Efficacy of a novel polyoxazoline-based hemostatic patch in liver and spleen surgery.

BACKGROUND: A new hemostatic sealant based on a N-hydroxy-succinimide polyoxazoline (NHS-POx) polymer was evaluated to determine hemostatic efficacy and long-term wound healing and adverse effects in a large animal model of parenchymal organ surgical bleeds. METHODS: Experiment 1 included 20 pigs that were treated with two NHS-POx patch prototypes [a gelatin fibrous carrier (GFC) with NHS-POx and an oxidized regenerated cellulose (ORC) with poly(lactic-co-glycolic acid)-NHS-POx:NU-POx (nucleophilically activated polyoxazoline)], a blank gelatin patch (GFC Blank), TachoSil® and Veriset™ to stop moderate liver and spleen punch bleedings. After various survival periods (1-6 weeks), pigs were re-operated to evaluate patch degradation and parenchymal healing. During the re-operation, experiment 2 was performed: partial liver and spleen resections with severe bleeding, and hemostatic efficacy was evaluated under normal and heparinized conditions of the two previous prototypes and one additional NHS-POx patch. In the third experiment an improved NHS-POx patch (GATT-Patch; GFC-NHS-POx and added 20% as nucleophilically activated polyoxazoline; NU-POx) was compared with TachoSil®, Veriset™ and GFC Blank on punch bleedings and partial liver and spleen resections for rapid (10s) hemostatic efficacy. RESULTS: NHS-POx-based patches showed better (GFC-NHS-POx 83.1%, ORC-PLGA-NHS-POx: NU-POx 98.3%) hemostatic efficacy compared to TachoSil® (25.0%) and GFC Blank (43.3%), and comparable efficacy with Veriset™ (96.7%) on moderate standardized punch bleedings on liver and spleen. All patches demonstrated gradual degradation over 6 weeks with a reduced local inflammation rate and an improved wound healing. For severe bleedings under non-heparinized conditions, hemostasis was achieved in 100% for Veriset™, 40% for TachoSil and 80-100% for the three NHS-POx prototypes; similar differences between patches remained for heparinized conditions. In experiment 3, GATT-Patch, Veriset™, TachoSil and GFC Blank reached hemostasis after 10s in 100%, 42.8%, 7.1% and 14.3%, respectively, and at 3 min in 100%, 100%, 14.3% and 35.7%, respectively, on all liver and spleen punctures and resections. CONCLUSIONS: NHS-POx-based patches, and particularly the GATT-Patch, are fast in achieving effective hemostatic sealing on standardized moderate and severe bleedings without apparent long-term adverse events.

A novel ex vivo perfusion-based mandibular pig model for dental product testing and training.

BACKGROUND: A translational ex vivo perfusion-based mandibular pig model was developed as an alternative to animal experiments, for initial assessment of biomaterials in dental and maxillofacial surgery and training. This study aimed to assess the face and content validity of the novel perfusion-based model. METHODS: Cadaveric porcine heads were connected to an organ assist perfusion device for blood circulation and tissue oxygenation. Dental professionals and dental trainees performed a surgical procedure on the mandibula resembling a submandibular extraoral incision to create bone defects. The bone defects were filled and covered with a commercial barrier membrane. All participants completed a questionnaire using a 5-point Likert scale to assess the face and content validity of the model. Validation data between the two groups of participants were compared with Mann-Whitney U test. RESULTS: Ten dental professionals and seven trainees evaluated the model for face and content validity. Participants reported model realism, with a mean face validity score of 3.9 ± 1.0 and a content validity of 4.1 ± 0.8. No significant differences were found for overall face and content validity between experts and trainees. CONCLUSION: We established face and content validity in a novel perfusion-based mandibular surgery model. This model can be used as an alternative for animal studies evaluating new biomaterials and related dental and maxillofacial surgical procedural training.

New polyoxazoline loaded patches for hemostasis in experimental liver resection.

