Closed or Open Abdomen for the Management of Abdominal Sepsis

Abdominal Sepsis Clinical Trial

Official title:

Closed Versus Open Abdomen in the Surgical Treatment of Severe Secondary Peritonitis: a Randomized Controlled Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03163095
• Other study ID #: REB16-1588-the COOL study
• Status: Recruiting
• Phase: N/A
• Start date: June 2, 2019
• Est. completion date: December 2025

Study information

• Verified date: February 2023
• Source: University of Calgary
• Contact: Andrew Kirkpatrick, MD
• Phone: 403-944-2888
• Email: andrew.kirkpatrick[@]ahs.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a prospective randomized clinical study. The study will comprise the randomized decision to either A) primarily close the fascia after laparotomy for intra-abdominal infection (CLOSED); or B) leave the fascia open after laparotomy and apply a temporary abdominal closure (TAC) device (OPEN) with a vacuum drain.

Although debatable, both procedures (CLOSED or OPEN abdomen) are acceptable based on current suggested standard of care. Thus, high quality data to direct clinical decision making in this highly lethal condition is urgently required.

Description:

Severe complicated intra-abdominal sepsis (SCIAS) is a World-Wide challenge, with high mortality rates, and ever increasing incidence. Most cases are subjected to 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, the resultant organ damage results in auto-amplifying biomediator generation and systemic inflammation. Mortality rates range from 10% to over 40% when shock is present. 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 intra-peritoneal inflammatory ascites and to ameliorate the systemic damage from SCIAS. Recent data from a randomized controlled trial including either severe peritonitis or trauma patients, showed the 30-days mortality differed between commercial open abdomen systems and non-commercial technique, which favored the more effective commercial device. Although there is a biologic rationale for such an intervention from animal models as well as non-standardized clinical utilization currently, the open abdomen management with ANPPT remains a novel therapy with much clinical equipoise. Thus, the Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial to address this issue.

There is a complex relationship between pressure, ischemia, and inflammation within the peritoneal cavity. Independently the damaged gut seems to act as a continued source of inflammation propagating systemic inflammatory response syndrome (SIRS) and potentiating multi-organ dysfunction syndrome (MODS). Although extremely complicated, visceral ischemia further generates multiple immunological mediators with the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), as well as inhibitive cytokines such as interleukin 10 (IL-10). Post-operative complications associate with increasing levels of systemic IL-6, and peritoneal TNF-α. Jansson and colleagues believe that peritoneal cytokines in humans respond more extensively compared to systemic cytokines, and that a normal postoperative course is characterized by decreasing levels of peritoneal cytokines based on studies of both elective and emergency surgery. Overall, the peritoneal cytokine response is much higher than the systemic response in peritonitis.

ANPPT therapy may be a more direct and focused solution to this complicated problem, and that will be complementary to the other benefits of open abdomen management in the sickest patients. Whether improved post-operative courses can be obtained through this relatively simple approach of actively removing peritoneal cytokines in humans is therefore a secondary objective of this trial.

Another potential benefit of ANPPT after severe infection may be the attendant decompression of the abdominal compartment and prevention of even modest degrees of intra-abdominal hypertension (IAH). Patients with intra-abdominal infections are at risk of elevated intra-abdominal pressure (IAP) both as a result of the primary intra-peritoneal disease, and as large fluid resuscitation often required maintaining organ perfusion. Recent studies have demonstrated a high prevalence of IAH following aggressive resuscitation of septic patients. Intra-abdominal hypertension is present in as many as 80% of septic medical and surgical ICU patients. Reintam also reported that septic patients with IAH had a 50% rate of mortality compared to 19% without IAH, making IAH a significant marker for an increased risk of death. Within our own institution, rates of IAH were over 87% of septic ICU patients and further 61% of these patients had severe IAH at levels commensurate with abdominal compartment syndrome (ACS). Although direct translation to humans is uncertain, even modest degrees of IAH (often clinically ignored) have been found to have profound effects on propagating multiple organ failure in animals with ischemia/intra-peritoneal infections.

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 an ANPPT temporary abdominal closure (TAC) device (OPEN).

