Gere S. diZerega

Clinical problem of intraperitoneal postsurgical adhesion formation following general surgery and the use of adhesion prevention barriers

Because of multiple studies demonstrating barrier efficacy, adhesion prevention adjuvants have received widespread acceptance in appropriate surgical settings. Many investigators are incorporating adhesion prevention barriers into their routine clinical practice and are achieving good results. Although both Seprafilm and Interceed barriers were shown to be safe and effective in all human clinical trials, their use did not eliminate adhesions in all patients. Efficacy of these barriers is limited to surgical situations in which the area in question can be completely covered. Physician acceptance is constrained by technical difficulties, including the need for hemostasis and removal of excess peritoneal fluid (Interceed), as well as limitations in application and handling properties within the surgical field (Seprafilm).

Effect of angiotensin II on hematopoietic progenitor cell proliferation.

Angiotensin II (AII) induced the proliferation of hematopoietic progenitor cells (HPC) isolated from murine bone marrow or human cord blood. The formation of colonies with more than 50 cells increased approximately five‐sevenfold in cultures of murine lineage‐negative (Lin−) bone marrow cells both in the presence (day 10) and absence (day 13) of colony‐stimulating factors (CSF). This could be blocked with addition of Losartan, an antagonist of AIITR1. The increase in proliferation of early hematopoietic progenitors (Lin−Sca l+ cells) by AII was approximately threefold and occurred only in the presence of CSF, suggesting that AII may affect mesenchymal stromal cells to induce CSF production and might directly affect early HPC. These in vitro studies were replicated with human HPC isolated from cord blood. AII also accelerated the proliferation and formation of colony‐forming units (CFU)‐granulocyte/erythroid/macrophage/megakaryocyte and CFU‐granulocyte/macrophage colonies by CD34+CD38− enriched progenitors but only in the presence of CSF. Additional studies also indicated that AII can act to increase proliferation in suspension culture. Exposure of CD34+ cells to AII in suspension culture, prior to placement in a semisolid medium with erythropoietin, increased the formation of colonies with more than 50 cells and erythroid progenitors approximately five‐ and 20‐fold, respectively. Further, mRNA for the AT1a receptor was expressed by human bone marrow CD34+CD38− cells, CD34+CD38− cells, and lymphocytes, but not mature myeloid cells. Similarly, mRNA for the AT1a receptor was expressed on human stromal cell clones, offering further support to the hypothesis that AII acts partially through the mesenchymal compartment of the bone marrow. These data suggest that AII may be a factor which stimulates the proliferation of hematopoietic progenitors.

A comparison of clindamycin-gentamicin and penicillin-gentamicin in the treatment of post-cesarean section endomyometritis.

A random comparison of clindamycin-gentamicin (C-G) and penicillin-gentamicin was made in 200 women who developed endomyometritis following cesarean section. All pretreatment profiles indicated similar populations. The clinical response was more favorable in the women receiving clindamycin-gentamicin. The implications of these results upon clinical practice is discussed.

Reduction of postsurgical adhesions with intergel® adhesion prevention solution: a multicenter study of safety and efficacy after conservative gynecologic surgery

OBJECTIVE To assess the safety and efficacy of the Intergel adhesion prevention solution, a 0.5% ferric hyaluronate gel, in reducing adhesions in patients undergoing peritoneal cavity surgery by laparotomy with a planned second-look laparoscopy. DESIGN Randomized, third-party blinded, placebo-controlled, parallel group. SETTING Eleven centers in the United States, and five centers in Europe. PATIENT(S) Women aged 18-46 years who wanted to retain their fertility. INTERVENTION(S) Patients received 300 mL of Intergel solution (n = 143) or lactated Ringers solution (n = 138) as an intraperitoneal instillate at the completion of surgery. MAIN OUTCOME MEASURE(S) At second-look laparoscopy 6-12 weeks later, the presence of adhesions was evaluated at 24 abdominal sites. RESULT(S) Patients treated with Intergel solution (n = 131) had significantly less adhesions compared to controls (n = 134). Adhesion extent and severity were also significantly reduced. The American Fertility Society score for adnexal adhesions was reduced 59% in the patients in whom the Intergel solution was used. The safety profile of the patients treated with the Intergel solution was comparable to those treated with lactated Ringers solution. CONCLUSION(S) The Intergel solution was safe and highly efficacious in reducing the number, severity, and extent of adhesions throughout the abdomen after peritoneal cavity surgery.

Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome

Serum measurements of bioactive (bio) luteinizing hormone (LH), immunoreactive (i) LH, iLH/follicle-stimulating hormone (FSH) ratios, serum androgens and estradiol (E2) were determined in 20 women with the clinical diagnosis of the polycystic ovary syndrome (PCO), and compared with the levels of 10 women with chronic anovulation (CA) and 10 control subjects in the early follicular phase. Women with CA and control subjects had similar levels of E2, androgens, bioLH, iLH, and iLH/FSH ratios. Fourteen of 20 women with PCO had levels of iLH exceeding 3 standard deviations (SD) of the levels of control women (21 mIU/ml), and 13 of 20 had iLH/FSH ratios above 3.2 (3 SD of control levels). Nineteen of 20 women, however, had bioLH levels above 70 mIU/ml (3 SD of control levels). Mean levels for bioLH were 131 +/- 18 in PCO, 39 +/- 3 in control subjects, and 40 +/- 3 in women with CA. The ratio of bioLH/iLH was 3.5 +/- 0.4 in control subjects and 3.2 +/- 0.3 in women with CA but significantly elevated in PCO (4.6 +/- 0.4, P less than 0.05). There was, however, a significant positive correlation between bioLH and iLH values in PCO (r = 0.64, P less than 0.01). A significant correlation was found between bioLH and serum testosterone as well as between bioLH and serum dehydroepiandrosterone sulfate (DHEA-S) (P less than 0.05), although no correlation was found between iLH and serum DHEA-S. Weight and obesity also did not correlate with either iLH or bioLH in women with PCO and CA. These data suggest that bioLH may be an important hormonal marker in the clinical diagnosis of PCO.

Reduction of adhesion formation by postoperative administration of ionically cross-linked hyaluronic acid

OBJECTIVE To examine the efficacy of various formulations of hyaluronic acid (HA), including HA ionically cross-linked with trivalent iron, in animal models of adhesion formation. DESIGN Hyaluronic acid formulation of varying concentrations and cross-linked densities were prepared and evaluated in a rabbit uterine horn model and a rabbit sidewall model. SETTING ETHICON, Inc., Somerville, New Jersey. SUBJECT(S) New Zealand White rabbits. INTERVENTION(S) Test formulations were applied as intraperitoneal instillates after surgery. MAIN OUTCOME MEASURE(S) Adhesion formation was assessed at 7 and 14 days (sidewall and uterine horn model, respectively). RESULT(S) Hyaluronic acid that was not ionically cross-linked was ineffective in reducing adhesions in these models even at high viscosity, whereas the ionically cross-linked formulations of HA with trivalent iron were highly effective. Efficacy improved with increased levels of ionic cross-linking. Flowable gels, which could be delivered readily by syringe and cannula, also were effective when administered at a site remote from injury and with saline present. CONCLUSION(S) Whereas previous studies show that HA was effective in reducing adhesions peripheral to the site of injury, HA ionically cross-linked with trivalent iron was effective in reducing adhesions at all sites. From these studies, a formulation of HA ionically cross-linked with trivalent iron, 0.5% Ferric Hyaluronate Gel (LUBRICOAT; ETHICON, Inc., Somerville, NJ), was identified for subsequent clinical evaluations.

