Phase I trial on the safety of olprinone for low central venous pressure management aimed at haemorrhage control during open and laparoscopic hepatectomy: a study protocol

Abstract

Introduction

Hepatectomy is the primary treatment for malignant liver tumours. It is crucial to control bleeding during liver parenchymal transection. Methods to reduce central venous pressure (CVP), such as fluid restriction and the use of vasodilators, are essential for minimising bleeding but can lead to haemodynamic instability. Phosphodiesterase-3 (PDEIII) inhibitors such as milrinone have shown efficacy in managing low CVP and maintaining haemodynamic stability. This study investigates olprinone, another PDEIII inhibitor with a potentially strong vasodilatory effect, for its safety and efficacy in CVP management during hepatectomy.

Methods and analysis

This single-centre phase I trial at Shizuoka Cancer Center evaluates the intraoperative administration of olprinone for open and laparoscopic hepatectomy. The trial employs a 3+3 cohort study design to determine the maximum tolerated dose (MTD) and identify dose-limiting toxicities. The study also assesses the trends in CVP and circulatory dynamics using the FloTrac System, alongside safety evaluations. The trial aims to establish the safety and MTD of olprinone during hepatectomy, potentially offering a method to control CVP without causing haemodynamic instability. This could lead to reduced blood loss, shorter operative time and fewer postoperative complications.

Ethics and dissemination

The study protocol was approved by the Certified Review Board of Shizuoka Cancer Center (approval number CRB4180010).

Trial registration number

jRCTs041230110 and jRCTs041230111.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The strength of this study is that the use of olprinone, a PDEIII inhibitor, during hepatectomy may achieve management of low CVP, maintaining stable haemodynamics through its lusitropic and vasodilatory effects, as well as inotropic effects.

• This approach potentially offers a method to control CVP without causing haemodynamic instability.

• A primary limitation of this study is the small number of patients.

• Other limitations include possible bias due to favourable patient backgrounds and the fact that the study will be conducted at a single institution.

Introduction

Hepatectomy is the primary treatment for malignant liver tumours such as hepatocellular carcinoma, intrahepatic cholangiocarcinoma and metastatic liver cancer. The liver is a blood-rich organ; thus, controlling bleeding is crucial for safe hepatectomy, while maintaining an optimal surgical field.¹ Haemorrhage during liver transection, specifically from the liver parenchyma, can be categorised into two types: bleeding from inflow vessels, such as the portal vein system and hepatic arteries, and bleeding from outflow vessels, such as the hepatic veins. Bleeding from inflow vessels can be controlled by techniques such as intermittent blood flow occlusion at the hepatic hilum, including Pringle’s manoeuvre and portal venous occlusion.^{2 3} In contrast, bleeding from the hepatic veins and outflow vessels hinges on maintaining a low central venous pressure (CVP).⁴,⁶ The decline of CVP facilitates venous drainage from the hepatic vein and sinusoids, thereby diminishing bleeding from the raw surfaces of the transected liver parenchyma caused by venous backflow.⁴,⁶ Methods to reduce CVP include fluid restriction, the use of vasodilators such as nitroglycerin, and inferior vena cava occlusion. However, these intraoperative efforts to achieve low CVP can decrease the effective circulating volume, potentially leading to hypotension and haemodynamic instability.^{6 7} This may result in electrolyte disturbances, renal function impairment, and other complications.^{6 7}

Phosphodiesterase-3 (PDEIII) inhibitors, generally indicated for cardiovascular diseases such as acute heart failure, possess inotropic, lusitropic and vasodilatory effects. A previous randomised controlled trial using milrinone, a PDEIII inhibitor, during hepatectomy reported low CVP was sufficiently controlled and bleeding was reduced while circulatory dynamics were maintained.⁶ Thus, it is considered that PDEIII can maintain adequate peripheral circulation while achieving low CVP management.^{6 8}

Olprinone, another PDE-III inhibitor, is considered to have a more potent vasodilatory effect than milrinone and may be more suitable for use during hepatectomy.⁹ Although previous studies have reported that the perioperative administration of olprinone to hepatectomy candidates could prevent postoperative liver failure,¹⁰ there are no reports on its role in low CVP management. PDEIII inhibitors are primarily used for the treatment of cardiovascular diseases, and the safety of olprinone during hepatectomy has not been established.

