Perioperative sildenafil citrate administration in hepatectomy: a study protocol of randomized controlled trial

Abstract

Background

Intraoperative blood loss (IBL) is the major concern in hepatectomy, which was closely relating to the central venous pressure (CVP). The controlled low central venous pressure (CLCVP) technique is moderately required for minimizing hemorrhage during hepatectomy nowadays. Nevertheless, an excessive reduction in CVP might give rise to the jeopardy of inadequate perfusion of vital organs. Sildenafil, being a first-line pharmaceutical for treating pulmonary hypertension, its mechanism of action lies in diminishing pulmonary vascular resistance (PVR) by dilating pulmonary arteries, and thereby alleviating the afterload of the right ventricle. We initially postulate that administration of sildenafil citrate in combination with intermittent Pringle’s maneuver (IPM) can exert a notable impact in efficaciously reducing intraoperative blood loss (IBL), enhancing the surgical field of vision, and augmenting the safety of the operation.

Methods

This research constitutes a double-blind, randomized, controlled trial. All patients fulfilling the criteria for open or laparoscopic hepatectomy will be randomly allocated to the sildenafil (S) group and the placebo (C) group via the block randomization approach. All surgeons, anesthesiologists, and outcome assessors will remain oblivious to the patient’s group details. The primary outcome is the intraoperative blood loss (IBL). Secondary outcomes include the classification of the surgical field, the cumulative consumption of nitroglycerine, hemodynamic parameters, blood gas analysis, coagulation function (comprising thromboelastogram (TEG), activated partial thromboplastin time (APTT), and prothrombin time (PT)), intraoperative urine output, adverse events in the recovery room (hypotension, hypoxemia and hematuria), biochemical markers (total bilirubin, total albumin, alanine aminotransferase, aspartate aminotransferase, creatinine, urea nitrogen), complete blood count (Hb, Plt, and Hct), cardiac function (brain natriuretic peptide, creatine kinase isoenzyme, troponin), postoperative hospital stay and indwelling time of drainage tube, and postoperative complications. These parameters will be comprehensively compared and analyzed in-depth through appropriate statistical means.

Discussion

This trial evaluated the influence of administration of sildenafil citrate combined with IPM on IBL and surgical results during open or laparoscopic hepatectomy, as well as its safety and feasibility. It is expected to provide an innovative management optimization plan for reducing the bleeding in hepatectomy, and to provide empirical support for the potential value of sildenafil citrate or sildenafil-like drugs in improving the safety and quality of perioperative hepatectomy patients.

Trial registration

This trial was registered on June 25, 2024, in the US Clinical Trials Registry ( https://register.clinicaltrials.gov ), with the ClinicalTrial.gov Identifier: NCT06237751. The protocol version is V1.0 (20,231,114).

Introduction

Background and rationale {6a}

Hepatectomy is an effective surgical method for treating benign and malignant liver tumors [1]. However, due to the characteristics of the rich blood supply and complex anatomy of the liver, excessive blood loss during liver resection is still one of the important factors affecting perioperative outcomes [2–4]. Furthermore, intraoperative blood transfusion will impact the prognosis and raise complications following liver resection in patients [5, 6]. Therefore, it is necessary to explore an effective and safe method to reduce hemorrhage during liver resection and improve the overall surgical results of patients.

Intermittent Pringle’s maneuver (IPM) is mainly carried out during liver resection and is regarded as a method to control intraoperative blood loss (IBL) [7]. However, hepatic venous hemorrhage inevitably occurs, and prolonged hepatic blood flow blockade increases the risk of ischemia–reperfusion injury (IRI) [8, 9]. Previous research [10, 11] has shown a strong correlation between intraoperative hemorrhage and central venous pressure (CVP). Controlled low central venous pressure (CLCVP) is a type of intraoperative reactive bleeding control strategy used in liver resection surgery [11]. It reduces the CVP and hemorrhage by restricting fluid infusion or using vasodilators [12]. However, the reduction in effective circulating volume raises the risk of hemodynamic instability and necessitates frequent administration of vasopressors. These measures not only increase the workload of anesthesiologists but also increase the risk of insufficient perfusion of important organs in patients [13], even leading to intraoperative cardiac arrest. Therefore, it is necessary to find a safe and effective method to reduce the bleeding during liver resection surgery.

Sildenafil, as a novel inhibitor of phosphodiesterase type 5 (PDE-5) whose mechanism of action is promoting the activation of the NO/cGMP pathway and increasing the content of NO in vascular smooth muscle, has the effect of directly vasodilatation by smooth muscle relaxation in the vessels [14–16]. Since its introduction in 1988, sildenafil has been used to treat nearly 27 million patients worldwide with erectile dysfunction (ED) due to various etiologies or comorbidities and has shown favorable efficacy and tolerability in more than 70% of cases [17, 18]. Notably, in 2005, the FDA approved sildenafil for the treatment of pulmonary arterial hypertension (PAH) [19]. In the SUPER-1 randomized double-blind placebo-controlled trial [20], 278 patients with pulmonary hypertension received placebo or different doses of sildenafil treatment, and the results showed that sildenafil significantly reduced the mean pulmonary artery pressure and improved the cardiac function classification. Therefore, sildenafil may help to reduce intraoperative blood loss in hepatic resection surgery based on its characteristics in dilating the pulmonary circulation and reducing pulmonary vascular resistance (PVR).

