The rates of adhesion development and the effects of crystalloid solutions on adhesion development in pelvic surgery

Transcription

1 FERTILITY AND STERILITY VOL. 70, NO. 4, OCTOBER 1998 Copyright 1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. The rates of adhesion development and the effects of crystalloid solutions on adhesion development in pelvic surgery David M. Wiseman, Ph.D.,* J. Richard Trout, Ph.D., and Michael P. Diamond, M.D. SYNECHION, Inc., Dallas, Texas; Rutgers University, New Brunswick, New Jersey; and Wayne State University School of Medicine, Detroit, Michigan Objective: To document rates of adhesion development after abdomino-pelvic surgery, stratified by adhesion type, access method, and use of crystalloid solution instillates. Design: Reports from a MEDLINE search (1/1/ /18/1996) detailing rates of adhesion development and meeting the inclusion criteria were subjected to meta-analysis. Setting: Meta-analysis. Patient(s): Patients undergoing abdomino-pelvic surgery. Intervention(s): Intraperitoneal crystalloid solution instillates. Main Outcome Measure(s): Percentage adhesion-free outcome in patients ( patients ) or surgical sites ( sites ). Result(s): Adhesion-free outcome (sites) was lowest for reformed (26.3% laparotomy; 14.3% laparoscopy), higher for de novo 1b (direct trauma) (45.2% laparotomy, 37.2% laparoscopy), and highest for de novo 1a (indirect trauma) adhesions (82.4% laparoscopy). Crystalloid solution instillates reduced adhesion-free outcome at sites (45.2% versus 20% de novo 1b adhesions in laparotomy) and in patients (43.5% versus 19.9% reformed, laparotomy; 71.7% versus 25% de novo 1b, laparoscopy). Conclusion(s): Adhesion-free outcome was lowest for reformed, higher for de novo 1b, and highest for de novo 1a adhesions. Surprisingly, it was lower in laparoscopy than in laparotomy for de novo 1b and reformed adhesions. Crystalloid instillates did not increase adhesion-free outcome. Although limited by the retrospective and heterogeneous nature of the data, these conclusions nonetheless provide a basis on which to formulate future hypotheses. (Fertil Steril 1998;70: by American Society for Reproductive Medicine.) Key Words: Adhesions, adhesion-free outcome, adhesion formation, gynecologic surgery, pelvic surgery, meta-analysis, laparotomy, laparoscopy, Ringer s lactate, crystalloids Received February 19, 1998; revised and accepted May 21, Supported by the Genzyme Corporation, Cambridge, Massachusetts. Reprint requests: David M. Wiseman, Ph.D., SYNECHION, Inc., 6757 Arapaho Road, Suite 711, Dallas, Texas (FAX: ; SYNECHION@AOL.COM). * SYNECHION, Inc. Department of Statistics, Rutgers University. Department of Obstetrics and Gynecology, Wayne State University School of Medicine /98/$19.00 PII S (98) Significant clinical (1 4) and economic (5, 6) problems are attributed to adhesions that develop after abdominal or pelvic surgery. In an attempt to solve these problems, a number of agents have been evaluated in animals (7, 8) but few have been subjected to the scrutiny of a randomized clinical study. Currently, three such agents are used for the prevention of adhesions at specific surgical sites: Interceed (TC7) Absorbable Adhesion Barrier (Ethicon, Inc., Somerville, NJ), Seprafilm Bioresorbable Membrane (Genzyme Corporation, Cambridge, MA), and Preclude Membrane (WL Gore & Associates, Inc., Flagstaff, AZ). As alternatives to these barriers, crystalloid solutions such as normal saline (9, 10), Ringer s lactate (11 13), or Ringer s lactate plus drugs such as heparin (12, 14) or corticosteroids (15) are commonly used, despite the absence of controlled, randomized studies which demonstrate their efficacy. These solutions (without drugs) are used in an attempt to keep adjacent peritoneal surfaces away from one another by hydroflotation. The continued use of the crystalloid solutions may be due to several reasons: 1. The crystalloids are inexpensive alternatives to the commercially available barriers. 2. If effective, solutions offer the possibility of preventing adhesions at all peritoneal surfaces, not just those at which a surgical procedure was performed. 3. The solutions are easy to apply, both by laparotomy and laparoscopy. 4. There is a prevailing perception in some 702

