About the Study

EXPANDED ABSTRACT

Introduction

Severe complicated intra-abdominal sepsis (SCIAS) is a World-Wide challenge, with high mortality rates, and ever increasing incidence. Mortality rates range from over 10% to 40% when shock is present. According to the WISS study of the World Society of Emergency Surgery (WSES) patients treated for severe peritonitis with a WISS score ≥ 7 experienced a mortality of 41.7%. Most cases result from secondary peritonitis in which there is a physical disruption of the integrity of the gastrointestinal (GI) tract leading to contamination of the peritoneal cavity. Ultimately, however the resultant organ damage that frequently becomes progressive and self-perpetuating results from auto-amplifying biomediator generation and systemic inflammation. The key principles of treating SIAS are early antibiotic administration and the earliest possible operative intervention to provide source control of GI perforations/disruptions. A further potential therapeutic option may be to utilize open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove Closed Or Open after Laparotomy (COOL trial)
11 with ANPPT in cases of SCIAS. Thus, high quality data to direct clinical decision making in this highly lethal condition is urgently required, a position espoused by both the Abdominal Compartment Society and the World Society of Emergency Surgery.

Intervention

The study intervention will comprise the randomized decision to either A) primarily close the fascia after laparotomy for SCIAS (CLOSED); or B) leave the fascia open after laparotomy for SCIAS and apply a ANPPT temporary abdominal closure (TAC)
device (OPEN).

Study Hypothesis

ANPPT will reduce the mortality of patients with SCIAS undergoing laparotomy for source control from 42% to 30%, and will reduce the degree of organ dysfunction in association with systemic reduction in Biomediator activation. The trial will be pragmatic permitting any procedure leaving the fascia open with some formal active negative pressure peritoneal therapy (ANPPT) device versus any that closes
the fascia. Thus, allowed techniques for open include are all the commercial OA techniques with or without fascial traction devices. Techniques without ANPPT such as the Barkers VAC PAC, Bagotta Bag, or mesh interposition without peritoneal suction will
not be eligible techniques.

Primary Outcome

90-Day hospital survival after laparotomy for SCIAS.
Secondary Outcomes: Secondary outcomes will be considered logistical, physiologic, and economic. Logistical outcomes will include Days Free Of (DFO); ICU, ventilation, renal replacement therapy, and hospital at 90 days from the Index Laparotomy. The physiological secondary outcomes will include change in APACHE II,
SOFA, RIFLE, ARDS scores after laparotomy. Biomediator outcomes for centres participating in COOL-Max will consist of the measurement of IL-6 and 10, Procalcitonin, Activated Protein C (APC), High-Mobility Group Box Protein 1, and mitochondrial DNA.
Economic secondary outcomes will comprise standard costing for utilization of hospital resources.

Inclusion Criteria:

Patients will be randomized intra-operatively once it is determined that severe complicated Severe Complicated Intra-Abdominal Sepsis (SCIAS) is present.

Severe will be inferred by the presence of septic shock as defined by the Sepsis-3 definition of those requiring vasopressors to maintain mean blood pressure greater than
65 mmHg and having a serum lactate level > 2 mmol/l OR

Predisposition-InfectionResponse-Organ
Dysfunction (PIRO) Score of 4 or more OR

a positive QuickSOFA (qSOFA) score. qSOFA will be calculated as it is considered as criteria for those likely to have a prolonged ICU stay or die. These simple predictors are; respiratory rate > 22/min;
altered mentation; systolic blood pressure < 100 mmHg, AND

COMPLICATED due to presence of purulent, feculent, or enteric spillage over at least 2 intra-peritoneal quadrants which can only be identified at laparotomy.

Recent studies have confirmed that the simple
qSOFA model performs similarly to more complex models like SOFA or LODS outside the ICU.

Exclusion Criteria

Among those undergoing laparotomy for secondary causes of SCIAS patients will be excluded if; a) pancreatitis, b) they are pregnant, c) physical inability of the surgical team to close the fascia without “undo pressure”; iv) absolute requirement for repeat laparotomy
including intra-peritoneal packing or non-anatomic post-surgical anatomy. It should be stated that there is an increasing use of the open abdomen technique after resection with delayed anastomosis for SCIAS, and therefore the screening log of non-eligible patients
with this indication will constitute a third important (albeit non-randomized) study group.

Allocation Methodology

Multicenter prospectively block randomized non-blinded controlled trial. Patients will be identified by the attending trauma surgeons of the participating centers as those undergoing urgent laparotomy for severe sepsis. Randomization will occur intraoperatively
with either the preoperative signing of informed consent or under waiver of consent depending on local Ethical Guidelines. Once COMPLICATED peritonitis involving more than 2 quadrants is confirmed eligible patients will be randomized to OPEN or
CLOSED through direct online randomization over the internet.
Closed Or Open after Laparotomy (COOL trial).  Sample Size: An reasonable estimate was for a 42% mortality closed versus 27% open,
given a sample size of 170 per arm, with an power of 80% and an alpha of 0.05. With 15 centres, this would mean about 11 patients per year over 2 years, and with 10 centres, 17 patients per year.

Measurements

Biomediators and standard hematological and chemical measurements to allow for APACHE II and SOFA scoring (WBC, lactate, ABGs, etc) will be measured every 6 hours
for 48 hours, followed by daily for 96 hours, and at the conclusion of the first week. The trial will be held on a web platform (Clinical Registers) through a dedicated web site: www.clinicalregisters.org (https://www.clinicalregisters.org/). Anticipated Study Schedule:
The COOL investigators hope to begin enrollment in Jan 2018 and will complete patient accrual by Jan 2020 with initial expedited publication of results in July 2020. COOL-Max versus COOL-Lite: The study will be powered to detect a mortality difference
between the 2 allocated therapies (COAST-SSP study). Thus the critical determinant of a potential geographical site being able to participate is ethical approval and willingness to randomly allocate eligible patients to either study protocol. All sites will be requested to
obtain serum and peritoneal fluid samples for Biomediator level determination (COOLMax). If a site does not have the laboratory or financial resources however to collect and
process study samples for Biomediator analysis they will be eligible to participate without the collection of the Biomediator samples (COOL-Lite). COOL-Mic: will also be considered regarding understanding the microbiology of secondary peritonitis in the OA arm of COOL-Lite and to follow the subsequent modifications in microbiologic flora including and patients in the CLOSED arm who require reoperation