Despite the lack of studies directly demonstrating the ability of sildenafil to reduce intraoperative bleeding (IBL) during hepatectomy, similar PDE-3 inhibitors, such as milrinone, have been shown to be effective in reducing intraoperative bleeding and stabilizing hemodynamics during hepatectomy in several studies [13, 21]. Milrinone modulates calcium channel activity in vascular smooth muscle and cardiomyocytes by inhibiting phosphodiesterase type 3 (PDE-3), which has the effect of increasing cAMP levels, indirectly dilating blood vessels, and enhancing myocardial contractility [22]. This suggests that PDE inhibitors may have a positive effect on increasing antegrade blood flow to the right heart by directly or indirectly dilating the pulmonary vasculature and decreasing right ventricular afterload, which may be of potential value in reducing hepatic trauma bleeding.

To test the hypothesis that perioperative administration of sildenafil citrate combined with IMP can reduce the IBL during open or laparoscopic hepatectomy and improve the surgical field, we conducted a randomized controlled trial.

Objectives {7}

Based on the pharmacological characteristics of sildenafil, this study aims to explore the influence of sildenafil citrate combined with IMP on hemorrhage and surgical results during hepatectomy as well as its safety and feasibility.

Trial design {8}

This study is a single-center, double-blind, superiority randomized controlled trial. The flowchart of the trial is shown in Fig. 1. Participants will be randomly divided into two groups in a ratio of 1:1, one of which will receive sildenafil citrate therapy and the other will receive placebo therapy half an hour before the start of the hepatectomy. This trial tests the hypothesis that the application of sildenafil citrate during hepatectomy will reduce intraoperative bleeding loss compared to placebo (calcium tablet), which will be recorded as the primary outcome. The protocol reporting follows the Standard Protocol Items for Clinical Trials 2022 (SPIRIT 2022).

Fig. 1.

Flowchart of the study protocol. Hb, hemoglobin; BMI, body mass index; CLCVP, control low central venous pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; HR, heart rate; CVP, central venous pressure; CO, cardiac output; SV, stroke volume; SVV, stroke volume variation; SVR, systemic vascular resistance; TBil, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aminotransferase; BUN, urea nitrogen; Cr, creatinine; Plt, platelets; Hct, hematocrit; BNP, brain natriuretic peptide; CK-MB, creatine kinase isoenzymes; cTn, cardiac troponin

Methods: participants, interventions, and outcomes

Study setting {9}

This trial will be conducted at the First People’s Hospital of Chenzhou, the Affiliated Chenzhou Hospital, University of South China, Hunan, China.

Eligibility criteria {10}

Inclusion criteria

1. All patients who are scheduled to undergo liver resection, whichever is open or laparoscopic, have written informed consent.

2. Patients 18–85 years of age

3. ASA grade I–III

4. Child–Pugh grade A–B

Exclusion criteria

1. Being allergic to the ingredients of sildenafil.

2. Pregnant or lactating women

3. Hb < 90 g/L

4. BMI > 35 kg/m² or < 18 kg/m²

5. Shock or uncontrolled hypertension: BP < 90/60 mmHg or > 180/110 mmHg

6. Child–Pugh C

7. Cr > 178 μmol/L

8. Severe heart diseases: active coronary heart disease, severe valvular stenosis, hypertrophic obstructive cardiomyopathy

9. History of cerebrovascular infarction

10. Patients who are currently using or are planned to use nitroglycerin and other nitrates or alpha-blocker antihypertensive drugs during the study period

11. Patients who have used sildenafil within the past three months prior to the study will be excluded

The terminating study criteria are as follows:

1. Intraoperative operations leading to hepatic vein rupture can cause massive bleeding or when the blood loss exceeds 800 ml.

2. Patients with SBP < 90 mmHg or MAP < 65 mmHg who are not responding to the drug for > 10 min; allergic symptoms occurring with any one of the drugs

3. Serious perioperative adverse events occurred: severe hypersensitivity or even anaphylactic shock, severe air embolism, myocardial infarction, respiratory arrest, and successful rescue.

Who will take informed consent? {26a}

In our study, obtaining informed consent from participants is paramount. An experienced anesthesia assistant (licensed medical doctors) will join our team to interface with patients and facilitate their involvement in the research. The principal and associate investigators will personally present the Participant Information and Consent Form, detailing the study’s purpose, procedures, benefits, risks, and confidentiality policies. They will also explain the participants’ right to withdraw at any time without repercussions. Patients will receive written materials to review and understand their participation rights and the study’s implications. Researchers will address any queries patients or their families may have, ensuring a comprehensive understanding before consent is given. The informed consent form must be signed by the patient (or legal representative) and research team members, confirming mutual agreement on the study’s terms. This confirmation occurs before the commencement of any study-related activities. Furthermore, to uphold study integrity, eligibility assessments based on predefined inclusion and exclusion criteria will be conducted prior to patient enrollment (Table 1).

Table 1.

