Restrictive or Individualized Goal-Directed Fluid Replacement Strategy in Ovarian Cancer Cytoreductive Surgery
Condition: Ovarian Cancer
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
Study type: Interventional

Summary: 
      This is a single center prospective randomized controlled study comparing the postoperative
      outcome after cytoreductive surgery in ovarian cancer patient after using restrictive or
      individualized goal-directed fluid replacement strategy (GDT). Aim of this study will be to
      test the hypothesis that intra-operative SVV-guided fluid optimization during ovarian cancer
      cytoreductive surgery:

        1. reduces the postoperative length of hospital stay,

        2. cost-effective,

        3. GDT will be more beneficial in cases of PDS compared to IDS or cytoreductive procedures
           of shorter duration.

        4. GDT improves intraoperative tissue perfusion/ oxygenation and improves immediate
           postoperative morbidity.

      Intra-operatively fluid of choice in both groups will be lactate-free crystalloid at 1.0
      ml/kg/h for maintenance and gelofusine for fluid bolus of 3ml/kg over 5 minutes. In group C
      intraoperative fluid therapy will include maintenance fluid and replacement of the surgical
      loss. Aim will be to maintain MAP > 65 mmHg, CVP 8-12 cm H2O and urine output > 0.5 ml/kg/h.
      In group G intraoperative fluid therapy will be targeted to SVV <13%, SVI > 35ml/m2/ beat,
      SVRI more than equal to 1900 dynes-sec/cm-5/m2 in addition to clinical parameters like MAP,
      CVP and urine output.

      Primary outcome will be length of hospital stay (LOS). Secondary outcomes will be cost of
      surgical treatment episode (admission till fit to discharge), postoperative morbidity survey
      (POMS) and 30 day morbidity and mortality.
    

Detailed description: 
      Aims & objectives:

      The purpose of the study is to test the hypothesis that intra-operative SVV-guided fluid
      optimization during ovarian cancer cytoreductive surgery -

        1. Reduces the postoperative length of hospital stay.

        2. GDT is more cost-effective.

        3. GDT will be more beneficial in cases of PDS compared to IDS.

        4. GDT reduces postoperative morbidity.

      Justification for study:

      Cytoreductive surgery in ovarian cancer 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), which was comparatively more in case of
      ovarian surgery. This results in hypotension and altered hemodynamics in the intra-operative
      and immediate

      post-operative settings and the need for rigorous hemodynamic monitoring in the perioperative
      period. Among 3 different strategies, liberal or conservative one is associated with risk of
      overhydration, whereas restrictive therapy can cause hypoperfusion and related complications.
      A goal-directed fluid therapy has been shown to optimise intravascular volume in major
      abdominal surgery, which is the key determinant of cardiac output and oxygen delivery to
      tissues. This strategy results in use of more advanced hemodynamic monitors and increased
      costs thereof, and possibly, more total fluid requirements. A restrictive fluid strategy
      targeting physiological parameters alone, utilizes less costly modalities of monitoring and
      less overall fluid infused. But total healthcare cost associated with reduced rate of
      complications and thereby less hospital stay can neutralize that extra-cost of advanced
      monitoring (approximately Rs 8,000 per patient for consumables) and become more cost
      effective. The current standard of care in Tata Medical Center (TMC) has been a fluid therapy
      guided by clinical parameters. Although there is strong evidence supporting goal-directed
      approach to perioperative fluid therapy in case of major abdominal surgery, which has also
      been incorporated in enhanced recovery protocol and adopted worldwide, there is no such
      evidence for gynaec-oncological surgery, especially in ovarian cancer. So, investigators
      would like to conduct the proposed study to find-out the optimal fluid management strategy
      for ovarian cytoreductive surgery. As previously mentioned, investigators' data might
      indicate that the standard approach may lead to tissue hypoperfusion and approximately 2-3
      liters of deficit which needs replacement under monitoring in order to avoid fluid overload.

      Arguably, all patients of major cytoreductive surgery should require goal directed therapy
      and therefore randomization can potentially harm a subset of patients who would then receive
      restricted therapy instead of goal directed therapy. However, the standard regimen which is
      currently used in our setting is restrictive and SVV is also being increasingly used
      routinely only at the clinician's discretion including in ovarian cancer cases. Therefore no
      harm is anticipated from this intervention in either group. The only implication is of cost
      and resources; goal directed therapy has resource implications- both in terms of availability
      of machine and additional cost to the patient due to the consumables. A non-randomized
      prospective observational study would be feasible but will not be able to select which
      patients would benefit maximum from GDT due to selection bias. Therefore, a randomized study
      may help to identify a select group of patients who might benefit the maximum and therefore
      SVV directed fluid administration could be further stratified to be cost-effective due to
      reduction of postoperative length of hospital stay and morbidity.

