Archives of Surgery

doi: 10.1001/archsurg.141.12.e1pmid: N/A

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Dervisoglou, Athanasios;Tsiodras, Sotirios;Kanellakopoulou, Kyriaki;Pinis, Stamatios;Galanakis, Nearchos;Pierakakis, Stephanos;Giannakakis, Panagiotis;Liveranou, Stavroula;Ntasiou, Panagiota;Karampali, Efstathia;Iordanou, Christos;Giamarellou, Helen

doi: 10.1001/archsurg.141.12.1162pmid: 17178957

Abstract Hypothesis Cephalosporins are widely used and considered to be effective as prophylaxis in biliary surgery. Nevertheless, they lack activity against enterococci. We conducted a study to compare the efficacy of ampicillin-sulbactam vs cefuroxime in preventing surgical site infections following elective cholecystectomy. Design A prospective randomized controlled trial. Setting A major tertiary care hospital. Patients Four hundred eighteen randomized patients (of 549 total), who from July 2002 to August 2004 underwent elective open or laparoscopic cholecystectomy with prospective assessment for development of surgical site infections for 1 month postoperatively. Intervention A single intravenous dose of 1.5 g of cefuroxime (group A, n = 207) or 3 g of ampicillin-sulbactam (group B, n = 211) was administered during induction of anesthesia. Bile and gallbladder mucosal cultures were taken intraoperatively from all patients. Main Outcome Measure Number of postoperative surgical site infections. Results A postoperative surgical site infection was noted in 19 (4.5%) of 418 patients, 18 from group A and 1 from group B (P<.001). In the group that received cefuroxime, 15 (83.3%) of 18 surgical site infections were due to Enterococcus species. Intraoperative bactibilia as well as intraoperative gallbladder rupture were associated with surgical site infections (P<.001). Conclusions A single dose of ampicillin-sulbactam favored better compared with cefuroxime for prevention of postoperative surgical site infections due to Enterococcus species after elective cholecystectomy. Ampicillin-sulbactam may be a better agent for antimicrobial prophylaxis in high-risk patients undergoing elective cholecystectomy, especially in a setting where the incidence of enterococcal infections is higher. The use of antimicrobial agents as a means of preventing surgical site infections (SSIs) is still controversial in elective cholecystectomy. Many authors believe that antibiotic prophylaxis may not be necessary in low-risk patients undergoing elective cholecystectomy.1-4 On the contrary, other randomized controlled trials, as well as a large meta-analysis, found significantly reduced rates of SSI with prophylactic antimicrobials and strongly recommend the use of prophylactic antimicrobials in patients undergoing elective biliary tract surgery.5-11The bacteria most often implicated in SSI following a cholecystectomy include Escherichia coli, Klebsiella species, and Enterococcus species4,12-16 Cefazolin as well as other cephalosporins, such as cefuroxime, have been used for prophylaxis in biliary surgery. Despite the wide use of cephalosporins as prophylaxis in elective biliary surgery, they lack activity against Enterococcus species.17-19 Ampicillin-sulbactam, on the other hand, has a broader spectrum, including enterococci. Thus, a prospective randomized study was designed to compare the use of cefuroxime vs ampicillin-sulbactam as single-dose prophylaxis in elective cholecystectomy. The main hypothesis was that fewer postoperative infections would be observed. Methods A prospective randomized controlled study comparing the prophylactic use of cefuroxime vs ampicillin-sulbactam was performed from July 2002 to August 2004 in a major tertiary care hospital in the Athens, Greece, metropolitan area. All patients undergoing elective cholecystectomy for cholelithiasis, either open or laparoscopic, with no known allergy to any of the perioperatively administered study drugs were eligible. Exclusion criteria included emergency cholecystectomy, cholecystectomy performed as a part of any other major operation, and evidence of acute pancreatitis. Furthermore, patients with colostomy, known colonic diverticulosis or intestinal fistula, and inflammatory bowel disease were excluded from the study, because they have supersaturated bile and an increased risk of bactibilia, which would alter the results of the bile and gallbladder mucosal wall culture samples.20 Finally, patients having received antimicrobials 2 weeks prior to the operation (except patients who underwent endoscopic retrograde cholangiopancreatography and received prophylaxis) were excluded from the study. Using a random-number generator (STATS version 1.1, 1998 program; Decision-Analyst Inc, Arlington, Tex), patients were randomly assigned to the antibiotic prophylaxis regimen to receive either 1.5 g of cefuroxime (group A) or 3 g of ampicillin-sulbactam (group B) intravenously during induction of anesthesia. Concerning patients with diabetes mellitus, glycemic control was established by close monitoring and insulin drips, if appropriate, perioperatively. Bile, as well as mucosal wall from the gallbladder, was collected for culture from all subjects during the operation. Data on the duration of surgery, intraoperative rupture of the gallbladder, and American Society of Anesthesiologists (ASA) score21,22 were carefully recorded. Patients were considered high risk if they had an ASA score higher than 1, if obesity (body mass index>30 [calculated as weight in kilograms divided by height in meters squared]) or diabetes were present, and if acute cholecystitis or obstructive jaundice were diagnosed recently (within the last 2 months). The patients were under weekly clinical and laboratory postoperative monitoring for SSI during a 30-day period. All of them were reminded of the appointment via telephone, and a structured clinical protocol was used. Postoperative superficial or deep incisional soft tissue SSI and intra-abdominal abscess were defined according to published criteria.23 Presence of fluid collection with local signs of inflammation with or without fever, with or without leukocytosis, and with negative culture results was defined as a sterile wound collection. Bactibilia was defined as any positive result of bile and/or gallbladder mucosal wall cultures. The study was approved by the ethics committee of the hospital. All patients participating in the study signed an informed written consent. Data are reported as mean (SD), rates, or odds ratio (OR) with 95% confidence interval (CI). We used a paired-sample t test for normally distributed data and a Wilcoxon signed rank test otherwise. Baseline characteristics were compared between the 2 groups for each of the study medications using nonparametric, independent-sample tests (Kruskal-Wallis and Wilcoxon rank) for continuous data and χ2 Fisher exact tests for categorical data. Relationships between surgical risk, specific coexisting diseases, ASA score, and antimicrobials administered intraoperatively; type and duration of operation; iatrogenic gallbladder perforation; bactibilia; and postoperative SSI were examined between the 2 groups. Backward stepwise logistic regression analysis was then conducted to determine independent correlates of SSI. Variables with P<.10 in the univariate analysis were considered for inclusion in the multivariate analysis. Significance was set at P<.05. It was estimated that for an expected reduction from 6% to 0.6% between patients exposed and unexposed to ampicillin-sulbactam, a power of 80%, and a 2-tailed α of .05, 206 patients would be required for each arm of the study. All statistical tests used were 2-sided. SPSS version 10.0 for Windows software (SPSS, Inc, Chicago, Ill) was used for data analysis. Results The main characteristics of the patients who participated in the study with respect to the prophylaxis group assigned are presented in Table 1. In total, 549 patients were evaluated and 418 patients were eligible and entered the protocol (Figure 1). The reasons for exclusion were emergency cholecystectomy (n = 44); patients who received antimicrobials 2 weeks prior to the operation, mainly because of cholecystitis (n = 37); cholecystectomy performed as a part of any other major operation (n = 26); prior allergy to cefuroxime or ampicillin-sulbactam (n = 19); colostomy (n = 2); inflammatory bowel disease (n = 2); and colonic diverticulosis (n = 1). All 418 eligible patients underwent elective cholecystectomy for cholelithiasis: 228 (54.5%) with the conventional and 190 (45.5%) with the laparoscopic method. The mean (SD) age of the entire group was 56.6 (13.7) years, 161 (38.5%) of 418 were male, and 217 (51.9%) were deemed high-risk patients (Table 1). High-risk cases were homogeneously distributed between the 2 antimicrobial groups (P = .20). Examining the distribution of high-risk patients according to the procedure performed, it was found that 133 (58.3%) of 228 who underwent conventional cholecystectomy presented a high operative risk. Also, 84 (44.2%) of 190 who underwent laparoscopic cholecystectomy were deemed high risk (P<.01). The mean (SD) hospitalization was 6.7 (3.1) and 3 (0.7) days for conventional and laparoscopic cholecystectomy, respectively. Cefuroxime was administered to 207 (49.5% [ie, group A]) of 418 patients, and 211 (50.5%) of 418 patients received ampicillin-sulbactam (ie, group B). A schematic diagram of the main findings of the study is depicted in Figure 2. Two patients developed a sterile wound collection and were not included in the analysis. Overall, 19 (4.5%) of 418 patients developed an SSI in both prophylaxis groups. Infection developed in 18 of 207 patients from group A and 1 of 211 from group B (P<.001). More specifically, 17 (97.3%) of 19 patients developed a soft tissue SSI, and 2 (1.7%) of 19 had a postoperative subhepatic abscess. Enterococcus species was the predominant organism and it was isolated in 15 (78.9%) of 19 patients, while E coli and Klebsiella species followed. All 15 SSIs that were attributed to an Enterococcus species occurred in the cefuroxime prophylaxis group. Fifteen (78.9%) of 19 patients who developed SSI were high risk. The main coexisting disease was diabetes mellitus in 14 (93.3%) of 15. Operative candidates with any condition carrying a higher operative risk developed postoperative SSI significantly more often (P = .02). This increased risk for SSI was particularly seen in patients with diabetes (P<.001) and obesity (P<.01). None of the 49 patients with diabetes from the ampicillin-sulbactam group vs 14 (29.2%) of 48 from the cefuroxime group had an infection (P<.001). In an analysis using ASA score of 3 or higher, such a score was found in 81 of 207 patients in the cefuroxime group vs 73 of 211 patients in the ampicillin-sulbactam group (P = .36) and in 13 of 19 patients with an SSI (P = .006). The presence of obstructive jaundice or an episode of acute cholecystitis within 2 months prior to operation was not associated with the development of an SSI postoperatively (P = .20 and P = .60, respectively). In a multivariate model that included age, diabetes, surgical technique, and type of antibiotic used, the use of ampicillin-sulbactam was significantly associated with protection against infection (OR, 0.04 [95% CI, 0.006-0.336]; P = .003), whereas the presence of diabetes was a significant predictor for the development of infection (OR, 12.9 [95% CI, 3.9-42.8]; P<.001). The intraoperative culture samples showed a total of 192 positive results (either in the bile, the gallbladder mucosal wall, or in both) in 116 (27.8%) of 418 patients, mainly in the high-risk group (n = 77; P<.01). All 19 noted infections occurred in patients with bactibilia, while none occurred in patients without bactibilia (P<.001). Intraoperative bactibilia was strongly associated with the development of an enterococcal SSI (P<.001). More than 1 isolate was seen in 17 (14.7%) of 116 patients, 13 of whom were of high surgical risk. The patients with positive intraoperative culture results were equally spread between the 2 groups (P = .60) (Table 1). Enterococcus species was isolated in 46 (39.7%) of 116 patients having positive intraoperative culture results. Among the latter, 23 of 46 received cefuroxime (group A) as prophylaxis and 15 (65.2%) of these 23 went on to develop an enterococcal SSI, while 23 (50%) of 46 patients received ampicillin-sulbactam (group B) and none developed a postoperative SSI. Two isolates from patients with bactibilia were identified as Enterococcus faecium, and 1 of them was vancomycin resistant. Nevertheless, these isolates were not associated with an SSI. The microorganisms isolated from the bile and mucosal wall intraoperative cultures were exactly the same as the ones recovered from wound or pus cultures in all patients who developed SSI. Results of the study according to operative risk (high vs low), type of surgery performed, and development of SSI are presented in Figure 2. No statistical association between type of procedure performed and development of SSI was observed. As evident from Figure 2, open surgery was more frequently performed in high-risk patients compared with low-risk patients. In subgroup analyses, open surgery in high-risk patients who received cefuroxime was associated with development of an SSI (P = .01). Postoperative SSI after cefuroxime administration was found in 13 (72.2%) of 18 and 5 (27.7%) of 18 patients who underwent an open or a laparoscopic cholecystectomy, respectively. Among 190 patients who were operated on laparoscopically, 0 of 93 had an infection in the ampicillin-sulbactam group and 5 of 97, in the cefuroxime group. Three of these 5 patients had a soft tissue SSI and 2 of 5, a subhepatic abscess. The mean (SD) operative time in all patients was 45.3 (15.5) minutes. Patients who developed a postoperative SSI had a significantly longer duration of operation (mean [SD], 78.9 [25.9] vs 43.7 [12.8] minutes; P<.01). Concerning technical difficulties during surgery, 52 (12.4%) of 418 patients had intraoperative gallbladder rupture (19 [8.3%] of 228 open procedures vs 33 [17.4%] of 190 laparoscopic procedures), mainly due to intense inflammation and adhesions found at the time of surgery. Bactibilia was noted in 38 (73.1%) of 52 of these patients who also underwent a lengthy operation (mean [SD] duration, 71.6 [21.0] minutes). Intraoperative gallbladder rupture was strongly associated with development of SSI (P<.001). Surgical site infection occurred in 16 (31%) of 52 who had a gallbladder rupture and in 3 (1%) of 366 without rupture (P<.001). In 11 (78.6%) of 14 patients who underwent the open procedure and developed SSI (Figure 2), intraoperative gallbladder rupture was noted. Nine of the latter 11 were high-risk patients. On the other hand, all patients who underwent a laparoscopic procedure and developed a postoperative SSI had intraoperative gallbladder rupture. Infection was treated in all patients by surgical debridement and pus drainage. Patients received antimicrobials according to the antibiotic susceptibility testing performed on pus culture either from the wound or the abscess. Apart from Enterococcus species, other bacteria isolated from the SSI sites included E coli, Klebsiella species, and Enterobacter cloacae (Table 2). All enterococcal isolates grown from cultures that were taken from the site of the SSI were susceptible to ampicillin-sulbactam. Both subhepatic abscesses grew Enterococcus species. Abscess was treated with reoperation, complete evacuation of the intra-abdominal purulence, drainage, and administration of antibiotics. No antibiotics were administered postoperatively in any of the other patients in the study. No postoperative death occurred. Comment The main goal of this study was to present the benefits of using ampicillin-sulbactam instead of cefuroxime as chemoprophylaxis within an elective cholecystectomy setting. As evident from the results, ampicillin-sulbactam prophylaxis fared better compared with cefuroxime for the prevention of SSI after elective cholecystectomy. Not only did the vast majority of infections occur in the cefuroxime group, but also the main pathogen involved was Enterococcus species, which is not covered by cefuroxime or any other cephalosporin. On the contrary, ampicillin-sulbactam is effective against enterococci—especially Enterococcus faecalis—as well as against other common aerobic gram-negative rods that colonize bile.24,25Enterococcus species are among the most common bacteria isolated in the bile of patients who undergo cholecystectomy for cholelithiasis along with E coli and Klebsiella species.26 On the other hand, no significant difference was found between the 2 groups for other pathogens. This may indicate similar efficacy of these 2 regimens concerning nonenterococcal