Schedule for enrollment, intervention, and evaluation

Abbreviations: D1 The day before surgery, -T1 half an hour before surgery, T0 entering the operating room, T1 post induction, T2 15 minutes after 30° head-up and foot-down position, T3 30 minutes after the start of liver resection, T4 60 minutes after the start of liver resection, T5 after liver resection, T6 at the end of the operation, D1 Postoperative day 1, D3 Postoperative day 3, D5 Postoperative day 5, IBL Total blood loss, Hb Hemoglobin, BMI body mass index, Cr Creatinine, CLCVP Control Low Central Venous Pressure, TBil Total bilirubin, ALB Albumin, ALT Alanine aminotransferase, AST Aminotransferase, BUN urea nitrogen, SBP Systolic blood pressure, DBP Diastolic blood pressure, MAP Mean arterial pressure, HR Heart rate, CVP Central venous pressure, CO Cardiac output, SV Stroke volume, SVV Stroke volume variation, SVR Systemic vascular resistance, Plt Platelets, BNP Brain natriuretic peptide, CK-MB Creatine kinase isoenzymes, cTn Cardiac troponin

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Blood sampling will be collected from each hepatectomy patient at predetermined time points (T1, T3, T4, T5) for routine blood gas analysis or thromboelastography, and the remaining blood samples will be discarded immediately. We will obtain informed consent from all participants in advance.

Interventions

Explanation for the choice of comparators {6b}

Choice of comparator and administration

In this trial, we chose calcium tablets as placebo to critically assess the efficacy and safety of sildenafil citrate in hepatectomy. Both the subject drug and the placebo were administered via nasogastric tube to ensure that there were no differences in appearance, taste, or texture. The drug was ground into powder through a special drug dispenser, diluted in a 10 ml syringe, and administered by the attending anesthesiologist half an hour before the start of the hepatectomy. This process ensured the integrity of the double-blind. Neither participants nor researchers involved in patient care or data collection were made aware of group assignments. Randomization sequences were generated by independent statisticians not involved in the day-to-day conduct of the trial. Drug dispensers followed a pre-made block randomization table.

Intervention description {11a}

Anesthesia preparation stage

Patients were routinely prohibited from drinking and eating before surgery. After entering the operating room, the intravenous access was opened, and oxygen was inhaled through the mask. After local infiltration anesthesia with 2% lidocaine, radial artery and internal jugular vein catheterization were performed to monitor SBP, DBP, MAP, CVP, CO, SV, SVV, SVR, HR, SpO2, and depth of anesthesia monitoring.

Anesthesia induction stage

In the induction period, sufentanil 0.4–0.6 μg/kg is given first, and then propofol 1.5–2 mg/kg is intravenously injected (slow injection). After waiting for the patient to lose consciousness (the disappearance of the eyelash reflex), cisatracurium 0.2–0.3 mg/kg is given (the entire induction drug administration process is completed within 1–2 min), and tracheal intubation for mechanical ventilation is performed 3 min later.

Anesthesia maintenance stage

During the operation, propofol is continuously pumped intravenously at 4–8 mg/kg/h, combined with a continuous intravenous infusion of remifentanil at 0.1–0.3 μg/kg/min, and sevoflurane is inhaled (not exceeding 1 MAC) for anesthesia maintenance. The depth of anesthesia monitoring value is maintained at about 50. When the depth of anesthesia is insufficient, the administration rate can be appropriately adjusted. Intermittently add muscle relaxants, and add an appropriate amount of sufentanil before incision.

During the operation, routine fluid infusion is controlled (3 ~ 5 ml/(kg·h), lactated Ringer's sodium crystal fluid). When the surgeon is performing liver resection, the IPM is combined to block the blood flow into the liver to reduce liver bleeding. The chief surgeon grades and scores the liver operative field according to the liver resection operative field scoring scale (Table 2) at 30 min after the start of liver resection (T3) and 60 min after the start of liver resection (T4) respectively to determine whether the CLCVP technology needs to be initiated. If the total score ≥ 70 points, no additional intervention is given. After liver resection (T5), the chief surgeon grades and scores the liver operative field again and conducts an overall satisfaction score according to the anesthesia quality satisfaction (Table 3).

Table 2.

The classification and scoring standards for evaluating the surgicals field of view

Grade	Description
	Caval/hepatic vein condition	Field bleeding	Surgical difficulty	Total score
I	Very relaxed	Minimal bleeding	Easy	90 ~ 100
II	Relaxed	Moderately less bleeding	Easier	70 ~ 89
III	Tense	Moderate bleeding	Difficult	50 ~ 69
IV	Highly tense	Excessive bleeding	Very difficult	0 ~ 49

This table provides a clear and professional translation suitable for medical and surgical documentation. It reflects the grading of the surgical field based on the condition of the vena cava/Hepatic veins, bleeding in the field, and the difficulty of the surgery, with corresponding score ranges. Through this system, the chief surgeon can quantitatively assess the complexity of the surgical field of view and make corresponding adjustments to the surgical strategy accordingly

Table 3.

The satisfaction score of anesthesia quality

Scoring items	1 point: very dissatisfied	2 points: dissatisfied	3 points: average	4 points: satisfied	5 points: very satisfied
Hemodynamic stable
The classification of the surgical field
Anesthesia depth management
Emergency handling
Overall satisfaction
Additional comments

Scoring instructions:

• Hemodynamic stable: The stability of the patient's vital signs during the operation

• The classification of the surgical field: The effect of the anesthesiologist on the control of bleeding on the liver wound surface

• Anesthesia depth management: The monitoring and adjustment of the anesthesia depth, as well as the support to the surgical process

• Emergency handling: The response and handling ability to the intraoperative emergency situations

• Overall satisfaction: From the perspective of the chief surgeon's surgical operation experience, evaluate the work done by the anesthesiologist in ensuring the comfort and safety of the patient, and give a satisfaction score

Anesthesia recovery stage

All maintenance drugs are stopped after the surgery. The patients will be sent to the post-anesthesia care unit (PACU) after the surgery, and observe whether there is hypotension, hypoxemia, and other adverse events during the recovery period, and then be sent back to the ward after awakening.