      From personal communication investigators know that, 3 trials of perioperative fluid therapy
      are ongoing now in India. Out of those 3 trials, 2 are in abdominal surgery and one is in
      hyperthermic intraperitoneal chemotherapy (HIPEC) surgery. Other cancer centers expressed
      interest to undertake similar trial in ovarian cytoreductive surgery. Therefore investigators
      may collaborate with other centers in future for a larger study based on the results;
      however, at present a single institutional study will be conducted to minimize bias
      associated with heterogeneity in surgical practice on cytoreduction.

      Benefit:

      This study will help investigators to guide fluid therapy in the perioperative period in
      ovarian cancer patients undergoing cytoreductive surgeries. This study should also help to
      find a strategy to prevent both fluid overload as well as under filling to avoid hypo
      perfusion and organ damage in this vulnerable group of patients. This strategy can even be
      adopted in other patient populations undergoing colorectal, hepatobiliary, thoraco-abdominal
      and HIPEC surgeries. These data will also inform whether a stratified approach can be adopted
      to selectively use SVV monitoring according to the predicted surgical complexity, type of
      cytoreduction and duration of surgery to optimize resources and improve cost-effectiveness.

      Risks This study will utilize an existing technology, which is already in use. Therefore SOPs
      will be followed including reporting of adverse events, monitoring, documentation and safety
      reporting. The intervention is fluid bolus guided by advanced haemodynamic parameters (EV1000
      monitor). Therefore risks are theoretical only. Risks related to the invasive procedures are
      same in both arms, which include pneumothorax, haemothorax, haemo-pneumothorax, bleeding,
      catheter-related infection and peripheral ischemia.

      Methodology:

      Site of Study OT complex and Intensive Care Unit, Department of Anaesthesiology & Critical
      Care, Tata Medical Center, Kolkata

      Study Structure Design:

      Prospective randomized controlled trial - Patients and assessors will be blinded.

      Population: All ovarian cancer patients undergoing major debulking surgery at TMC Kolkata
      (except- completion staging).

      Sample size:

      The study design was based on a retrospective audit at TMC that found the current median
      postoperative length of stay to be 10 days after cytoreductive surgery in ovarian cancer. To
      detect a reduction of 2 post-operative days with median postoperative length of stay to be 10
      days in the restrictive group and 8 days in the goal directed group with a SD=3 days for 80%
      power at a significance level of 0.05, 37 patients are needed in each group (Total=74). As
      there is a difference in the median postoperative length of stay between the PDS and IDS
      group as mentioned earlier, at least 20 patients in each of the IDS and PDS groups would be
      needed for both the goal directed and restrictive group.

      So the study would continue till each of the four combinations: Goal Directed (IDS), Goal
      Directed (PDS), Control (IDS) and Control (PDS) have at least 20 patients. To account for
      possible 10% attrition rate/ loss to follow up, 44 patients would be required in each group

      Method of Randomization:

      In addition to having higher median LOS in hospital, patients undergoing PDS are more likely
      to have ascites, major peritoneal stripping, higher surgical complexities and intraoperative
      fluid loss. Therefore, pre-randomization stratification will be done for type of surgery.
      Patients would be enrolled separately into PDS and IDS groups. Then for each group, patients
      would be randomized to get the standard or the goal directed therapy mentioned in the sealed
      envelopes based on computer generated random numbers.

      After randomization and inclusion into a study arm, patients will be excluded in an event of
      the following: the procedure is abandoned/ open and close, duration of procedure is less than
      4 hours, and any critical incident during operation (i.e. major blood loss/ medical
      condition/ shock) requiring intense fluid resuscitation. Following factors will be analyzed
      for univariate and multivariate analysis: ASA status, duration of surgery in minutes,
      surgical complexity score, intraoperative fluid loss, total vs. partial peritonectomy,
      comorbidities (Possum-P), massive blood loss and transfusion. Analysis will be on a per
      protocol basis as well as intention to treat.

      Blinding:

        -  As the envelope would be opened after induction of GA, the patient will be blinded to
           the group she is allocated to.

        -  Post operative data will be collected by the ICU Consultant/ medical officer and
           Gynaec-oncosurgery team, who would not be part of the study and unaware about the
           allocation will follow up patients and decide on fitness to discharge. Outcome will also
           be verified according to predefined criteria by other clinicians from Gynaec-oncosurgery
           team, who are not aware about the allocated study group.

      Statistical Analysis:

      All statistical analyses and all summary tables and listings will be prepared using SASÒ
      release 8.3 or higher (SAS Institute, Inc., Cary, NC). Standard descriptive summaries will
      include the N, mean, median, standard deviation, minimum and maximum for continuous
      variables, and the number and percent for categorical variables. All statistical test of
      comparison will be based on 5% level of significance.
    

Intervention name(s): EV1000(FloTrac System 4.0)
Intervention type(s): Device
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Flotrac System 4.0 Edwards Lifesciences, Irvine, CA, USA
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Ovarian cancer; goal-directed fluid therapy; SVV