pathogens. We were not able to find any similar randomized study analyzing in a systematic fashion the effect of an appropriate prophylactic regimen against enterococci in the development of SSI after elective cholecystectomy. A study that assessed cefazolin sodium vs piperacillin in open cholecystectomy found a better in vitro activity of piperacillin in comparison with cefazolin against bacterial isolates recovered from bile cultures.27 However, only 5 of 34 isolates from biliary cultures were identified as enterococci, and only 1 mixed infection with Enterococcus species and 3 other gram-negative pathogens were observed in the piperacillin group.27 One other study of 80 patients found equal efficacy between ampicillin-sulbactam and cefoxitin sodium as prophylaxis in biliary surgery.28 Our results contradict those of a small study that compared the use of 3 instead of 1 perioperative doses of amoxicillin–clavulanate potassium (a combination similar to the one used in the present study) to 1 dose of ceftibuten and found more infections in the group that received amoxicillin–clavulanate potassium.29 Another study that looked at 205 patients with upper abdominal surgery (including biliary operations) found no statistical differences in wound infections between amoxicillin–clavulanate potassium and cefotaxime sodium, a third-generation cephalosporin. Nevertheless, this study may have been underpowered since fewer wound infections occurred in the amoxicillin–clavulanate potassium group (4.5% vs 7.4%).30 The discovery of bactibilia in the present study was associated with subsequent development of SSI. When SSI occurred, it was caused mainly by exactly the same pathogen(s) found in intraoperative cultures. This is an issue for further research as our findings concur with previous findings10,24 but exactly the opposite has been reported by others.31 Bactibilia was noted in a significant fraction of the patient population, mainly in those with a high risk for infection. A large percentage of patients had positive intraoperative culture results for Enterococcus species. This finding confirms the role of enterococci on biliary tract infections and provides further rationale for administering antimicrobials with antienterococcal activity in cholecystectomies.12-16,32Enterococcus faecium, a species that frequently exhibits resistance to β-lactams, was very rarely isolated in our series and was not associated with any SSI. Contaminated bile can lead to pyogenic fluid collection if the gallbladder ruptures during the operation. Survival depends on the ultimate management of such a collection.33,34 Perforation during gallbladder surgery is attributed to traction, grasping, dissection, and removal of the gallbladder and occurs in 10% to 15% of conventional and 15% to 25% of laparoscopic cholecystectomies.34,35 The vast majority of SSI occurred in patients who experienced intraoperative gallbladder rupture. The rest occurred in high-risk patients with diabetes mellitus. This is likely not attributed to poor surgical technique, since it was exclusively noted in patients who received cefuroxime. On top of appropriate surgical technique, perioperative prophylactic antimicrobials seem to play a significant role, and if administered, fewer SSIs occur.11 In contrast, some authors support that the incidence of SSI is not altered by gallbladder rupture, if thereafter a clean surgical technique is applied.35,36 Several studies performed so far examining antimicrobial prophylaxis in elective cholecystectomy have given conflicting results. Antibiotic prophylaxis may not be warranted in low-risk patients undergoing laparoscopic cholecystectomy.1-4 Nevertheless, large studies seem to suggest that neither laparoscopic nor open cholecystectomy should be performed without adequate perioperative antimicrobial prophylaxis.5-11 The role of prophylaxis may be more important in high-risk patients.1-4 Approximately half of the population that participated in the present study was classified as high risk and carried a higher risk for infection. Postoperative SSI in the majority occurred in such high-risk patients. The large percentage of high-risk patients included in the study facilitated documenting a differential effect of therapy and could have biased our results toward a beneficial effect of prophylaxis. On the other hand, both patients who developed a subhepatic abscess and required reoperation were of low operative risk, emphasizing that SSI may occur in low-risk patients too. The current study is strengthened by an unusually high percentage of follow-up. In fact, all patients were contacted about the follow-up appointment in the surgical department to avoid follow-up loss. During this conversation, the patients were specifically asked for symptoms or signs of SSI in order not to miss such an event. On the other hand, the study is limited by its lack of stratification of patients according to type of operation and risk at the beginning of the study and the high incidence of enterococci noted in this cohort. This could be attributed to (1) the large increase in the incidence of enterococcal infections in general (now the third most common cause for bacteremia in the United States),37 (2) a rising incidence of enterococcal infections in Greece, especially in the nosocomial setting,38-40 and (3) the fact that about a quarter of the patients underwent an open procedure and were high risk, and thus, they were more prone to colonization with enterococcus. The current results only confirm the protective role of ampicillin-sulbactam in a setting where there is a high prevalence of enterococcus. The biliary tract can serve as a “leverage-point” environment for such a study. However, in a prophylactic setting, the most important parameter may be the detailed knowledge regarding the microbiological characteristics of the area of concern and the institution's antibiogram. The use of prophylaxis should be based on these results. In addition, several other regimens containing agents with antienterococcal activity (eg, piperacillin-tazobactam) may provide similar results. The high rates of open procedures observed have to do with the individual surgeon's choices after obtaining the written informed consent of the patient. The procedure followed (ie, open or laparoscopic surgery) was the one that the participating surgeon chose and not one enforced by the research team. Nevertheless, it is exactly this population that would benefit the most from the prophylactic regimen proposed, especially if the incidence of enterococcal infections is higher. Moreover, we believe that the inclusion of open procedures is an additional strength of this article. In conclusion, evidence that ampicillin-sulbactam may be a better regimen than cefuroxime for antimicrobial prophylaxis during routine elective—either conventional or laparoscopic—cholecystectomy procedures is provided in a large randomized study. The need for antienterococcal activity in the prophylaxis regimens used in biliary surgery was unclear until now, and this is the major contribution of this effort. It is also evident that an uncomplicated operation with a good operative technique plays an important role in avoiding SSIs. Nevertheless, this is not always the case since intense inflammation and adhesions in the gallbladder's surgical site are not an unusual finding in such patients. Although competent surgeons may argue that prophylaxis is not necessary,41 no means have been yet devised to completely eliminate bacteria from the wound. While awaiting further studies that will confirm the presented results (a future study should stratify patients according to type of operation and risk), we believe that agents with, rather than agents without, antienterococcal activity—such as cephalosporins—may be a better choice for surgeons willing to use antimicrobial prophylaxis in elective cholecystectomy procedures. Correspondence: Athanasios Dervisoglou, MD, Second Department of Surgery, “Agios Panteleimon” State General Hospital, 79-81 Mpotasi St, 18537, Piraeus, Greece ([email protected]). Accepted for Publication: September 19, 2005. Author Contributions: Drs Dervisoglou and Tsiodras contributed equally to this work. Study concept and design: Dervisoglou, Tsiodras, Kanellakopoulou, and Giamarellou. Acquisition of data: Dervisoglou, Tsiodras, Pinis, Galanakis, Pierakakis, Giannakakis, Liveranou, Ntasiou, Karampali, and Iordanou. Analysis and interpretation of data: Dervisoglou and Tsiodras. Drafting of the manuscript: Dervisoglou, Tsiodras, Kanellakopoulou, Pinis, Galanakis, Pierakakis, Giannakakis, Liveranou, Ntasiou, Karampali, and Iordanou. Critical revision of the manuscript for important intellectual content: Dervisoglou, Tsiodras, and Giamarellou. Statistical analysis: Dervisoglou and Tsiodras. Administrative, technical, and material support: Dervisoglou, Tsiodras, Pinis, Galanakis, Pierakakis, Giannakakis, and Liveranou. Study supervision: Dervisoglou, Tsiodras, Kanellakopoulou, Pinis, Galanakis, and Giamarellou. Financial Disclosure: None reported. References 1. Catarci MMancini SGentileschi PCamplone CSileri PGrassi GB Antibiotic prophylaxis in elective laparoscopic cholecystectomy: lack of need or lack of evidence? Surg Endosc 2004;18638- 641PubMedGoogle ScholarCrossref 2. Koc MZulfikaroglu BKece COzalp N A prospective randomized study of prophylactic antibiotics in elective laparoscopic cholecystectomy. Surg Endosc 2003;171716- 1718PubMedGoogle ScholarCrossref 3. Dobay KJFreier DTAlbear P The absent role of prophylactic antibiotics in low-risk patients undergoing laparoscopic cholecystectomy. Am Surg 1999;65226- 228PubMedGoogle Scholar 4. Cainzos MPotel JPuente JL Prospective randomized controlled study of prophylaxis with cefamandole in high risk patients undergoing operations upon the biliary tract. Surg Gynecol Obstet 1985;16027- 32PubMedGoogle Scholar 5. Meijer WSSchmitz PIJeekel J Meta-analysis of randomized, controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg 1990;77283- 290PubMedGoogle ScholarCrossref 6. Stone HHHooper CAKolb LDGeheber CEDawkins EJ Antibiotic prophylaxis in gastric, biliary and colonic surgery. Ann Surg 1976;184443- 452PubMedGoogle ScholarCrossref 7. Harnoss BMHirner ADibbelt HHaring RRodloff RLode H Perioperative antibiotic prophylaxis in bile-duct interventions. Chemotherapy 1987;33297- 301PubMedGoogle ScholarCrossref 8. Kaufman ZEngelberg MEliashiv AReiss R Systemic prophylactic antibiotics in elective biliary surgery. Arch Surg 1984;1191002- 1004PubMedGoogle ScholarCrossref 9. Sykes DBasu PK Prophylactic use of cefotaxime in elective biliary surgery. J Antimicrob Chemother 1984;14 ((suppl B)) 237- 239PubMedGoogle ScholarCrossref 10. Lewis RTAllan CMGoodall RG et al. A single preoperative dose of cefazolin prevents postoperative sepsis in high-risk biliary surgery. Can J Surg 1984;2744- 47PubMedGoogle Scholar 11. Lippert HGastinger J Antimicrobial prophylaxis in laparoscopic and conventional cholecystectomy. Chemotherapy 1998;44355- 363PubMedGoogle ScholarCrossref 12. Grant MDJones RCWilson SE et al. Single dose cephalosporin prophylaxis in high-risk patients undergoing surgical treatment of the biliary tract. Surg Gynecol Obstet 1992;174347- 354PubMedGoogle Scholar 13. Wilson SEHopkins JAWilliams RA A comparison of cefotaxime versus cefamandole in prophylaxis for surgical treatment of the biliary tract. Surg Gynecol Obstet 1987;164207- 212PubMedGoogle Scholar 14. American Society of Health-System Pharmacists, Therapeutic guidelines on antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 1999;561839- 1888PubMedGoogle Scholar 15. Rahman MHAnson J Peri-operative antibacterial prophylaxis. The Pharmaceutical Journal 2004;272743- 745http://www.pjonline.com/pdf/cpd/pj_20040612_perioperative04.pdf. Accessed August 8, 2005Google Scholar 16. Antimicrobial prophylaxis for surgery. Med Lett Drugs Ther 2004;227- 32Google Scholar 17. AMA Drug Evaluations. Chicago, Ill American Medical Association1995;1413- 1480 18. Dancer SJ The problem with cephalosporins. J Antimicrob Chemother 2001;48463- 478PubMedGoogle ScholarCrossref 19. Powell LLWilson SE The role of beta-lactam antimicrobials as single agents in treatment of intra-abdominal infection. Surg Infect (Larchmt) 2000;157- 63PubMedGoogle ScholarCrossref 20. Pereira SPBain IMKumar DDowling RH Bile composition in inflammatory bowel disease. Aliment Pharmacol Ther 2003;17923- 933PubMedGoogle ScholarCrossref 21. Klotz HPCandinas DPlatz A et al. Preoperative risk assessment in elective general surgery. Br J Surg 1996;831788- 1791PubMedGoogle ScholarCrossref 22. Sidi ALobato EBCohen JA The American Society of Anesthesiologists' physical status: category V revisited. J Clin Anesth 2000;12328- 334PubMedGoogle ScholarCrossref 23. Mangram AJHoran TCPearson MLSilver LCJarvis WR Guideline for prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol 1999;20250- 278PubMedGoogle ScholarCrossref 24. Edwards GFLindsay GTaylor EW A bacteriological assessment of ampicillin with sulbactam as antibiotic prophylaxis in patients undergoing biliary tract operations. J Hosp Infect 1990;16249- 255PubMedGoogle ScholarCrossref 25. Bush LMCalmon JJohnson CC Newer penicillins and beta-lactamase inhibitors. Infect Dis Clin North Am 1995;9653- 686PubMedGoogle Scholar 26. Brook I Aerobic and anaerobic microbiology of biliary tract disease. J Clin Microbiol 1989;272373- 2375PubMedGoogle Scholar 27. Krajden SYaman MFuksa M et al. Piperacillin versus cefazolin given perioperatively to high-risk patients who undergo open cholecystectomy: a double-blind, randomized trial. Can J Surg 1993;36245- 250PubMedGoogle Scholar 28. Wittmann DHKoltowski POleszkiewicz JWalker AP Infectious complications after 809 biliary tract operations and results of a prospective randomized single-blind study comparing cefoxitin versus ampicillin plus an inhibitor of beta-lactamases. Infection 1990;1841- 47PubMedGoogle ScholarCrossref 29. Orozco HSifuentes-Osornio JChan C et al. Comparison of ceftibuten vs. amoxicillin/clavulanic acid as antibiotic prophylaxis in cholecystectomy and/or biliary tract surgery. J Gastrointest Surg 2000;4606- 610PubMedGoogle ScholarCrossref 30. Tonelli FMazzei TNovelli AMazzoni PFicari FItalian Cooperative Group, Amoxicillin/clavulanic acid versus cefotaxime for antimicrobial prophylaxis in abdominal surgery: a randomized trial. J Chemother 2002;14366- 372PubMedGoogle ScholarCrossref 31. Willis RGLawson WCHoare EMKingston RDSykes PA Are bile bacteria relevant to septic complications following biliary surgery? Br J Surg 1984;71845- 849PubMedGoogle ScholarCrossref 32. Sheen-Chen SChen WEng H et al. Bacteriology and antimicrobial choice in hepatolithiasis. Am J Infect Control 2000;28298- 301PubMedGoogle ScholarCrossref 33. Carlin CBKent RB JrLaws HL Spilled gallstones complications of abdominal wall abscesses. Surg Endosc 1995;9341- 343PubMedGoogle ScholarCrossref 34. Karan JARoslyn JJ Cholelithiasis and cholecystectomy. Zinner MJSchwartz SIEllis Heds Maingot's Abdominal Operations. Vol 210th ed. Stamford, Conn Appleton & Lange1997;1717- 1738Google Scholar 35. Kimura TGoto HTakeuchi Y et al. Intra-abdominal contamination after gallbladder perforation during laparoscopic cholecystectomy and its complications. Surg Endosc 1996;10888- 891PubMedGoogle ScholarCrossref 36. Assaff YMatter ISabo E et al. Laparoscopic cholecystectomy for acute cholecystitis and the consequences of gallbladder perforation, bile spillage, and “loss” of stones. Eur J Surg 1998;164425- 431PubMedGoogle ScholarCrossref 37. Wisplinghoff HBischoff TTallent SM et al. Nosocomial bloodstream infections in US hospitals. Clin Infect Dis 2004;39309- 317PubMedGoogle ScholarCrossref 38. Routsi CPlatsouka EPaniara O et al. Enterococcal infections in a Greek intensive care unit: a 5-y study. Scand J Infect Dis 2000;32275- 280PubMedGoogle ScholarCrossref 39. Christidou AGikas AScoulica E et al. Emergence of vancomycin-resistance enterococci in a tertiary hospital in Crete, Greece: a cluster of cases and prevalence study on intestinal colonisation. Clin Microbiol Infect 2004;10999- 1005PubMedGoogle ScholarCrossref 40. Sofianou DPournaras SGiosi M et al. Substantially increased faecal carriage of vancomycin-resistance enterococci in a tertiary Greek hospital after a 4 year time interval. J Antimicrob Chemother 2004;54251- 254PubMedGoogle ScholarCrossref 41. Higgins ALondon JCharland S et al. Prophylactic antibiotics for elective laparoscopic cholecystectomy: are they necessary? Arch Surg 1999;134611- 613PubMedGoogle ScholarCrossref

Valverde, Alain;Msika, Simon;Kianmanesh, Reza;Hay, Jean-Marie;Couchard, Anne-Cécile;Flamant, Yves;Fingerhut, Abe;Fagniez, Pierre-Louis;Research, French Associations for Surgical

doi: 10.1001/archsurg.141.12.1168pmid:

