The Unrestricted Global effort to complete the Closed Or Open after Source Control Laparotomy for Severe Complicated Intra-Abdominal Sepsis (COOL) Trial
Authors: Kirkpatrick Andrew W , Coccolini Federico , Tolonen Matti , Minor Samuel , Catena Fausto , Gois Emanual , Doig Christopher J , Hill Michael , Ansaloni Luca , Chiurgi Massimo , Tartaglia Dario , Ioannidis Orestis , Sugrue Michael , Colak Elif , Hameed S Morad , Lampela Hanna , Agnoletti Vanni , McKee Jessica L , Garraway Naisan , Sartelli Massimo , Ball Chad G , Parry Neil G , Voght Kelly , Julien Lisa , Kroeker Jenna , Roberts Derek J , Faris Peter , Tiruta Corina , Moore Ernest E , Ammons Lee Anne , Anestiadou Elissavet , Bendinelli Cino , Bouliaris Konstantinos , Carroll Rosemarry , Ceresoli Marco , Favi Fracesco , Gurrado Angela , Rezende-Neto Joao , Isik Arda , Cremonini Camilla , Strambi Silivia , Konstantoudakis Georgios , Testini Mario , Trpcic Sandy , Pasculli Alessandro , Picarello Erika , Adeyeye Ademola , Augustin Goran , Alconchel Felipe , Altinel Yuksel , Amin Luz Adriana Hernandez , Aranda Jose Manuel , Baraket Oussama , Biffl Walter L , Baiocchi Luca , Bonavina Luigi , Brisinda Giuseppe , Cardinali Luca , Celotti Andrea , Chaouch Mohamed , Chiarello Maria , Costa Gianluca , de'Angelis Nicola , Manzini Nicolo , Delibegovic Samir , Saverio Salomone Di , Simone Belinda , Dubuisson Vincent , Fransvea Pietro , Garulli Luca , Giordano Alessio , Gomes Carlos , Hiyati Firdaus , Huang Jinjian , Ibrahim Aini Fahriza , Huei Tan Jih , Jailan Ruhi Fadzlyana Binti , Khan Mansour , Luna Alfonso Palmieri , Malbrain Manu , Marwah Sanjay , McBeth Paul , Mihailescu Andrei , Morello Alessia , Mulita Francesk , Murzi Valentina , Mohammad Ahmad Tarmizi , Parmar Simran , Pal Ajay , Wong Michael Pak-Kai , Pantalone Desire , Podda Mauro , Puccioni Caterina , Rasa Kemal , Ren Jianen , Roscio Francesco , Gonzalez-Sanchez Antonio , Sganga Gabriele , Scheiterlem Maximilian Leonardo Federico , Slavchev Mihail , Smirnov Dmitry , Tosi Lorenzo , Trivedi Anand , Vega Jaime Andres Gonzalez , Waledziak Maciej , Xenaki Sofia , Winter Desmond , Wu Xiuwen , Zakaria Andeen , Zakaria Zaidia 
Published: February 2023

Abstract
· Background: Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. A further therapeutic option may be open abdomen (OA) management with negative peritoneal pressure therapy (NPPT) to remove inflammatory ascites and attenuate the systemic damage from SCIAS, although there are definite risks of leaving the abdomen open whenever it might possibly be closed. This potential therapeutic paradigm is the rationale being assessed in the Closed Or Open after Laparotomy (COOL-trial)(https://clinicaltrials.gov/ct2/show/NCT03163095). Initially, the COOL-trial received Industry sponsorship; however, this funding mandated the use of a specific trademarked and expensive NPPT device in half of patients allocated to the intervention (open) arm. In August 2022, the 3M/Acelity Corporation without consultation but within the terms of the contract cancelled the financial support of the trial. Although creating financial difficulty, there is now no restriction on specific NPPT devices and removing a cost-prohibitive intervention creates an opportunity to expand the COOL trial to a truly global basis. This document describes the evolution of the COOL trial, with a focus on future opportunities for global growth of the study.
· Methods: The COOL trial is the largest prospective randomized controlled trial examining the random allocation of SCIAS patients intra-operatively to either formal closure of the fascia or use of the OA with application of an NPPT dressing. Patients are eligible if they have free uncontained intra-peritoneal contamination and physiologic derangements exemplified by septic shock OR severely adverse predicted clinical outcomes. The primary outcome is intended to definitively inform global practice by conclusively evaluating 90-day survival. Initial recruitment has been lower than hoped but satisfactory, and the COOL steering committee and trial investigators intend with increased global support to continue enrollment until recruitment ensures a definitive answer.
· Discussion: OA is mandated in many cases of SCIAS such as the risk of abdominal compartment syndrome associated with closure, or a planned second look as for example part of ‘damage control’, however improved source control (locally and systemically) is the most uncertain indication for an OA. The COOL-trial trial seeks to expand potential sites and proceed with evaluation of NPPT agnostic to device, to properly examine the hypothesis that this treatment attenuates systemic damage and improves survival. This approach will not affect internal validity and should improve the external validity of any observed results of the intervention.
· Trial registration: National Institutes of Health (https://clinicaltrials.gov/ct2/show/NCT03163095).