A new cost-effective NHS functionalized polyoxazoline (POx) loaded polymer with strong hemostatic properties has been developed. In this study, we investigate POx loaded hemostatic patches regarding hemostatic efficacy, local inflammatory reaction and wound-healing, as compared to the non-POx treated blanks and commercially available hemostatic products. Hundred and ten rats divided into 11 groups of 10 animals underwent partial liver lobe resection. Eight groups received experimental patches, two groups commercially available hemostatic patches (TachoSil® and Veriset™, positive controls), one group with gauzes (negative control). Each animal received twice a patch with a size 1.5 × 2.5 cm, on each partially resected lobe. Primary endpoint was time to hemostasis (TTH). The rats were sacrificed at different time points (1, 3, or 7 days) to measure local inflammatory response and early wound healing. Of the POx loaded patches, GFC NHS-POx (TTH 20.4 s, p = .019) and GFC-NHS-POx1.5 (TTH 0.0 s, p = .003) showed significantly faster TTH compared to TachoSil® (TTH 95.4 s), and were comparable to Veriset™ (TTH 17.0 s). Three patches, GFC-NHS-POx 1.5 (TTH 0.0 s, p = .016), ORC NHS-POx:NU-POx (TTH 91.4 s, p = .033), and ORC-PLGA NHS-POx:NU-POx (TTH 105.6 s, p = .04) had a lower TTH compared to their own blank carrier (TTH 74.9, 157.8, and 195.7 s, respectively). With regard to biocompatibility, all POx loaded patches showed results comparable to TachoSil® and Veriset™. NHS-POx-loaded hemostatic patch demonstrate fast and effective hemostasis, comparable or better than commercially available hemostatic patches, with similar early biocompatibility.

The Efficacy of an Ultrapure Alginate Gel in Reducing Adhesion Formation in a Rat Model of Blood Contamination.

BACKGROUND: Formation of peritoneal adhesions is the most frequent complication of abdominal and pelvic surgery and comprises a lifelong risk of adhesion-related morbidity and mortality. Some of the existing antiadhesive barriers are less effective in the presence of blood. In this study, we investigate the efficacy and safety of ultrapure alginate gel in the presence of blood. METHODS: In experiment 1 (30 rats), 1 mL ultrapure alginate gel was compared with no intervention in a model of cecal abrasion and persisting peritoneal bleeding by incision of the epigastric artery. In experiment 2 (30 rats), 2 mL ultrapure alginate gel was compared with no intervention in a model where a 1 mL blood clot was instilled intra-abdominally and a cecal resection was performed. The primary endpoint was the incidence and severity of adhesions after 14 d. RESULTS: In experiment 1, seven of 15 rats in the experimental group had intra-abdominal adhesions compared with 13 of 15 rats in the control group (P = 0.05); 3 of 15 rats had adhesions at the site of injury compared with 12 of 15 rats in the control group (P < 0.01). The severity and extent of adhesions was also reduced (P < 0.01). In experiment 2, 12 of 13 rats had adhesions compared with 13 of 14 rats in the control group (P = 1.00). CONCLUSIONS: Ultrapure alginate gel reduces the incidence and severity of adhesion in the presence of persisting bleeding, but not in a model of cecal resection and blood clot.

Innate glycosidic activity in metallic implants for localized synthesis of antibacterial drugs.

Iron-containing metallic implants are shown herein to mediate hydrolysis of glycosidic linkages. Using glucuronide prodrugs for broad-spectrum fluoroquinolone antibacterial agents, we capitalize on this behaviour and perform localized synthesis of antimicrobials which affords a significant zone of inhibition of bacterial growth around the metallic material.

Microbial Glucuronidase Inhibition Reduces Severity of Diclofenac-Induced Anastomotic Leak in Rats.