Intraoperative low central venous pressure remedial measures intervention

If the total score after the surgeon assesses the liver operative field according to (Table 2) is less than 70 points, the anesthesiologist needs to initiate the CLCVP technology and control the CVP at 3–5 mmHg (or > 50% decreases were achieved) by restricting fluid infusion (1 ml/(kg·h) and nitroglycerine pumping, and record the consumption dose of nitroglycerine. If the MAP during the operation is less than 65 mmHg and lasts for 1 min, then 50–100 ml of hydroxyethyl starch is used for bolus volume expansion. If the MAP during the operation is less than 65 mmHg and lasts for 5 min, and the bolus volume expansion is ineffective, then 10–50 μg of epinephrine is intravenously pushed or pumped, and the consumption amount of epinephrine is also recorded. If the Hb during the operation is less than 80 g/L, then concentrated red blood cells are infused. After liver transection, according to the goal-directed fluid therapy, the CVP is raised to 6–12 mmHg.

Criteria for discontinuing or modifying allocated interventions {11b}

1. Patients who withdraw consent during the study

2. Serious adverse events during the perioperative period

Strategies to improve adherence to interventions {11c}

To objectively assess the patients’ compliance, the following procedures will be implemented:

1. Education and Communication: Before patients are enrolled in the group, detailed education and communication will be provided to explain the purpose, procedures, and expected treatment plan of the study, ensuring that patients fully understand and consent to participate.

2. Postoperatively, multiple laboratory tests will be conducted, including liver and kidney function, coagulation function, blood routine, and brain natriuretic peptide levels, to evaluate the recovery and safety of patients.

3. Regular follow-up: During the study period, we will arrange regular follow-ups to monitor the rehabilitation of the patients.

Relevant concomitant care permitted or prohibited during the trial {11 d}

Combined use of drugs such as nitroglycerin and alpha blockers without hemodynamic monitoring is prohibited during the trial, which can lead to hypotension.

Provisions for post-trial care {30}

The inspection and treatment costs related to the injuries associated with the study drugs will be borne by our research team. During the clinical research process, when any adverse event occurs, regardless of whether there is a causal relationship with the study, the researchers will actively take appropriate and timely treatment measures for the subjects, conduct follow-up investigations, and follow up until the symptoms of the adverse event disappear or other causes are found, to ensure that the damage to the subjects is minimized and the safety of the subjects is fully guaranteed.

Outcomes {12}

This study is designed as a double-blind, randomized, controlled superiority trial. Patients will be randomly assigned to receive either sildenafil citrate or placebo (calcium). The primary outcome of this trial is the IBL. The secondary outcome includes the classification of the surgical field, the consumption of nitroglycerine, hemodynamic parameters, biochemical indicators, blood routine, cardiac function, coagulation function, blood gas analysis, adverse events in the recovery room, hospital stay and drainage tube indwelling time, and postoperative complications. All data are recorded by the data collector, and the surgeon, the anesthesiologist, and the nursing staff are not aware of the specific grouping situation of the patients. The trial is designed to determine whether sildenafil citrate is superior to placebo in reducing IBL.

1. Feasibility/effectiveness evaluation indicators:

Primary outcomes:

• Intraoperative blood loss: To quantify the IBL by calculating the amount of blood in the suction bottle (actual blood loss amount - saline irrigation amount) and the weight of the gauze blood pad ((weight of the gauze block after blood absorption in g − weight of the gauze block before blood absorption in g)/1.054 (average density of blood in g/ml)).More importantly, we will focus on comparing the standardized blood loss per unit time during the actual hepatectomy period (from T3 to T5). To more accurately assess the efficacy of sildenafil citrate administered via nasogastric tube half an hour before hepatectomy in reducing bleeding from the liver surgical field. This approach allows for a more precise evaluation of the intervention’s.

Secondary outcomes:

• The classification of the surgical field: At T3 and T4, the surgeon will rate and score the liver surgical field according to Table 2. If the score is lower than 70 points, CLCVP technique will be initiated to improve the surgical conditions. At T5, the surgeon will re-evaluate the surgical field to assess the effectiveness of the CLCVP technique. At the same time, the surgeon will independently evaluate the performance of the anesthesiologist in controlling the surgical field and ensuring the patient’s safety, so as to comprehensively reflect the contribution of anesthesia management to the surgery. To ensure the objectivity of the assessment, the lead surgeon will remain blind to the patient group situation throughout the process.

• Cumulative consumption of nitroglycerine: Based on the criterion of CLCVP, record whether the patient needs to use nitroglycerine during the operation and the dose used.

• Hemodynamic parameters: Collect data such as SBP, DBP, MAP, CVP, CO, SV, SVV, SVR, HR, SpO2 at the time when the patient enters the operating room (T0), after induction (T1), 15 min after adjusting the body position (T2), 30 min after the start of liver resection (T3), 60 min after the start of liver resection (T4), after liver resection (T5), and at the end of the operation (T6) to assess the influence of sildenafil on the intraoperative hemodynamic stability.

• b)Safety evaluation indicators:

• Blood gas analysis: Measure Hb, PH, and Lac at T1, T3, T4, and T5 to understand the patient’s internal environment status.

• Coagulation function: Understand the changes in the coagulation function of the patient during the operation by measuring the TEG of the patient at T2 and T5, and measure the APTT and PT values at D1, D3, and D5 to understand whether there is an impact on the patient’s postoperative coagulation function after taking sildenafil.

