Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.

BACKGROUND: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. METHODS: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. TRIAL REGISTRATION: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.

Carboxyhaemoglobin formation and ECG changes during hysteroscopic surgery, transurethral prostatectomy and tonsillectomy using bipolar diathermy.

Diathermy is known to produce a mixture of waste products including carbon monoxide. During transcervical hysteroscopic surgery, carbon monoxide might enter the circulation leading to the formation of carboxyhaemoglobin. In 20 patients scheduled for transcervical hysteroscopic resection of myoma or endometrium, carboxyhaemoglobin was measured before and at the end of the surgical procedure, and compared with levels measured in 20 patients during transurethral prostatectomy, and in 20 patients during tonsillectomy. Haemodynamic data, including ST-segment changes, were recorded. Levels of carboxyhaemoglobin increased significantly during hysteroscopic surgery from median (IQR [range]) 1.0% (0.7-1.4 [0.5-4.9])% to 3.5% (2.0-6.1 [1.3-10.3]%, p < 0.001), compared with levels during prostatectomy or tonsillectomy. Significant ST-segment changes were observed in 50% of the patients during hysteroscopic surgery. Significant correlations were observed between the increase in carboxyhaemoglobin and the maximum ST-segment change (ρ = -0.707, p < 0.01), between the increase in carboxyhaemoglobin and intravasation (ρ = 0.625; p < 0.01), and between intravasation and the maximum ST-segment change (ρ = -0.761; p < 0.01). The increased carboxyhaemoglobin levels during hysteroscopic surgery appear to be related to the amount of intravasation and this could potentially be a contributing factor to the observed ST-segment changes.

Paradoxical gas embolism by transpulmonary passage of venous emboli during hysteroscopic surgery: a case report and discussion.

After an episode of apparent venous gas embolism in a patient undergoing surgical hysteroscopy, transoesophageal echocardiography revealed air in the left but not in the right heart. Contrast echocardiography failed to demonstrate anatomical right-to-left shunts, making it likely that venous emboli overwhelmed the capacity of lungs to filter emboli, resulting in paradoxical embolization.

Short-term effect of surgical trauma on rat peritoneal fibrinolytic activity and its role in adhesion formation.

BACKGROUND: Fibrin deposition, the primary step in the formation of post-surgical adhesions, is the result of a disbalance between the fibrin-forming and the fibrin-dissolving capacity of the peritoneum. Literature data suggest a transient reduction in local plasminogen activator activity after peritoneal trauma, which results in a reduction of fibrinolysis and permits deposited fibrin to become organized into fibrous, permanent adhesions. In the present study, the fibrinolytic parameters tissue-type plasminogen activator (tPA; antigen and activity) and plasminogen activator inhibitor type-1 (PAI-1; antigen and activity) were measured in peritoneal fluid, in peritoneal biopsies and in plasma to establish the time course of changes in fibrinolytic activity. DESIGN: A standardized peritoneal adhesion model in the rat. OUTCOME MEASURES: Analysis, over a 72-h period following surgical trauma. of the main fibrinolytic parameters in peritoneal lavage, in biopsies of damaged and undamaged peritoneum, and in plasma, and determination of fibrin and fibrin(ogen)-degradation products in peritoneal lavage fluid. RESULTS: At all time intervals, tPA antigen was found to be about six-fold increased in peritoneal lavage after surgical trauma. This significant rise in tPA antigen was accompanied by a large increase in its main inhibitor PAI-1, resulting in tPA activity levels similar to, or slightly higher than, those found in control animals. tPA activity was lowest at 4 h and increased thereafter. Also in biopsies from damaged peritoneum, tPA antigen was significantly increased. Tissue tPA activity was also lowest at 4 h, after which it increased, significantly so at 24 and 72 h. Similar, though smaller, changes were seen in the biopsies from undamaged areas of the peritoneal wall in operated rats. PAI-1 (antigen and activity) was not detected in peritoneal biopsies. Fibrin-related material (especially fibrin monomer/fibrinogen, an indicator of forming fibrin) in peritoneal fluid was slightly increased at 4 h, and abundantly present at 16 and 24 h, returning to control levels at 72 h. Fibrin degradation products were always present. From 2 h onward, adhesions were found. CONCLUSIONS: In contrast to the view that adhesions are formed as a result of a reduced fibrinolytic activity, our results demonstrate that tPA activity remained unchanged or slightly increased after surgical trauma, and point to increased fibrin formation rather than diminished fibrinolytic activity as the main cause of fibrin deposition after peritoneal trauma. Therapies directed at prevention of adhesion formation should therefore aim at avoiding massive fibrin production and at promoting fibrinolytic activity during the early period after trauma.

