hospitals in Japan. Patients were examined for manifestations of drug allergic reactions (skin rash and anaphylactic shock) in the operating room. Prospective observations for the development of SSI and UTI were continued until postoperative day (POD) 4 and then performed again at 1 month, when the patient made the first postoperative visit to the outpatient clinic. If a patient showed any symptom of UTI, additional blood and urine tests were performed to reach or exclude the diagnosis. Blood tests for liver and renal dysfunction were performed on POD 3. Liver and renal dysfunction were diagnosed clinically by the patient’s own physician and the author, and included cases in which function deteriorated compared to preoperative laboratory data. An infection at a surgical site was diagnosed as an SSI if treatments such as surgical drainage or antibiotic therapy were considered necessary. Whenever surgical drainage was performed, microbial cultures were also taken. Sample size calculation The sample size calculation was based on the primary outcome of differences in the frequency of SSI. The frequency of SSI after thyroid surgery is reportedly 0.09–2 %. We hypothesized SSI frequencies of 0.1 % in the AMP group and 1 % in the control group, so 1,101 participants per group would be required to provide a significance level of 0.05 and a power of 80 %. We expected 20 % attrition from the
study. The total number of patients to be included in the study was therefore 2,700, to allow for potential dropouts. Statistical analysis The Mann–Whitney U test and Fisher’s exact test were used to analyze differences between two groups, and values of p \ 0.05 were considered statistically significant.
Results Since the number of events, including side effects of PIPC and CEZ, was quite low, and specific differences between Groups A and B were not found, statistical analyses were performed to compare the AMP and control groups. Table 1 shows the clinical characteristics of each group. No significant differences were evident between groups in terms of age, gender, disease, surgical procedure, operation time, intraoperative blood loss, or incidence of diabetes. Table 2 shows the intra- and postoperative complications encountered. Skin rash developed in 2 patients in the control group, probably as a side effect of the anesthetic agents, but both rashes proved completely self-limiting without any treatment. No acute drug reactions, diarrhea or development of a Clostridium difficile infections related to PIPC or CEZ were seen in the AMP group despite careful prospective observation. No significant differences in the development of liver or renal dysfunction were identified between groups. All cases of liver and renal dysfunction recovered in response to conservative treatment. Unexpectedly, the incidence of UTI was significantly higher in the control group than in the AMP group (p = 0.002). All patients with UTI had been catheterized intraoperatively and had remained catheterized until at least 3 h after returning to their own room. The 20 patients with UTI consisted of 13 women and 7 men (median age, 51 years; range, 22–75 years), with a median operation time of 104 min (range, 40–135 min). All patients with UTI received medical treatment for the UTI and were quickly cured. The frequency of SSI was very low, at only 0.09 % (1 case) in the AMP group and 0.28 % (3 cases) in the control group, and no significant difference was apparent between groups (p = 0.371). Characteristics of the 4 patients with postoperative SSIs are shown in Table 3. One of the 4 patients with SSI was found during the hospital stay (POD 3), while the other 3 patients were diagnosed after discharge (POD 11–16). Only 1 patient was obese, and none of the 4 patients had diabetes. None of the 4 patients showed any other risk factors for SSI, such as cirrhosis, weight loss, malnutrition, or history of blood transfusions, systemic steroid therapy, chemotherapy, or radiation therapy.
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World J Surg Table 1 Clinical characteristics of the 2,164 patients randomized into 3 groups
Antimicrobial prophylaxis
AMP group (n = 1,082)
Control group (n = 1,082)
(Group A/Group B) Yes (PIPC/CEZ)
(Group C) No
p value
Mean ± SD
52 ± 15.1
52 ± 14.7
0.67
Median
53 (55/52)
53
0.95
Range
12–85 (12–85/12–83)
18–88
169 (87/82) 913 (454/459)
161 921
Age (years) (52 ± 15.0/51.1 ± 15.2)
Gender Male Female
0.63
Disease* Nodular goiter
362 (180/182)
316
Thyroid cancer
570 (284/286)
629
0.012
Graves’ disease
97 (46/51)
84
0.35
Hyperparathyroidism
42 (23/19)
46
0.74 0.32
Thyroidectomya Total/Near total
419 (205/214)
397
Subtotal/Lobectomy
590 (297/293)
616
None
73 (39/34)
69
CND
430 (216/214)
501
MND (ipsilateral)
79 (38/41)
85
MND (bilateral)
19 (12/7)
10
Partial None
21 (13/8) 533 (262/271)
8 478
0.020
42 (23/19)
45
0.74
74.7 ± 38.1
76.1 ± 34.0
0.37 0.030
0.79
Lymph node dissectionb
Parathyroidectomy
0.88
Operation time (min) Mean ± SD CND central node dissection, MND modified neck dissection * Statistical significance was evaluated by Fisher’s exact test. w/wo cancer (p = 0.012), w/wo Graves’ disease (p = 0.35), w/wo Hyperparathyroidism (p = 0.74) a
Statistical significance was evaluated by Fisher’s exact test. Total/near total versus others (p = 0.32), none versus others (p = 0.79)
b
Statistical significance was evaluated by Fisher’s exact test. MND versus less than CND (p = 0.88), none versus others (p = 0.02)
(74.5 ± 38.6/75 ± 37.5) Median
66 (66/67)
68
Range
15–400 (15–400/23–312)
16–310
70 ± 98.9
60.9 ± 85.9
0.024 0.027
Blood loss (ml) Mean ± SD
(67.7 ± 96.4/72.1 ± 101.3) Median
38 (36/41)
35
Range
1–1033 (1–870/1–1033)
1–1228
Diabetes Yes
48 (28/20)
31
No
1,034 (513/521)
1,051
911
900
171
182
Urinary catheterization Yes No
Discussion Although guidelines for AMP to prevent SSI exist, clinical evidence supporting these guidelines for thyroid surgeries is insufficient. Most reports on the incidence of SSI after thyroid surgery are old, and no reports of
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0.051 0.52
randomized clinical trials for methods to prevent SSI after thyroid surgery are available. The recent incidence of SSI after clean thyroid surgery thus needs to be investigated, because great advances have been made in surgical instruments such as absorbable sutures and vessel-sealing devices.