• Intraoperative urine output: By recording the intraoperative urine output value of the patient at T6.

• Adverse events in the recovery room: It is evaluated by measuring whether the patient has hypotension and whether there is hypoxemia in the recovery room.

• Biochemical markers (Liver and kidney functions): It is evaluated by measuring the levels of TBil, Alb, AST, ALT, Cr, BUN of the patients on days −D1 D1, D3, and D5.

• Complete blood count: At –D1, D1, D3, and D5, it is evaluated by measuring the patient’s postoperative Hb, Plt, and Hct.

• Cardiac function: By comparing the levels of BNP, CK-MB, and cTn of the patients on days D1 to assess whether sildenafil has an impact on the patient’s cardiac function.

• Postoperative hospital stay and drainage indwelling time: Record the patient’s hospital stay and drainage tube placement time to assess the patient’s recovery speed.

• Postoperative complications: Whether to enter the ICU after surgery, liver failure, bleeding, bile leakage, ascites, pleural effusion, and incision site infection.

• Prolonged (> 4 h) and abnormal erections: Male patients were observed for the presence of abnormal erections in the PACU (> 4 h) and for specific discomfort during the follow-up phase.

Participant timeline {13}

The participant timeline is shown in Table 1.

Sample size {14}

Sample size calculations were based on the primary endpoint: intraoperative blood loss. Based on the fact that this is an exploratory study, the first time sildenafil has been used in hepatectomy, preliminary experiments at our center found that the mean (standard deviation (SD)) bleeding during hepatectomy in the placebo group was 345 (200) ml, and in the experimental group it was 188 (150) ml. Assuming a type I error of 0.05 and a type II error of β of 0.80, the sample size was calculated to be 34 cases. Considering the expected dropout rate of 15% during the hypothetical period, the final selection of 40 patients was appropriate (G power program, one-tailed).

Recruitment {15}

This recruitment will be conducted from February 1, 2024, to October 30, 2024. A total of 40 patients who are eligible for the inclusion and exclusion criteria will be enrolled in this study.

Assignment of interventions: allocation

Sequence generation {16a}

After being included in the trial, randomization adopts the simple block randomization method (1:1 ratio, 8 cases in each block), and the random numbers are generated by statisticians through the computer software (SAS 9.4 or other).

Concealment mechanism {16b}

Eligible participants, after providing informed consent, will be assigned to blocks of eight by an independent statistician. Within each block, they will be randomly allocated to either the experimental or control group at a 1:1 ratio using computer-generated numbers. The allocation details will be kept confidential in sealed opaque envelopes, stored in cabinets within the research office. An independent statistician, uninvolved in-patient care, oversees this randomization to ensure the process is both random and fair.

Implementation {16c}

Patients in the sildenafil citrate group received 100 mg of sildenafil citrate tablet administered via nasogastric tube with < 10 ml clear liquid half an hour before the start of hepatectomy. Patients in the control group were given placebo treatment < 10 ml clear liquid half an hour before the start of hepatectomy.

Assignment of interventions: blinding

Who will be blinded {17a}

Everyone except the anesthesiology assistant will be blinded; all patients will receive 100 mg of sildenafil citrate tablet administered via nasogastric tube with < 10 ml clear liquid half an hour before the start of hepatectomy. The blinded independent outcome assessor will collect postoperative outcome data. The attending medical staff in the PACU and the nursing staff in the surgical ward will be unaware of the group allocation. The data analyst will be oblivious to the group allocation.

Patients will be recruited by the chief investigator by providing participant information and consent forms (PICF) to each patient and family member. The anesthesiology assistant will group the recruited patients through block randomization and supervise the patients taking the medication.

Procedure for unblinding if needed {17b}

• A)In case of medical necessity or a surgery-related emergency, the anesthesiology assistant can decide to unmask and notify the patient and the attending medical staff.
• B)If there are circumstances such as medical needs or emergency situations that require unmasking, the principal investigator will be notified and will make the final decision and report to the ethics committee.

Data collection and management

Plans for assessment and collection of outcomes {18a}

The outcome assessors will collect data from the electronic medical record system and postoperative follow-up. All participants will undergo liver resection surgery at the First People’s Hospital of Chenzhou City, University of South China. Recruitment started on February 1, 2024, and was completed on October 30, 2024, with a 5-day postoperative follow-up.

Demographic data:

• Age, year

• Gender, male/female

• Body mass index, kg/m²

Preoperative laboratory tests:

• TBil, μmol/L

• ALB, g/L

• ALT, U/L

• AST, U/L

• BUN, mmol/dl

• Cr, μmol/L

• Hct, %

• Hb, g/L

• Plt, 10⁹/L

• Coagulation function (PT, APTT)

Intraoperative parameters:

• Surgical site, left/right

• Operation time, min

• Hepatic portal occlusion time, min

• Total blood loss, ml

• Cumulative consumption of nitroglycerine, µg

• The classification of the surgical field, grade I to IV and 1–100 points

• Intraoperative infusion volume, ml

• Intraoperative blood transfusion, yes (ml)/no

• Intraoperative urine output, ml

• Blood gas analysis: Hb, pH, Lac

• Coagulation function: TEG

• Hemodynamic parameters: SBP, DBP, MAP, HR, CVP, CO, SV, SVV, SVR.