BACKGROUND: The non-steroidal anti-inflammatory drug diclofenac has been associated with intestinal anastomotic leakage, although the underlying pathophysiology is unclear. Previous data suggest that reactivation of biliary diclofenac metabolites by microbial ß-glucuronidases in the gut plays a role in harming the intestinal mucosa, and that microbiome-targeted glucuronidase inhibition prevents this damage. Here, the microbial glucuronidase inhibitor Inh1 was examined for its ability to reduce diclofenac-induced anastomotic leakage in rats. METHODS: Ninety male Wistar rats were allocated to five groups. In the two diclofenac groups, group DCF received diclofenac (3 mg/kg per day) and group DCF-Inh1 additionally received 800 mcg/kg per day of glucuronidase inhibitor Inh1 solution orally. In non-diclofenac groups, animals received either Inh1 (800 mcg/kg per day; group Inh1) solution, the vehicle (methylcellulose; group Veh), or no solution (group Ctrl). All solutions were provided from the day of surgery until sacrifice on day three. Plasma concentrations of diclofenac were determined. Outcomes were anastomotic leakage, leak severity, and anastomotic strength. RESULTS: Anastomotic leak rates were 89% in group DCF and 44% in group DCF-Inh1 (p = 0.006). Leak severity was reduced in group DCFic-Inh1 (p = 0.029). In non-diclofenac cohorts, mostly minor leakage signs were observed in 25% in group Ctrl, 39% in group Inh1 (0.477), and 24% in group Veh (p = 1.000). Bursting pressure and breaking strength were not significantly different. Plasma concentrations of diclofenac were not changed by Inh1. CONCLUSION: Microbial glucuronidase inhibitor reduces diclofenac-induced anastomotic leakage severity, which suggests a harmful effect of diclofenac metabolite reactivation in the gut. This finding improves the understanding of the pathogenesis of anastomotic leakage.

Self-expandable tubular collagen implants.

Collagen has been extensively used as a biomaterial, yet for tubular organ repair, synthetic polymers or metals (e.g., stents) are typically used. In this study, we report a novel type of tubular implant solely consisting of type I collagen, suitable to self-expand in case of minimal invasive implantation. Potential benefits of this collagen scaffold over conventional materials include improved endothelialization, biodegradation over time, and possibilities to add bioactive components to the scaffold, such as anticoagulants. Implants were prepared by compression of porous scaffolds consisting of fibrillar type I collagen (1.0-2.0% (w/v)). By applying carbodiimide cross-linking to the compressed scaffolds in their opened position, entropy-driven shape memory was induced. The scaffolds were subsequently crimped and dried around a guidewire. Upon exposure to water, crimped scaffolds deployed within 15-60 s (depending on the collagen concentration used), thereby returning to the original opened form. The scaffolds were cytocompatible as assessed by cell culture with human primary vascular endothelial and smooth muscle cells. Compression force required to compress the open scaffolds increased with collagen content from 16 to 32 mN for 1.0% to 2.0% (w/v) collagen scaffolds. In conclusion, we report the first self-expandable tubular implant consisting of solely type I collagen that may have potential as a biological vascular implant.

Safety and Efficacy of Alginate Adhesion Barrier Gel in Compromised Intestinal Anastomosis.