2 quarters that barrier agents are no more efficacious than the crystalloid instillates, the efficacy of which has been demonstrated in a number of animal studies (16 19). Other animal studies (20, 21), however, have failed to demonstrate such efficacy. In the absence of well-designed clinical trials that evaluate the efficacy of crystalloid solutions in adhesion prevention, we reviewed available data of the rates of adhesion formation with and without the use of crystalloid solutions in an attempt to determine whether they are efficacious. Although others (22, 23) have discussed this subject generally, this analysis will, to our knowledge for the first time, document in a critical manner the rates of adhesion development (both de novo and reformed) after laparotomy and laparoscopy. Such documentation would provide not only a key for understanding the efficacy of crystalloid solutions, but also serve as a basis for understanding the efficacy of other treatments. MATERIALS AND METHODS Because this was a meta-analysis of written reports that did not involve the study of human subjects, no Institutional Review Board approval was required. The MEDLINE on-line database for the period 1/1/ /18/1996 was searched for clinical reports containing details of rates of adhesion development after abdomino-pelvic surgery. The search strategy used is shown in Table 1. Each abstract in the final result set was reviewed for possible relevance to this project. Reports that were considered relevant were then examined more closely for conformance with the inclusion criteria. For consideration for inclusion in this analysis, reports must have: 1. Involved human subjects who underwent abdominal or pelvic surgery. Reports in which acute infection was likely to have played a role in the etiology of adhesions at the initial surgery were excluded. 2. Included details of, or ability to derive, the incidence of adhesions at the time of initial surgery and at a subsequent observation point. Some reports described only a selected population of patients, such as those who failed to conceive, subsequent to an initial surgery. Because the ability to conceive may be related to the absence of adhesions, the rate of adhesion formation in patients not conceiving may be an overestimate of the rate of adhesion formation in the whole population undergoing the initial surgery. If this type of bias could not be accounted for, the report was excluded from this analysis. Only data regarding incidence of adhesions (i.e., presence or absence) were analyzed. Analysis of adhesion grade was not done because of the diversity of scoring systems. 3. Contained sufficient information to distinguish between type 1a de novo, type 1b de novo, and reformed adhesions. The classification proposed by Diamond and Nezhat (24) was used: TABLE 1 Search strategy run 12/18/96: database: MEDLINE 1966 present. Set Keyword searched No. of matches 001 adhesions/ 4, limit 1 to human 3, second-look.tw. 1, (second adj look).tw. 1, third-look.tw thirdlook.tw secondlook.tw (third adj look).tw (second adj3 look).tw. 1, (third adj3 look).tw or 9 or 10 1, and reoperation/ 20, and not exp heart/ 220, exp heart diseases/ 370, exp lung/ 104, exp lung diseases/ 283, or/ , not pericard$.tw. 12, heart surgery/ 12, or 23 24, not exp abdomen/ 40, exp digestive system diseases/ 610, exp digestive system/ 507, exp urogenital system/ 428, exp urogenital diseases/ 169, exp pelvis/ exp genital diseases, female/ 204, or/ ,523, and not abdom$.ti,ab,sh. or intra-abdom$.tw. 93, and or or 36 1,556, and 13 6, limit 40 to human 6, (adhesion$ or adher$ or synech$).tw. 57, and not or or Note: This is the strategy used to search the MEDLINE database for reports containing data regarding rates of adhesion formation in human subjects. Each line (set) represents a query to the database. Sets may be combined by Boolean logic and standard MEDLINE operating terms and syntax (e.g. tw title word) to limit or expand the scope of the query. Type 1. De novo adhesions: Adhesions occurring at sites with no previous adhesion. 1a: De novo adhesions at sites where no surgical procedure was performed, e.g., adhesions caused by indirect trauma. FERTILITY & STERILITY 703

3 1b: De novo adhesions at sites of a surgical procedure other than adhesiolysis, e.g., adhesions caused by direct trauma. Type 2. Reformed adhesions: Adhesions reforming at sites of previous adhesiolysis. 2a: Adhesions occurring at sites of adhesiolysis only. 2b: Adhesions occurring at sites of adhesiolysis, plus sites of another procedure, e.g., treatment of endometriosis. 4. Clearly delineated between those procedures performed by laparotomy and those performed by laparoscopy. 5. Included a description of whether an instillate of saline, Ringer s lactate, or other crystalloid was used. Patient populations treated with instilled adjuvants such as Dextran 70 or hyaluronic acid were excluded from this analysis. In addition to the MEDLINE search, the personal literature files of two of the authors (D.M.W. and M.P.D.) were examined for other reports not identified by the search. Statistical Methods All statistical comparisons were based on Fisher s exact test. Each group in these comparisons was formed by combining patient populations from one or more studies. Different patient populations formed each of the groups. This meta-analysis was not analyzed in the usual manner because no study had patients or sites which were in both groups that were being compared. Each group was formed by combining the results