Synergistic effects of INTERCEED(TC7) * and heparin in reducing adhesion formation in the rabbit uterine horn model † ‡

Surgical adjuvants are commonly employed to reduce the frequency of postoperative adhesion development after reproductive pelvic surgery. The ability of indomethacin, promethazine dexamethasone, Intralipid, progesterone, and heparin to reduce adhesion formation in combination with INTERCEED(TC7) (Johnson and Johnson Medical, Inc., New Brunswick, NJ), an absorbable barrier that alone reduces adhesion formation, was examined in a rabbit uterine horn model. A significant reduction in adhesion formation was only observed with the combination of INTERCEED(TC7) plus heparin. In addition studies, heparin delivery by intraperitoneal (IP) lavage, intravenous injection, or intra-abdominal instillation failed to demonstrate efficacy. Similarly, heparin delivery with other barriers or IP instillates (carboxymethylcellulose or 32% Dextran 70) failed to reduce adhesion formation. We conclude that INTERCEED(TC7) can be efficaciously utilized as a carrier to deliver heparin to traumatized surfaces, thereby reducing adhesion formation.

Gynaecological endoscopic evaluation of 4% icodextrin solution: a European, multicentre, double-blind, randomized study of the efficacy and safety in the reduction of de novo adhesions after laparoscopic gynaecological surgery

BACKGROUND Gynaecological laparoscopic surgery outcomes can be compromised by the formation of de novo adhesions. This randomized, double-blind study was designed to assess the efficacy and safety of 4% icodextrin solution (Adept(®)) in the reduction of de novo adhesion incidence compared to lactated Ringers solution (LRS). METHODS Patients undergoing laparoscopic surgery for removal of myomas or endometriotic cysts were treated with randomized solution as an intra-operative irrigant and 1l post-operative instillate. De novo adhesion incidence (number of sites with adhesions), severity and extent were independently scored at a second-look procedure and the efficacy of the two solutions compared. The effect of surgical covariates on adhesion formation was also investigated. Initial exploratory analysis of individual anatomical sites of clinical importance was progressed. RESULTS Of 498 patients randomized, 330 were evaluable (160 LRS--75% myomectomy/25% endometriotic cysts; 170 Adept--79% myomectomy/21% endometriotic cysts). At study completion, 76.2% LRS and 77.6% Adept had ≥ 1 de novo adhesion. The mean (SD) number of de novo adhesions was 2.58 (2.11) for Adept and 2.58 (2.38) for LRS. The treatment effect difference was not significant (P = 0.909). Assessment of surgical covariates identified significant influences on the mean number of de novo adhesions regardless of treatment, including surgery duration (P = 0.048), blood loss in myomectomy patients (P = 0.019), length of uterine incision in myomectomy patients (P < 0.001) and number of suture knots (P < 0.001). There were 15 adverse events considered treatment-related in the LRS patients (7.2%) and 18 in the Adept group (8.3%). Of 17 reported serious adverse events (9 LRS; 8 Adept) none were considered treatment-related. CONCLUSIONS The study confirmed the safety of Adept in laparoscopic surgery. The proportion of patients with de novo adhesion formation was considerably higher than previous literature suggested. Overall there was no evidence of a clinical effect but various surgical covariates including surgery duration, blood loss, number and size of incisions, suturing and number of knots were found to influence de novo adhesion formation. The study provides direction for future research into adhesion reduction strategies in site specific surgery.

Reduction of epidural fibrosis in lumbar surgery with Oxiplex adhesion barriers of carboxymethylcellulose and polyethylene oxide.