BACKGROUND: For any anti-adhesive barrier developed for abdominal surgery, the use under conditions in which anastomotic healing is compromised needs to be investigated. The current study evaluates the effect of a new ultrapure alginate gel on early healing of high-risk anastomoses in the ileum and compares this with the gold standard used in clinical practice. MATERIALS AND METHODS: In 75 adult male Wistar rats, a 5 mm ileal segment was resected and continuity was restored by construction of an inverted anastomosis. Rats were divided randomly into a control group and groups receiving either alginate gel or a sodium hyaluronate carboxymethylcellulose (HA/CMC) film around the anastomosis (n = 25 each). Carprofen, given in a daily dose of 1.25 mg/kg, was used to compromise anastomotic healing. At day three, animals were killed and scored for signs of anastomotic leakage and the presence of adhesions. RESULTS: The incidence of adhesion formation was 95% in the HA/CMC film group, which was significantly higher than in the controls (64%, p = 0.010) and the alginate gel group (52%, p = 0.004). The adhesion score was nearly 40% lower in the alginate gel group compared with the HA/CMC film group. The incidence of ileal leakage in the HA/CMC film group (92%) was significantly higher than in the controls (68%, p = 0.016). Leakage rate did not differ between the alginate gel and control groups. There was no significant difference between groups in either incision bursting pressure or incision breaking strength. CONCLUSION: Ultrapure alginate gel does not interfere with repair of ileal anastomoses constructed under conditions in which chances of anastomotic dehiscence are high. The alginate gel performs better than the HA/CMC film.

Repeated remote ischemic preconditioning and isoflurane anesthesia in an experimental model of renal ischemia-reperfusion injury.

BACKGROUND: In animal studies, remote ischemic preconditioning (RIPC) and anesthetic preconditioning are successful in reducing renal ischemia reperfusion injury (IRI), however the protective effect of RIPC may be improved by repeating the RIPC stimulus. METHODS: Sprague-Dawley rats underwent unilateral nephrectomy followed by 30 min of renal pedicle clamping. Animals were allocated into six groups: sham, control (IRI), RepISO (daily isoflurane anesthesia), RIPC (single dose isoflurane anesthesia and single dose RIPC), RepISO + RIPC (7-day isoflurane anesthesia and single dose RIPC) and RepISO + RepRIPC (7-day isoflurane anesthesia with 7-day RIPC). RIPC was applied by 3×5 min of cuff inflation on both thighs. Serum creatinine and urea levels were measured and histology was obtained at day two. RESULTS: RepISO diminished renal IRI, as reflected by a significant reduction in serum creatinine levels as compared to the control group, 170 ± 74 resp. 107 ± 29 µmol/L. The other preconditioning protocols showed similar reduction in serum creatinine levels as compared to the control group. No significant differences were observed between the different preconditioning protocols. For urea levels, only RepISO + RIPC resulted in significantly lower levels as compared to the control group, 14 ± 4 resp. 22 ± 7 mmol/L (p = 0.010). In the preconditioning groups only RepISO showed less histological damage as compared to controls 1.73 ± 1.19 resp. 2.91 ± 1.22 (p = 0.032). CONCLUSIONS: In this study no additional protective effect of repeated ischemic preconditioning was observed as compared to single dose RIPC. Repeated administration of isoflurane provided stronger protection against renal IRI as compared to single dose isoflurane.

Efficacy and Safety of Ultrapure Alginate-Based Anti-Adhesion Gel in Experimental Peritonitis.

BACKGROUND: Intra-abdominal infection may lead to adhesion and abscess formation. An adhesion barrier can reduce these complications but also aggravate intra-peritoneal infection, causing the opposite effects. The fear of infection propagation has limited clinical adhesion barrier use in a contaminated or infected abdomen. This study evaluated both adhesion and abscess reduction and infection propagation of a new ultrapure alginate-based anti-adhesive barrier gel in a rat peritonitis model. METHODS: In 64 male Wistar rats, bacterial peritonitis was induced via intra-abdominal injection of a mixture of sterile feces, 10(5) colony-forming units (CFU) of Escherichia coli, and 10(4) CFU of Bacteroides fragilis. Surgical debridement and peritoneal lavage were performed 1 h after inoculation. Animals were randomly allocated in equal numbers to a control group or an alginate gel group. Animals were sacrificed on day five post-operatively. Death and the presence and size of intra-abdominal abscesses were noted, and adhesions were scored. All outcomes were compared in the two groups. RESULTS: Seventeen rats (27%) died prematurely without any difference between the groups. Of the surviving rats in the alginate gel group, 88% developed abscesses vs. 100% of the control group. There was no significant difference in the abscess scores or incidence rates of adhesion formation between the groups. The adhesion scores were lower for the alginate gel group compared with control animals (p=0.04). CONCLUSION: Ultrapure alginate gel reduces adhesion severity but not abscesses. The gel seemed to be safe, not aggravating intra-peritoneal infection in this abdominal infection model.