Quantitative analysis of the inflammatory reaction surrounding sutures commonly used in operative procedures and the relation to postsurgical adhesion formation.

Inflammatory reaction as well as the extent of postsurgical adhesion formation are described as varying according to suture material or diameter used. Whether the inflammatory reaction influences the formation of adhesions or is a mere consequence of surgical trauma itself or of type and amount of foreign body material used has never been elucidated entirely. In this study a quantitative analysis of both variables was therefore performed, according to previously described techniques, and correlated within 120 peritoneal defects of a standard side wall-uterine horn adhesion model in the rat. Three different suture characteristics, material (Prolene, Vicryl, Catgut), diameter (USP gauges 3/0, 5/0, 6/0) and knot configuration (2 = 2, S x S x S x S x S) were analysed for this purpose. Both the inflammatory reaction and the adhesion percentage showed significant differences within and in between suture characteristics, but no significant correlation between the two variables was found after statistical analysis. The conclusion is made that, when evaluated after 14 d, the extent of postsurgical adhesion formation is not related to the inflammatory reaction.

Comparison of neuroendocrine and behavioral effects of ipsapirone, a 5-HT1A agonist, in three stress paradigms: immobilization, forced swim and conditioned fear.

Ipsapirone is an anxiolytic drug and a serotonin1A (5-HT1A) agonist. The aim of the present study was to investigate the effects of low doses of ipsapirone on the hormonal and behavioral response to three stress procedures: immobilization, forced swim and conditioned emotional response (CER). We examined the effect of ipsapirone (0.1, 0.5 or 1.0 mg/kg) on plasma renin concentration (PRC), adrenal corticotropic hormone (ACTH), corticosterone, prolactin and defecation in rats exposed to immobilization, forced swim or CER stress. All three stressors significantly elevated all the hormone levels (P less than 0.01). Immobilization-induced elevations of PRC, and corticosterone were inhibited by the highest doses of ipsapirone (0.5 and 1 mg/kg, i.p.). However, ipsapirone did not modify the immobilization-induced elevations of plasma ACTH, prolactin or defecation. Ipsapirone was relatively ineffective at reducing the endocrine responses to forced swim. Ipsapirone reduced some, but not all of the hormonal responses to CER stress. CER-induced elevations of corticosterone and prolactin were not inhibited by ipsapirone. However, the ACTH response to CER was significantly (P less than 0.01) inhibited by all doses of ipsapirone and the highest dose of ipsapirone attenuated the renin response. In contrast with the hormonal responses, ipsapirone inhibited all of the behavioral responses to CER stress. Ipsapirone inhibited CER-induced freezing behavior and defecation, while dose-dependently reversing the suppressive effect of CER on exploring, grooming and rearing behaviors. In conclusion, there is a dissociation between the influence of ipsapirone on the endocrine and behavioral responses to CER stress. Ipsapirone also has differential effects on the neuroendocrine response to the three stressors studied. Ipsapirone was most effective in attenuating the hormonal responses to CER, followed by immobilization and swim stress. Of the hormones studied, the stimulation of renin secretion after exposure to the three stressors was most sensitive to ipsapirone, while corticosterone and prolactin were the least sensitive to ipsapirone.

Long-term analysis of peritoneal plasminogen activator activity and adhesion formation after surgical trauma in the rat model.