from the appropriate reports with the combination weighted on the number of patients in each study. Results were considered statistically significant if the two-sided P value was.05. All analyses were performed using Fisher s exact test. Statistical analyses were not performed when only one patient population comprised the group. Patient populations were segregated according to whether the data related to laparotomy versus laparoscopy; de novo 1a, de novo 1b, or reformed adhesions; treatment with crystalloid instillates; or whole patients versus individual surgical sites. If only one anatomical site was examined (e.g., incision line), it was included under the sites categories. This type of datum was not placed in the patients categories that we reserved for data sets containing aggregated information about more than one anatomical site in a way that did not permit identification of adhesion rates at individual anatomical sites. RESULTS Number of Reports Identified A total of 259 reports were identified by the computer search. Of these, 14 were included in this analysis together with 8 reports known to us, but not identified by the search. A summary of the 22 reports analyzed is given in Table 2. In some cases, more than one patient or anatomic site population were derived from one report, thus 31 study populations were available (Table 3). If crystalloid treatments were used in the included reports, they were in all cases Ringer s lactate solution. It was not possible in the reports studied to distinguish adequately between the two types of reformed adhesions. Nature of Exclusions Reports were excluded from the analysis for various and often multiple reasons. Many reports related to patient populations which were treated with Dextran 70 (Pharmacia, Inc., Piscataway, NJ) (47, 48), or based on methods cited, were likely to have included some patients treated with Dextran 70 (49, 50). In the report by the Operative Laparoscopy Study Group (51), one author (M.P.D.) was aware personally that instillates were used in some patients entered into the study. Other reports may have introduced selection biases because only patients failing to conceive (9, 52), or only those patients who had a laparotomy previously and who underwent a subsequent laparoscopy (53), were studied. It was not possible to combine data from reports (14, 54) which used diverse scoring systems. Studies in which rates of adhesion formation for various organs (e.g., adnexa, intestines, omentum) to an operation site (e.g., myomectomy incision) were given, but may have overlapped (14); i.e., the overall rate of adhesion formation for the operation site could not be determined. Studies in which data for de novo and reformed adhesions (55, 56), data for patients with no or only mild adhesions (57), and data for laparotomy and laparoscopy (58) overlapped were also rejected from this analysis, as were studies (59, 60) in which active infection was likely to have been present at the time of first surgery. A number of studies were identified in which de novo adhesions were not segregated into types 1a or 1b. Because of the clear differences between the rates of formation of these two adhesion types, and because data for these studies would depend only on the happenstance and unknown mixture of the adhesion types, comparisons between groups containing these data were considered to be highly unreliable and were not performed. Furthermore, these data are not presented here. Segregation of data for adhesion reformation into the two subtypes 2a and 2b was not possible from the mixed nature of the data given in the reports. Other studies were rejected from the analysis simply because they were obviously irrelevant, e.g., they were reviews, papers dealing with surgical techniques, or papers dealing with other types of complications. Rates of Adhesion Formation and the Effects of Ringer s Lactate on Adhesion Formation in Pelvic Surgery The following comparisons were noted from Table 3. De Novo 1a Versus De Novo 1b Adhesions Comparisons were made between sites capable of developing de novo 1a adhesions and those capable of developing de novo 1b adhesions both for procedures performed at laparotomy (group 4 versus 5) and at laparoscopy (group Wiseman et al. Crystalloids and rate of adhesion development Vol. 70, No. 4, October 1998