Therefore, the present study aims to evaluate the safety of intraoperative administration of olprinone in patients scheduled for hepatectomy and to assess its efficacy in managing low CVP.

Methods and analysis

Objective

Intraoperative administration of olprinone (Coretec) in patients scheduled for open or laparoscopic hepatectomy, within the dose range described in the package insert, will be prospectively evaluated for safety and efficacy in low CVP management. This study is a single-centre phase I trial at Shizuoka Cancer Center and will be conducted separately for open and laparoscopic hepatectomy, as the dynamics of CVP in laparoscopic hepatectomy differ from those in open surgery owing to the application of pneumoperitoneum pressure.¹¹ The study protocol was approved by the Certified Review Board of Shizuoka Cancer Center (approval number CRB4180010).

Study design

Based on the clinical hypothesis that administering olprinone (Coretec) during hepatectomy is safe at doses approved for acute heart failure, this study aimed to determine the maximum tolerated dose (MTD) and identify dose-limiting toxicity (DLT) as the primary investigation item, employing a 3+3 cohort study design as a reliable phase I trial methodology for determining the MTD.¹² The efficacy of suitable low-CVP management will also be examined as a secondary endpoint. The initial dosage is set at 10 µg/kg/5 min, as described in the package insert. If DLT occurs during this loading phase, the administration will be discontinued. If no DLT is observed in the initial 5 min period, olprinone administration will continue at rates ranging from 0.1 to 0.3 µg/kg/min, with dose increases in increments of 0.05 µg/kg/min in each 3+3 cohort) (figure 1). Olprinone administration begins before liver transection and is discontinued once liver transection is complete. The transection process starts after the olprinone loading is finished. The initial dose (Level 1) is set at 0.10 µg/kg/min, with subsequent levels increasing by 0.05 µg/kg/min from Level 2 onwards, reaching a maximum dose of 0.30 µg/kg/min at Level 5. At each level, three patients are initially enrolled. If no DLTs are observed in these three patients at Levels 1–4, progression to the next dose level will occur. If no DLTs occur in three patients at Level 5, this level will be considered the MTD. In cases where two or fewer of the initial three patients at any level develop DLTs, an additional three patients will be treated at the same dose. If three or fewer out of these six patients (including the additional patients) exhibit DLTs, progression to the next level is allowed for Levels 1–4. Under these circumstances, Level 5 is deemed to be the MTD. Conversely, if three or more out of six patients (including the additional three patients) develop DLTs, the dose one level lower will be designated as the MTD. At Level 1, if three or more out of six patients experience DLTs, the study will be terminated due to the absence of an MTD. Similarly, if all three initial patients experience DLTs at Level 1, the study will be terminated, as no MTD was identified.

Figure 1. A schematic illustration of the maintenance dose of olprinone and determination of dose-limiting toxicity occurrence and maximum tolerated dose using a 3+3 cohort study design. γ, mg/kg/min. DLT, dose-limiting toxicity. MTD, maximum tolerated dose.

If DLTs occur in all three patients at Levels 2–5, the dose one level lower will be considered to be the MTD. If the initial three patients at Levels 1–4 do not experience a DLT and the cohort is advanced to a higher dose, but all three patients at this level experience DLTs, three additional patients will then be enrolled at a dose one level lower. If fewer than two of these six patients (at the dose one level lower) experience DLTs, this dose will be confirmed as the MTD. However, if three of these six patients experience DLTs, the dose one level lower will again be established as the MTD.

This study will also investigate the trends in CVP associated with olprinone administration, alongside safety evaluations.

Primary endpoints

The primary endpoint is the occurrence of DLTs. Anticipated adverse events during treatment with olprinone, established as perioperative DLTs, include arrhythmias, hypotension, hypertension, and renal dysfunction. The details are as follows.

1. Intraoperative: Blood pressure elevation that is refractory to antihypertensive drugs is associated with an inotropic action (systolic blood pressure >180 mm Hg). Blood pressure decreases and is refractory to vasopressors. This decrease is associated with a vasodilation effect, with systolic blood pressure falling below 70 mm Hg.