Galandiuk, Susan

doi: 10.1001/archsurg.141.12.1175pmid: N/A

Mechanical bowel preparation before elective colorectal resection has been intensely debated for almost 50 years. Recent reports suggest that bowel preparation may be associated with more complications than if none is given.1-3 This concept is supported by observations made following primary closure of traumatic colon injuries.4,5 Why do surgeons give patients preoperative bowel preparation and study different types of bowel preparations (as presented herein6)? There are several reasons. The first is ease of bowel handling. Second, for safety with respect to electrocautery (eg, with large amounts of fecal matter and bacteria), substantial amounts of combustible gases may be present within the colon. Third, with stapled colorectal anastomoses, solid stool within the distal colon or rectum could interfere with transanal stapler insertion and firing. The elective at-home bowel preparation used today is a far cry from the in-hospital night-before-surgery bowel preparation used years ago. As the authors state, intraoperative spillage of liquid fecal matter is a problem, leading to efforts to find the ideal bowel preparation. The study by the French Associations for Surgical Research comparing povidone-iodine and sodium hypochlorite enemas slightly favors povidone-iodine, particularly in terms of tolerability. However, I surmise that US patients would not prefer the combined use of an oral laxative and 2-L enemas on successive days over a traditional oral preparation alone. The reader may then ask “What can I learn from this article?” The French Associations for Surgical Research have tried to identify safer practices in surgery and have for years systematically evaluated various surgical practices with respect to alimentary tract surgery.7,8 In the United States, the Surgical Care Improvement Project is a partnership of organizations also committed to improving the safety of surgery by reducing postoperative complications, with a goal by 2010 of a 25% reduction in surgical complications.9 It is likely that the forthcoming Surgical Care Improvement Project report will place several issues in clearer perspective regarding elective colon surgery.10 Colorectal resections are associated with significant morbidity, mortality, and cost in the Medicare population.11 As such, they remain a focal point for further studies of quality and safety in the transition toward pay for performance in the United States. Correspondence: Dr Galandiuk, Department of Surgery, University of Louisville School of Medicine, 550 S Jackson St, Louisville, KY 40292 ([email protected]). Financial Disclosure: None reported. References 1. Ram ERam ESherman Y et al. Is mechanical bowel preparation mandatory for elective colon surgery? a prospective randomized study. Arch Surg 2005;140285- 288PubMedGoogle ScholarCrossref 2. Bucher PMermillod BGervaz PMorel P Mechanical bowel preparation for elective colorectal surgery: a meta-analysis. Arch Surg 2004;1391359- 1364[notice of duplicate publication appears in Arch Surg. 2006;141:217]PubMedGoogle ScholarCrossref 3. Guenaga KFMatos DCastro AAAtallah ANWille-Jorgensen P Mechanical bowel preparation for elective colorectal surgery. Cochrane Database Syst Rev 2005; ((1)) CD001544PubMedGoogle Scholar 4. Demetriades DMurray JAChan L et al. Committee on Multicenter Clinical Trials. American Association for the Surgery of Trauma, Penetrating colon injuries requiring resection: diversion or primary anastomosis? an AAST prospective multicenter study. J Trauma 2001;50765- 775PubMedGoogle ScholarCrossref 5. Singer MANelson RL Primary repair of penetrating colon injuries: a systematic review. Dis Colon Rectum 2002;451579- 1587PubMedGoogle ScholarCrossref 6. Valverde AMsika SKianmanesh R et al. for the French Associations for Surgical Research, Povidone-iodine vs sodium hypochlorite enema for mechanical preparation before elective open colonic or rectal resection with primary anastomosis: a multicenter randomized controlled trial. Arch Surg 2006;1411168- 1175Google ScholarCrossref 7. Merad FYahchouchi EHay JMFingerhut ALaborde YLanglois-Zantain OFrench Associations for Surgical Research, Prophylactic abdominal drainage after elective colonic resection and suprapromontory anastomosis: a multicenter study controlled by randomization. Arch Surg 1998;133309- 314PubMedGoogle ScholarCrossref 8. Fingerhut AHay JMFrench Association for Surgical Research, Single-dose ceftriaxone, ornidazole, and povidone-iodine enema in elective left colectomy: a randomized multicenter controlled trial. Arch Surg 1993;128228- 232PubMedGoogle ScholarCrossref 9. Surgical Care Improvement Project (SCIP) project information,MedQIC Web site. http://www.medqic.org/scip/.Accessed September 7, 2006 10. Polk HCLewis JNGarrison RNVanVlack JPHouck PMHunt DR Process and outcome measures in specialty surgery: early steps in defining quality. Bull Am Coll Surg 2005;908- 15Google Scholar 11. Sung JWessel MGallagher SFMarcet JMurr MM Failure of Medicare health maintenance organizations to control the cost of colon resections in elderly patients. Arch Surg 2004;1391366- 1370PubMedGoogle ScholarCrossref