ARE INTRAVITREAL INJECTIONS WITH ULTRATHIN 33-G NEEDLES LESS PAINFUL THAN THE COMMONLY USED 30-G NEEDLES?

PURPOSE: This study investigated whether pain from intravitreal injections (IVIs) can be reduced by injecting with a 33-G needle instead of the commonly used 30-G needle. Additionally, several pain-related psychological factors were explored as predictors of outcome. METHODS: This randomized crossover trial included 36 patients who received injections with both needles in randomized order. After the injection, patients rated IVI pain on a 0 to 10 scale. Before injection, distress and pain expectations were assessed. Afterward, patients rated the IVI procedure and anticipated consequences. In addition, we assessed the force necessary to penetrate the sclera for both needles in porcine eyes. RESULTS: The 33-G needle did not result in lower IVI pain (2.8 vs. 3.1, P = 0.758) but tended to cause less vitreal reflux (0 vs. 5 times, P = 0.054). Factors related to more pain were distress, expecting IVI pain and discomfort, dissatisfaction with the preparation procedure, anticipating negative consequences, and female gender. Patients regarded povidone-iodine disinfection as particularly unpleasant. Exploration of the needles' mechanical properties showed that 33-G needles penetrate the sclera more easily. CONCLUSION: The thinner 33-G needle does not reduce IVI pain but may limit scleral damage. Future efforts could be aimed at optimizing patient information, reducing distress, and the use of better tolerable disinfectants.

Diclofenac causes anastomotic leakage in the proximal colon but not in the distal colon of the rat.

BACKGROUND: Nonsteroidal anti-inflammatory drugs have been associated with anastomotic leakage. It was studied if diclofenac affects anastomoses differently depending on the location in the gut. METHODS: Ninety-five rats were randomized to 6 groups with an anastomosis in either ileum (IL), proximal colon (PC), or distal colon (DC). Groups IL+ (n = 10), PC+ (n = 30), and DC+ (n = 10) received diclofenac (3 mg/kg/day) from day 0 until sacrifice on day 3. Group PC- (n = 15) did not receive diclofenac. Groups PC1+ and PC2+ (n = 15 each) were given diclofenac from day 1 to 4 and from day 2 to 5. RESULTS: Leak rates were 10/10 in group IL+, 22/30 in PC+, 1/10 in DC+, and 1/15 in PC-. Delayed administration of diclofenac by 1 or 2 days (6/15, P = .05) resulted in reduced leakage rates. Mechanical strength results corresponded with leak rates. CONCLUSIONS: Diclofenac causes leakage of anastomoses in rat IL and PC, but not in the DC. This suggests a role for the ileal and proximal colonic content in diclofenac-induced leakage.

Serosal abrasion of bowel ends does not enhance anastomotic healing.