BACKGROUND CONTEXT Postsurgical epidural adhesions and fibrosis after surgery for lumbar disc herniation are a consequence of normal wound healing. The presence of fibrosis renders reoperations risky, and in some patients fibrosis may lead to nerve root tethering. PURPOSE One approach to minimizing the risk of developing epidural adhesions is to provide a barrier between the dural membrane and the healing connective tissues. The purpose of these studies was to evaluate such a barrier device. STUDY DESIGN/SETTING In vivo investigation in an animal model at a university laboratory. PATIENT SAMPLE Rabbit. OUTCOME MEASURES Gross and histomorphic evaluation. METHODS Barriers comprised of carboxymethylcellulose (CMC) and polyethylene oxide (PEO) (Oxiplex; FzioMed, Inc., San Luis Obispo, CA) were studied as devices to reduce epidural adhesion formation in rabbit laminotomy and laminectomy models. The barriers tested were either a gel alone (gel) or a gel covered with a film (gel/film combination). Two laminotomy or laminectomy sites (depending on the surgical method) were created in each rabbit at L4 and L6. One site was treated with a CMC/PEO gel, or CMC/PEO gel/film combination, and the other site served as a surgical control. Two surgical models that differed in the extent of adhesion formation at untreated injury sites and the method of injury generation were used. RESULTS Model A, which did not incorporate dural abrasion, resulted in up to 40% adhesion-free laminectomy sites in controls. Model B, which did incorporate abrasion of the dural membrane, resulted in less than 10% adhesion-free laminotomy sites in controls. Compositions of CMC/PEO gels (2.5% to 10% PEO) and films (22.5% PEO) were tested in both models. Efficacy parameters included measuring the number of sites free of epidural fibrosis and reduction in the severity of fibrosis (adhesions). Both gels and gel/film combinations consistently reduced the frequency and the extent of epidural fibrosis in both models. Gels of CMC/PEO containing a higher content of PEO (10%) and a higher molecular weight of PEO (4.4 mD) were most effective in Model B and resulted in up to 84% laminotomy sites with minimal or no epidural fibrosis, whereas controls exhibited over 90% of the sites with epidural fibrosis. Histological evaluation of the surgical sites indicated that the reduction of epidural fibrosis was accompanied by normal bone healing. In addition, these experiments demonstrated that the gel/film combination provided no additional benefit to that obtained by the gel alone. CONCLUSIONS Gels of CMC/PEO reduced epidural fibrosis and did not impair normal heal ing.

Ibuprofen inhibition of postsurgical adhesion formation: a time and dose response biochemical evaluation in rabbits

Recently, a reduction in postoperative adhesion formation in rabbits which received high-dose ibuprofen (280 mg/kg/day) treatment in the perioperative interval was reported. Because these results could have resulted from a nonspecific effect of ibuprofen, the effects of ibuprofen on peritoneal injury in a time and dose response fashion was evaluated. Seventy rabbits were assigned to seven groups. All rabbits received a dose of ibuprofen 1 hr prior to surgery. The time of the second dose was either 8 or 12 hr after the surgical procedure; 8 hr for groups A, C, and E; 12 hr for groups B, D, and F (A, B: 70 mg/kg; C, D: 35 mg/kg; E, F: 17.5 mg/kg, respectively). Thereafter, rabbits received further dosing every 6 hr to complete a total 10-dose regimen. Group G served as a nontreatment control. Surgical injury was induced by either abrasion or ischemia of the right uterine horn. Immediately after closing the incision, 10 muCi of 14C-labeled glucosamine and 10 muCi of 14C-labeled proline were injected into each rabbit. All rabbits underwent a second laparotomy on the fifth postoperative day for evaluation of adhesion formation. Uterine tissue adjacent to the site of uterine healing was excised for determination of glycosaminoglycan and collagen concentration. In the nontreatment control group G, 5 of the 10 rabbits had severe grade 2 adhesions at the time of second laparotomy, 3 had grade 1 filmy adhesions, and 2 had no adhesions. This is in marked contrast (P less than 0.025) to the group that received ibuprofen at 70 mg/kg/day with the first postoperative dose 8 hr after surgery (group A). In this group, no rabbits had severe grade 2 adhesions, 3 rabbits had filmy grade 1 adhesions, and 7 rabbits were free of pelvic adhesions. A gradual tendency towards more adhesions and more severe adhesions was apparent in groups B-F as the dose of ibuprofen was decreased and the time of first postoperative injection was prolonged. The recovery of 14C-labeled glucosamine from the glycosaminoglycan extraction demonstrated a positive correlation between the cpm recovered and the severity of adhesions formed. Groups A and B had, overall, the lowest ratios of glucosamine (1.47 +/- 0.08 and 1.56 +/- 0.09, respectively) which were statistically different from the nontreatment control group G (1.76 +/- 0.11, P less than 0.05). There was also a positive correlation between the formation of severe adhesions and the ratio of 14C-labeled proline recovered by collagen extraction.(ABSTRACT TRUNCATED AT 400 WORDS)