Grazi, Gian Luca

doi: 10.1001/archsurg.141.12.1176pmid: 17178959

Abstract Hypothesis The Internet has led to widespread Web consulting, the proportions of which are not yet known; there is not yet agreement on its management. Design We verified the typology and needs of people and patients of a single-language population inquiring about a homogeneous group of diseases treated in tertiary reference centers and their reason for writing. Data were extracted and coded from e-mail messages received over 27 months by a noninstitutional Web site devoted to surgically treatable hepatopancreatobiliary diseases. Consultation activity was verified by the number of answers and subsequent messages. Main Outcome Measures One thousand forty-seven users sent 1788 messages to one of the Web site addresses; 1179 (94.6%) of them inquired about clinical problems. Data were collected on the demographics of senders and patients, the nature of the clinical problem, and the reasons for the messages. Results A mean of 2.1 messages per day were received. Queries were sent by patients in 260 instances (22.1%) and by others in 750 (63.6%). Two hundred thirty-seven (20.1%) e-mails had medical enclosures. The presence of a malignant disease was reported in 705 messages (59.8%). Description of previously undertaken therapy was present in 613 cases (52.0%). An answer was given to 1177 first messages (94.4%) and a follow-up message was received from 401 users (34.1%). Second messages were characterized by a shorter time to receive an answer (mean, 2.5 ± 3.6 days vs 3.5 ± 5.3 days). Each user sent a mean number of 1.4 ± 0.7 messages (range, 1-8). Conclusions Web consulting is a powerful tool for patients and health professionals that emerged owing to physician communication problems. Nevertheless, the Internet is still pushing physicians toward a reconsideration of the principles of medical ethics and a reevaluation of rules and regulations to deal with these new communication methods. The increasingly easy access to the World Wide Web has led to an increased diffusion of health news over the Internet. One third of Europeans and 43% of Americans already use the Internet to get health information.1 Information can be shared by professional medical systems and physicians to advertise their activity, by groups of patients suffering from a common specific disease, and by individuals looking for treatment for themselves or for relatives. During the late 1990s, there was real enthusiasm for the introduction of e-mail as a vehicle of communication between patients and physicians.2 Internet use has been welcomed just as the use of regular mail and telephones was in the past.2,3 Besides the routine patient-provider communication,4,5 the sending of e-mails to an interactive health Web site raises the problem of unsolicited messages and Web consulting.6,7 We report on a large series of Internet-based consulting generated by a single surgical Web site that has been analyzed from a clinical point of view and found not to have a marketing-oriented purpose. The analysis takes into consideration the interaction of a single-language population for a homogeneous group of diseases routinely treated by the researchers (physicians working in a tertiary reference center).8-10 Data were collected on the demographics of senders and patients, the nature of the clinical problem, and the reasons for the messages, obtained without specific request and with full respect for the privacy of the people involved. Methods In February 2002, a Web site devoted to surgically treatable hepatopancreatobiliary diseases was created with the second-level domain name http://www.chirurgiadelfegato.it. The Web site is noninstitutional because it does not directly refer to any public or private institution even though most of the researchers are surgeons working at the University of Bologna (Bologna, Italy), a tertiary referring center for hepatopancreatobiliary diseases. At the time of writing, the Web site contained 26 pages, all written in Italian and revised by me. Since it was decided that a full report would be written on this activity, no other pages have been added; only the contents of those already published have been periodically reviewed. Contact page A contact page was used to allow people to send generic or specific questions. This page includes a form in which first name, surname, address, ZIP code, city, age, e-mail address (required field), and questions (free-text field) can be inserted. It is specified on this page that: . . . the question-submission service by e-mail is completely free. The service provides a physician's answer to questions sent by the users. The time interval between question and answer varies and depends on the number of questions received in the period, how many consumers ask similar questions and the importance of the question. The service is not a substitute for a medical consultation or for the opinion of a physician and it is not, in any way, a remote medical consultation. If a personalized opinion is expressed on the diagnosis, the therapy, or the interpretation of laboratory data, this answer has to be considered purely indicative, not binding, not substitutive or corrective of the opinion of the patient's own physician and given for informative purposes. It is always necessary for the patient to consult his/her own physician in the case of symptoms or illness. Answers provided As a general rule, the e-mail response given further emphasizes the relationship between the patient or his or her relatives and the physician in charge of the patient. The answer never contained elements that could jeopardize the relationship between the patients or their relatives, or the physicians caring for the patients. When appropriate, patients were always advised to have a new medical consultation with their own family practitioner or a further interview with the physicians who were in charge of those mentioned in the message. If patients were asking for a second opinion, they were informed of the existence of consensus conferences, guidelines, or strong evidence on a specific topic. When there was not enough information to formulate an opinion, the author of the message was invited to give further information or to address the same question to his or her family practitioner (in particular when the problem was the interpretation of symptoms or of laboratory tests), or to the physician in charge of the patient. Web site validation The contents of the Web site were submitted to the judgment of 2 different institutions. The first was the Health on the Net Foundation (HON), created in 1995, which is a nongovernmental organization under the aegis of the Direction Générale de la Santé Département de l'Action Sociale et de Santé (République et Canton de Genève, Switzerland). Health on the Net Foundation's mission is to guide laypersons or nonmedical users and medical practitioners to useful and reliable medical and health information on the Internet. Health on the Net Foundation reviewed the Web site and on April 2, 2002, released a certificate (HON code PIN number: HONConduct731628) confirming that it respects and pledges to honor the 8 principles of the HON Code of Conduct.11 The second institution was the local College of Physicians. In a communication dated November 10, 1999, the Italian College of Physicians stated that Internet publicity has to respect the dictates of law No. 175, as well as article 53 of the Medical Code of Ethics. For these reasons the entire contents of the Web site were submitted to the College of Physicians of Bologna, which expressed a positive opinion on its publication. Web site diffusion There were no efforts to promote the existence of the Web site through media or other electronic systems. The address was submitted to the main Italian and international search engines and is easily reachable by keyword searches. A few other Web sites decided to place a hyperlink to this Web site in their own pages. From March 2, 2002, to June 30, 2004, the home page was visited 40 648 times. At the end of the study period the entire Web site had an average of 451 visitors per day, with visitors reading an average of 1.54 pages per visit. Mail collection Users were given the possibility to send questions to the site Webmaster or to individual surgeons. No fees or personal data were asked of the visitors to gain access to the Web site. Providing personal data was absolutely optional, left to the discretion of the visitor, and handled in compliance with the Italian law on privacy (Italian Law No. 675 of December 31, 1996, titled, Protection of People and Other Subjects in the Handling of Personal Data). Message coding All queries were read on the same day they were received and an effort was made to give an answer in the shortest time possible. I then reviewed the messages for coding to reduce bias due to text misinterpretation. Duplicate or empty messages were discarded. The following characteristics were analyzed and recorded for the first message sent: date of the message; type of inquiry (generic vs clinical); sex, age, and domain extension of the sender; address to which the mail was sent; whether or not an answer was given; date of the answer; and total number and date of possible subsequent messages sent by the same person on the same topic. For messages with questions related to clinical situations, the following data were also recorded: sex, age, and degree of relationship to the patient; diseased organ (liver, biliary tract, or pancreas); type and subtype of the disease; kind of disease (benign vs malignant); presence of e-mail enclosures; main subject of the message (onset of symptoms, uncertainty in the diagnosis, therapy, or prognosis of the disease); approach to therapy (first opinion, second opinion, failure of a previous treatment, or general advice); therapy already followed or already proposed; and therapy under inquiry. In messages regarding patients with malignant disease, care was taken to identify any signs of advanced disease, if possible (peritoneal dissemination, vessel infiltration or thrombosis, or distant metastases). All the discharge or case history summaries, and laboratory, radiographs, or pathology reports that were added in any form to the e-mail message were treated as enclosures. All enclosures, together with the personal data included in the message, were treated in accordance with the Italian law on privacy. Statistical analysis Messages and answers were stored in the Netscape Communicator 4.51 mail client (Netscape Communications Corp, Mountain View, Calif) and processed with the SPSS statistical package (SPSS Base 11.0; SPSS Inc, Chicago, Ill) after coding. When some of the data could not be identified in the message they were treated as missing in the analysis. Results were expressed as mean ± SD and compared using the t test; χ2 analysis was performed to evaluate categorical variables. A P value less than .05 was considered statistically significant. Results Between March 11, 2002, and June 30, 2004 (842 days), a total of 1788 messages were received at one of the Web site addresses, giving a mean of 2.1 messages per day (Figure). Of these, 1247 were censored as first messages and they are the main subject of the study. The majority of the senders' e-mail addresses had the Italian extension (.it) in the address domain (1072 [86.0%]); 141 (11.3%) had.com, 14 (1.1%) had.net, 1 (0.1%) had.org, and the remaining 19 senders (1.5%) had a variety of domain names. Messages were sent directly to the personal addresses of the authors in 96 cases (7.7%). Table 1 reports the demographic information of the senders. The mean age of senders was significantly lower when the message came from the patient (38.6 ± 12.3 years vs 55.6 ± 17.5 years; P<.001). There was no difference in gender distribution whether or not the sender was the patient. Messages inquired about clinical problems in 1179 cases (94%) and about generic questions in 68 (5.4%). These 2 groups were considered separately when analyzing the main topic of the messages and together when evaluating global activity. Clinical questions Table 1 reports the main demographic characteristics of the patient mentioned in the message. In total, 488 (41.4%) messages dealt with parents' health problems. The mean age of senders was significantly lower when the message came from the patient (38.6 ± 12.3 years vs 55.6 ± 17.5 years; P<.001). There was no difference in gender distribution whether or not the sender was the patient. Two hundred thirty-seven queries (20.1%) had medical enclosures. There was no difference in the presence of enclosures by gender. Enclosures were present in messages from senders with an older mean age (41.5 ± 11.9 years vs 37.7 ± 12.2 years; P<.05) and when dealing with older patients (58.1 ± 15.0 years vs 55.0 ± 18.1 years; P<.05). Table 2 summarizes the organs and diseases that were the subject of inquiries. Patients wrote more frequently than others regarding symptoms (4.7% vs 2.7%; P<.05). Senders who were not the patients included enclosures more frequently than patients (14.8% vs 6.3%; P<.01), after the failure of a previous treatment (12.7% vs 1.2%; P<.001), and inquired more frequently about cancer (56.8% vs 3.3%; P<.001), diagnosis-related problems (8.5% vs 4.2%; P<.05), therapy-related problems (53.7% vs 11.1%; P<.001), and receiving a second opinion (27.9% vs 6.5%; P<.001). Nature of the disease Malignant disease was reported in 705 messages (59.8%), and a benign disease was reported in 466 cases (39.5%), while in 8 cases (0.7%) these data could not be determined. The mean age of senders who wrote for others did not differ according to the nature of the disease. On the contrary, the mean age of senders who wrote for themselves varied depending on the nature of the disease, with younger senders (aged 40.5 ± 12.7 years) dealing with benign diseases and older senders (aged 55.3 ± 12.9 years) with malignant diseases (P<.001). The mean age of the patients was higher in those inquiring about malignant diseases (63.4 ± 11.9 years vs 44.0 ± 18.1 years), without differences in who the sender was. The main topic of messages dealing with cancer was therapy (44.8% vs 15.4%; P<.001), and usually included asking for therapy solutions (45.5% vs 14.7%; P<.001). According to our criteria, of the 705 messages dealing with malignancies, 327 (46.4%) met criteria consistent with advanced disease and 108 (15.3%) were consistent with limited disease; the remaining 270 (38.3%) were not assessable. Messages reporting advanced malignancies more frequently included enclosures (12.1% vs 9.5%; P<.05). Treatment already followed Descriptions of previously undertaken therapy were included in 613 cases (52.0%). The most common was medical treatment in 166 cases (27.1%), chemotherapy in 146 (23.8%), hepatic resection in 78 (12.7%), operative endoscopy in 46 (7.5%), explorative laparotomy in 45 (7.3%), percutaneous ablation in 37 (6.0%), other surgery in 34 (5.5%), cadaveric liver transplantation in 32 (5.2%), transarterial chemoembolization in 25 (4.1%), and living-related liver transplantation in 4 (0.7%). Requested advice Table 1 summarizes the categorization of the main questions contained in the messages. Senders other than patients more frequently requested information for second opinions (27.9% vs 6.5%; P<.005), malignancies (23.1% vs 9.6%; P<.001), advanced diseases (20.7% vs 17.6%; P<.05), and therapy-related problems (28.2% vs 4.2%; P<.001). Treatment inquiries A total of 597 messages (50.6%) requested advice on specific therapies. Liver resection was the most frequent, with 269 messages (45%), followed by cadaveric liver transplantation in 133 (22.3%), medical treatment in 52 (8.7%), living-related liver transplantation in 41 (6.9%), chemotherapy in 25 (4.2%), percutaneous ablation therapy in 19 (3.2%), and other therapies in 58 (9.7%). Senders asked whether liver resection could be appropriate after the patient had undergone chemotherapy (10.3%), a previous resection (5.1%), medical therapy (4.2%), or after no prior treatment (17.5%). Inquiries were also made about cadaveric liver transplantation after medical therapy (8.8%), chemotherapy (2.9%), a previous transplant (2.5%), and after no prior treatment (4.4%). Consulting activity An answer was given to 1177 first messages (94.4%) and not given in 70 cases (5.6%). The mean time for an answer was 3.29 ± 5.0 days, ranging from 0 to 58 days (median, 2 days). Following an answer, a second message was received in 259 cases (22.0%). An acknowledgment message was received from 186 users (15.8%). As a total, 401 single users (34.1%) sent at least 1 further message. The second message was received 27.1 ± 64.6 days (range, 0-528 days) after the first and 22.7 ± 56.5 days (range, 0-412 days) after the answer was given. Second messages were characterized by a shorter response time (2.5 ± 3.6 days vs 3.5 ± 5.3 days; P<.005). This difference was not noted for acknowledgment messages. Second messages were sent more frequently by users who were not patients (27.9% vs 6.5%; P<.005), when dealing with malignant diseases (23.1% vs 9.6%; P<.05), and for therapy-related problems (28.2% vs 4.2%; P<.001). A third message was sent by 63 users (5.4%). The third message was received 88.0 ± 136.2 days (range, 2-648 days) after the first one and 68.7 ± 133.3 days (range, 0-647 days) after the second. In total, 1247 users sent 1788 messages, with a mean number of 1.4 ± 0.7 messages (minimum, 1; maximum, 8; median, 1). The design of the study and the absence of an institutional connection with the Web site prevented the evaluation of a possible increase in the volume of outpatient activity or in the number of surgical procedures. Comment There are several aspects of electronic communication that need to be considered by health professionals. The most common considerations are the rules for publication of Web sites, the use of e-mail as an instrument for the patient-physician relationship, and the management of unsolicited e-mail messages and Web consulting. Despite the widespread existence of these problems, very few reports are available in the scientific literature. Most of these have been published in highly specific journals, the vast majority of them coming from the United States. Only sporadic reports are from European countries.12-14 The only consistent forum appeared in 1998 in a single issue.2,3,12,15-18 For someone who is new to the Web it is difficult, if not impossible, to get an idea of how the medical community wants to present itself to the vast stage of Internet users. But while some guidelines have already been published for the first 2 topics,19,20 less information is currently available on the origin and the management of unsolicited mails. Table 3 summarizes the few reports already present in the literature. Most of the remaining reports based their data on postcounseling surveys.14,23 With 1788 messages received over 27 months, this is the most consistent series of consulting e-mails reported. It also offers the most accurate analysis of the users and the patients who asked for a Web opinion, because it investigates many aspects of those who ask for suggestions on their own health or the health of relatives. The data we present here can give rise to several analyses of the people who are consulting the Internet on health matters and on what they want. We have to stress that specific topics of the Web site are diseases that are not the subject of primary care but are usually treated by specialists of tertiary referring institutions.9 For these diseases, more than others, a correct referring system is fundamental. There is no doubt that one of the major causes at the root of this phenomenon is the presence or the persistence of difficult-to-treat diseases. More then half of the patients' mentioned in the received messages had already had at least 1 kind of treatment for their disease. Sixty percent of all the messages concerned neoplastic conditions and half of them reported features of already advanced diseases. The Internet is accessible and surfing on the Web and sending e-mail is a very easy way to try to find the most appropriate solution to a life-threatening situation; but what emerged from the repeated reading of our messages, when received and during coding, is that their true origin lies in a substantial lack of satisfactory communication between patients and their health providers. While this aspect could not be easily translated into categories, most of the patients who were the subject of our messages already had a diagnosis, an indication for therapy, or had already been treated for a disease (surgically in 24.1% of the cases and with chemotherapy in 23.8%). Senders were nevertheless still looking for greater clarification on the nature of their illness, for support or an alternative to the proposed therapy, or for further treatment in the case of failure. They do this very easily, without worries of any legal- or privacy-related considerations: one fifth of our first messages had clinical enclosures and this proportion increased when considering messages dealing with advanced malignant diseases. A large percentage of them were looking for more than a simple answer, because in 34.1% of the cases, a second, unrequested message was received. If perfect communication existed between patient and physician, there would not be any need for health searching over the Internet. Obviously, this is not the case. On one side, there is uncontrollable and fully justifiable search by the patients themselves or by their relatives for health problem solutions, even for irreversibly deteriorated clinical situations. This is not controllable or correctable by health professionals. On the other hand, our analysis revealed that the need for an answer from a physician very often remains unsatisfied, regardless of the kind of need.16 On several occasions the feeling was that the relationship between the patient or his or her relatives and the physician was unfinished and left hanging in the balance. Electronic messaging and Web consulting represent the obvious continuation of the relationship. It could be argued that our Web site received messages from highly sensitized people, representing a strict minority of cases; but the number of similar Web sites (with or without advertising; whether or not commercial or interactive) and newsgroups easily reachable through the most common search engines give an idea of the magnitude of the problem. Even our major newspaper has recently opened separate forums for major diseases, including those treatable only in tertiary referring centers.24 It is both inappropriate and beyond the scope of this article to put forward possible criticisms on the use of the Internet for health-related problems (Table 4). In fact, the use of e-mail was quickly welcomed when applied to medical communications,2 but the appearance and the continuous growth of unsolicited e-mails and Web-based inquiries should create new concerns for the medical community on the effectiveness of its communication with patients and on its own ability and capacity to interact with colleagues as a full and unique referring network. There are 2 main points physicians should consider when thinking about Web-based consulting: (1) the possible structural modification of the relationship between patient and primary physician (“Will I still trust my family doctor if I am able to find more appropriate or updated therapies for my disease from a Web consultation? Should I go to the physician suggested by my family doctor if I can have an e-mail consultation with one who appeals to me more?”)25 and (2) the chance that the decision of choosing a treating physician would be influenced more by the attractive appearance of a Web site or by the promptness in answering e-mail, as emerges from this study, in comparison with the appropriateness, the experience, and the skill of a named physician.26 What has changed in the 7 years since the first report on this phenomenon?21 The time that has passed is long for the Internet, but only a moment in terms of time for the medical communication system to change. Six years ago some hospitals and state agencies promoted the deletion of these messages.2 Is this still applicable? The further increase in patients consulting the Internet should encourage physicians to change their attitude.7 If this is not the case, patients will change providers; the Internet patient already makes this change on the basis of nonprofessional considerations.25 The medical community does not seem able to properly deal with the problem,7 nor to have the tools to effectively deal with it. Perhaps it is no accident that many of the articles on this subject are found in the unspecialized press instead of in major scientific journals.19 Even the HON code does not seem to represent a fully satisfactory tool. In this way, today the Internet is pushing us towards a reconsideration of the principles of medical ethics and a reevaluation of the rules and regulations.7 In conclusion, we have confirmed that Web consulting is a powerful tool for both patients and health professionals. Unfortunately the communication problems with the physicians themselves are the main reason why patients surf the Internet searching for the best consultations. In the last few years nothing has changed in medical practice to achieve a rational but also ethically correct management of the resources made available by the Internet. Correspondence: Gian Luca Grazi, MD, Liver and Multi Organ Transplant Unit, University of Bologna, Policlinico Sant’Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy ([email protected]). Accepted for Publication: October 4, 2005. Financial Disclosure: None reported. Acknowledgement: A particular thanks to my colleagues and friends Matteo Cescon, MD; Massimo Del Gaudio, MD; Giorgio Ercolani, MD; Andrea Gardini, MD; Matteo Ravaioli, MD; Giovanni Varotti, MD; and Gaetano Vetrone, MD. Without their support, encouragement, and help, but above all without their friendship, this Website would never have been founded and it would not have been able to aid the large number of patients that today visit in the search for a solution for themselves or for their relatives. References 1. Eaton L A third of Europeans and almost half of Americans use internet for health information. BMJ 2002;325989Google ScholarCrossref 2. Spielberg AR On call and online: sociohistorical, legal, and ethical implications of e-mail for the patient-physician relationship. JAMA 1998;2801353- 1359PubMedGoogle ScholarCrossref 3. Lindberg DAHumphreys BL Medicine and health on the Internet: the good, the bad, and the ugly. JAMA 1998;2801303- 1304PubMedGoogle ScholarCrossref 4. White CBMoyer CAStern DTKatz SJ A content analysis of e-mail communication between patients and their providers: patients get the message. J Am Med Inform Assoc 2004;11260- 267PubMedGoogle ScholarCrossref 5. Liederman EMMorefield CS Web messaging: a new tool for patient-physician communication. J Am Med Inform Assoc 2003;10260- 270PubMedGoogle ScholarCrossref 6. Huntley AC The need to know: patients, e-mail and the internet. Arch Dermatol 1999;135198- 199PubMedGoogle ScholarCrossref 7. Collste G The internet doctor and medical ethics: ethical implications of the introduction of the internet into medical encounters. Med Health Care Philos 2002;5121- 125PubMedGoogle ScholarCrossref 8. Grazi GLMazziotti AJovine E et al. Total vascular exclusion of the liver during hepatic surgery: selective use, extensive use, or abuse? Arch Surg 1997;1321104- 1109PubMedGoogle ScholarCrossref 9. Grazi GLErcolani GPierangeli F et al. Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value. Ann Surg 2001;23471- 78PubMedGoogle ScholarCrossref 10. Grazi GLCescon MRavaioli M et al. Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics: evaluation of clinicopathologic features and comparison of risk factors for long-term survival and tumour recurrence in a single centre. Aliment Pharmacol Ther 2003;17 ((suppl 2)) 119- 129PubMedGoogle ScholarCrossref 11. HON Code of Conduct (HONcode) for medical and health web sites. http://www.hon.ch/HONcode/Conduct.html. Accessed September 6, 2004 12. Eysenbach GDiepgen TL Responses to unsolicited patient e-mail requests for medical advice on the World Wide Web. JAMA 1998;2801333- 1335PubMedGoogle ScholarCrossref 13. Labiris GCoertzen IKatsikas A et al. An eight-year study of internet-based remote medical counselling. J Telemed Telecare 2002;8222- 225PubMedGoogle ScholarCrossref 14. Umefjord GPetersson GHamberg K Reasons for consulting a doctor on the Internet: survey of users of an ask the doctor service. J Med Internet Res 2003;5e26PubMedGoogle ScholarCrossref 15. Goggins MLietman AMiller RE et al. Use and benefits of a web site for pancreatic cancer. JAMA 1998;2801309- 1310PubMedGoogle ScholarCrossref 16. Borowitz SMWyatt JC The origin, content, and workload of e-mail consultations. JAMA 1998;2801321- 1324PubMedGoogle ScholarCrossref 17. Ferguson T Digital doctoring—opportunities and challenges in electronic patient-physician communication. JAMA 1998;2801361- 1362PubMedGoogle ScholarCrossref 18. Hubbs PRRindfleisch TCGodin P et al. Medical information on the Internet. JAMA 1998;2801363PubMedGoogle ScholarCrossref 19. Bovi AMCouncil on Ethical and Judicial Affairs of the American Medical Association, Use of health-related online sites. Am J Bioeth 2003;3W- IF3PubMedGoogle Scholar 20. Kane BSands DZAMIA Internet Working Group, Task force on guidelines for the use of clinic-patient electronic mail. J Am Med Inform Assoc 1998;5104- 111PubMedGoogle ScholarCrossref 21. Widman LETong DA Requests for medical advice from patients and families to health care providers who publish on the World Wide Web. Arch Intern Med 1997;157209- 212PubMedGoogle ScholarCrossref 22. Shuyler KSKnight KM What are patients seeking when they turn to the Internet? Qualitative content analysis of questions asked by visitors to an orthopaedics Web site. J Med Internet Res 2003;5e24PubMedGoogle ScholarCrossref 23. O’Connor JBJohanson JF Use of the Web for medical information by a gastroenterology clinic population. JAMA 2000;2841962- 1964PubMedGoogle ScholarCrossref 24. Abdominal Tumor Forum.,http://www.corriere.it/corrforum/corriere/Intro?forumid=436. Accessed September 6, 2004 25. Ziebland SChapple ADumelow C et al. How the internet affects patients' experience of cancer: a qualitative study. BMJ 2004;328564- 569PubMedGoogle ScholarCrossref 26. Berland GKElliott MNMorales LS et al. Health information on the Internet: accessibility, quality, and readability in English and Spanish. JAMA 2001;2852612- 2621PubMedGoogle ScholarCrossref

Bold, Richard J.;Liederman, Eric

doi: 10.1001/archsurg.141.12.1182pmid: N/A

Access to electronic health information and communication is no longer a future anticipation of patients but a current expectation. In this issue, Grazi breaks new ground by reporting his observations of electronic communications to surgeons via a European Web site written in a non-English language (Italian), related specifically to a non–primary care topic, surgical hepatopancreatobiliary disease, and in which the physician recipients had no prior clinical relationship with the patients. Almost all reports to date in the scientific and lay press about e-mail and Web messaging between patients and providers have focused on primary care in the United States and on communication written in English. Remarkably, given the relative nonavailability of physician-patient electronic messaging in Europe, the Web site was visited 40 648 times over 27 months, and 1247 patients or proxies sent 1788 electronic messages. The senders' ages ranged, in years, from mid 30s (primarily for benign conditions) to the 60s (primarily for cancer).1-3 Surgeons who believe that their patients do not wish to communicate with them online would be well advised to read Grazi's article. While the author should be commended for offering and measuring electronic connectivity to Italian patients about surgical diseases—both firsts in the literature—their purely descriptive study raises more questions than it answers. No analysis is presented about what prompted patients to write, nor what happened after the e-mails. Were the patients and their proxies motivated, as the author concludes, by dissatisfaction with their physicians, or, perhaps, instead by a desire to increase their knowledge about the serious diseases affecting them? Did the patient return to the treating physician? Was therapy altered because of the Web-based communication? Would traffic volume or outcomes differ if a fee had been charged? Additional far-reaching concerns for the practicing surgeon include the ease and rapidity with which patients and/or family members will provide private health-related information, the apparent need for second opinions and clarification of treatment or disease-related outcomes, and the frequency with which users access Web-based resources. Although many uncertainties remain about Web-based consulting, electronic communication, and Internet-based information, surgeons should consider offering this mode of communication to their patients, and respond when they use it. Correspondence: Dr Bold, Division of Surgical Oncology, Suite 3010, UC Davis Cancer Center, 4501 X St, Sacramento, CA 95817 ([email protected]). References 1. Houston TKSands DZJenckes MWFord DE Experiences of patients who were early adopters of electronic communication with their physician: satisfaction, benefits, and concerns. Am J Manag Care 2004;10601- 608PubMedGoogle Scholar 2. Hassol AWalker JMKidder D et al. Patient experiences and attitudes about access to a patient electronic health care record and linked web messaging. J Am Med Inform Assoc 2004;11505- 513PubMedGoogle ScholarCrossref 3. Liederman EMLee JCBaquero VHSeites PG Patient-physician web messaging: the impact on message volume and satisfaction. J Gen Intern Med 2005;2052- 57PubMedGoogle ScholarCrossref