Arrhythmias include paroxysmal atrial tachycardia, atrial fibrillation, atrial flutter, ventricular tachycardia (including torsade de pointes) and ventricular fibrillation. Excessive tachycardia (heart rate, >140 beats per min).

• 2 1From the end of surgery to 24 hours postoperatively: Arrhythmias and excessive tachycardia will be assessed as described above. Renal dysfunction after surgery (on admission to the intensive care unit). Serum creatinine elevation (>2.00 mg/dL).
• 2 2On or after the day following the operation: For laparoscopic hepatectomy, presence of renal dysfunction on the first, third and fifth postoperative days. For open hepatectomy, it will be assessed on the first, third, fifth and seventh postoperative days. Serum creatinine elevation (>2.00 mg/dL).

Secondary endpoints

Secondary endpoints include the assessment of CVP and circulatory parameters obtainable with the FloTrac System (Edwards Lifesciences, Irvine, USA),¹³ and intraoperative blood loss. The details are as follows.

1. CVP dynamics: Measure every 20 s from the start of surgery, focusing on the following time points: the start of surgery, before olprinone loading, before liver transection, during liver transection (using mean and median values due to variation in excision time), after liver transection and at the end of surgery. The percentage change in CVP is evaluated immediately before and during liver transection, as described above.

2. The transition of circulatory parameters will be acquired using the FloTrac System and measured every 20 s, particularly during the same periods as the CVP assessments.

3. The transition of arterial pressure will be recorded every 20 s, particularly during the same period as the CVP assessments.

4. Intraoperative blood loss, including blood loss during hepatic transection, will be evaluated.

Inclusion criteria and exclusion criteria

Prior to entry to the study, patients must fulfil the following inclusion criteria:

1. Planned for open or laparoscopic hepatectomy.

2. Age between 18 and 75 years as of the date of consent.

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

4. No obstructive ventilation disorder (forced expiratory volume in 1 s (FEV1.0%) ≥70%).¹¹

5. No history of angina pectoris or myocardial infarction.

6. No moderate or severe valvular heart disease (based on transthoracic echocardiographic findings).

7. The following laboratory criteria must be met: white cell count between 2.5 × 10⁹/L and 10 × 10⁹/L, platelet count ≥100 × 10⁹/L, aspartate aminotransferase ≤100 IU/L, alanine aminotransferase ≤100 IU/L, total bilirubin ≤2.0 mg/dL (up to 4.0 mg/dL in patients with jaundice), serum creatinine ≤1.0 mg/dL.

8. Documented consent obtained directly from the patient.

Exclusion criteria are as follows:

1. History of arrhythmias (excluding premature contractions).

2. Undergoing hepatectomy without discontinuing antiplatelet drugs.

3. History of allergy to PDEIII inhibitors.

4. Cases deemed inappropriate for this trial by the attending surgeon.

Cases will be registered consecutively if they meet the above inclusion and exclusion criteria, except during the transition period for the dose level.

Circulatory parameters

1. CVP: A central venous catheter is inserted and measured using a pressure transducer. The zero-point is set at the intersection of the fourth intercostal space and midaxillary line, each time the patient is repositioned.

In addition to blood pressure and heart rate, the following parameters of circulatory dynamics obtained using the FloTrac System were acquired to assess changes over time before and after the administration of olprinone.

• 2 1Cardiac output: Stroke volume×heart rate (mL/min). Indicators of contractility.
• 2 2Cardiac index: Cardiac output divided by the body surface area (mL/min × m²). Index of contractility.
• 2 3Stroke volume: The volume of blood that the ventricle expels in one contraction (mL). This is a measure of contractility.
• 2 4Stroke volume index: Stroke volume divided by body surface area (mL/m²). Index of contractility.
• 2 5Stroke volume variation: Percentage change in respiratory variability of stroke volume (%). Indicator of preload.
• 2 6Systemic vascular resistance: Resistance to left ventricular output (dynes/s/cm⁵). Indicator of afterload.
• 2 7Systemic vascular resistance index: Cardiac coefficient used instead of cardiac output when calculating systemic vascular resistance (dynes/s/cm⁵/m²). Indicator of afterload.

