Assessing the Impact of Goal-Directed Fluid Therapy Protocol on Perioperative Outcomes in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy: A Comparison with Standard Institutional Fluid Therapy Protocol

Peritoneal carcinomatosis (PC) represents a widespread metastatic dissemination throughout the abdomen and pelvis of many organ-based malignancies, particularly carcinomas of the gastrointestinal tract and ovaries. The most common malignancies that can develop peritoneal carcinomatosis include (1) mucinous appendiceal neoplasms and appendix cancer, (2) colorectal cancer, (3) ovarian cancer and primary peritoneal carcinomas, (4) peritoneal mesothelioma, (5) gastric cancer, (6) small bowel cancer, (7) pancreatic cancer, and (8) sarcomas.

In the 1980s, Dr Paul Sugarbaker introduced the ‘Sugarbaker procedure’ for peritoneal mesotheliomas, wherein heated chemotherapeutic drugs were directly applied to the abdomen after surgically removing any visible tumours. 1 Since then Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is indicated as treatment for these neoplasms. It consists of almost complete removal of the peritoneal surface, multiple visceral resections, a variable number of intestinal anastomosis, followed byperfusion of chemotherapy inside the abdominal cavity, for 90 min at 42 °C.2,3

The wide extent of surgical resection and physicochemical trauma of the HIPEC alters capillary permeability, resulting in tissue damage and facilitating abdominal and systemic complications with postoperative morbidity and mortality ranging from 22 to 41 % and from 2 to 5 % respectively, with a significant increase in ICU stay and hospitalization time. 4, 5

Also, cytoreductive surgery is usually associated with significant fluid shift attributable to suboptimal nutritional status, prolonged preoperative starvation, intraoperative blood and fluid loss, pharmacological vasodilation by neuraxial (epidural) and systemic anaesthetic drugs, intraoperative evaporative loss and the vasodilation due to systemic inflammatory response to surgery (SIRS) resulting in hypotension and altered hemodynamics in the intra-operative and immediate post-operative settings. So, there is need for rigorous hemodynamic monitoring and appropriate fluid therapy in the perioperative period. Permissive infusion regimen was proposed in the past 6, 7to counteract fluid, blood, and protein losses; however, it excessively exposes the patient to the risk of fluid overload, tissue edema, and severe abdominal complications. On the other hand, the use of restrictive infusional regimens may expose the patient to hemodynamic instability, detrimentaltissue hypoperfusion, organ damage, and worsen the nephrotoxic chemotherapy drug effect. Different markers of global perfusion are serum lactate, mixed and central venous oxygen saturation (ScvO2), Co2 gap in between central venous and arterial blood, (P v-a CO2), left ventricular strain and markers of local perfusion are temperature gradient (Tc-toe), skin mottling, capillary refill time, peripheral perfusion index (PPI), tissue oxygen saturation (Sto2) and transcutaneous oxygen measurement (Ptco2). 8

The current standard of care in our centre Institute rotary cancer hospital (IRCH) has been a fluid therapy guided by clinical parameters. Although there is strong evidence supporting goal-directed approach (using Flotrac/Vigileo system) to perioperative fluid therapy in case of major abdominal surgeries, leading to significant reduction of systemic complications and enhanced recovery 9-11, there is no concrete evidence for CRS/HIPEC surgery. So, we would like to conduct the proposed study to findout the optimal fluid management strategy in CRS/HIPEC. Primary end points will be serum NGAL levels. Secondary end pointswill be serum lactate levels (surrogate marker of tissue perfusion) intraoperatively and post operatively, incidence of renal complications (defined by AKIN criteria), length of ICU stay (till fit to discharge based on ICU physician discretion) and 30-day mortality.

**Preliminary work done if any:**The present topic is new and not much researched worldwide. PI has done an extensive review and found gap in knowledge and lack of existing trials evaluating the type of fluid therapy protocol on incidence of acute kidney injury in patients undergoing CRS/HIPEC surgery. Also, till date serum NGAL levels as biomarker for AKI in CRS/HIPEC surgery has not been evaluated before. Considering the novelty of the topic and overall need for such research we strongly believe that the results of this study would be beneficial to population at large.

**The relevance and expected outcome of the proposed study:**Patients undergoing CRS/HIPEC surgery are prone to develop acute kidney injury in the post- operative period due to various factors such as use of chemotherapeutic agent (cisplatin) as well as due to hemodynamic fluctuations happening throughout the surgery. Although there is strong evidence supporting goal-directed approach (using Flotrac/Vigileo system) to perioperative fluid therapy in case of major abdominal surgeries, leading to significant reduction of systemic complications and enhanced recovery, there is no concrete evidence for CRS/HIPEC surgery. Through this study we will be able to assess and compare the institutional fluid therapy protocol versus goal directed fluid therapy protocol in patients undergoing CRS/HIPEC surgery and see the effect of goal-directed therapy on post-operative neutrophil gelatinase-associated lipocalin. Also, we will compare length of ICU stay and 30-day mortality.

**Aim:**This study is aimed to assess whether the use of Goal directed fluid therapy protocol is associated with significant change in perioperative outcomes compared to standard institutional fluid therapy protocol guided by clinical parameters in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.