OBJECTIVE: Recent literature has shown that a common pathway in postsurgical adhesion formation is a transient reduction in local plasminogen activator activity, shortly after peritoneal trauma. This deficit in fibrinolysis permits deposited fibrin to become organized into fibrous, permanent adhesions. Although adhesion formation is a process that continues beyond the first postoperative days, long-term analysis of this theory has not been performed. DESIGN: A standardized peritoneal adhesion model in the rat. MAIN OUTCOME MEASURE(S): Long-term analysis of the peritoneal fibrinolytic activity (extraction technique) was related to the extent of postsurgical adhesion formation, up to 1 year postoperatively. RESULT(S): Total and tissue plasminogen activator activity were significantly increased at days 3 and 8, and 1 month postoperatively. A mean adhesion percentage of 75% per peritoneal defect was found to persist throughout all evaluation times, which was directly related to the increase of fibrinolysis. CONCLUSION(S): In contrast to the classical concept that adhesion formation is related to a reduction in fibrinolysis, an impressive increase of the fibrinolysis was found to be associated with the persistence of adhesions.

Different surgical techniques to reduce post-operative adhesion formation: a systematic review and meta-analysis.

INTRODUCTION Adhesion formation is the most common complication following peritoneal surgery and the leading cause of small bowel obstruction, acquired infertility and inadvertent organ injury at reoperation. Using a 'good surgical technique' is advocated as a first step in preventing adhesions. However, the evidence for different surgical techniques to reduce adhesion formation needs confirmation. METHODS Pubmed, Embase and CENTRAL were searched to identify randomized controlled trials that investigated the effect of various aspects of surgical technique on adhesion-related outcomes. Clinical outcomes and incidence of adhesions were the primary endpoints. Identification of papers and data extraction were performed by two independent researchers. RESULTS There were 28 papers with 27 studies included for a systematic review. Of these, 17 studies were eligible for meta-analysis and 11 for qualitative assessment only. None of the techniques that were compared significantly reduced the incidence of adhesive small bowel obstruction. In a small low-quality trial, the pregnancy rate increased after subserous fixation of suture knots. However, the incidence of adhesions was lower after laparoscopic compared with open surgery [relative risk (RR) 0.14; 95% confidence interval (CI): 0.03-0.61] and when the peritoneum was not closed (RR 0.36; 95% CI: 0.21-0.63). CONCLUSIONS None of the specific techniques that were compared reduced the two main adhesion-related clinical outcomes, small bowel obstruction and infertility. The meta-analysis provides little evidence for the surgical principle that using less invasive techniques, introducing less foreign bodies or causing less ischaemia reduces the extent and severity of adhesions.

Efficacy of polyethylene glycol adhesion barrier after gynecological laparoscopic surgery: Results of a randomized controlled pilot study.

Postoperative adhesions are the most frequent complication of peritoneal surgery, causing small bowel obstruction, female infertility and chronic pain. This pilot study assessed the efficacy of a sprayable polyethylene glycol (PEG) barrier in the prevention of de novo adhesions. 16 patients undergoing laparoscopic gynecological surgery were randomly assigned by shuffled sealed envelopes to receive either the adhesion barrier or no adhesion prevention. Incidence and severity of adhesions were scored at eight sites in the pelvis and reassessed by second look laparoscopy. Adhesion prevention was considered successful if no de novo adhesion were found at second look laparoscopy. One patient was excluded before randomization. Nine patients were randomized to treatment and six patients to control group. De novo adhesions were found in 0/9 patients who received the PEG barrier compared to 4/6 without adhesion prevention (0% vs. 67%, P = 0.01). Reduction in adhesion score was significantly greater in patients receiving PEG barrier (-2.6 vs. -0.06, P = 0.03). Meta-analysis of three randomized trials demonstrated that PEG barrier reduces the incidence of adhesions (odds ratio [OR] = 0.27; 95% CI 0.11-0.67). From this study, PEG barrier seems effective in reducing postoperative formation of de novo adhesions.

Natural course of postsurgical adhesions.

To evaluate the natural course of postsurgical adhesion formation, a descriptive animal study was performed in a standardized rat adhesion model, involving the uterine horn and peritoneal side wall. Extent and type of postsurgical adhesion formation was evaluated at increasing postoperative time intervals up to 1 year, both through inter- and intra-animal observations (laparotomy and repeated-laparotomy group). The extent of the adhesions was found to be similar while the type of the adhesions changed markedly, especially during the early observation periods. From day 1 until 1 month post- operatively, the adhesions became increasingly more organized and vascular and were separable with sharp dissection only. From the present study it was concluded that spontaneous lysis of postsurgical adhesions, once they are established, does not seem to occur. The most optimum time for surgical intervention when scheduled to lyse newly formed adhesions will be between 8 days and 1 month after the initial procedure.