Intraoperative anaesthetic management

Anaesthetic management with standardised general anaesthesia or general and epidural anaesthesia without premedication. Induction is with propofol (0.8–3.5 mg/kg), maintenance anaesthesia is with remifentanil (0.02–0.30 µg/kg/min), inhalation of 1–2% sevoflurane or 4–7% desflurane and muscle relaxation with rocuronium (0.17–0.41 mg/kg). Observational arterial manometry, ECG waveforms, arterial blood oxygen saturation, end-expiratory carbon dioxide partial pressure, bladder temperature and CVP are routinely monitored. The CVP should be set at the intersection of the fourth intercostal space and midaxillary line according to the change in position. Intraoperative fluids should be administered at a rate of 5–8 mL/kg/hour. Phenylephrine, ephedrine, dopamine, norepinephrine, nicardipine and landiolol are used to maintain haemodynamic control. The maximum airway pressure should be maintained below 15 cm H₂O. Fresh-frozen plasma and red blood cell transfusions are administered as necessary to maintain stable haemodynamics. However, this does not apply to unacceptable changes in respiratory and circulatory status during anaesthesia, and drug adjustments and ventilator settings should be made as necessary.

Measurement of blood loss

The amount of blood loss is measured according to the volume of suction and the weight of the gauze used. The amount of blood loss from suction is calculated as 1 g per 1 mL and the amount of blood loss from gauze is calculated by subtracting the preuse weight. In addition to the total intraoperative blood loss, the blood loss during liver transection is counted separately. Measurement of the bleeding during liver transection is started after collecting all gauze in the abdominal cavity before completing the liver transection preparation and administering olprinone, and after liver transection is complete, the unnecessary gauze in the abdominal cavity is collected to finalise the count.

Evaluation items

The evaluation items for this study are summarised in table 1, and the schedule is provided in online supplemental table 1.

Table 1. Evaluation items.

Evaluation phase	Category	Item
Preregistration	Background	Gender, age, ECOG performance status, height, weight, alcohol consumption history, smoking history, presence of comorbidities (eg, gastrointestinal ulcers, diabetes, liver diseases, kidney diseases, ischaemic heart diseases, stroke, peripheral arterial disease, heart failure, asthma, connective tissue diseases, mental disorders), history of abdominal surgery, use of antiplatelet drugs
	Blood tests	White cell count, platelet count, AST, ALT, total bilirubin, creatinine
	Disease background	Diagnosis before surgery (eg, hepatocellular carcinoma, cholangiocarcinoma, etc)
Preoperative	Blood tests	White cell count, haemoglobin platelet count, total protein, albumin, AST, ALT, LDH, total bilirubin, creatinine, CRP, fasting blood sugar, HbA1c, BNP, NT-proBNP, CK, CK-MB, prothrombin time, prothrombin activity, prothrombin-INR, activated partial thromboplastin time
Intraoperative	Surgical information	Surgery date, surgical procedure, vascular combined resection (hepatic artery, portal vein)
	Operative metrics	Olprinone administration, operative time, blood loss, blood pressure, heart rate, CO, CI, SV, SVV, SVRI
Postoperative
Within 24 hours	Echocardiography	Echocardiography findings: occurrence of arrhythmias
Observation period(up to postoperative day 5 in laparoscopic hepatectomy and day 7 in open hepatectomy)	Body temperature	Maximum body temperature
	Blood tests	White cell count, haemoglobin, platelet count, AST, ALT, LDH, creatinine, BNP, NT-proBNP, CK, CK-MB, total bilirubin, prothrombin time, prothrombin activity, prothrombin-INR, activated partial thromboplastin time
	Complications	Postoperative liver failure: graded according to the ISGLS definition; postoperative bile leakage: graded according to the ISGLS definition; other postoperative complications: graded according to the Clavien-Dindo classification
Follow-up period	Others	Length of postoperative hospital stay, in-hospital mortality: date of occurrence and cause of death, histopathological diagnosis

ALTalanine aminotransferaseASTaspartate aminotransferaseBNPbrain natriuretic hormoneCIcardiac indexCRPC reactive proteinECOGEastern Cooperative Oncology GroupISGLSInternational Study Group of Liver SurgeryLDHlactate dehydrogenaseNT-proBNPN-terminal pro-brain natriuretic peptideSVstroke volumeSVRsystemic vascular resistanceSVRIsystemic vascular resistance indexSVVstroke volume index

Safety monitoring and auditing

Monitoring will be conducted to ensure the reliability and quality of the research and its documentation. Monitoring will be conducted annually. To ensure the appropriate implementation of clinical research, a monitoring officer will be appointed, and detailed monitoring procedures will be stipulated in a separate monitoring protocol. Although an audit is not scheduled for this study, an audit may be considered if any issues are identified during the research, such as through monitoring.