Patients will be randomized intra-operatively once it is determined that COMPLICATED and SEVERE Intra-Abdominal Infection (SCIAS) is present. SEVERE will be defined and denoted by the presence of any organ dysfunction exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score > 3 or a World-Society-of-Emergency-Surgery-Sepsis-Severity-Score > 8, and COMPLICATED with the presence of purulent, feculent, or enteric spillage over at least 2 intra-peritoneal quadrants.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 550
• Est. completion date: December 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Presence of purulent, feculent, or enteric spillage over at least 2 intra-peritoneal quadrants intra-operatively;

• Septic shock, or

• Predisposition-Infection-Response-Organ Dysfunction Score > 3, or

• World-Society-of-Emergency-Surgery-Sepsis-Severity-Score > 8

Exclusion Criteria:

• Pregnant;

• Confirmed or strongly suspected severe IAH (IAP>20 mmHg);

• No intentional of providing ongoing care;

• pancreatitis as the source of peritonitis;

• uncontrolled bleeding

Related Conditions & MeSH terms

• Abdominal Infection
• Abdominal Sepsis
• Intraabdominal Infections
• Sepsis

Intervention

Device:
• Open Abdomen Management with ANPPT dressing
The abdominal fascia will not be closed, but a temporally abdominal closure (TAC) dressing, such as AbThera dressing, will be placed to protect the viscera with active Negative Pressure Peritoneal Therapy. The time that the TAC dressing will be changed will be left to the discretion of the attending surgeon, but practice guidelines mandate either formal abdominal closure or dressing change at 24-72 hours from placement. Blood samples and peritoneal fluid will be drawn up to 72 hours after enrollment.

Other:
• Closed Abdomen Management
Primary closure of the abdominal fascia with placement of an intra-peritoneal drain (such as a Jackson-Pratt drain). This strategy will allow drainage of intra-peritoneal fluid for both clinical reasons and to facilitate intra-peritoneal fluid testing. Closure or not of the skin will be left to the attending surgeons discretion. Any decision to perform a relaparotomy (Relaparotomy on Demand) will be at the discretion of the treating critical care teams, and in no way mandated by this recruitment. Blood samples and peritoneal fluid (if available) will be drawn up to 72 hours after enrollment.

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta

Sponsors (2)

Lead Sponsor	Collaborator
University of Calgary	Alberta Health services

Country where clinical trial is conducted

Canada, 

References & Publications (20)

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-20010 — View Citation

De Waele JJ. Abdominal Sepsis. Curr Infect Dis Rep. 2016 Aug;18(8):23. doi: 10.1007/s11908-016-0531-z. — View Citation

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimm — View Citation

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimm — View Citation

Kirkpatrick AW, Roberts DJ, De Waele J, Jaeschke R, Malbrain ML, De Keulenaer B, Duchesne J, Bjorck M, Leppaniemi A, Ejike JC, Sugrue M, Cheatham M, Ivatury R, Ball CG, Reintam Blaser A, Regli A, Balogh ZJ, D'Amours S, Debergh D, Kaplan M, Kimball E, Olve — View Citation

Kirkpatrick AW, Roberts DJ, Faris PD, Ball CG, Kubes P, Tiruta C, Xiao Z, Holodinsky JK, McBeth PB, Doig CJ, Jenne CN. Active Negative Pressure Peritoneal Therapy After Abbreviated Laparotomy: The Intraperitoneal Vacuum Randomized Controlled Trial. Ann Su — View Citation

Kirkpatrick AW, Sugrue M, McKee JL, Pereira BM, Roberts DJ, De Waele JJ, Leppaniemi A, Ejike JC, Reintam Blaser A, D'Amours S, De Keulenaer B, Malbrain MLNG. Update from the Abdominal Compartment Society (WSACS) on intra-abdominal hypertension and abdominal compartment syndrome: past, present, and future beyond Banff 2017. Anaesthesiol Intensive Ther. 2017;49(2):83-87. doi: 10.5603/AIT.a2017.0019. Epub 2017 May 14. No abstract available. — View Citation

Kubiak BD, Albert SP, Gatto LA, Snyder KP, Maier KG, Vieau CJ, Roy S, Nieman GF. Peritoneal negative pressure therapy prevents multiple organ injury in a chronic porcine sepsis and ischemia/reperfusion model. Shock. 2010 Nov;34(5):525-34. doi: 10.1097/SHK — View Citation