4 TABLE 2 Summary of 22 studies analyzed. Author (reference) Year Type of surgery No. of patients/sites* O/C Time to evaluation Notes Myomectomy Adhesion 1995 Myomectomy S 27 O 2 6 wk Study Group (25) Becker et al. (26) 1996 Ileal pouch anastomosis S 90 O 8 12 wk Incision line only; some patients with chronic systemic steroids Hyvarinen et al. (27) 1990 Cholecystectomy S 100 O Autopsy ANT Azziz (28) 1993 Pelvic sidewall adhesiolysis S 134 O d Sekiba et al. (29) 1992 Infertility and endometriosis S 63 O d Nordic Adhesion Prevention Study Group (30) 1995 Infertility S 198 O 4 10 wk Ovaries, tubes, and fimbriae recorded separately Diamond and Sepracoat 1996 Gynecological surgery S 1,734 O 6 wk RL Study Group (31) P 108 O RL Tulandi et al. (32) 1993 Myomectomy S 25 O 6 wk RL (500 ml) Canis et al. (33) 1992 Endometrioma/cystectomy S 36 C 3 6 mo ANT Greenblatt et al. (34) 1993 Polycystic ovarian disease S 7 C 28 d Mais et al. (35) 1995 Myomectomy S 25 C wk Keckstein et al. (36) 1996 Ovarian cystectomy S 17 C 8 30 wk Mais et al. (37) 1995 Endometriosis S 16 C wk Moore et al. (38) 1995 Pediatric urology P 41 C wk Li and Cooke (39) 1994 Microsurgical adhesiolysis P 27 O 3 14 wk HC (IP in 30 ml Intralipid) Swolin (40) 1967 Ectopic pregnancy P 42 O 3 mo Some patients received IP HC acetate (2 g) Jansen (41) 1988 Infertility surgery P 65 O 12 d Some patients received IP and systemic steroids; some patients received IP heparin in ml RL Jansen (42) 1985 Infertility surgery P 61 O 12 d Some patients received IP and systemic steroids; all patients received ml RL Perez (43) 1991 Adhesiolysis P 150 O 7 d Patients treated with RL plus heparin (volume unstated). Instillation assumed. Portuondo et al. (44) 1984 Ovarian wedge resection P 36 C 3 72 mo ANT Gurgan et al. (45) 1992 Polycystic ovarian disease P 19 C 3 4 wk RL (150 ml) Gurgan et al. (46) 1991 Polycystic ovarian disease P 17 C 3 4 wk RL (150 ml) heparin (5 U/mL) Note: ANT treatment unstated, assumed to be none; HC hydrocortisone; RL Ringer s lactate; IP intraperitoneal. * Number of patients (P) or sites (S) considered for analysis. O/C: Procedures performed by open (O, laparotomy) or closed (C, laparoscopy) technique. Time to second-look evaluation of adhesions in days (d), weeks (wk), or months (mo). Denotes a study not identified by the literature search. Intralipid fat emulsion (Pharmacia & Upjohn, Stockholm, Sweden). versus 8). In both cases the adhesion-free outcome was higher for de novo 1a adhesions (group 4, 72%; group 7, 82.4%) than it was for de novo 1b adhesions (group 5, 20%; group 8, 36%). In both comparisons, the groups representing de novo 1a adhesions contained only one study population. For group 4, the study included a large number of anatomical sites (1,734), which, had a statistical comparison made (which it was not, because only one population was involved), some adjustment may have been required to either control or account for the inequity in the sample sizes. De Novo 1b Versus Reformed Adhesions Two comparisons (group 2 versus 3; group 8 versus 9) were made between sites capable of reforming adhesions and those capable of forming de novo 1b adhesions. Both comparisons involved patients not treated with crystalloids. The overall adhesion-free outcome for all of these groups was between 14% and 46%. In surgical sites undergoing laparotomy, the adhesion-free outcome for de novo 1b adhesions (45.2%) was significantly higher (P.00001) than for re- FERTILITY & STERILITY 705

5 TABLE 3 Rates of adhesion formation and reformation from published studies. Type Subtype Crystalloid Adhesion-free outcome* Percentage Number/total No. of patient populations included P value Reference Sites: open 1. De novo 1a No ND 2. De novo 1b No /217 3 (25 27) 3. Reform No / vs. 2 (28 30) 4. De novo 1a Yes ,245/1,734 1 (31) 5. De novo 1b Yes / vs. 2 (32) 6. Reform Yes ND Sites: closed 7. De novo 1a No /17 1 (33) 8. De novo 1b No /51 3 NS vs. 2 (33 35) 9. Reform No /21 2 NS vs. 3 (36, 37) vs De novo 1a Yes ND 11. De novo 1b Yes ND 12. Reform Yes ND Patients: open 13. De novo 1a No /27 1 (39) 14. De novo 1b No ND 15. Reform No /69 3 **(39, 40) 16. De novo 1a Yes 4.6 5/108 1 (31) 17. De novo 1b Yes ND 18. Reform Yes / vs. 15 (41 43) Patients: closed 19. De novo 1a No ND 20. De novo 1b No /53 2 (38, 44) 21. Reform No ND 22. De novo 1a Yes ND 23. De novo 1b Yes / vs. 20 (45, 46) 24. Reform Yes ND Note: ND no data; NS not significant. * Adhesion-free outcome [number of adhesion-free sites (patients)/total sites (patients)]. This number is expressed in both percentage and fractional format. Determined by Fisher s exact test (two-tailed) against group shown. Includes ovaries, tubes, and fimbriae recorded as separate sites in one report (n 66 per site) (30). Includes two data sets from same report (32). One of 16 patients with a posterior myomectomy incision and 4/9 patients with an anterior or fundal incision were free of adhesions at second look. Not included are 99/101 trocar sites free of adhesions after laparoscopic, pediatric urological procedures (38). Comprises the data set from Li and Cooke (39) in which patients were given 750 ml of hydrocortisone acetate in 30 ml Intralipid, IP at the conclusion of surgery. ** Includes one data set from Li and Cooke (39) and two data sets from Swolin (40). In Li and Cooke patients were given 750 ml of hydrocortisone acetate in 30 ml Intralipid, IP at the conclusion of surgery. Nine of 27 patients were adhesion-free. In