Statistical analysis

For the primary endpoint, the proportion of patients experiencing DLTs is calculated, using the number of patients treated with olprinone at each dosage level as the denominator. A 95% CI corresponding to a two-tailed α value of 0.05 is also calculated. For the secondary endpoints, summary statistics are calculated for each of the six time points: at the start of surgery, before loading with olprinone, immediately before hepatic dissection, during hepatic dissection, immediately after hepatic dissection, and at the end of surgery. These statistics include CVP, arterial pressure and circulatory parameters obtained using the FloTrac System. The summary values of the central venous pressure at each time point for each case are connected and presented. Data at each time point are plotted as a box-and-whisker diagram, with the mean and median values plotted over time and combined into one diagram. Additionally, the frequency of patients with a reduction in central venous pressure before hepatectomy is calculated, in relation to the values at the start of surgery and immediately before the administration of olprinone with a corresponding 95% CI. The mean, SD, median, minimum, and maximum values are presented for each metric. In cases of missing values, the number of missing values is also reported.

Data management

The investigators and the research secretariat (principal investigator) will record the information of registered cases using the electronic case report form (eCRF) in accordance with the provisions of the trial implementation protocol. The principal investigator will ensure that the submitted CRF is accurate, complete and submitted within the appropriate deadline. Additionally, the data recorded in the CRF must be consistent with the original data and must not contradict it.

eCRF Platform: Smart EDC

URL: https://sedc.anchor-scchr.net/entry

Registration of the protocol and study period

The study protocol was registered on the website of the Japan Registry of Clinical Trials (jRCT) (clinical research plan number, open hepatectomy version: jRCTs041230111, laparoscopic hepatectomy version: jRCTs041230110) on 1 January 2024. The research began on 1 January 2024 and is scheduled to conclude on 31 December 2025. Case registration is expected to be completed by 28 February 2025.

Ethics and dissemination

The study protocol was approved by the Certified Review Board of Shizuoka Cancer Center (approval number CRB4180010) on 21 November 2023. The study complies with the Declaration of Helsinki and the principles of Good Clinical Practice. All patients who fulfil the inclusion criteria will provide written informed consent. Serious adverse events will be reported to the safety desk of the trial, the Data and Safety Monitoring Board. On completion of this clinical research or the completion of all analyses, the principal investigator and the research secretariat will take necessary measures to protect the human rights of the research subjects and their relatives, as well as the rights and interests of the research team and their relatives. The results of the research will be published in medical journals or presented at academic conferences. Confidentiality of the research subjects will be strictly maintained during the publication of the results.

Discussion

This trial aims to validate the safety and establish the MTD of olprinone during both open and laparoscopic hepatectomy and, secondarily, to investigate circulatory dynamics, including CVP. Reducing blood loss during liver resection not only provides a better operative field, but also reduces operative time, which further contributes to blood loss reduction. In turn, this may lead to a reduction in postoperative complications.¹,⁵ Properly controlled CVP management is crucial to achieve these outcomes. However, efforts to manage low central venous pressure, such as limiting infusion and using vasodilators, can lead to haemodynamic instability.^{6 7} On the other hand, PDEIII inhibitors may achieve management of low CVP, maintaining stable haemodynamics by lusitropic and vasodilatory effects, as well as inotropic effects. While there are reports of effective CVP management using milrinone,^{6 8} there is a lack of data on olprinone, which is considered to have a stronger vasodilatory effect than milrinone, and may therefore be more suitable for CVP management. As olprinone is primarily used for treating cardiovascular diseases, and its safety during hepatic resection has not yet been established, this study aimed to verify its safety and efficacy, setting the stage for a subsequent phase I prospective trial.