Tien, Homer C. N.;Tremblay, Lorraine N.;Rizoli, Sandro B.;Gelberg, Jacob;Chughtai, Talat;Tikuisis, Peter;Shek, Pang;Brenneman, Frederick D.

doi: 10.1001/archsurg.141.12.1185pmid: 17178960

Abstract Hypothesis Admission blood alcohol concentration (BAC) is associated with in-hospital death in patients with severe brain injury from blunt head trauma. Design Retrospective cohort study. Setting Academic level I trauma center in Toronto, Ontario. Patients Using trauma registry data, between January 1, 1988, and December 31, 2003, we identified 1158 consecutive patients with severe brain injury from blunt head trauma. Intervention There was no active intervention. The primary exposure of interest was the BAC at admission, stratified into the following 3 levels: 0, no BAC; 0 to less than 230 mg/dL, low to moderate BAC; and 230 mg/dL or greater, high BAC. Main Outcome Measure In-hospital death. Results In patients with severe brain injury, low to moderate BAC was associated with lower mortality than was no BAC (27.9% vs 36.3%; P = .008). High BAC was associated with higher mortality than was no BAC (44.7% vs 36.3%), although this was not statistically significant (P = .10). These associations were all statistically significant after adjusting for demographic data and injury factors using logistic regression analysis. The odds ratio for death was 0.76 (95% confidence interval, 0.52-0.98) for low to moderate BAC compared with no BAC. The odds ratio for death was 1.73 (95% confidence interval, 1.05-2.84) for high BAC compared with no BAC. Conclusions Low to moderate BAC may be beneficial in patients with severe brain injury from blunt head trauma. In contrast, high BAC seems to have a deleterious effect on in-hospital death in these patients, which may be related to its detrimental hemodynamic and physiologic effects. Alcohol-based fluids may have a role in the management of patients with severe brain injury after they have been well resuscitated. Traumatic brain injury (TBI) from blunt head trauma is a leading cause of death and disability in young adults.1 The pathophysiology of TBI is such that not all neurologic damage occurs immediately but evolves with time.2 This secondary brain injury results from ongoing ischemia and contributes to the overall mortality of TBI. Reducing secondary brain injury is the basis of the medical management of TBI.2 Alcohol is a major risk factor for injury; 30% to 50% of all patients hospitalized with trauma are intoxicated at the time of injury.3 Even so, the effect of alcohol on TBI outcomes is still controversial. Many animal studies have reported negative effects of alcohol on TBI outcomes.4-8 Other studies, however, have reported no effect on TBI outcomes9 or have even suggested that alcohol may be neuroprotective.10-17 Similarly, clinical studies have reported conflicting results. Some of the controversy may be the result of heterogeneous study objectives. For example, some investigators were challenging the anecdotal belief that alcohol relaxes victims, thereby resulting in less severe injuries. Therefore, they compared Injury Severity Scores (ISS) and mortality between drivers with blood alcohol concentration (BAC) greater than 0 and those with BAC of 0. Alcohol use was associated with more severe injuries and, therefore, higher mortality.18-20 Waller et al21 controlled for injury severity by using vehicle deformation as a surrogate and found that alcohol was still associated with an increased likelihood of death. Other investigators focused on the public health implications of alcohol intoxication and looked for differences in outcome between legally intoxicated vs nonintoxicated patients (BAC <100 mg/dL or ≥100 mg/dL). In these studies, intoxication was associated with either worse outcome22 or no difference in outcome.23-27 Only 2 studies have reported that alcohol was associated with improved trauma outcomes. Both sets of investigators found that an admission BAC greater than 0 was associated with reduced trauma-related mortality compared with BAC of 0, given injuries of equal severity.28,29 Ward et al28 concluded that alcohol may have some pharmacologic effect in the postinjury period that reduced mortality. The objective of our study was to determine whether admission BAC is associated with in-hospital death in patients with severe TBI after blunt head trauma, given injuries of equal severity. Methods The trauma registry at Sunnybrook and Women's College Health Sciences Centre, an urban level I trauma center in Toronto, Ontario, was used to identify all trauma patients evaluated between January 1, 1988, and December 31, 2003 (16 years). Adult patients (age, 15-90 years) with a blunt mechanism of injury and who arrived directly from the scene of injury were selected for further analysis. Patients who were referred from other hospitals or who had sustained any penetrating injury or burns were excluded. Patient demographic data, injury mechanism, ISS, abbreviated ISS (AIS), length of hospital stay (days), intensive care unit stay (days), total units of blood transfused, and in-hospital outcome (death or survival) were determined from our trauma registry. The ISS and AIS were calculated by trauma registry staff after discharge or death in each patient. Patients with severe traumatic brain injury: study group Our study group of patients with severe TBI was selected by identifying all patients with an AIS score of 4 or 5 for the head and neck region. Patients with severe torso injury: tracer condition We identified severe torso injury, with no or mild head injury, as a tracer condition. This group included all patients with AIS-chest or AIS-abdomen scores of 4 or 5 who also had AIS–head and neck score of 3 or less. Independent variable: admission bac Our trauma registry includes the BAC in each patient at arrival at our trauma center. A histogram was constructed for mortality vs increasing BAC to look for a possible dose effect in patients with severe TBI (Figure). Patients were observed to have lower mortality when BAC was less than 230 mg/dL and higher mortality when BAC was 230 mg/dL or greater. Survival, therefore, was analyzed at 3 BAC levels: 0 mg/dL, no BAC; less than 230 mg/dL, low to moderate BAC; and 230 mg/dL or greater, high BAC. Outcome measure The primary outcome was defined as in-hospital death in the study group of patients with severe TBI. We also analyzed mortality in patients with the tracer condition of severe torso injury to determine whether there was a lack of difference. No difference would be expected, given the hypothesized neuroprotective effects of alcohol. Statistical analysis We compared in-hospital mortality in patients with severe TBI whose blood tests at admission demonstrated no, low to moderate, and high BAC, using the χ2 test and, where appropriate, the Fisher exact test. In addition, we constructed a multivariate model by subjecting baseline demographic and injury factors to stepwise logistic regression analysis and, thereby, obtained an adjusted comparison of risk of death in patients whose blood tests at admission demonstrated no, low, and high BAC. We checked for main effects for all covariates and then analyzed for interactions. The same analysis was performed in patients with the tracer condition of severe torso injury, with mild or no head injury, to determine whether there was a lack of difference. All P values are 2-tailed and adjusted for multiple comparisons using the Bonferroni method, where applicable. Means and odds ratios were reported with 95% confidence intervals, and all data were analyzed using SAS software (version 8.02; SAS Institute Inc, Cary, NC). Results During the 16-year study period, 12 105 patients were evaluated at our trauma service. Of these, 4099 patients were adults (age, 15-90 years) with blunt trauma who arrived directly from the scene of injury. The BAC from the initial trauma room blood tests was reported as unknown in 424 patients (10.3%), and they were excluded from subsequent analysis. Thus, 3675 patients met the inclusion criteria and had a known BAC. Patients with unknown BAC were older than those with known BAC (mean age, 44.4 vs 41.1 years) and had a shorter length of hospital stay (15.8 vs 19.6 days). Also, those with unknown BAC had higher mortality than those with known BAC (31.4% vs 14.2%). A higher percentage of deaths occurred in the trauma room in patients with unknown BAC compared with those with known BAC (48.5% vs 12.6%). Of the 3675 patients who met inclusion criteria and had a known BAC, 1158 patients were identified as having severe TBI and 528 patients were classified as having severe torso injuries with only mild or no head injuries. Baseline characteristics of the study group are given in Table 1. Admission blood tests in the 1158 patients demonstrated that 740 (63.9%) had no BAC, 315 (27.2%) had low to moderate BAC, and 103 (8.9%) had high BAC. Patients with BAC greater than 0 were more likely male and younger compared with patients with BAC of 0. Male patients were more likely to have a higher BAC compared with female patients. No obvious differences were apparent in ISS, blood transfusion requirements, or length of hospital stay. Similarly, in the group with severe torso injury, patients with a BAC greater than 0 were more likely to be male and younger compared with patients with a BAC of 0. Otherwise, ISS, transfusion requirements, and length of hospital stay were similar for patients with a BAC greater than 0 and a BAC of 0. Baseline characteristics in patients with the tracer condition are given in Table 2. In patients with severe TBI, the overall risk of dying in the hospital was significantly lower in patients with a low to moderate BAC compared with no BAC (27.9% vs 36.3%; P = .008). Patients with a high BAC had higher mortality compared with patients with no BAC; this finding bordered on being statistically significant (44.7% vs 36.3%; P = .10). There was also a trend suggesting that patients with a high BAC died earlier during their hospital stay than did patients with no BAC (Table 3). To gauge the robustness of this finding, we analyzed mortality in patients with the tracer condition. As expected, there were no significant differences in mortality between patients with a low BAC compared with no BAC (15.4% vs 14.9%; P = .90) and between patients with a high BAC compared with no BAC (13.0% vs 14.9%; P = 1.0). There still was a trend, however, suggesting that patients with a high BAC died earlier in their hospital stay compared with patients with no BAC (Table 4). We used logistic regression to create a multivariate model to control for underlying confounders. Variables were screened at P = .25 and were included in the final model if P<.05. Sex; age; ISS; units of transfused red blood cells; AIS-chest, AIS-abdomen, and AIS–head and neck; year of admission; and mechanism of injury (occupants of motorized vehicle vs other) were all used in the model. Except for sex, year of admission, and AIS-chest and AIS-abdomen, all of these variables had main effects that were found to be significant in patients with severe TBI (Table 5). Admission BAC was also found to be an independent predictor of death. A low to moderate BAC was associated with better survival than no BAC (odds ratio, 0.76; 95% confidence interval, 0.52-0.98), and a high BAC was associated with worse survival compared with no BAC (odds ratio, 1.73; 95% confidence interval, 1.05-2.84; Table 5). No interactions were found to have significant effects and were excluded from the final model. The final model was found to have good discriminatory power (receiver operating characteristic curve, 0.82) and adequate calibration (P = .15, Hosmer-Lemeshow goodness-of-fit test). We similarly constructed a multivariate model for our tracer condition using the same baseline characteristics as for our study group. Age, ISS, AIS-abdomen, units of blood transfused, and mechanism of injury were also found to have main effects that were significant predictors of death. Sex, date of admission, AIS-chest, and AIS–head and neck were not significant predictors. Also, as expected, low and high admission BAC were not significant predictors for death for our tracer condition (odds ratio, 1.6; 95% confidence interval, 0.82-3.03, and odds ratio, 2.02; 95% confidence interval, 0.48-8.51, respectively; Table 5). No interactions were found to be significant. The final model had good discriminatory power (receiver operating characteristic curve, 0.86) and adequate calibration (P = .60, Hosmer-Lemeshow goodness-of-fit test). Comment Alcohol use has been well established as the most important personal risk factor for fatal injuries, contributing to approximately one third of all deaths from injury.30 Intoxication increases the risk of all types of injury, including motor vehicle collisions, falls, assaults, and self-inflicted injuries, by impairing motor skills, reaction time, and judgment.31,32 Furthermore, acute alcohol use has been shown to be associated with more severe injuries in drivers,18-20 in part because intoxicated victims were not using safety devices such as seat belts or helmets at the time of injury.33,34 Although there is no disagreement about the negative effects of alcohol on the risk of injury and the likelihood of sustaining more severe injuries, the effects of alcohol on traumatic brain injury outcomes in the postinjury period is still controversial. Some investigators believe that alcohol is deleterious in patients with TBI. Studies have shown that a high BAC can cause hypotension and apnea in animal models of TBI and unresuscitated hemorrhagic shock.4-6 Also, in canine models of TBI and shock, investigators have found that alcohol can increase susceptibility to hemorrhagic shock by eliminating the host homeostatic compensatory mechanisms of preserving cerebral oxygenation and perfusion.35,36 This failure of homeostasis may account for the observation by Luna et al37 that intoxicated motorcyclists with critical head injury had twice the mortality of nonintoxicated motorcyclists, even after controlling for helmet use and ISS. In contrast, Fabian and Proctor9 found that the physiologic consequences of alcohol intoxication do not affect TBI outcomes in a swine model if adequate resuscitation takes place. Similarly, Huth et al24 evaluated injured automobile drivers who were aggressively resuscitated in a trauma center and found that alcohol did not affect hospital course or outcome. Basic science investigators are also beginning to elucidate potential beneficial pharmacologic effects of alcohol if administered after injury has occurred. Specifically, experimental evidence shows that alcohol in low to moderate doses (<240 mg/dL) can reduce secondary brain injury.10-13 These neuroprotective effects seem to be mediated by alcohol's inhibition of N-methyl-D-aspartate receptor-mediated excitotoxicity. Mitigation of excitotoxicity can reduce secondary brain injury by attenuating the tendency of injured neurons to release neurotransmitters that cause further injury and death.14 This effect is analogous to an experimental finding in stroke research in which alcohol and caffeine were shown to reduce the volume of cerebral infarction.15-17 These neuroprotective effects were absent, however, at high doses of alcohol. We studied adult patients with trauma who had severe TBI from blunt head injury. We found that a low to moderate BAC at admission was associated with improved mortality when compared with no BAC. Patients with TBI with a high BAC had higher mortality compared with patients with no BAC. Furthermore, this effect was specific to head injury. Alcohol was not significantly associated with mortality in patients with our tracer condition of severe torso injury with no or mild head injuries. Our findings are consistent with both studies that suggest potential neuroprotective effects of alcohol in low to moderate concentrations and studies that suggest that alcohol detrimentally affects the host homeostatic compensatory response to shock. Our study was performed within a large, well-organized, urban trauma system. Therefore, the negative effects of alcohol may be overshadowed by its neuroprotective effects, especially in the context of short time to arrival at the hospital and aggressive resuscitation by emergency medical service staff before arrival at the hospital. At low and moderate doses (<240 mg/dL), alcohol was shown in animal studies to be neuroprotective10-13; in our study, BAC less than 230 mg/dL was likewise associated with a survival benefit, compared to BAC of 0. Increased mortality was observed in patients with severe TBI with a high BAC. It is presumed that, at such high doses, alcohol reduced the compensatory response to shock despite resuscitation. At high doses (>240 mg/dL), alcohol was shown in animal studies to be deleterious to neurologic outcomes.10-13 In our study, a BAC of 230 mg/dL or greater was shown to be associated with higher mortality than a BAC of 0. Also, there was a trend in both our study group and in our tracer group to suggest that patients with a high BAC were more likely to die earlier after trauma compared with patients with no BAC. This finding would be consistent with the experimental finding that high doses of alcohol can reduce the host ability to compensate for hemorrhagic shock.35,36 There are major sociologic implications from implying that intoxicated patients with severe TBI have better outcomes than nonintoxicated patients. We stress that our study only examined the role of alcohol on outcome in the postinjury phase because we examined only in-hospital deaths. Fifty percent of all trauma-related deaths occur in the prehospital setting.38,39 Alcohol-related deaths tend to be overrepresented in this subgroup of patients who die in the prehospital setting40 because alcohol use increases the likelihood of severe injury18,19 and impedes the body's ability to compensate for shock.35 Overall, people are still at much greater risk of dying if they drive while intoxicated. What our study implies is that there may be a role for an alcohol-based resuscitation fluid in improving outcomes in adequately resuscitated patients with severe head injury. Limitations Our study is not a randomized controlled study, and, therefore, the results may be exaggerated by confounders and biases. Approximately 10% of patients who met inclusion criteria had an unknown BAC, and these patients were systematically different from those with a known BAC. These patients were older and were much more likely to die in the trauma room than were those with a known BAC. Like patients who died in the prehospital setting, patients with an unknown BAC were probably more likely to have a BAC greater than 0.40 These patients were more likely to die in the trauma room because they were more severely injured and possibly because alcohol had detrimental effects on their homeostatic compensatory mechanisms. For patients with a known BAC, we attempted to adjust for known predictors of trauma-related death, such as age,41 sex,42 and ISS,43 in our multivariate model. We also adjusted for mechanism of injury in our final model. Alcohol may affect mortality in occupants of motorized vehicles in many ways apart from any pharmacologic effect in the postinjury period. Intoxicated