World J Surg Table 2 Intraoperative and postoperative complications
Statistical significance was evaluated by Fisher’s exact test
Antimicrobial prophylaxis
AMP group (Group A/Group B) Yes (PIPC/CEZ) n = 1,082 (541/541)
Control group (Group C) No n = 1,082
p value
Skin rash (allergic)
0 (0/0)
2
1
Anaphylactic shock
0 (0/0)
0
1
Liver dysfunction Renal dysfunction
7 (2/5) 1 (1/0)
8 2
1 1
Urinary tract infection
3 (2/1)
17
0.002
Surgical site infection
1 (0/1)
3
0.37
Table 3 Characteristics of the patients with postoperative surgical site infections AMP No
Age Gender
Disease
Diabetes
BMI
Surgical procedure
Duration (min)
Blood loss (ml)
Surgical drainage
Onset (POD)
Microorganisms isolated
51 y/o
PTC
No
29.0
LO CND
57
101
Yes
3
Staphylococcus aureus
PTC Recurrence
No
19.2
PND
49
15
Yes
16
Klebsiella pneumoniae Streptococcus sp.
PTC Graves
No
19.4
LO CND
66
17
Yes
11
Staphylococcus aureus
AG
No
22.3
LO
61
97
Yes
11
Streptococcus sp.
Female Yes
55 y/o Female
No
51 y/o Female
No
28 y/o Female
PTC papillary thyroid cancer, AG adenomatous (nodular) goiter, LO thyroid lobectomy, TT total thyroidectomy, PND partial neck dissection, CND central node dissection
The first research endpoint of the present study was whether AMP prevents SSI after thyroid surgery. The results showed no significant difference in the frequency of SSI according to AMP use. One probable reason for this result is that our hospital has an almost ideal clean operating room. Another reason is that absorbable sutures contribute to a decreased incidence of SSI in comparison with non-absorbable silk sutures [13, 14]. In addition, new surgical devices and vessel-sealing systems were used in some of our cases, and contribute to decreasing the frequency of ligation, intraoperative blood loss, and operation times [15, 16]. As a result, SSI was only in 4 of 2,164 patients (0.18 %) in the present trial. Because of the small number of SSI events, the statistical power achieved with 2,164 participants may have been inadequate to demonstrate a statistically significant difference. If an ideal clean surgical environment is not available, because of the equipment in the hospital, regional situation or other socioeconomic reasons, the incidence of SSI will unfortunately be higher. Under such conditions, AMP may be useful to decrease the relatively higher risk of SSI even after clean surgery. PIPC and CEZ infusions to prevent SSI are very safe and entail low risks of complications and side effects. The present results confirmed the safety of these drugs as a secondary endpoint.
Unexpectedly, omission of AMP was associated with a higher incidence of UTI (p = 0.002). All patients with a UTI had been catheterized intraoperatively and had remained catheterized until at least 3 h after returning to their own room. Despite the relatively short duration of catheterization of low-risk patients, the incidence of UTI after catheter removal was too high. One reason for the relatively high incidence of UTI in the control group (without AMP) may have been the long interval between the time of catheter removal and first urination, because of the reductions in both fluid intake and activities of daily life after the operation and general anesthesia. The Infectious Diseases Society of America does not recommend routine systemic AMP at the time of catheter removal or replacement [17]. In-and-out catheterization of the patient at the end of the procedure might thus have been preferable to leaving in an indwelling catheter, with the inherent increase in the risk of UTI. Otherwise, patients who do not receive AMP may have to adhere more strictly to water intake, or the volume of the drip infusion may need to be increased as a means of maintaining adequate urinary volume to reducing the risk of UTI after urinary catheter removal. In conclusion, AMP is not necessary to prevent SSI after clean thyroid or parathyroid surgery.
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World J Surg Acknowledgments The authors are grateful to the medical staff and members of the Division of Health Information Management of Ito Hospital, with particular thanks to Ms. Mayumi Tanaka for her precise data managements.
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