BACKGROUND: Anastomotic leakage rates remain unacceptably high, warranting reconsideration of current anastomotic technique. Anastomotic healing may improve by abrading the serosal surface of bowel ends that are invertedly anastomosed, based on the concept that serosal damage evokes inflammatory adherent processes. It is studied if local abrasion leads to stronger anastomoses and reduces leakage. METHODS: Ninety-eight Wistar rats were allocated to six groups. Either a regular anastomosis (RA) or abraded anastomosis (AA) was constructed in the proximal colon. Animals were sacrificed at day 3 (groups RA3 and AA3, n = 2 × 17) or day 5 (groups RA5 and AA5, n = 2 × 17). Groups RA-Dic and AA-Dic (n = 2 × 15) received diclofenac from day 0 until sacrifice on day 3 to impair anastomotic healing. Outcomes were leakage, bursting pressure, breaking strength, adhesions, and histological appearance. RESULTS: Both in abraded (AA3 and AA5) and control (RA3 and RA5) groups without diclofenac, 1 of 17 anastomoses leaked (6%). Leak rate was 9 of 15 (60%) in group AA-Dic and 8 of 15 (53%) in RA-Dic (P = 1.0). The bursting pressure in group RA3 (127 ± 44 mm Hg) was higher (P = 0.006) compared with group AA3 (82 ± 34 mm Hg), breaking strength was comparable (P = 0.331). Mechanical strength was similar between groups RA5 and AA5. Abrasion did not increase mechanical strength in the diclofenac groups. Adhesion formation was not different between groups. Histology showed dense interserosal scar formation in abraded groups, compared with loose connective tissue in control anastomoses. CONCLUSIONS: Abrasion of serosal edges of large bowel ends invertedly anastomosed does not improve anastomotic strength, neither does it reduce leakage in anastomoses compromised by diclofenac.

Ultrapure alginate gel reduces adhesion reformation after adhesiolysis.

PURPOSE: Adhesiolysis at repeat surgery induces adhesion reformation which seems more virulent than development of de novo adhesions. We studied the effect of a new ultrapure alginate gel on adhesion reformation. METHODS: In 46 male Wistar rats, adhesion formation was induced using the cecal abrasion and peritoneal sidewall excision procedure. Two weeks later, a second laparotomy was performed, adhesions were graded, and surgical adhesiolysis was performed. The animals were then allocated to one of two equal groups, a control group without further intervention and a group receiving 1-ml ultrapure alginate gel to the two opposing and damaged surfaces. Two weeks after the second surgery, rats were sacrificed. Primary endpoint was the incidence of adhesion reformation at areas of injury. Secondary endpoints were adhesion scores, extent of adhesions, and tissue histology. RESULTS: Ultrapure alginate gel significantly (p = 0.046) reduced the incidence of adhesion reformation from 100 % in controls to 78 % in experimental rats. Both the adhesion score (p = 0.009) and the extent of adhesions (p = 0.001) were significantly lower in the alginate group. Tissue healing histology was similar in both groups. CONCLUSION: Ultrapure alginate gel reduces adhesion reformation following adhesiolysis.

Ultrapure alginate anti-adhesion gel does not impair colon anastomotic strength.

BACKGROUND: Ultrapure alginate gel is promising in terms of adhesion prevention. Because anti-adhesive barriers have been shown to disturb healing of bowel anastomoses, the effect of ultrapure alginate gel on the repair of colon anastomoses was studied. MATERIALS AND METHODS: In 102 male Wistar rats, a 0.5-cm segment was resected from the descending colon and continuity was restored by an inverted single-layer end-to-end anastomosis. Animals were randomized into a control, an alginate gel, and a sodium hyaluronate carboxymethyl cellulose film group, each n = 34. Half of each group was sacrificed at day 3 and 7 postoperatively. Anastomotic strength was assessed by measuring both bursting pressure and breaking strength. Hydroxyproline content was measured and histologic analysis was performed. The incidence of adhesion and abscess formation was scored at sacrifice. RESULTS: No difference in either anastomotic-bursting pressure or breaking strength was found between experimental groups and the controls at any time point. Both the incidence of adhesion formation (35% versus 71%, P = 0.007) and the adhesion score (0.38 versus 0.79, P = 0.009) were significantly lower in the alginate gel group than in the controls. The abscess rate was higher (46% versus 18%, P = 0.030) in the hyaluronate carboxymethyl cellulose group than in the controls and unchanged in the alginate gel group. CONCLUSIONS: While reducing adhesion formation, ultrapure alginate gel does not interfere with the development of colonic anastomotic strength during the crucial early healing period.