Swolin (40), one population of patients received no treatment (1/18 adhesion-free) and another received a single IP dose of 2 g hydrocortisone acetate (20/24 patients adhesion-free). Includes data sets in which some patients were treated with systemic or systemic steroids plus IP hydrocortisone sodium succinate. The data are not stratified as to which patients received steroids and by which route. In one data set (42), 8/61 patients failed to reform adhesions. In another study (41), 1/30 and 3/35 patients failed to reform adhesions after receiving ml of Ringer s lactate with or without heparin (5 U/mL), respectively. Data and other information from this study were obtained by direct examination of the graphs given by Jansen (41) and from Jansen (personal communication). Also includes patients treated with Ringer s lactate plus heparin (dose and volume not stated) as irrigation, assumed also to have remained after surgery (43). Thirty-five of 113 patients with adhesiolysis only, and 8/47 patients with adhesiolysis and treatment of endometriosis failed to reform adhesions. These data do not include 24/24 patients adhesion-free after ovarian biopsy from the report by Portuondo et al. (44). Included were 1/12 patients undergoing ovarian wedge resection free of adhesions. Includes one data set (46) in which patients were treated with Ringer s lactate plus heparin 5 U/mL, 3/17 of which were adhesion-free. formed (26.6%) adhesions. In sites undergoing laparoscopy, there was a similar trend between the two types of sites (de novo 1b 37.2% versus 14.3% reformed adhesions), although this difference did not reach significance (P.092). Laparoscopy Versus Laparotomy Two comparisons (group 8 versus 2; group 9 versus 3) were available between sites undergoing laparoscopy versus laparotomy. Crystalloids were not used in any of the groups. 706 Wiseman et al. Crystalloids and rate of adhesion development Vol. 70, No. 4, October 1998

6 In both cases, the adhesion-free outcome was greater in laparotomy (45.2% de novo 1b; 26.6% reformed) than in laparoscopy (37.2% de novo 1b; 14.3% reformed). Use of Ringer s Lactate Four comparisons (group 5 versus 2; group 16 versus 13; group 18 versus 15; and group 23 versus 20) were available to assess the effect of Ringer s lactate on adhesion development. For de novo 1b adhesions at sites undergoing laparotomy, the adhesion-free outcome was greater (P.018) without crystalloid use (45.2%) than with crystalloid use (20%). In patients undergoing laparotomy, the adhesion-free outcome was greater without crystalloid treatment than with it, although only one patient population was present in each group, and the group without crystalloid treatment received steroids. In patients undergoing laparoscopy, the adhesionfree outcome for de novo 1b adhesions was again greater (P.00003) in patients who did not receive Ringer s lactate (71.7%) than in those who did (25%). DISCUSSION Study Inadequacies Before attempting to draw conclusions from this review, we wish to stress that the data contain many obvious inadequacies, thus our conclusions serve only to summarize a trend in the cumulative surgical experience and to permit formulation of hypotheses for future definitive studies. Inadequacies Related to Inclusion of Drug-Treated Patients We included patient populations (26, 39, 40, 42) who were treated (in part or whole) with steroids. Because evidence suggesting that steroids reduce adhesion development is equivocal at best, the commingling of patients treated with steroids with those not so treated is arguably unlikely to influence this analysis. Mainly on the basis of early work by Swolin (40), some have used intraperitoneal (IP) doses of steroids to reduce adhesion formation. Jansen (42) concluded that IP steroids may have a deleterious effect (i.e., to increase adhesions), although the combination of systemic and local steroids may reduce adhesion scores. Larsson (61) found that IP methylprednisolone sodium succinate had no effect on adhesion reformation but may have reduced de novo (possibly type 1b) adhesions in pelvic laparotomy. Systemically and chronically administered steroids may reduce adhesions in patients with bowel disease (26). We also included some patient populations treated with crystalloids containing heparin (41, 43). Jansen concluded that the inclusion of heparin in instillates does not reduce adhesion formation. These inclusions are of course subject to challenge. Inadequacies Related to Time Factors We did not segregate data according to the time elapsed after the initial surgical procedure. Generally, it is believed that early adhesiolysis is helpful because adhesions are still somewhat filmy and easy to lyse, although data to support this assertion have not been forthcoming. We did not analyze data for severity of adhesions; however, there are several indications that the incidence of adhesions