A semiquantitative rat model for intraperitoneal postoperative adhesion formation.

A reproducible and semiquantitative rat model for the evaluation of therapeutic modalities used for the prevention of postoperative adhesion formation is designed within three experiments. In all experiments, a standard peritoneal defect was excised, sutured and adhesion formation was evaluated after 2 weeks according to the extent. Variation in extent of adhesions and type of tissue involved depended on the experimental design. While neither cecum nor colon descendens participated in the adhesions after a clamping trauma, the uterine horn was found to participate in almost all cases, especially when sutured proximally and distally to the peritoneal defect. The peritoneal defect/uterine horn model proved to be valid and reproducible and allowed a semiquantitative scoring. Additionally, the amount of blood loss as graded did not influence the presented rat adhesion model.

Evidence that the serotonin agonist, DOI, increases renin secretion and blood pressure through both central and peripheral 5-HT2 receptors.

DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCI] is a serotonin (5-HT1C/5-HT2) agonist, with potent cardiovascular effects. The purpose of the present studies was to determine the identity and location of the 5-HT receptor subtype(s) mediating the renin and blood pressure responses to DOI. Injection (i.p.) of DOI to conscious male rats elevated plasma renin activity in a dose-dependent manner. The 5-HT1C/5-HT2 antagonist ritanserin completely blocked the DOI-induced increase in plasma renin activity. In order to distinguish the 5-HT2- from the 5-HT1C- mediated effect of DOI, spiperone was administered before DOI. Low doses of spiperone (0.01 and 0.1 mg/kg, s.c.) significantly reduced the renin response to DOI. Because spiperone has a higher affinity for 5-HT2 than 5-HT1C receptors, these data suggest that DOI stimulates renin secretion through 5-HT2 receptors. To separate central from peripheral 5-HT receptors, we injected DOI into rats pretreated with saline or xylamidine, a 5-HT2 antagonist which does not cross the blood-brain barrier. Xylamidine produced a shift to the right and suppression of the maximal effect of DOI on plasma renin activity, suggesting a role for peripheral 5-HT2 receptors in the effect of DOI. On the other hand, i.c.v. administration of DOI, using doses lower than the peripherally effective doses, caused a significant elevation of plasma renin activity at 200 micrograms/kg. These experiments suggest that DOI's elevation of plasma renin activity has both peripheral and central sites of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that ACTH secretion is regulated by serotonin2A/2C (5-HT2A/2C) receptors.

The present study characterized the serotonin (5-HT) receptor subtypes mediating adrenal corticotropic hormone (ACTH) and corticosterone responses to 5-HT agonists in conscious rats. The 5-HT2A/5-HT2C agonist (+/-(-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HC1 (DOI) increased plasma ACTH and corticosterone in a dose-dependent manner. The 5-HT2A/5-HT2C antagonist ritanserin (0.01 and 0.1 mg/kg sc) inhibited the DOI-induced increase in plasma ACTH, but not corticosterone. Low doses of spiperone (0.01 and 0.1 mg/kg sc) significantly reduced the ACTH response to DOI. Because spiperone has a higher affinity for 5-HT2A than 5-HT2C receptors, these data suggest that DOI stimulates ACTH secretion through 5-HT2A receptors. 5-methoxy-3-[1,2,3,4-tetrahydro-4-pyridinyl]-1H-indole (RU 24969) is a potent 5-HT1A/1B and moderate 5-HT2C agonist that also has been suggested to release 5-HT. However, p-chlorophenylalanine (PCPA) did not reduce the effect of RU 24969 on plasma ACTH, suggesting that RU 24969 only acts as a direct agonist. 6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid (LY53857) injected into the lateral cerebral ventricles (i.c.v.) inhibited the ACTH, but not corticosterone response to peripheral injection of RU 24969, suggesting that central 5-HT2A/2C receptors mediate the ACTH response. LY53857 injection (i.c.v.) also inhibited the effect of p-chloroamphetamine (i.c.v.) on plasma ACTH. However, the corticosterone response was not inhibited by LY53857, suggesting a distinct location of 5-HT receptors regulating corticosterone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of five different barrier materials on postsurgical adhesion formation in the rat.