Tacrolimus does not affect early wound healing in a rodent model of bowel anastomoses and abdominal wall closure.

BACKGROUND: Use of immunosuppressant drugs has been associated with complications in wound healing. The calcineurin inhibitor tacrolimus is thought to have a relatively low complication rate, but preclinical research has yielded contradictory data, prompting the current comprehensive study. METHODS: Three groups of 33 male Wistar rats received a daily subcutaneous dose of 0,5, 2 or 5 mg/kg tacrolimus. A control group received saline. On day 0 a resection of 1 cm ileum and 1 cm colon was performed, and end-to-end anastomoses were constructed. Ten rats of each group were killed on day 3 and day 5 and the remaining animals on day 7. Both anastomoses and the wound in the abdominal wall were analyzed. Wound strength was the primary outcome parameter. RESULTS: Mean strength of the abdominal wall increased significantly over time in all groups (p<0.0001). Both the breaking strength and the bursting pressure of the ileum and colon anastomoses followed the same pattern. No differences were observed between control and experimental groups. In addition, no consistent differences were found between groups regarding wound hydroxyproline content and the activities of matrix metalloproteinase-2 and -9. CONCLUSION: Tacrolimus does not affect early wound healing.

Carprofen for perioperative analgesia causes early anastomotic leakage in the rat ileum.

BACKGROUND: There is increasing evidence that perioperative use of NSAIDs may compromise the integrity of intestinal anastomoses. This study aims to characterize the negative effects of carprofen on early anastomotic healing in the rat ileum. RESULTS: In 159 male Wistar rats an anastomosis was constructed in the ileum. In experiment 1 eighty-four rats were divided over control and experimental groups, which received daily buprenorphine or carprofen, respectively, as an analgesic and were killed on day 1, 2 or 3 after surgery. In experiment 2 three groups of 15 rats received carprofen either immediately after surgery or with a delay of 1 or 2 days. Animals were killed after 3 days of carprofen administration. In experiment 3 three groups of 10 rats received different doses (full, half or quarter) of carprofen from surgery. In significant contrast to buprenorphine, which never did so, carprofen induced frequent signs of anastomotic leakage, which were already present at day 1. If first administration was delayed for 48 hours, the leakage rate was significantly reduced (from 80 to 20%; p = 0.0028). Throughout the study, the anastomotic bursting pressure was lowest in animals who displayed signs of anastomotic leakage. Loss of anastomotic integrity did not coincide with reduced levels of hydroxyproline or increased activity of matrix metalloproteinases. CONCLUSIONS: Carprofen interferes with wound healing in the rat ileum at a very early stage. Although the mechanisms responsible remain to be fully elucidated, one should be aware of the potential of NSAIDs to interfere with the early phase of wound repair.

Paracetamol does not compromise early wound repair in the intestine or abdominal wall in the rat.

BACKGROUND: Paracetamol is a cornerstone for perioperative pain relief. Its mechanism of action may include a local anti-inflammatory effect with inhibition of cyclooxygenase isoenzymes. The scarce literature available on its effects on wound healing consists of preclinical studies into the effect of paracetamol on healing of the musculoskeletal system. Although the drug is used abundantly for pain relief after surgery of the gastrointestinal tract, there are no published data on the influence of paracetamol on anastomotic and abdominal healing. This also holds for the crucial, early inflammatory phase of repair. The recovery of wound strength could therefore conceivably be affected by paracetamol. METHODS: In 78 male Wistar rats, we constructed an anastomosis in colon and ileum. The rats received either low- or high-dose (50 or 200 mg/kg/d, divided over 2 doses) paracetamol or vehicle (controls) until they were killed on day 3 or 7 after surgery (n = 13 each). In anastomoses, the main outcome variables were 2 independent measures for wound strength, bursting pressure, and breaking strength, the latter being the primary outcome variable. In addition, collagen levels were measured and histology was performed. In fascia, breaking strength was analyzed. RESULTS: No significant differences were found between control and paracetamol-treated groups at any time point for any of the variables. Wound strength increased significantly from day 3 to day 7 in all groups. In the colon anastomosis, the breaking strength increased from 130 ± 9 g (mean ± SEM) at day 3 to 232 ± 17 g at day 7 in the control group, from 144 ± 10 to 224 ± 9 g in the low-dose group, and from 130 ± 12 to 263 ± 28 g in the high-dose group. The lower limit for the 95% confidence interval was -11 for the difference between control and low-dose groups at day 3 and -25 for the difference between control and high-dose groups. No differences in collagen levels were found between the high-dose and control groups. Histology did not indicate the presence of gross differences between groups. CONCLUSIONS: Perioperative use of paracetamol in a rat model of intestinal surgery does not significantly impede wound repair in the early postoperative period.