changes little over time. Trimbos-Kemper et al. (62) showed that the incidence of adhesions was approximately the same in (dextran and corticosteroid treated) patients given early (8 day) or late ( 12 month) second-look examinations. This finding must be tempered with possible selection bias because of the slightly increased pregnancy rate in the first group. In other studies involving gynecologic pelvic surgery, no relationship was found between time to second-look procedure and various measures of adhesion formation (28, 49). Inadequacies Related to Etiology, Anatomic Site, and Technique Because infections are themselves highly variable and because they could introduce additional complexity to the current analysis, we specifically excluded patient populations (59, 60) in which an infection was ongoing at the time of the first surgery. Other than to exclude patients with adhesions associated with an active infection, we did not segregate data according to etiology or reason for surgery, such as endometriosis or ovarian cyst. The inflammatory processes associated with endometriosis may well enhance adhesion development. In one study, patients (29) undergoing adhesiolysis by laparotomy with and without endometriosis were reported separately. Only 18% (5/28) of pelvic sidewalls of patients with severe endometriosis were adhesion-free at second look, compared with 29% (9/31) of pelvic sidewalls of patients without endometriosis. We did not attempt to segregate data according to the techniques used such as sharp dissection, laser, and electrocautery, nor have we segregated data according to surgical site, e.g., incision lines or ovaries. Although one study was identified which reported the rate of adhesion formation to trocar sites (38), these data were not aggregated with other data for de novo 1b adhesions because this type of injury was not considered to be representative of the other sites included in this category. For a similar reason the patient population undergoing ovarian biopsy was also excluded (44). Surgical technique may play a major role in the development of adhesions. For example, in a study rejected from this analysis, Kadanah et al. (54) found that adhesion scores in patients undergoing pelvic and paraaortic lymphadenectomy were significantly lower when the peritoneum was left open. In another study (63), excluded because of the use of Dex- FERTILITY & STERILITY 707

7 tran 70, no statistically significant difference was found in the incidence of adhesions to the anterior abdominal wall, with or without peritoneal closure. Inadequacies Related to Patient Populations Most of the studies used in this analysis involved patients undergoing gynecological procedures. Only three reports involved other procedures or sites; namely, abdominal incision lines (26), cholecystectomy (27), and pediatric urological procedures (38). Perhaps the most interesting and significant procedures occur in general surgery where bowel adhesions may occur, of which there are none represented in this analysis. There are several estimates of the prevalence of adhesions after general surgery. Meier et al. (64) found that 2.6% of pediatric laparotomies resulted in adhesive strangulation. Direct estimates of the rates of adhesion formation after general surgery are, however, few. In a large series of autopsies at a Swiss Cantonal hospital (65), only 33% of patients who had undergone surgery were free of adhesions. This number was reduced to 19% and 7% for patients with major and multiple procedures, respectively. Similarly, Menzies and Ellis (2) found that 93% of patients who had undergone at least one previous abdominal operation had adhesions, compared with only 10.4% of patients who had never had a previous abdominal operation. Furthermore, 1% of all laparotomies developed obstruction as a result of adhesions within 1 year of surgery. Expansion of these data for general surgery will be essential to understanding the impact of agents designed to reduce adhesion development. Other Inadequacies Although a comprehensive literature search was considered to have been conducted, clearly a number of studies known to us were not captured by the search. One of these studies (26) was published just shortly before the search was conducted and may not yet have been entered into the database. Another study (31) was in abstract form only. This leaves six other studies (29, 35, 36, 40 42) for which exclusion from the search could not be accounted for. The reports discussed herein represent surgery performed over a period of approximately 30 years and in several countries. The association between surgical glove powder and adhesions has been known for many years (66). Weibel and Majno (65) found that foreign bodies were associated with adhesions in two thirds of the cases examined; in two-thirds of these the foreign body was talcum powder. Starch-powdered gloves may