drivers tend to drive faster and more recklessly31 than do nonintoxicated drivers, and do not use safety devices such as seat belts as often.33 We also adjusted for the year of admission. Our study included patients admitted during 16 years. Trauma care has improved during this time. Improvements in care may have preferentially benefited nondrinking drivers because increased public health efforts have resulted in fewer patients who were intoxicated while driving in more recent years than at the beginning of our study.44 Use of ais to define severe tbi We used AIS–head and neck score greater than 3 as our operational definition of severe TBI to avoid the selection bias of using a physiologic score (ie, Glasgow Coma Scale), which misclassifies intoxicated patients with mild TBI as having severe TBI.45 Using AIS–head and neck, however, has important limitations. One major problem is that AIS–head and neck is also dependent, though to a much smaller extent than the Glasgow Coma Scale, on the duration of unconsciousness46 and, therefore, does not completely eliminate the bias of using a physiologic score. We attempted to estimate the effect of this bias on our study group by examining length of hospital stay and duration of intensive care unit stay across the BAC groups and found that they were almost identical. If alcohol intoxication resulted in a significant bias, one would assume that the length of hospital stay and intensive care unit stay would be significantly shorter in the groups with BAC greater than 0. Another problem with using AIS–head and neck is that it is not specific for brain injury.46 Cervical spine fractures and skull or facial fractures would also be coded within the framework of AIS–head and neck. This results in a nonspecific measure of severe TBI because patients with mild head injury with associated injuries would be misclassified as having severe TBI. However, skull or facial fractures and cervical spine fractures are often associated with severe TBI47,48 and are likely to be equally distributed across BAC levels. Using AIS–head and neck will likely result in overestimation of the number of patients with severe TBI. In our study, almost one third of the patients had severe TBI, using AIS–head and neck score greater than 3 as our operational definition. This is substantially higher than Centers for Disease Control and Prevention estimates for the United States.49 However, this discrepancy is only partially due to our use of AIS–head and neck. Another reason is that at our institution isolated mild to moderate head injuries are referred through the emergency department directly to the neurosurgical service and are not included in our trauma registry. Our trauma registry, therefore, preferentially includes patients with severe TBI. Use of units of packed red blood cells as a surrogate for hypotension Another limitation of our study was the use of units of transfused red blood cells as a surrogate for hypotension as a covariate in our final model. Even one episode of hypotension has been shown to dramatically increase mortality in patients with severe brain injury.50,51 There are numerous situations, however, where blood transfusion requirements poorly correlate with hypotension. False-positive findings occur when patients receive transfusions based solely on hemoglobin-based transfusion triggers. In the past, a common transfusion trigger was a hemoglobin level less than 100 g/dL, irrespective of hemodynamic status.52 Trauma patients treated using these protocols would receive blood transfusions despite having a normal hemodynamic status. False-negative findings occur in patients who have episodes of hypotension but no requirement for blood transfusion. False-negative findings would occur, therefore, if patients had class II shock, as defined by the American College of Surgeons in the Advanced Trauma Life Support Course for Physicians53; the hypotension would respond to crystalloid resuscitation alone and they would have no requirement for blood transfusion. The major effect of using transfusion requirements as a surrogate for hypotension comes from the false-negative findings. Alcohol is known to have hemodynamic effects, and can cause hypotension.45 Alcohol-induced hypotension is treatable with fluid resuscitation only and would not require blood transfusion. As a result, transfusion requirements would underestimate the degree of hypotension in patients with BAC greater than 0. False-positive findings would more likely affect estimates of hypotension across time, not across BAC groups. Trauma patients early in the study would more likely receive blood despite having a normal hemodynamic status, because of more liberal transfusion practices, compared with patients later in the study. There should be no significant differences in transfusion practices across BAC groups. Starting time bias Starting time bias54 is associated with using admission BAC as our independent variable. Alcohol is metabolized quickly. Therefore, patients with a BAC greater than 0 at the time of injury may be misclassified as having a BAC of 0 at admission because the alcohol in their blood may be eliminated via metabolism. We minimized this bias by only including patients who arrived directly from the scene of injury. On average, patients arrived at our institution within 1 hour after injury (data not shown). Comorbidities We did not adjust for comorbidities in our multivariate models because these are not reliably coded in our trauma registry. Persons who are alcohol dependent tend to have underlying chronic diseases,55 and the injured patient with a BAC greater than 0 is more likely to have chronic alcoholism than is the nondrinker.56 Milzman et al57 demonstrated that preexisting disease is a strong predictor of trauma-related mortality. They reported 25% mortality in patients with 3 preexisting diseases compared with 3.2% in healthy persons. This bias likely results in an underestimate of the beneficial effects of a low to moderate BAC compared with no BAC because those patients with BAC greater than 0 were more likely to have comorbidities. However, this bias likely results in an overestimate of the deleterious effects of a high BAC compared with no BAC. The observed increase in mortality may be accounted for by the comorbidities in the high BAC group because these patients are more likely to have chronic alcoholism. Time of injury Time of injury also biases our results. Alcohol-associated trauma tends to occur during the night and on weekends.58 Investigators have observed an association between after-hours and weekend hospitalization, and increased mortality.59 It is presumed that this effect is secondary to the presence of fewer staff, the absence of more experienced staff, and larger relative workloads during these times. Conclusions We conducted a retrospective cohort study in which we examined the effect of alcohol on mortality in patients with severe TBI. Compared with no BAC, at admission, a low BAC was associated with lower mortality and a high BAC was associated with higher mortality. Alcohol may have neuroprotective effects at low and moderate doses; however, these effects are likely overshadowed at higher doses by its hemodynamic and physiologic effects. There may be a role for alcohol-based resuscitation fluids in well-resuscitated patients with severe traumatic head injury. Prospective studies are needed to confirm this result. Correspondence: Homer C. N. Tien, MD, FRCSC, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Suite H186, Toronto, Ontario, Canada M4N 3M5 ([email protected]). Accepted for Publication: October 6, 2005. Author Contributions:Study concept and design: Tien, Tremblay, Rizoli, Shek, and Brenneman. Acquisition of data: Tien, Rizoli, and Gelberg. Analysis and interpretation of data: Tien, Tremblay, Rizoli, Chughtai, and Tikuisis. Drafting of the manuscript: Tien, Tremblay, Rizoli, and Tikuisis. Critical revision of the manuscript for important intellectual content: Tien, Tremblay, Rizoli, Gelberg, Chughtai, Shek, and Brenneman. Statistical analysis: Tien, Gelberg, and Tikuisis. Obtained funding: Rizoli and Shek. Administrative, technical, and material support: Tien, Rizoli, and Brenneman. Tien, Tremblay, Rizoli, and Brenneman. Financial Disclosure: None reported. Previous Presentation: This paper was presented at the annual scientific meeting of the Trauma Association of Canada; April 7, 2005; Whistler, British Columbia. Acknowledgments: We thank Donald A. Redelmeier, MD, for methodologic advice; and Cyndy Rogers for abstracting the data from the Trauma Registry and for providing advice about variables included in the registry. References 1. Gabriel EJGhajar JJagoda A et al. Brain Trauma Foundation, Guidelines for the prehospital management of traumatic brain injury. 2000;http://www2.braintrauma.org/guidelines/downloads/btf_guidelines_prehospital.pdf. Accessed August 16, 2004 2. Bullock MRChesnut RMClifton GL et al. Brain Trauma Foundation, Guidelines for the management of severe traumatic brain injury. March14 2003;http://www2.braintrauma.org/guidelines/downloads/btf_guidelines_management.pdf. Accessed August 16, 2004 3. Lowenfels ABMiller TT Alcohol and trauma. Ann Emerg Med 1984;131056- 1060PubMedGoogle ScholarCrossref 4. Knott DHBarlow GBeard JD Effects of alcohol ingestion on the production of and response to experimental hemorrhagic stress. N Engl J Med 1963;269292- 295PubMedGoogle ScholarCrossref 5. Knott DHBeard JD The effect of chronic ethanol administration on the response of the dog to repeated acute hemorrhages. Am J Med Sci 1967;254178- 188Google ScholarCrossref 6. Zink BJWalsh RFFeustel PJ Effects of ethanol in traumatic brain injury. J Neurotrauma 1993;10275- 286PubMedGoogle ScholarCrossref 7. Zink BJSheinberg MAWang XMertz MStern SABetz AL Acute ethanol intoxication in a model of traumatic brain injury with hemorrhagic shock: effects on the early physiological response. J Neurosurg 1998;89983- 990PubMedGoogle ScholarCrossref 8. Zink BJStern SAWang XChudnofsky CC Effects of ethanol in an experimental model of combined traumatic brain injury and hemorrhagic shock. Acad Emerg Med 1998;59- 17PubMedGoogle ScholarCrossref 9. Fabian MJProctor KG Hemodynamic actions of acute ethanol after resuscitation from traumatic brain injury. J Trauma 2002;53864- 875PubMedGoogle ScholarCrossref 10. Kelly DFLee SMPinanong PAHovda DA Paradoxical effects of acute ethanolism in experimental brain injury. J Neurosurg 1997;86876- 882PubMedGoogle ScholarCrossref 11. Tureci EDashti RTanriverdi TSanus GZOz BUzan M Acute ethanol intoxication in a model of traumatic brain injury: the protective role of moderate doses demonstrated by immunoreactivity of synaptophysin in hippocampal neurons. Neurol Res 2004;26108- 112PubMedGoogle ScholarCrossref 12. Janis LSHoane MRConde DFulop ZStein DG Acute ethanol administration reduces the cognitive deficits associated with traumatic brain injury in rats. J Neurotrauma 1998;15105- 115PubMedGoogle ScholarCrossref 13. Dash PKMoore ANMoody MRTreadwell RFelix JLClifton GL Post-trauma administration of caffeine plus ethanol reduces contusion volume and improves working memory in rats. J Neurotrauma 2004;211573- 1583PubMedGoogle ScholarCrossref 14. Hayes RLJenkins LWLyeth BG Neurotransmitter-mediated mechanisms of traumatic brain injury: acetylcholine and excitatory amino acids. J Neurotrauma 1992;9S173- S187PubMedGoogle ScholarCrossref 15. Crews FTSteck JCChandler LJYu CJDay A Ethanol, stroke, brain damage, and excitotoxicity. Pharmacol Biochem Behav 1998;59981- 991PubMedGoogle ScholarCrossref 16. Strong RGrotta JCAronowski J Combination of low dose ethanol and caffeine protects brain from damage produced by focal ischemia in rats. Neuropharmacology 2000;39515- 522PubMedGoogle ScholarCrossref 17. Piriyawat PLabiche LABurgin WSAronowski JAGrotta JC Pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke. Stroke 2003;341242- 1245PubMedGoogle ScholarCrossref 18. Tulloh BRCollopy BT Positive correlation between blood alcohol level and ISS in road trauma. Injury 1994;25539- 543PubMedGoogle ScholarCrossref 19. Pories SEGamelli RLVacek PGoodwin GShinozaki THarris F Intoxication and injury. J Trauma 1992;3260- 64PubMedGoogle ScholarCrossref 20. Fabbri AMarchesini GMorselli-Labate AM et al. Positive blood alcohol concentration and road accidents: a prospective study in an Italian emergency department. Emerg Med J 2002;19210- 214PubMedGoogle ScholarCrossref 21. Waller PFStewart JRHansen ARStutts JCPopkin CL et al. Rodgman EA The potentiating effects of alcohol on driver injury. JAMA 1986;2561461- 1466PubMedGoogle ScholarCrossref 22. Gurney JGRivara FPMueller BANewell DWCopass MKJurkovich GJ The effects of alcohol intoxication on the initial treatment and hospital course of patients with acute brain injury. J Trauma 1992;33709- 713PubMedGoogle ScholarCrossref 23. Jurkovich GJRivara FPGurney JG et al. The effects of acute ethanol intoxication and chronic alcohol abuse on outcome from trauma. JAMA 1993;27051- 56PubMedGoogle ScholarCrossref 24. Huth JFMaier RVSimonowitz DAHerman CM Effect of acute ethanolism on the hospital course and outcome of injured automobile drivers. J Trauma 1983;23494- 498PubMedGoogle ScholarCrossref 25. Alexander SKerr MEYonas HMarion DW The effects of admission alcohol level on cerebral blood flow and outcomes after severe traumatic brain injury. J Neurotrauma 2004;21575- 583PubMedGoogle ScholarCrossref 26. Shih HCHu SCYang CCKo TJWu JKLee CH Alcohol intoxication increases morbidity in drivers involved in motor vehicle accidents. Am J Emerg Med 2003;2191- 94PubMedGoogle ScholarCrossref 27. Tate PSFreed DMBombardier CHHarter SLBrinkman S Traumatic brain injury: influence of blood alcohol level on post-acute cognitive function. Brain Inj 1999;13767- 784PubMedGoogle ScholarCrossref 28. Ward REFlynn TCMiller PWBlaisdell WF Effects of ethanol ingestion on the severity and outcome of trauma. Am J Surg 1982;144153- 157PubMedGoogle ScholarCrossref 29. Blondell RDLooney SWKrieg CLSpain DA A comparison of alcohol-positive and alcohol-negative trauma patients. J Stud Alcohol 2002;63380- 383PubMedGoogle Scholar 30. Li GKeyl PMSmith GSBaker SP Alcohol and Injury severity: reappraisal of the continuing controversy. J Trauma 1997;42562- 569PubMedGoogle ScholarCrossref 31. Poole GVLewis JLDevidas MHauser CJMartin RWThomae KR Psychopathologic risk factors for intentional and nonintentional injury. J Trauma 1997;42711- 715PubMedGoogle ScholarCrossref 32. Li GBaker SPSmialek JESoderstrom CA Use of alcohol as a risk factor for bicycling injury. JAMA 2001;285893- 896PubMedGoogle ScholarCrossref 33. Spaite DWCriss EAWeist DJValenzuela TDJudkins DMeislin HW A prospective investigation of the impact of alcohol consumption on helmet use, injury severity, medical resource utilization, and health care costs in bicycle-related trauma. J Trauma 1995;38287- 290PubMedGoogle ScholarCrossref 34. Andersen JAMcLellan BAPagliarello GNelson WR The relative influence of alcohol and seatbelt usage on severity of injury from motor vehicle crashes. J Trauma 1990;30415- 417PubMedGoogle ScholarCrossref 35. Gettler DTPilgritten FF Effects of ethanol intoxication on the respiratory exchange and mortality rate associated with acute hemorrhage n anesthetized dogs. Ann Surg 1963;158151- 158PubMedGoogle ScholarCrossref 36. Malt SHBaue AE The effect of ethanol as related to trauma in the awake dog. J Trauma 1971;1176- 86PubMedGoogle ScholarCrossref 37. Luna GKMaier RVSowder LCopass MKOreskovich MR The influence of ethanol intoxication on outcome of injured motorcyclists. J Trauma 1984;24695- 700PubMedGoogle ScholarCrossref 38. Sauaia AMoore FAMoore EE et al. Epidemiology of trauma deaths: a reassessment. J Trauma 1995;38185- 193PubMedGoogle ScholarCrossref 39. Stewart RMMyers JGDent DL et al. Seven hundred fifty-three consecutive deaths in a level I trauma center: the argument for injury prevention. J Trauma 2003;5466- 70PubMedGoogle ScholarCrossref 40. Zink BJMaio RFChen B Alcohol, central nervous system injury, and time to death in fatal motor vehicle crashes. Alcohol Clin Exp Res 1996;201518- 1522PubMedGoogle ScholarCrossref 41. Osler THales KBaack B et al. Trauma in te elderly. Am J Surg 1988;156537- 543PubMedGoogle ScholarCrossref 42. George RLMcGwin G JrMetzger JChaudry IHRue LW III The association between gender and mortality among trauma patients as modified by age. J Trauma 2003;54464- 471PubMedGoogle ScholarCrossref 43. Van Natta TLMorris JA Injury scoring and trauma outcomes. Mattox KLFeliciano DLMoore EEeds Trauma. 4th ed. New York, NY McGraw-Hill Co2000;Google Scholar 44. Elder RWShults RASleet DA et al. Effectiveness of mass media campaigns for reducing drinking and driving and alcohol-involved crashes: a systematic review. Am J Prev Med 2004;2757- 65PubMedGoogle ScholarCrossref 45. Brickley MRShepherd JP The relationship between alcohol intoxication, injury severity and Glasgow Coma Score in assault patients. Injury 1995;26311- 314PubMedGoogle ScholarCrossref 46. The Abbreviated Injury Scale, 1990 revision (1998 Update). Des Plaines, Ill Association for the Advancement of Automotive Medicine1998; 47. Iida HTachibana SKitahara THoriike SOhwada TFujii K Association of head trauma with cervical spine injury, spinal cord injury, or both. J Trauma 1999;46450- 452PubMedGoogle ScholarCrossref 48. Martin RC IISpain DARichardson JD Do facial fractures protect the brain or are they a marker for severe head injury. Am Surg 2002;68477- 481PubMedGoogle Scholar 49. Thurman DJAlverson CDunn KAGuerrero JSniezek JE Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehabil 1999;14602- 615PubMedGoogle ScholarCrossref 50. Winchell RJSimons RKHoyt DB Transient systolic hypotension: a serious problem in the management of head injury. Arch Surg 1996;131533- 539PubMedGoogle ScholarCrossref 51. Manley GKnudson MMMorabito DDamron SErikson VPitts L Hypotension, hypoxia and head injury: frequency, duration and consequences. Arch Surg 2001;1361118- 1123PubMedGoogle ScholarCrossref 52. Goodnough LTBrecher MEKanter MHAuBuchon JP Transfusion medicine, second of two parts: blood conservation. N Engl J Med 1999;340525- 533PubMedGoogle ScholarCrossref 53. American College of Surgeons Committee on Trauma, Advanced Trauma Life Support for Doctors. 7th ed. Chicago, Ill American College of Surgeons1997; 54. Fletcher FHFletcher SWWagner EH Clinical Epidemiology: The Essentials. 3rd ed. Baltimore, Md Lippincott Williams & Wilkins1996; 55. Schenker SBay MK Medical problems associated with alcoholism. Adv Intern Med 1998;4327- 78PubMedGoogle Scholar 56. Rivara FPJurkovich GJGurney JG et al. The magnitude of acute and chronic alcohol abuse in trauma patients. Arch Surg 1993;128907- 912PubMedGoogle ScholarCrossref 57. Milzman DPBoulanger BRRodriguez ASoderstrom CAMitchell KAMagnant CM Pre-existing disease in trauma patients: a predictor of fate independent of age and injury severity score. J Trauma 1992;32236- 243PubMedGoogle ScholarCrossref 58. Lucas CELedgerwood AMKline RA Alcohol and drugs. Mattox KLFeliciano DLMoore EEeds Trauma. 4th ed. New York, NY McGraw-Hill Co2000;1059- 1074Google Scholar 59. Bell CMRedelmeier DA Mortality among patients admitted to hospitals on weekends as compared with weekdays. N Engl J Med 2001;345663- 668PubMedGoogle ScholarCrossref