• Intraoperative erection without stimulation in male patients, n

• Intraoperative catheterization difficulties in male patients, n

Postoperative laboratory parameters:

• TBil, μmol/L

• ALB, g/L

• ALT, U/L

• AST, U/L

• BUN, mmol/dl

• Cr, μmol/L

• Hct, %

• Hb, g/L

• Plt, 10⁹/L

• Coagulation function: PT, APTT

• BNP, pg/mL

• CK-MB, ng/L

• cTn, ug/L

Postoperative follow-up data: The surgeon and the data collector will jointly assess the postoperative complications of the patients, and be unaware of the patients’ research allocation status.

• PACU complications: hypotension, hypoxemia and hematuria

• Prolonged (> 4 h) and abnormal erections, n

• Drainage indwelling time, days

• Postoperative hospital stay, days

• Postoperative pain score, points

• Admission to ICU, n

• Postoperative Complications: A Detailed Overview

  • Hepatic dysfunction [25]: Recognized through the application of the “50–50 criteria” on the fifth day following surgery, which provides a comprehensive assessment of liver function.
  • Hemorrhage [26]: Identified by a significant drop in hemoglobin levels postoperatively, where the decrease surpasses 3 g/dL from the initial postoperative measurement.
  • Biliary leakage [27]: Detected through a marked increase in drainage bilirubin levels on the third day post-surgery, indicating a rise of at least three times the standard concentration.
  • Ascites [28]: Characterized by the daily monitoring of drainage fluid, where a volume greater than 10 mL/kg is indicative of fluid accumulation in the peritoneal cavity.
  • Pleural effusion [29]: Managed based on clinical symptoms or the requirement for therapeutic thoracentesis or drainage to alleviate respiratory compromise.
  • Wound infection [29]: Treated with targeted antibiotic therapy after verification through leukocyte count elevation, radiographic evidence, or microbiological culture of the infected site.

• Adverse events (AE) and serious adverse events (SAE).

Plans to promote participant retention and complete follow-up{18b}

Based on the pharmacological characteristics of sildenafil, we will conduct a 5-day postoperative follow-up for all subjects. Most patients are still in the hospital during this period. Therefore, we will do our best to ensure that participants take part in all evaluations as much as possible and with careful consideration of their individual status.

Data management {19}

In this study, professional doctors will execute all interventions and assess outcomes. Total blood loss, a primary outcome, will be jointly evaluated by the chief anesthesiologist and the chief surgeon for objectivity. The classification of the surgical field will be rated by the surgical team. Data, collected by trained recorders on Case Report Forms (CRFs), will be cross-checked for accuracy before initial entry into Excel. A second independent entry will confirm data accuracy; discrepancies will be resolved before final submission. Electronic data will be securely stored for exclusive use by data recorders, who will access and compile data post-trial. Statistical analysis will follow trial completion. The Biomedical Ethics Committee of the First People’s Hospital of Chenzhou City, University of South China, will oversee the study’s safety and ethical compliance.

Confidentiality {27}

During the trial, personal identifiers will be separated from research data to maintain participant anonymity. Data sharing will be restricted to situations necessary for trial-related activities. After the trial, personal information will be destroyed in a secure manner, ensuring that participants’ confidentiality is maintained.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Not applicable. We will perform blood sampling for blood gas analysis or thromboelastography, and no genetic or molecular analyses are planned in this study. The samples will be discarded immediately after analysis.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The trial was designed to test the superiority of sildenafil over placebo (calcium tablets) for the primary outcome using analysis of variance. Superiority was tested by comparing the IBL in the two groups.

After assessing the normality of the data, continuous variables will be expressed as the mean ± standard deviation for data that are normally distributed. For such data, we will employ parametric tests, specifically the independent samples t-test, to compare the means between the two groups. Conversely, for data not conforming to a normal distribution, these will be presented as the median (interquartile range, 25%, 75%), and we will utilize non-parametric tests, such as the Mann–Whitney U test, to assess the differences.

To further understand the mechanism by which sildenafil reduces intraoperative bleeding and improves the surgical field in hepatectomy, we will record and analyze the relationship between intraoperative blood loss and CVP. This exploratory analysis will provide insights into the hemodynamic effects of sildenafil and its potential role in blood loss management during hepatectomy. Categorical variables, including rank information and incidence rates, will be represented by numbers and percentages (%). The Mann–Whitney U test will be applied for rank information to compare the two groups. For the comparison of incidence rates, we will use the chi-square test, and where appropriate, Fisher’s exact test will be applied, particularly for smaller sample sizes or rare events. To ensure the accuracy of the results, covariate analysis will be adopted to adjust for potential confounding factors such as operation time and liver disease type. Additionally, in our analysis, we will stratify the data by gender to evaluate potential differences in response to sildenafil. This stratification will help us understand if there are any variations in efficacy and safety based on sex, which could be crucial for developing personalized treatment strategies in the future. The surgical field rating will be compared through the Wilcoxon rank sum test, which is suitable for paired or related samples.

For secondary continuous outcomes that involve repeated measures, we will employ repeated measures ANOVA to assess the differences within groups over time, adjusting for multiple comparisons as necessary. If the data are not normally distributed or the assumptions of ANOVA are not met, we will use non-parametric tests such as the Friedman test for repeated measures on more than two levels, followed by post hoc comparisons using the Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons.

A p-value < 0.05 is considered significant. All statistical analyses are performed by SPSS version 20 and GraphPad Prism version 8.0.1.

