Proactive Hemodynamic Management During Cytoreductive Surgery and HIPEC

Official title

HEMOdynamic Proactive Management During Cytoreductive Surgery and Intraperitoneal hyPErthermic Chemotherapy for Advanced Ovarian Cancer

Overview

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a complex surgical procedure carried out through laparotomic approach. After CRS-HIPEC morbidity and mortality rates go up to 20%-40% and 3% respectively, and acute kidney injury and pulmonary effusion/oedema are the most frequent postoperative complications. Intraoperative hypotension and risk of fluid overload are common. Efficient and accurate control of arterial pressure and cardiac output is a major concern during CRS-HIPEC. The aim of this study is to perform a pilot study describing a hemodynamic management protocol based on artificial intelligence - derived parameters, that allows to implement the standard goal directed therapy (GDT) protocol in term of amount of IOH and stroke volume (SV) optimization. Specifically, this study aims to test the hypotheses that a hemodynamic protocol based on HPI-AFM monitoring compared to standard GDT helps clinicians reduce IOH during surgery and improve the time "in-target" range of SV index. The study cohort will be compared to an historical cohort of 50 patients underwent to CRS-HIPEC between 2022 and 2024, managed with an institutional goal directed therapy protocol.

Detailed description

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a complex surgical procedure carried out through laparotomic approach. Intraoperative management represents a challenge for anesthesiologist: hemodynamic instability (due to extremely destructive surgery with fluids shift and blood loss), biochemical abnormalities (worsened by cytotoxic chemotherapic agents peritoneal infusion, with profound metabolic acidosis and electrolytes disturbance), and extreme thermal fluctuations related to the different phases of surgery.

CRS-HIPEC is fraught with significant drawbacks: morbidity and mortality rates go up to 20%-40% and 3% respectively, and acute kidney injury and pulmonary effusion/oedema are the most frequent postoperative complications. More than 70% of the patients are admitted in Intensive Care Unit after the surgery.

Intraoperative hypotension (IOH) during CRS-HIPEC is common, and as it is associated with the potential for harm \[9\]. At the same time, extensive fluid resuscitation in peritoneal cancer patients is associated with a poor postoperative outcome, and avoiding fluid overload is recommended. Optimizing flow and pressure requires repeated measurement of both variables and use of established protocols for vasopressor and fluid administration (the so called "individualized hemodynamic management") has been shown to be associated with decreased postoperative complications compared to routine care. Efficient and accurate control of arterial pressure and cardiac output is a major concern during CRS-HIPEC, because it requires frequent manual adjustments of vasopressor infusion rates and timely fluid administration.

A peculiar aspect of CRS-HIPEC is the delicate phase of intraoperative chemotherapy. During this procedure, hyperthermia and the extensive cytolysis caused by the chemotherapeutic drug lead to multifactorial metabolic acidosis and intense vasodilation: managing fluid therapy and vasoconstrictor drugs is often extremely challenging.

The aim of this study is to perform a pilot study describing a hemodynamic management protocol based on artificial intelligence - derived parameters, that allows to implement the standard goal directed therapy (GDT) protocol in term of amount of IOH and stroke volume (SV) optimization during CRS-HIPEC.

All patients included in the study will have a radial arterial catheter inserted before or immediately after anesthesia induction and connected to Hemosphere. The clinician will follow an algorithm based on Assisted Fluid Management (AFM) for fluid infusion and on Hypotension Prediction Index (HPI) to titrate vasopressors and inotropes. AFM will be set as "medium" during cytoreductive phase and "restrictive" during HIPEC. A maximum volume of fluids per patients will be set at 10 ml/kg/hr.

Specifically, this study aims to test the hypotheses that a hemodynamic protocol based on HPI-AFM monitoring compared to standard GDT helps clinicians reduce IOH during surgery and improve the time "in-target" range of SV index (a value that estimates the time with SVI within target range, characterizing optimization of cardiac function), avoiding a detrimental fluid overload.

Two hierarchical primary endpoints were defined. The first primary endpoint will be the time-weighted average (TWA) - MAP less than 65 mmHg (expressed in mmHg) throughout surgery. The second primary endpoint will be the time spent during surgery in an optimized range of SVI (the "in target" range will be defined at the beginning of hemodynamic monitoring).

Secondary endpoints will be total norepinephrine dose and total amount of fluids.

Exploratory outcomes will be the fraction of AFM software-prompted boluses that resulted in the desired increase in SV, the incidence of post-operative complications (specifically postoperative Pulmonary Complications), ICU and hospital length of stay (LOS) and the analysis of hospital costs related to the adoption of AFM software in the clinical practice of our hospital.