Eastman, A. Brent

doi: 10.1001/archsurg.141.12.1192pmid: N/A

This is a well-designed, retrospective study using a large Canadian trauma system database. Tien et al examine the hypothesis that “admission blood alcohol concentration is associated with in-hospital death in patients with severe brain injury from blunt head trauma.” There is a long-held myth that intoxicated trauma victims are more relaxed and, therefore, fare better than nonintoxicated patients. In the interest of public health, this is a myth to be discredited. However, this study did find that the cohort of patients with severe TBI and a low BAC had a higher survival rate than those with no BAC. This finding should stimulate clinical research to better understand the potential neuroprotective effects of a low BAC, but it should clearly not be a call for trauma patients with severe TBI to premedicate with alcohol. Rather, the emphasis more appropriately should be placed on the fact that 30% to 50% of all hospitalized trauma patients are intoxicated at the time of injury. Conversely, a high BAC was associated with higher mortality. This suggests a detrimental effect of a high BAC on homeostasis (eg, hypotension), and we know that hypotension is a critical, negative factor in secondary brain injury. This finding should also stimulate clinical research to better understand and counter these negative physiologic changes. It also speaks to the trauma prevention dictum that decries drinking and driving. This study should be further impetus for clinical research that will better define the dose-related effect, positive or negative, of alcohol on the physiologic status and outcome in patients with severe TBI. Perhaps this research can help answer the question as to whether there is a therapeutic role for alcohol in our management of the patient with severe TBI after adequate resuscitation. Correspondence: Dr Eastman, Scripps Memorial Hospital, 4275 Campus Point Ct, CP222, San Diego, CA 92121 ([email protected]). Financial Disclosure: None reported

Engeland, Christopher G.;Bosch, Jos A.;Cacioppo, John T.;Marucha, Phillip T.