Postsurgical adhesion formation is a significant clinical problem within every surgical specialism. Due to the problems that adhesions cause, a wide variety of adjunctive treatments to prevent the formation and reformation of adhesions have been proposed. One of the modalities that has been studied extensively and that has been showing the most promising results is the so-called barrier method. The purpose of the present study was to compare the efficacy of five of these barrier materials in the prevention of postsurgical adhesion formation in a standardized rat adhesion model. It was concluded that no beneficial effect of Ringer's lactate on adhesion formation was seen. Significant reductions (P < 0.0001) in adhesion percentages compared to control animals were seen with Polyactive((TM)), PRECLUDE Peritoneal Membrane((TM)), Seprafilm((TM)) and Tissucol((TM)), but only PRECLUDE Peritoneal Membrane and Seprafilm significantly reduced adhesions (P < 0.01) when the barrier-treated peritoneal defects were compared with contralateral control-side peritoneal defects. The results of our study suggest that Seprafilm and PRECLUDE Peritoneal Membrane are superior to Tissucol and Polyactive in preventing adhesion formation. When Polyactive was still attached to the site of application during the second laparotomy, similar results to Seprafilm and PRECLUDE Peritoneal Membrane were seen. Future studies on the efficacy of a material to decrease adhesion formation should always include a comparison of several control materials in the same model. Our study indicates that Seprafilm or PRECLUDE Peritoneal Membrane might be used as standards of control.

Central stimulation of renin secretion through serotonergic, noncardiovascular mechanisms.

The aims of the study were to determine; (1) whether activation of serotonin (5-HT) receptors in the brain increases renin secretion, and (2) whether the hypertensive effects of a 5-HT agonist and 5-HT releaser obscure their ability to stimulate renin release. Various drugs that increase serotonergic neuro-transmission can activate the secretion of renin from the kidneys. Many of these drugs can also elevate blood pressure. Changes in blood pressure can alter renin secretion by activating renal baroreceptor mechanisms, so that a decrease in perfusion pressure will increase renin secretion and vice versa. To address the first objective, the 5-HT agonist RU 24969 (0, 10, 100 and 200 micrograms/kg) and the 5-HT releaser p-chloroamphetamine (0, 50, 500 and 1,000 micrograms/kg) were injected intracerebroventricularly (ICV) at doses lower than those that are peripherally effective. ICV injection of RU 24969 dose-dependently increased plasma levels of renin. ICV injection of the 5-HT2A/5-HT2C antagonist LY53857 (50 micrograms/kg) inhibited the renin response to peripherally injected RU 24969 (0, 1, 5 and 10 mg/kg i.p.), suggesting that 5-HT2A/5-HT2C receptors in the brain mediate the effect of peripherally injected RU 24969 on renin secretion. In contrast, ICV injection of p-chloroamphetamine decreased renin secretion. To determine whether hypertensive actions could account for the differences between RU 24969 and p-chloroamphetamine, we measured the effects of both p-chloroamphetamine and RU 24969 on blood pressure and heart rate. ICV injection of p-chloroamphetamine (1,000 micrograms/kg) produced a large rise of 44 mm Hg at 2 min and 25 mm Hg at 5 min after injection, while ICV injection of RU 24969 (200 micrograms/kg) caused a slower and smaller blood pressure elevation of 18 mm Hg at 5 min after injection. To determine whether the hypertensive effects of both RU 24969 and p-chloroamphetamine could mask their effects on renin secretion, rats were pretreated with the alpha 1 antagonist prazosin. Administration of prazosin (1 mg/kg s.c.), which prevents the hypertensive effects of p-chloroamphetamine, exposed a stimulatory effect of ICV-injected p-chloroamphetamine (500 micrograms/kg) on renin secretion and potentiated the effect of RU 24969 (5 mg/kg i.p.) on renin release. In conclusion, these data suggest that both RU 24969 and p-chloroamphetamine increase renin secretion through central 5-HT receptors, and that these effects are partially obscured by their hypertensive actions.