The study cohort will be compared to an historical cohort of 50 patients underwent to CRS-HIPEC between 2022 and 2024, managed with an institutional goal directed therapy protocol.

Interventions

• Device Assisted Fluid Management
  Intraoperative fluid infusion will be regulated according to the Assisted Fluid Management (AFM) software and on Hypotension Prediction Index (HPI) will be used to titrate vasopressors and inotropes.
• Other Goal Directed Fluid Therapy (GDT)
  Institutional goal directed therapy protocol used to optimize SVI and reduce intraoperative hypotension

Primary outcome measures

• TWA-MAP<65mmHg [Time frame: Perioperative]
• TIT-SVI [Time frame: Perioperative]

Secondary outcome measures (2)

• Vasopressors [Time frame: Perioperative]
• Fluids [Time frame: Perioperative]

Eligibility criteria

Inclusion criteria

• age > 18 years
• patient scheduled for CRS for ovarian cancer

Exclusion criteria

• patients' refusal
• cardiac arrythmia
• pregnancy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• IRCCS Fondazione Policlinico A. Gemelli — Rome

Publications

• van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HWR, Hermans RHM, de Hingh IHJT, van der Velden J, Arts HJ, Massuger LFAG, Aalbers AGJ, Verwaal VJ, Kieffer JM, Van de Vijver KK, van Tinteren H, Aaronson NK, Sonke GS. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018 Jan 18;378(3):230-240. doi: 10.1056/NEJMoa1708618. PMID 29342393
• Ghirardi V, Trozzi R, Scanu FR, Giannarelli D, Santullo F, Costantini B, Naldini A, Panico C, Frassanito L, Scambia G, Fagotti A. Expanding the Use of HIPEC in Ovarian Cancer at Time of Interval Debulking Surgery to FIGO Stage IV and After 6 Cycles of Neoadjuvant Chemotherapy: A Prospective Analysis on Perioperative and Oncologic Outcomes. Ann Surg Oncol. 2024 May;31(5):3350-3360. doi: 10.1245/s10 PMID 38411761
• Wang JY, Gross M, Urban RR, Jorge S. Intraperitoneal and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Ovarian Cancer. Curr Treat Options Oncol. 2024 Mar;25(3):313-329. doi: 10.1007/s11864-023-01171-3. Epub 2024 Jan 4. PMID 38270801
• Kajdi ME, Beck-Schimmer B, Held U, Kofmehl R, Lehmann K, Ganter MT. Anaesthesia in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: retrospective analysis of a single centre three-year experience. World J Surg Oncol. 2014 May 1;12:136. doi: 10.1186/1477-7819-12-136. PMID 24886171
• Mendonca FT, Guimaraes MM, de Matos SH, Dusi RG. Anesthetic management of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC): The importance of hydro-electrolytic and acid-basic control. Int J Surg Case Rep. 2017;38:1-4. doi: 10.1016/j.ijscr.2017.07.011. Epub 2017 Jul 10. PMID 28719887
• Esteve-Perez N, Ferrer-Robles A, Gomez-Romero G, Fabian-Gonzalez D, Verd-Rodriguez M, Mora-Fernandez LC, Segura-Sampedro JJ, Tejada-Gavela S, Morales-Soriano R. Goal-directed therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a prospective observational study. Clin Transl Oncol. 2019 Apr;21(4):451-458. doi: 10.1007/s12094-018-1944-y. Epub 2018 Sep 14. PMID 30218305
• Lim MC, Chang SJ, Park B, Yoo HJ, Yoo CW, Nam BH, Park SY; HIPEC for Ovarian Cancer Collaborators. Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer: A Randomized Clinical Trial. JAMA Surg. 2022 May 1;157(5):374-383. doi: 10.1001/jamasurg.2022.0143. PMID 35262624
• Frassanito L, Giuri PP, Vassalli F, Piersanti A, Garcia MIM, Sonnino C, Zanfini BA, Catarci S, Antonelli M, Draisci G. Hypotension Prediction Index guided Goal Directed therapy and the amount of Hypotension during Major Gynaecologic Oncologic Surgery: a Randomized Controlled clinical Trial. J Clin Monit Comput. 2023 Aug;37(4):1081-1093. doi: 10.1007/s10877-023-01017-1. Epub 2023 Apr 29. PMID 37119322

Identifiers

NCT: NCT07070973 · 7488

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