doi: 10.1001/archsurg.141.12.1193pmid: 17178961

Abstract Hypothesis It remains unclear whether aging delays wound healing, as past human studies have not adequately controlled for confounding factors such as morbidity and medications. Furthermore, although dermal wounds heal more quickly in women than in men, clinical observations suggest that the opposite may be true for mucosal healing. We assessed age and sex differences in mucosal wound healing, and we hypothesized that aging delays healing and sex modulates healing independent of age. Design and Setting Clinical experimental study performed from June 2000 to August 2003 involving younger and older adult volunteers from the general community. Participants Two hundred twelve male and female volunteers aged 18 to 35 years (n = 119) or 50 to 88 years (n = 93). Intervention Standardized 3.5-mm circular wounds were placed on the oral hard palates of volunteers. Main Outcome Measure Wound videographs were taken daily for 7 days after wounding to assess wound closure. Results Wounds healed significantly more slowly in older adults compared with younger adults (P<.001) regardless of sex. This remained true even when individuals receiving medication and/or having a coexisting medical condition were excluded. Mucosal wounds healed more slowly in women than in men (P = .008) regardless of age. These effects were independent of demographic factors such as ethnicity, alcohol or nicotine use, or body mass index. Conclusions Wound closure in older individuals was clearly delayed even when eliminating potential age-related confounds, indicating that aging does slow wound healing. Wound closure in women was also delayed, suggesting that wound healing is modulated by different mechanisms depending on tissue type. These findings may help target patients with increased surgical risks and greater need for postsurgical care. The fastest-growing population in Western countries is the elderly population (aged ≥65 years). In the United States, elderly persons account for 12.4% (35.9 million) of the total population and will likely compose 20% (71.5 million) of the population by 2030.1 Presently, the treatment of impaired healing costs United States health services more than $9 billion per year.2 Much of this has been attributed to age-associated delays in wound closure that, in turn, relate to higher rates of infection and medical complications. Thus, the role of aging in wound healing is an important issue, as it severely impacts national health care costs. It has commonly been reported that people heal more slowly with increasing age.3-5 A chief criticism of such findings, however, is that studies have not adequately controlled for confounding factors that are more common in aged persons, such as medication use and morbidity.6-9 Other studies9-11 report no difference in the healing rates of older vs younger adults. Thus, it remains controversial whether aging per se delays wound healing in humans.6-9 The aim of the present study was to examine the effects of age on the healing of standardized mucosal wounds while accounting for such factors. It is well accepted that skin morphology changes with aging.6 For instance, older skin has been associated with reductions in vascularization,10 collagen density or production,10-12 granulation tissue,10 and elastin.9,13 However, many of these changes that occur in aged skin are due to extrinsic aging factors such as sun exposure.9,12 Mucosal tissue is not exposed to the sun and thus may provide a better assessment of the effects of intrinsic aging on wound healing. Mucosal wounds occur frequently, and the healing of the mucosa is important in most surgical outcomes. Oral wounds are a common type of mucosal wound and are comparable to other mucosal tissues in both repair rates and susceptibility to infection. However, little is currently known regarding the effects of aging on the healing of mucosal tissue. Sex has been implicated as a factor in wound healing, and a number of studies14-16 clearly show a female advantage in human healing rates. However, these findings are mainly derived from dermal wound studies, and a female advantage in the healing of nondermal wounds is unapparent. A number of clinical studies17-19 observed no sex difference in the healing of the oral mucosa. Other studies that examined the healing of mucosal tissues after third-molar surgery found that women healed significantly more slowly20,21 and needed additional postsurgery treatment21,22 compared with men. Taken together, aging and sex may additively or synergistically affect the healing of mucosal wounds. This study examined age and sex differences in the healing of standardized mucosal wounds created on the oral hard palate. Potentially confounding effects, such as individuals reporting morbidity or medication usage, were eliminated by the exclusion of these subjects from specific follow-up analyses. Using this rigorous approach, our results indicate the following: (1) older adults heal mucosal wounds more slowly than young adults, even when factors such as medication use and morbidity are eliminated; and (2) women heal mucosal wounds more slowly than men, independent of age. These findings further indicate that older women are at the highest risk for delayed healing of mucosal tissue. Methods Participants This study involved 212 volunteers aged 18 to 35 years (52 men; 67 women) or 50 to 88 years (33 men; 60 women). All of the individuals gave written informed consent and received monetary compensation for their participation. Questionnaires were used to determine demographics, health behaviors, a detailed history of health, and current medication use (type, dose, frequency, and purpose) for each individual. Participants were excluded from the study only if they had an oral disease needing emergency treatment or medical problems that made them a high surgical risk (eg, unstable angina or the presence of an infectious disease, such as active hepatitis, tuberculosis, or AIDS). These limited exclusion criteria allowed for a broad subject base to enhance the generalization of the results. All of the wounding was performed by a periodontist (P.T.M.). All of the procedures were carried out in the College of Dentistry Clinical Research Center, The Ohio State University, Columbus, and met with institutional review board and ethics committee approval by The Ohio State University. Procedures Subjects arrived and were seated in the dental clinic between 9:30 AM and 10:30 AM. Wounds were created between the first and second molar approximately 3 mm from the marginal gingiva. The wound site was anesthetized with 2% lidocaine, after which the wound was outlined using a 3.5-mm tissue punch. A scalpel was then used to remove the surface epithelium and superficial connective tissue, creating a uniform wound 1.5 mm deep. Afterward, wounds were not dressed and participants were instructed not to change their normal hygiene procedures with the exception of abstaining from alcohol-based mouthwash. There were no differences in oral hygiene between age or sex groups (ie, the frequency of toothbrushing or the use of mouthwash or floss). Wounds were videographed at 24-hour intervals for 7 days after wounding or until considered healed by visual inspection. A standard 6-mm label was placed around the wound to account for variation due to magnification and angulation. Wound images were then transferred to a Macintosh computer (Apple Computer, Inc, Cupertino, Calif), blind coded, measured (for area), and expressed as a ratio of the wound size to the standard label size. All of the wound ratios were determined by a single investigator (April Logue, MS). Changes in health status and medication use were assessed each postwounding day by questionnaires. Statistical analysis Data were analyzed using a mixed-design analysis of variance that treated the wound sizes for 7 days after wounding as a within-subject factor and sex and age as between-subject factors. Separate analyses of variance were used for post hoc comparisons. Correlations were determined using Pearson product moment correlations (r), and χ2 tests were used to assess between-group differences in healing rates. Demographic analyses consisted of analyses of variance and correlations. Age was treated as a covariate when determining sex differences within younger or older groups. All of the hypothesis tests were 2-tailed and used α = .05 to determine significance. Data were analyzed using SPSS version 11.5 for Windows (SPSS, Inc, Chicago, Ill). Results Healing rates were unrelated to ethnicity, body mass index, exercise, alcohol consumption, or nicotine use (although only 31 subjects smoked). Age effects Younger participants displayed a different pattern of wound healing than older participants (F1,208 = 31.67; P<.001). Although all of the wounds were initially the same size, younger individuals had smaller wounds by day 2; this difference continued to the end of the study (P<.001 for each day) (Figure 1A). In addition, the proportion of individuals who were considered healed (wounds >90% closed) was significantly higher in younger subjects than in older subjects on days 5 through 7 (Figure 1B). Studies that have assessed healing in aged persons have been criticized because analyses have not accounted for the higher occurrences of medication use and morbidity in elderly individuals. In this study, 4 sets of analyses that excluded the following individuals were performed: (1) those receiving any type of medication (excluding allergy medication, birth control, or nutritional supplements [eg, vitamins]); (2) those who presently have or in the past had a serious medical condition (eg, diabetes, cancer, stroke, heart disease, hypertension, hypothyroidism, arthritis, irritable bowel disease, bacterial meningitis, psychopathological abnormalities); (3) those who reported to not be in good overall health; or (4) those who fit all of these criteria. After applying these exclusion criteria, older individuals still exhibited significantly larger wounds, and thus slower healing, than younger individuals for all of the analyses (see Figure 1 for results that excluded individuals receiving medication). Interestingly, within the older group, medication produced a different pattern of wound healing (F6,540 = 4.40; P<.001). Individuals receiving medication (as defined earlier) had significantly smaller wounds on days 1 and 2 (P≤.02) than those not receiving medication (Figure 1A). Wound sizes on subsequent days were similar. Subjects receiving medication had no differences in oral hygiene or in general health behaviors (exercise, alcohol or nicotine use) from subjects not receiving medication (data not shown). Common classes of medication included α- and β-blockers, diuretics, vasodilators, calcium blockers, and others. No individual classes of medication were found to significantly alter wound closure on their own. Sex effects Men exhibited a different pattern of wound healing than women (F1,208 = 7.13; P = .008). Although all of the wounds were initially the same size, at 24 hours after wounding, men had significantly smaller wounds; this difference was apparent until day 5 (Figure 2A). In addition, the proportion of individuals considered healed was significantly higher for men than for women on days 5 and 6 (Figure 2B). Age and sex The effects of age occurred regardless of sex, as older subjects healed significantly more slowly than younger subjects for both women (F1,125 = 24.13; P<.001) and men (F1,83 = 10.79; P = .001). Wounds were significantly larger in older women compared with younger women on all 7 days (P≤.002). Within men, a significant day × age interaction occurred (P<.001), as wound sizes were similar on day 1 but significantly larger in older men than in younger men on days 2 through 7 (P≤.02) (data not shown). Compared with the older subjects, the proportion of individuals considered healed was significantly higher in younger women on days 5 through 7 (P≤.007) and in younger men on days 6 and 7 (P≤.009 each day) (data not shown). The effects of sex occurred regardless of age, as there were significant day × sex interactions within both younger (F6,696 = 3.36; P = .003) and older (F6,540 = 2.95; P = .008) subjects. Women had significantly larger wounds (ie, slower healing) than men on days 3 through 5 in the younger group (P≤.02) and on day 1 in the older group (P = .002) (data not shown). Also, within each age group, a higher proportion of men than women were considered healed. In younger subjects, this effect approached significance on day 5 (P = .08) and was significant on day 6 (P = .02); in older subjects, this effect approached significance on days 5 and 6 (P = .05 and .09, respectively) (data not shown). The magnitudes of these age and sex effects on wound healing were substantial. For example, observing values obtained 5 days after wounding, wounds were 56% larger in older subjects as compared with younger subjects, and younger individuals were 3.7 times more likely to be considered healed than older individuals. Similarly, the wounds of women were 27% larger than those of men, and men were 2.5 times more likely than women to be considered healed. Older women were the slowest to heal, and their wounds as compared with those of younger men were 95% larger by 5 days after wounding. Thus, older women appear to be at the greatest risk for delayed wound closure. Comment A chief strength of this study was that all of the wounds were created under the same experimental conditions and were standardized for size, depth, site, and time of placement. The results were also independent of common demographic factors (eg, ethnicity), allowing for a more clear determination of the roles of age and sex in wound healing. In this study, older adults (aged ≥50 years) healed oral mucosal wounds significantly more slowly than younger adults (aged 18-35 years). This remained true even when individuals who were receiving medication and/or had a coexisting medical condition were removed from the analyses. A common criticism of past studies is that the inclusion of such individuals may exaggerate or even account for age-associated healing impairments.6-9 Surprisingly, the exclusion of individuals receiving medication strengthened our findings (Figure 1), and within the older group, those receiving medication had an improved pattern of healing. This suggests that age-associated delays in wound healing are not generally exaggerated by medication use. Furthermore, the deleterious effects of age on healing may be stronger than previously suspected. Much of the current literature14-16 on wound healing stems from dermal wounds, and a clear sex difference in favor of women is evident. However, the current study indicates that men heal oral mucosal wounds more quickly than women. This male advantage in mucosal healing is a robust effect, and we have recently replicated this finding in another clinical study using young adults (n = 193; mean ± SD age, 20.14 ± 0.15 years; age range, 18-31 years). These results suggest that there are fundamental differences between the healing of mucosal vs dermal wounds. Compared with skin, mucosal epithelial turnover is more rapid and its tissue is more vascularized. As a result, it takes less time to recruit inflammatory cells to a mucosal wound site. Furthermore, immunomodulating compounds such as growth factors are more readily supplied to the site via mucosal secretions (ie, saliva), and lower levels of neutrophils, macrophages, and their associated cytokines have been reported in mucosal wounds as compared with dermal wounds.23 These differences all likely contribute to the divergent healing rates seen in these tissues and may help to explain why the sexual dimorphism in these rates varies between tissue types. Sex hormones likely modulate oral mucosal wound healing, as they have been shown to play a role in both dermal wound healing2,14,15 and periodontal disease.24,25 We hypothesize that sex hormones modulate both oral mucosal and dermal wound healing but do so differentially, perhaps driving healing in opposite directions. Lower inflammatory responses have been associated with faster wound healing26,27 and inflammation appears to be substantially reduced in mucosal wounds as compared with dermal wounds,23,28 possibly explaining why mucosal wounds heal more rapidly.23,28 Given that testosterone has potent anti-inflammatory qualities29,30 and is abundant in saliva and other mucosal fluids,31 testosterone is a putative mechanism for explaining the faster healing of mucosal wounds observed in men in this study. Conclusions Our results indicate that women heal oral mucosal wounds more slowly than men, which is the opposite of the sex effect reported in dermal wound healing. Often, dermal and mucosal wounds are equated and direct comparisons are commonly made between their underlying healing processes. However, our findings suggest that healing in these tissues is differentially modulated and that direct comparisons between dermal and mucosal tissues may be inappropriate. These findings also indicate, to our knowledge for the first time, that older adults heal standardized wounds more slowly than younger adults, even when factors such as medication use and morbidity are removed from the analyses. Thus, both age and sex appear to be influential factors in mucosal wound healing, and older women may be at the highest risk for delayed healing following oral or mucosal surgery or injury. With an increasing number of surgical procedures being performed owing to the rising age of the population and for aesthetic purposes, a greater emphasis needs to be placed on expediting the healing process. Determining the mechanisms that underlie these age and sex differences will help target treatment strategies to reduce postsurgical recovery times. This, in turn, will decrease the risk of infection and improve ultimate healing outcomes. Funding/Support: This study was supported by grants P01 AG-16321 and P50 DE-13749 from the National Institutes of Health. Correspondence: Phillip T. Marucha, DMD, PhD, College of Dentistry, University of Illinois at Chicago, 801 S Paulina St, Room 458, M/C 859, Chicago, IL 60612 ([email protected]). Accepted for Publication: October 12, 2005. Author Contributions: Drs Engeland and Marucha had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Engeland, Bosch, Cacioppo, and Marucha. Acquisition of data: Engeland, Bosch, and Marucha. Analysis and interpretation of data: Engeland, Bosch, Cacioppo, and Marucha. Drafting of the manuscript: Engeland. Critical revision of the manuscript for important intellectual content: Engeland, Bosch, Cacioppo, and Marucha. Statistical analysis: Engeland. Obtained funding: Cacioppo and Marucha. Engeland, Bosch, and Marucha. Financial Disclosure: None reported. Role of the Sponsor: The funding organization did not participate in the design and conduct of this study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. Acknowledgment: We gratefully acknowledge April Logue, MS, for her time in helping to coordinate this study and in scoring wound videographs. References 1. US Census Bureau, Interim Projections Consistent With Census 2000. Washington, DC US Census Bureau2004; 2. Ashcroft GSMills SJ Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest 2002;110615- 624PubMedGoogle ScholarCrossref 3. Gerstein ADPhillips TJRogers GSGilchrest BA Wound healing and aging. Dermatol Clin 1993;11749- 757PubMedGoogle Scholar 4. Fenske NALober CW Structural and functional changes of normal aging skin. J Am Acad Dermatol 1986;15571- 585PubMedGoogle ScholarCrossref 5. Goodson WH IIIHunt TK Wound healing and aging. J Invest Dermatol 1979;7388- 91PubMedGoogle ScholarCrossref 6. Ashcroft GSMills SJAshworth JJ Ageing and wound healing. Biogerontology 2002;3337- 345PubMedGoogle ScholarCrossref 7. Ashcroft GSHoran MAFerguson MW Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model. J Invest Dermatol 1997;108430- 437PubMedGoogle ScholarCrossref 8. Ashcroft GSHoran MAFerguson MW The effects of ageing on cutaneous wound healing in mammals. J Anat 1995;1871- 26PubMedGoogle Scholar 9. Thomas DR Age-related changes in wound healing. Drugs Aging 2001;18607- 620PubMedGoogle ScholarCrossref 10. van de Kerkhof PCVan Bergen BSpruijt KKuiper JP Age-related changes in wound healing. Clin Exp Dermatol 1994;19369- 374PubMedGoogle ScholarCrossref 11. Cook JLDzubow LM Aging of the skin: implications for cutaneous surgery. Arch Dermatol 1997;1331273- 1277PubMedGoogle ScholarCrossref 12. Gosain ADiPietro LA Aging and wound healing. World J Surg 2004;28321- 326PubMedGoogle ScholarCrossref 13. Ashcroft GSKielty CMHoran MAFerguson MW Age-related changes in the temporal and spatial distributions of fibrillin and elastin mRNAs and proteins in acute cutaneous wounds of healthy humans. J Pathol 1997;18380- 89PubMedGoogle ScholarCrossref 14. Ashcroft GSAshworth JJ Potential role of estrogens in wound healing. Am J Clin Dermatol 2003;4737- 743PubMedGoogle ScholarCrossref 15. Ashcroft GSDodsworth Jvan Boxtel E et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med 1997;31209- 1215PubMedGoogle ScholarCrossref 16. Jorgensen LNSorensen LTKallehave FVange JGottrup F Premenopausal women deposit more collagen than men during healing of an experimental wound. Surgery 2002;131338- 343PubMedGoogle ScholarCrossref 17. Yumiba TIto TIkushima H et al. Effect of mucosal suture on the healing of mucosal defect in laparoscopic intragastric surgery. Gastric Cancer 2003;696- 99PubMedGoogle Scholar 18. Lopez RFernandez OJara GBaelum V Epidemiology of necrotizing ulcerative gingival lesions in adolescents. J Periodontal Res 2002;37439- 444PubMedGoogle ScholarCrossref 19. Heard RHMellonig JTBrunsvold MALasho DJMeffert RMCochran DL Clinical evaluation of wound healing following multiple exposures to enamel matrix protein derivative in the treatment of intrabony periodontal defects. J Periodontol 2000;711715- 1721PubMedGoogle ScholarCrossref 20. Conrad SMBlakey GHShugars DAMarciani RDPhillips CWhite RP Jr Patients' perception of recovery after third molar surgery. J Oral Maxillofac Surg 1999;571288- 1294PubMedGoogle ScholarCrossref 21. Phillips CWhite RP JrShugars DAZhou X Risk factors associated with prolonged recovery and delayed healing after third molar surgery. J Oral Maxillofac Surg 2003;611436- 1448PubMedGoogle ScholarCrossref 22. Benediktsdottir ISWenzel APetersen JKHintze H Mandibular third molar removal: risk indicators for extended operation time, postoperative pain, and complications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97438- 446PubMedGoogle ScholarCrossref 23. Szpaderska AMZuckerman JDDiPietro LA Differential injury responses in oral mucosal and cutaneous wounds. J Dent Res 2003;82621- 626PubMedGoogle ScholarCrossref 24. Mascarenhas PGapski RAl Shammari KWang HL Influence of sex hormones on the periodontium. J Clin Periodontol 2003;30671- 681PubMedGoogle ScholarCrossref 25. Ito IHayashi TYamada KKuzuya MNaito MIguchi A Physiological concentration of estradiol inhibits polymorphonuclear leukocyte chemotaxis via a receptor mediated system. Life Sci 1995;562247- 2253PubMedGoogle ScholarCrossref 26. Dovi JVSzpaderska AMDiPietro LA Neutrophil function in the healing wound: adding insult to injury? Thromb Haemost 2004;92275- 280PubMedGoogle Scholar 27. Dovi JVHe LKDiPietro LA Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 2003;73448- 455PubMedGoogle ScholarCrossref 28. Lee HGEun HC Differences between fibroblasts cultured from oral mucosa and normal skin: implication to wound healing. J Dermatol Sci 1999;21176- 182PubMedGoogle ScholarCrossref 29. Giglio TImro MFilaci G et al. Immune cell circulating subsets are affected by gonadal function. Life Sci 1994;541305- 1312PubMedGoogle ScholarCrossref 30. McCruden ABStimson WH Sex hormones and immune function. Ader RCohen Neds Psychoneuroimmunology. New York, NY Academic Press1991;475- 493Google Scholar 31. Le Goascogne CSananes NEychenne BGouezou MBaulieu EERobel P Androgen biosynthesis in the stomach: expression of cytochrome P450 17 alpha-hydroxylase/17, 20-lyase messenger ribonucleic acid and protein, and metabolism of pregnenolone and progesterone by parietal cells of the rat gastric mucosa. Endocrinology 1995;1361744- 1752PubMedGoogle Scholar

Barbul, Adrian

doi: 10.1001/archsurg.141.12.1198pmid: N/A

The comprehensive understanding of the biology of wound healing remains an elusive goal. Perturbations in healing, manifested as either wound failure or exuberant fibroplastic responses, account for more than 50% of cases presented at surgical morbidity and mortality conferences as well as for huge health dollar expenditures. Historically, surgeons have always been interested in the results of their surgical interventions. Mainly, retrospective studies have been carried out to examine wound outcomes and to attempt to identify clinical factors that are associated with impaired healing responses. Typical wounds studied include skin incisions, anastomoses, bone fractures, tendon repairs, and cutaneous burns. Most frequently, age, American Society of Anesthesiologists status, diabetes, use of steroids or other immunosuppressive agents, and impaired circulation have been associated with poor outcomes.1 The effect of age as an independent variable affecting wound healing may be related to impairment in the biology of the healing response or may be a surrogate marker for the presence of other diseases and factors that adversely affect reparative responses.2-4 Human models of healing include subcutaneously implanted polytetrafluoroethylene catheters, incisions, or creation of small superficial dermal defects. Many studies5 in aged volunteers have confirmed an impairment in the process of epithelialization but have yielded inconclusive results in regard to the synthesis of collagen. The study by Engeland and colleagues used an interesting model of buccal mucosal injury created by a surgical punch to examine the effect of sex and age on mucosal closure. This process involves resurfacing the defect by mucosal migration and regeneration, similar to dermal reepithelialization. The study, which was well designed and adequately powered, demonstrates that age impairs mucosal healing. The effect of age persisted even when patients receiving medications or having adverse medical conditions were removed from the analysis, strongly supporting a biological degradation of surface healing with age. The finding that female sex is a strong negative influence on healing at all ages is surprising. This is one of the few instances, if not the only instance, where being a woman is a negative biological factor. Female sex has been associated with increased collagen deposition as well as better survival and outcomes following trauma and operative intervention.6-8 This finding, if confirmed, raises interesting questions. Is the healing of the buccal mucosa in the aerodigestive tract predictive of response elsewhere in the gastrointestinal tract? Are there differences in oral flora by sex that may explain these differences in healing? The stimulatory role of bacteria to wound healing is well known and may play a role. The study by Engeland and colleagues adds to our understanding of the biology of healing, raises important questions, and points to the value of well-designed studies in volunteers as a means of advancing the science of healing responses. Correspondence: Adrian Barbul, MD, Sinai Hospital/Johns Hopkins University, 2401 W Belvedere Ave, Baltimore, MD 21215 ([email protected]). Financial Disclosure: None reported. References 1. Witte MBBarbul A General principles of wound healing. Surg Clin North Am 1997;77509- 528PubMedGoogle ScholarCrossref 2. Thomas DR Age-related changes in wound healing. Drugs Aging 2001;18607- 620PubMedGoogle ScholarCrossref 3. Van de Kerkhof PCMVan Bergen BSpruijt KKuiper JP Age-related changes in wound healing. Clin Exp Dermatol 1994;19369- 374PubMedGoogle ScholarCrossref 4. Gosain ADiPietro LA Aging and wound healing. World J Surg 2004;28321- 326PubMedGoogle ScholarCrossref 5. Holt DRKirk SJRegan MCHurson MLindblad WJBarbul A Effect of age on wound healing in healthy humans. Surgery 1992;112293- 298PubMedGoogle Scholar 6. Jorgensen LNSorensen LTKallehave FVange JGottrup F Premenopausal women deposit more collagen than men during healing of an experimental wound. Surgery 2002;131338- 343PubMedGoogle ScholarCrossref 7. Gannon CJPasquale MTracy JKMcCarter RJNapolitano LM Male gender is associated with increased risk for post-injury pneumonia. Shock 2004;21410- 414PubMedGoogle ScholarCrossref 8. George RLMcGwin G JrMetzger JChaudry IHRue LW III The association between gender and mortality among trauma patients as modified by age. J Trauma 2003;54464- 471PubMedGoogle ScholarCrossref