The HYSTER study: the effect of intracervically administered terlipressin versus placebo on the number of gaseous emboli and fluid intravasation during hysteroscopic surgery: study protocol for a randomized controlled clinical trial

The primary objective of the study is to determine whether the intracervical utilization of terlipressin reduces the incidence and severity of gas embolism as detected by transesophageal echocardiography (TEE).

The secondary objective is to study the effects of the intracervical utilization of terlipressin on the amount of intravasation, global hemodynamics, myocardial ventricular systolic strain and myocardial diastolic function using TEE.

In a recent study we observed venous embolism in 98% of the patients undergoing hysteroscopic surgery using TEE. In addition, a positive correlation has been found between the amount of intravasation and the number of venous emboli. We consider it likely that venous emboli will be observed in all patients undergoing transcervical resection of myomas or endometrium (TCR-M or TCR-E, respectively) using bipolar diathermia. Previous studies have shown a 45–65% reduction in the amount of intravasation using intracervically administered vasopressin [17]. Assuming a similar rate of reduction in emboli, we have calculated our sample size keeping in mind that there will be 45% less intravasation while using terlipressin. Power analysis reveals that 24 patients need to be included in both groups in order to achieve an alpha value of 0.05 assuming that terlipressin does not result in a 45 to 65% reduction of venous emboli.

Forty-eight patients (ASA classification 1 or 2) scheduled for transcervical resection of large, types 1–2 myomas or extensive TCR-E will be included. All patients are recruited and treated in the OLVG Hospital in Amsterdam.

Exclusion criteria include patients not expected to benefit from diminished intravasation due to terlipressin utilization. These include patients undergoing transcervical operations for small myomas and minor TCR-E procedures. Procedures that are expected to be short lasting (less than 30 min) are excluded.

Patients with a known contraindication for TEE, such as severe esophageal or gastric disease, hepatic cirrhosis or esophageal varices, will be excluded from the study. In addition, patients aged < 18 years or > 70 years, patients with a history of pulmonary embolism or cardiac disease and patients with a language barrier will be excluded.

Eligible patients are informed of the study by gynecologists and anesthesiologists in the outpatient clinic. All patients receive oral and written information about the study. Final inclusion is always done by one of the researching anesthesiologists. If informed consent is obtained randomization will be done on the day of surgery. From that moment on collection of data starts.

The patients in our study will be treated with either intracervically administered terlipressin (Glypressine®, Ferring Pharmaceutical) or placebo. Terlipressin treatment will consist of 20 ml diluted terlipressin at a concentration of 0.0425 mg/ml (one vial Glypressine® 8.5 ml containing 0.1 mg/ml terlipressin diluted with 11.5 ml 0.9% saline (NaCl)). The placebo treatment consists of 20 ml 0.9% saline. The maximum dose of terlipressin administered intracervically will be 0.85 mg. The investigational product will be used in the same way as is commonly used in conization: at the start of the procedure patients will receive a maximum of 20 ml investigational product intracervically injected clockwise in the cervix at four points.

Randomization for intracervically administered terlipressin or placebo will be performed by our hospital pharmacologist, using blocked randomization in blocks of eight patients with a standard randomization scheme, on a 1:1 ratio. The blinded vials (containing 20 ml diluted terlipressin or 20 ml placebo) will be delivered at the day of surgery to the operating team. Echocardiographic images will be evaluated off line by a trained observer, who is also blinded for the treatment group.

The main study parameter is the appearance of any embolic event, either venous or paradoxical in origin. To quantify the degree of embolism by TEE a five-grade scale is used:

The secondary endpoints collected during the study are:

These endpoints are measured as follows:

Furthermore, intravasation will be calculated by the difference between pre- and post-procedure hematocrit (Ht) and hemoglobin (Hb) concentration according to the formula reported by Drobin et al. [21] and Johansson et al. [22]:

where ECFV = extracellular fluid volume, postop = postoperative, preop = preoperative, Cl = plasma chloride concentration

The SPIRIT figure HYSTER (Additional file 1) shows in detail the schedule of enrollment, interventions and assessments. For flow diagram HYSTER study see (Fig. 1).

Paper, patient records are stored in a designated locker, only accessible to authorized researchers. Electronic patient data are either stored in the hospital electronic health record system or on a password-secured local Sharepoint (Microsoft) server, also only accessible to authorized researchers. Individual files containing patient data are password protected separately. Researchers with access to patient data are BROK-certified. BROK (Basic course on Regulations and Organization for clinical investigators) is a legally required certificate for academic researchers issued by the Dutch Federation for University Hospitals.

Every included patient is allocated a personal study number. If an unexpected finding is discovered requiring further examination (for example, during offline analysis of echocardiography) blinded data can be traced back to individual patients.

Adverse events, serious adverse events and suspected unexpected serious adverse reactions (AEs, SAEs and SUSARs, respectively) related to the hysteroscopic procedure will be treated according to generally accepted guidelines. Firstly, if needed, the hysteroscopic procedure is stopped. AEs and SAEs related to the installation of the TEE probe (esophageal lacerations, bleeding, etc.) will be treated following consultation with a gastroenterologist and a surgeon. In case of serious cardiac adverse events patients will be treated following consultation with a cardiologist. Owing to its pronounced vasoconstrictive effect within the circulation, the use of terlipressin may result in hypertension with or without reflex bradycardia. This will be treated, if necessary, with the appropriate drugs commonly used in general anesthesic practice Preventive measures in this respect are a proper injection technique (aspiration before injection in order to prevent intravascular injection) and extensive monitoring of heart rate and blood pressure. A 24-h Emergency Code Break and Drug Information can be provided by the hospital pharmacist.

SAEs and SUSARs are always reported to the involved Research Ethics Committee. All AEs, SAEs and SUSARs will be followed up until they have abated, or until a stable situation has been reached. Depending on the event, follow-up may require additional tests, medical procedures, and/or referral to the general physician or a medical specialist. Interim analysis will be done after 25 patients have been included.

As legally required a liability insurance covers potential physical harm inflicted to patients through study procedures.