Interim analyses {21b}

Not applicable. An interim analysis is not planned for this trial. The main reasons for this are that the study is a single-center, randomized, controlled trial with a relatively small sample size (20 cases per group) and that the primary aim of the study was to assess the effect of sildenafil administration on IBL in hepatectomy. In this case, interim analyses may not provide sufficient statistical power to detect a significant effect of the intervention and may even lead to unnecessary bias in the interpretation of the results. In addition, given the exploratory nature of the study and resource constraints, not performing an interim analysis would have ensured the integrity of the study and the reliability of the data. If larger multicentre studies are conducted in the future, interim analyses may be considered to better assess intervention effects and safety.

Methods for additional analyses (e.g., subgroup analyses) {20b}

We will compare the primary outcome, the total IBL, between the two groups in each pair using an independent two-sample t-test or Wilcoxon rank-sum test as appropriate. In addition, we will conduct subgroup analysis according to surgical types (laparoscopic surgery or open surgery), Grading of surgical difficulty according to the amount of liver lobectomy, patients with or without cirrhosis, and tricuspid regurgitation for pairwise comparison to evaluate the impact of these factors on IBL. Multiple comparisons for subgroup analysis will be adjusted using Bonferroni correction. One-way analysis of variance (ANOVA) with Tukey’s test will be used to perform pairwise comparisons for other outcomes. If the data do not satisfy normality, the Kruskal–Wallis test and Dunn’s method will be used to perform multiple comparisons.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

As all participants will be offered a protocol of sildenafil and placebo (calcium), there will be no problems with non-compliance with the protocol in this trial. The likelihood of missing values for the primary outcome is very low as the data collector will be collecting data on the total IBL. For some secondary indicators, however, sensitivity analyses for missing data (loss to follow-up, death, withdrawal, etc.) will be performed using multiple imputation.

Plans to give access to the full protocol, participant level data, and statistical code {31c}

The corresponding author may consider sharing participant-level dataset data upon receipt of a reasonable request.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5 d}

The coordinating center is composed of the Anesthesiology Department and the Hepatobiliary Surgery Department of the Medical Center of the First People’s Hospital of Chenzhou City, University of South China. The trial steering committee is composed of the principal investigator and the associate investigator, who are responsible for providing guidance. The research assistant is responsible for recruiting patients and signing the informed consent.

Composition of the data monitoring committee, its role and reporting structure {21a}

The progress of the trial, related events, and data quality will be evaluated by the Medical Ethics Review Committee of the First People’s Hospital of Chenzhou City, University of South China. The entire trial process will be supervised and monitored by surgeons and data analysts throughout the entire trial.

Adverse event reporting and harms {22}

The principal investigator will report any serious adverse events to the Institutional Review Board within 5 days after notification. Minor adverse events and injuries will be reported within 3 days after notification. When reporting adverse events or injuries, we should also report the causal relationship, occurrence time, severity, seriousness, management provided, and the relationship with the current clinical trial.

Frequency and plans for auditing trial conduct {23}

The principal investigator will submit an interim report every 3 months, and auditing will be conducted every 3 months by the Medical Ethics Review Committee of the First People’s Hospital of Chenzhou City from the University of South China. The auditing process will be independent of the investigators and the sponsor.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Any revisions to the protocol will be documented in the trial registry following approval from the Institutional Review Board.

Dissemination plans {31a}

The final data will be publicly disseminated. The results will be presented at relevant meetings and published in appropriate journals after the trial and analysis.

Discussion

This study is the first randomized controlled trial to use sildenafil for hepatectomy, aiming to evaluate the effectiveness and safety of taking sildenafil citrate perioperatively combined with the total hepatic inflow occlusion method in reducing IBL in hepatectomy.

Previous studies [13, 21] have indicated that milrinone effectively reduces IBL and stabilizes hemodynamics when used in hepatectomy procedures. However, the positive inotropic effects of milrinone may raise safety concerns in certain patient populations, particularly in those without heart failure. In contrast to sildenafil, it does not exhibit the side effect of increasing myocardial contractility, potentially making it a safer therapeutic option [30–32].

Sildenafil, as a medication that is both cost-effective and widely accessible, holds significant potential for reducing bleeding during hepatectomy. Its application could play a crucial role in enhancing the safety of surgical procedures and in the reduction of healthcare costs.

Compared to the traditional CLCVP technique, our approach leverages the pharmacological effects of sildenafil to overcome the limitations of conventional CLCVP. Unlike the method that relies on reducing preload to decrease CVP and control bleeding, our strategy focuses on diminishing PVR to reduce the afterload on the right ventricle, with forward blood flow at the core of our therapeutic approach. This not only optimizes fluid management during surgery, easing the workload of anesthesiologists, but also significantly reduces the risk of inadequate perfusion to vital organs in patients and, in severe cases, even leads to intraoperative cardiac arrest. With this innovative method, we anticipate a significant reduction in intraoperative bleeding during hepatectomy, while enhancing the safety and efficiency of the procedure.

As mentioned earlier, PDE inhibitors may have potential positive effects during liver resection. Some sildenafil analogs, such as tadalafil, can also diminish PVR. However, compared to sildenafil, tadalafil has a longer duration of efficacy [33]. This characteristic is particularly beneficial for patients with cirrhosis, as their liver resection surgeries are often more complex and time-consuming. The longer duration of efficacy may help to more effectively reduce bleeding during the surgical procedure. Nevertheless, we must also note that the longer duration of efficacy may increase the risk of postoperative hypotension. Besides PDE inhibitors, drugs such as levosimendan, as a calcium sensitizer [34], have demonstrated effects of increasing cardiac output, diminishing PVR, and improving pulmonary hemodynamics in some animal experiments [35, 36]. This indicates that drugs like levosimendan may also have important application prospects in reducing bleeding during hepatectomy.