Leppaniemi A, Kimball EJ, De Laet I, Malbrain ML, Balogh ZJ, De Waele JJ. Management of abdominal sepsis--a paradigm shift? Anaesthesiol Intensive Ther. 2015;47(4):400-8. doi: 10.5603/AIT.a2015.0026. Epub 2015 May 14. — View Citation

Malbrain ML, Chiumello D, Pelosi P, Wilmer A, Brienza N, Malcangi V, Bihari D, Innes R, Cohen J, Singer P, Japiassu A, Kurtop E, De Keulenaer BL, Daelemans R, Del Turco M, Cosimini P, Ranieri M, Jacquet L, Laterre PF, Gattinoni L. Prevalence of intra-abdo — View Citation

Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC. The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*. Crit Care Med. 2014 Jul;42(7):1714-21. doi: 10.1097/CCM.0000000000000325. — View Citation

Regueira T, Bruhn A, Hasbun P, Aguirre M, Romero C, Llanos O, Castro R, Bugedo G, Hernandez G. Intra-abdominal hypertension: incidence and association with organ dysfunction during early septic shock. J Crit Care. 2008 Dec;23(4):461-7. doi: 10.1016/j.jcrc — View Citation

Reintam A, Parm P, Kitus R, Kern H, Starkopf J. Primary and secondary intra-abdominal hypertension--different impact on ICU outcome. Intensive Care Med. 2008 Sep;34(9):1624-31. doi: 10.1007/s00134-008-1134-4. Epub 2008 May 1. — View Citation

Sartelli M, Abu-Zidan FM, Ansaloni L, Bala M, Beltran MA, Biffl WL, Catena F, Chiara O, Coccolini F, Coimbra R, Demetrashvili Z, Demetriades D, Diaz JJ, Di Saverio S, Fraga GP, Ghnnam W, Griffiths EA, Gupta S, Hecker A, Karamarkovic A, Kong VY, Kafka-Rits — View Citation

Sartelli M, Abu-Zidan FM, Catena F, Griffiths EA, Di Saverio S, Coimbra R, Ordonez CA, Leppaniemi A, Fraga GP, Coccolini F, Agresta F, Abbas A, Abdel Kader S, Agboola J, Amhed A, Ajibade A, Akkucuk S, Alharthi B, Anyfantakis D, Augustin G, Baiocchi G, Bal — View Citation

Sartelli M, Viale P, Catena F, Ansaloni L, Moore E, Malangoni M, Moore FA, Velmahos G, Coimbra R, Ivatury R, Peitzman A, Koike K, Leppaniemi A, Biffl W, Burlew CC, Balogh ZJ, Boffard K, Bendinelli C, Gupta S, Kluger Y, Agresta F, Di Saverio S, Wani I, Esc — View Citation

Slade E, Tamber PS, Vincent JL. The Surviving Sepsis Campaign: raising awareness to reduce mortality. Crit Care. 2003 Feb;7(1):1-2. doi: 10.1186/cc1876. Epub 2003 Jan 8. — View Citation

Tellor B, Skrupky LP, Symons W, High E, Micek ST, Mazuski JE. Inadequate Source Control and Inappropriate Antibiotics are Key Determinants of Mortality in Patients with Intra-Abdominal Sepsis and Associated Bacteremia. Surg Infect (Larchmt). 2015 Dec;16(6 — View Citation

Tolonen M, Sallinen V, Mentula P, Leppaniemi A. Preoperative prognostic factors for severe diffuse secondary peritonitis: a retrospective study. Langenbecks Arch Surg. 2016 Aug;401(5):611-7. doi: 10.1007/s00423-016-1454-8. Epub 2016 May 30. — View Citation

Xiao Z, Wilson C, Robertson HL, Roberts DJ, Ball CG, Jenne CN, Kirkpatrick AW. Inflammatory mediators in intra-abdominal sepsis or injury - a scoping review. Crit Care. 2015 Oct 27;19:373. doi: 10.1186/s13054-015-1093-4. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The numbers of participants who are survival in hospital stay	The rate of survival of participants in both arms	90 days after participants enrolled in the study
Secondary	The days of intensive care unit stay	The median length of days in ICU needed by participants in both arms	30 days after participants enrolled in the study
Secondary	The pg/ml of blood Interleukin-6	The mean concentrations of blood IL-6 in participants in both arms	72 hours after participants enrolled in the study