The effect of fibrin glue on the early healing phase of intestinal anastomoses in the rat.

PURPOSE: Protecting the anastomotic integrity using suture or staple line reinforcement remains an important goal for ongoing research. The present comprehensive study aims to establish the effects of fibrin glue on the early phase of anastomotic healing in the rat intestine. METHODS: One hundred and eight young adult male Wistar rats underwent resection and anastomosis of both the ileum and colon. In half, fibrin glue was applied around the anastomoses. Parameters for repair included wound strength, both bursting pressure and breaking strength at days 1, 3, and 5 after operation; hydroxyproline content; and histology, the latter also after 7 days. RESULTS: A transient colonic ileus was observed in the experimental group. Anastomotic breaking strength was always similar in both the control and fibrin glue groups. Anastomotic bursting pressures remained low at days 1 and 3, without any differences between the groups. In both groups, the bursting pressure increased sharply (p < 0.001) between days 3 and 5. At day 5, the bursting pressure in the fibrin glue group remained below than that in the controls, although only significantly (p = 0.0138) so in the ileum. At day 5, but not at day 7, the wounds in the fibrin glue group contained less collagen. Other aspects of microscopic wound architecture appeared to be the same. CONCLUSIONS: There is no justification for using fibrin glue on patent anastomoses constructed under low-risk conditions. Its potential benefit under conditions where chances for anastomotic leakage are enhanced needs further investigation.

Intraoperative versus early postoperative intraperitoneal chemotherapy after cytoreduction for colorectal peritoneal carcinomatosis: an experimental study.

BACKGROUND: Perioperative intraperitoneal chemotherapy is used as an adjunct to cytoreductive surgery (CS) for peritoneal carcinomatosis (PC) in order to prolong survival. Worldwide, hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and combinations of the two are used. It remains unclear which regimen is most beneficial. METHODS: The rat colon carcinoma cell line CC-531 was injected into the peritoneal cavity of 80 WAG/Rij rats to induce PC. Animals were randomized into four treatment groups (n = 20): CS only, CS followed by HIPEC (mitomycin 35 mg/m(2) at 41.5°C), CS followed by EPIC during 5 days (i.p. injection of mitomycin on day 1 and 5-fluorouracil on days 2-5), and CS followed by HIPEC plus EPIC. Primary outcome was survival. RESULTS: In rats treated with CS only, median survival was 53 days (95% confidence interval (CI) 49-57 days). In rats treated with CS followed by HIPEC, survival was significantly (P = 0.001) increased (median survival 94 days, 95% CI 51-137 days). In the group treated with EPIC after CS, 12 out of 20 rats were still alive at the end of the experiment (P < 0.001 as compared with CS only). In the group receiving both treatments, 11 rats died of toxicity, and therefore this group was not included in the survival analysis. CONCLUSIONS: Both EPIC and HIPEC were effective in prolonging survival. The beneficial effect of EPIC on survival seemed to be more pronounced than that of HIPEC. Further research is indicated to evaluate and compare the possible benefits and adverse effects associated with both treatments.