Our study has several limitations. First, although sildenafil, a PDE-5 inhibitor, is administered via a nasogastric tube and is known to undergo first-pass metabolism, we will not measure its plasma drug concentrations. This limits our understanding of its bioavailability and in vivo activity. Second, we omitted the measurement of pulmonary artery pressure, a key indicator for assessing sildenafil’s impact on PVR, restricting our direct evaluation of its vasodilatory effects. In order to address these issues as much as possible and ensure that the medication works optimally during the surgery, when the duration of the surgery exceeds 4 h, we will appropriately supplement the medication through the nasogastric tube based on the progress of the surgery and the actual clinical situation.

Given its half-life of 4 to 6 h and hepatic metabolism, patients with liver disease may be at risk of delayed clearance, potentially increasing the risk of postoperative complications like hypotension, which could be exacerbated after partial hepatectomy. Third, given its exploratory nature to ensure safety, we enrolled only 20 patients per group, a small sample size that may affect the statistical power and generalizability of our findings. To enhance the reliability and generalizability of our conclusions, we plan to conduct multicenter, large-sample clinical trials in the future to further validate our results.

In summary, this trial protocol is designed against this backdrop to further explore the impact of perioperative sildenafil administration on reducing bleeding during hepatectomy and improving surgical outcomes, thereby providing a reference for optimizing the management of intraoperative bleeding in liver resection surgery.

Trial status

This trial was reviewed and approved by the Ethics Committee of the First People’s Hospital of Chenzhou City, University of South China on December 25, 2023 (ethical reference number: 2023139). The protocol was registered with the US Clinical Research Information Service on January 25, 2024 (NCT06237751). The protocol version is V1.0 on 14 November 2023. Recruitment started on February 1, 2024, and is expected to be completed by October 30, 2024.

Abbreviations

IBL

Intraoperative blood loss

PVR

Pulmonary vascular resistance

IPM

Intermittent Pringle’s maneuver

CLCVP

The Controlled low central venous pressure

PDE-5

Phosphodiesterase type 5

PDE-3

Phosphodiesterase type 3

ED

Erectile dysfunction

FDA

Food and Drug Administration

PAH

Pulmonary arterial hypertension

BMI

Body mass index

MAC

Minimum alveolar concentration

TBiL

Total bilirubin

ALB

Albumin

ALT

Alanine aminotransferase

AST

Aminotransferase

BUN

Urea nitrogen

Cr

Creatinine

Hct

Hematocrit

Hb

Hemoglobin

Plt

Platelets

APTT

Activated partial thromboplastin time

PT

Prothrombin time

BNP

Brain natriuretic peptide

CK-MB

Creatine kinase isoenzymes

cTn

Cardiac troponin

pH

Potential of hydrogen

Lac

Lactate

TEG

Thromboelastogram

SBP

Systolic blood pressure

DBP

Diastolic blood pressure

MAP

Mean arterial pressure

HR

Heart rate

CVP

Central venous pressure

CO

Cardiac output

SV

Stroke volume

SVV

Stroke volume variation

SVR

Systemic vascular resistance

Authors’ contributions {31b}

CQS played a pivotal role in drafting the manuscript and devising the study’s methodology and operational components. PSX was instrumental in the study design, manuscript preparation, and overseeing the trial’s management. ZYY and LSZ managed the recruitment process for the trial. XF contributed to the conceptualization of the study design. YY, WP, PXR, and ZCB were responsible for designing the health economic analysis. XAW and ZZM served as the principal investigators and grant holders, overseeing comprehensive trial management, study design, and manuscript review. All authors have reviewed and approved the final draft of the manuscript.

Funding {4}

This work was supported by the General Program of the Medical and Health Science and Technology Development Research Center, National Health Commission (Grant No. WKZX2024CX301203);the Health Appropriate Technology Promotion Project of Hunan Provincial Health Commission (No. 202319019440); the Hunan Provincial Natural Science Foundation (Grant No. 2024JJ7030); the Research Special Fund of Wu Jieping Medical Foundation (No. 320.6750.2024-15-131);the Chenzhou Science and Technology Innovation Project (2023 Chenzhou Technology R&D Center, Social Development Category No. 3) and the Medical Research Fund of Hunan Medical Association (No. HMA202101004). The funding agencies were not involved in the design, data collection, data analysis, or data interpretation of this study.

Data availability {29}

At the moment, the research data is not publicly accessible. Upon the study’s conclusion, the data may be requested from the corresponding author for legitimate purposes. Following the completion of data collection, we aim to prepare a comprehensive report of our findings and submit it for peer review and potential publication in a suitable academic journal, with an expected timeframe of three months thereafter.

Declarations

Ethics approval and consent to participate {24}

The Institutional Review Board of Chenzhou Hospital/Chenzhou First People’s Hospital, University of South China, approved the study protocol on December 25, 2023 (ethical reference number: 2023139). Written informed consent will be obtained from all the participants.

Consent for publication {32}

All participants provided written informed consent for the publication of their anonymized data. The study protocol was approved by the Institutional Review Board of Chenzhou Hospital/Chenzhou First People’s Hospital, University of South China, on December 25, 2023 (ethical reference number: 2023139). Copies of the consent form are available for review upon request.

Competing interests {28}

The authors declare that they have no competing interests.