also leave residues, depending on whether the gloves were washed prior to surgery (6), and starch itself may act as a vector for endotoxin (67). Thus unknown variations in the types of glove used among surgeons, hospitals, and even between different time periods may temper the conclusions drawn in this analysis. In some studies the use or nonuse of instillate solutions was not always positively indicated in the paper reviewed. In one case (51), instillates were in fact used in some patients, although this was not indicated in the report. Rates of Adhesion Development Some general conclusions can be drawn from the data presented herein, although these conclusions must be tempered by a consideration of the inadequacies of this analysis as well as the paucity of data in some of the study populations. The rate of adhesion development appears, in general, to be highest for reformed adhesions, lower for de novo 1b adhesions, and lowest for de novo 1a adhesions. This accords with empirical clinical experience implied by Diamond and Nezhat s (24) classification of adhesions into types 1a, 1b, 2a, and 2b. Many clinicians continue to suggest that adhesion development is less after laparoscopy than laparotomy, although clinical data do not substantiate this notion. In a prospective trial, Lundorff et al. (52) found that patients undergoing surgery for ectopic pregnancy by laparotomy developed more adhesions than those undergoing similar procedures by laparoscopy. Unfortunately, not all patients were evaluated at second look and therefore, this study could not be included in the present analysis. Characterizing more precisely the benefit of laparoscopy in reducing adhesion development, there have been several suggestions (68) that de novo (type 1a) adhesions are eliminated almost completely in laparoscopy. We have insufficient data to support this notion. Comparing the rates of adhesion development for de novo 1b and reformed adhesions, we found that the adhesion-free outcome was slightly reduced in laparoscopy compared with laparotomy in both cases. If this finding is correct, this may be a reflection of a reduced ability of surgeons to handle tissues atraumatically at direct sites of surgery. Use of Crystalloids In three sets of comparisons, we found that the use of crystalloids decreased the adhesion-free outcome. On the basis of results from animal studies, we believe that a number of factors may influence the efficacy of the crystalloid solution, including the volume of solution (69) and temperature (70). One study (71) demonstrated a reduction in adhesions using Ringer s lactate saturated with carbon dioxide but not with normal saline solution that was similarly saturated. Clinically, there are several lines of evidence that suggest that crystalloid solutions are ineffective. In patients undergoing infertility procedures, Rosenberg and Board (48) compared the effects of Ringer s lactate (200 ml) with those of Dextran 70. Although no data on incidence of adhesions were presented, patients treated with Ringer s lactate experienced a net increase in adhesion score from first-look 708 Wiseman et al. Crystalloids and rate of adhesion development Vol. 70, No. 4, October 1998

8 laparotomy to second-look laparoscopy. In contrast, the use in other studies (28 30, 55) of good surgical technique alone (without Ringer s lactate solution) resulted in an improvement in adhesions from first to second looks. In separate studies performed by Larsson and colleagues using identical scoring systems, adhesion scores obtained with good surgical technique, but no saline instillate (30), were comparable to those obtained with saline instillation (72), suggesting that the effect of saline was negligible. The effects, or lack thereof, may be specific to different procedures. Jansen (42) conducted an intricate analysis of the effects of Ringer s lactate and other adjuvants in patients undergoing a variety of pelvic operations. Improvements in adhesions scores (first look to second look) were observed in patients undergoing salpingolyses and operations for endometriosis, and those treated with Ringer s lactate only. Improvements were not observed in patients undergoing tubal resections and anastomoses. Other lines of evidence, albeit circumstantial, suggest that crystalloid solutions are unlikely to reduce the formation of adhesions. It is widely believed (7, 8, 22) that adhesions may be prevented if peritoneal surfaces are kept apart during the period of remesothelialization, believed to last 3 7 days in uncomplicated circumstances. Two studies suggest that fluid absorption is too rapid for sufficient fluid to be present for activity, if indeed hydroflotation is the mechanism of action. In the first of these studies, Shear et al. (73) measured the rate of absorption from the abdomen after IP infusion of 1,000 ml saline into four patients with renal disease or metastatic melanoma. After equilibration, fluid was absorbed at a rate of ml/h. Thus, an instillation of 350 ml would be absorbed within 10 hours, well before the time taken for peritoneal healing. Using ultrasound examinations in patients undergoing pelvic procedures for adhesion prevention, Sites et al. (11) found by ultrasonographic methods that 24 hours after instillation of 250 ml of Ringer s lactate, the volume of fluid found in the pelvis was 12 ml. This was no different (7 ml) from the volume found in patients in whom no fluid was instilled. Furthermore, because Hyskon was found to persist longer than Ringer s lactate, and Hyskon itself is only marginally efficacious in adhesion prevention, it is unlikely that the efficacy of Ringer s lactate will be any better, assuming a similar mechanism of action. Other studies suggest that peritoneal lavage may in fact deplete resident macrophages which appear to protect against adhesion formation. Ar Rajab et al. (74) found that a peritoneal lavage in rabbits increases adhesion formation, an effect that could be reversed by reconstituting the rabbits with peritoneal cells from animals activated prior to surgery with peptone broth. Arguments have been made that the IP placement of large volumes of instillate may also compromise bacterial clearance and may enhance infection after surgery (23). As a counter to these arguments, it must be noted that hyperosomotic crystalloid solutions (often containing glucose) have been used for many years in chronic peritoneal dialysis. A small number (0.9%) (75) of patients may develop sclerosing encapsulating peritonitis, which involves, inter alia, extensive peritoneal adhesions, the causes of which may be multifactorial. The pathogenesis of this and related conditions such as tanned peritoneum syndrome (in which the peritoneum is dry, wrinkled, and light brown in color, with a leathery appearance) has been described extensively (76) in the nephrology literature but has not received extensive consideration in the literature of surgical adhesions. Nonetheless, there have been several attempts, in animals, to use dialysis solutions for adhesion prevention either by single (77, 78) or multiple (79) doses. Comments Regarding Reporting of Data for Adhesions in Clinical Studies Because of the differences suggested in this analysis between the rates of development of de novo 1a, de novo 1b, and reformed adhesions, it seems imperative that future reports concerning adhesions should describe clearly the types of adhesions under study. This would also permit more efficient decision making concerning potential treatments for adhesions. In addition, reports should include a statement of the absolute number of sites and/or patients that are free of adhesions, for each type of adhesion. Because patient populations may be subjected to a selection bias as a result of drop-outs, this must be described carefully in any report concerning rates of adhesion development. Scoring systems designed to describe the extent and severity of adhesions are clearly needed. Even standardized scoring systems are subject to intraobserver and interobserver (80 82) variation. Nonstandardized scoring systems are somewhat helpful in determining an overall trend. However, it is difficult to compare one study to the next and to perform meta-analyses, even at a low degree of sophistication such as in the analyses performed here. The surgeon s goal of achieving adhesion-free surgery can be measured by recording the presence and absence of adhesions at distinct anatomical sites. This type of measurement is easily understood, quantified, and subjected to statistical analysis. We propose therefore, that even if a scoring system is used, it should be supplemented by a statement of the number of sites and/or patients that have or do not have adhesions. In conclusion, our stated objectives were to review in a critical manner the rates of adhesion development (de novo and reformed; laparotomy and laparoscopy) with and without the use of crystalloid solutions in an attempt to determine whether they are efficacious. Tempered by obvious inadequacies inherent in this type of analysis, we confirmed em- FERTILITY & STERILITY 709

9 pirical surgical impressions that the rate of adhesion development appears to be highest for reformed adhesions, lower for de novo 1b adhesions, and lowest for de novo 1a adhesions. Surprisingly, adhesion-free outcome was reduced slightly in laparoscopy compared with laparotomy for both de novo 1b and reformed adhesions. This may be a reflection of a reduced ability of tissues to be handled atraumatically at direct sites of laparoscopic surgery. The use of crystalloid solution instillates did not appear to reduce adhesion development. Thus, in the absence of a definitive, controlled clinical trial, their use is not warranted. 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