Ethical considerations in conducting surgical research in severe complicated intra-abdominal sepsis

Christopher J Doig, Stacey A Page, Jessica L McKee, Ernest E Moore, Fikri M Abu-Zidan, Rosemary Carroll, John C Marshall, Peter D Faris, Matti Tolonen, Fausto Catena, Federico Cocolini, Massimo Sartelli, Luca Ansaloni, Sam F Minor, Bruno M Peirera, Jose J Diaz, Andrew W Kirkpatrick, Closed Or Open after Laparotomy (COOL) after Source Control for Severe Complicated Intra-Abdominal Sepsis Investigators, Derek J Roberts, Ari Leppaniemi, Craig N Jenne, Osvaldo Chiara, Paul Kubes, Braden Manns, Yoram Kluger, Gustavo P Fraga, Bruno M Pereira, Michael Sugrue, Teresa Holm, Jianan Ren, Chad G Ball, Raul Coimbra, Zsolt J Balogh, Elijah Dixon, Walter Biffl, Anthony MacLean, Ian Ball, John W Drover, Paul B McBeth, Juan G Posadas-Calleja, Neil G Parry, Salomone Di Saverio, Carlos A Ordonez, Cino Bendinelli, Bradeon MacDonald, Michael Dunham, Artan Reso, Kelly N Vogt, Annika Reintam Blaser, Manu Malbrain, Dario Tartaglia, Jan De Waele, Vincent Dubuisson, Hanna Lampela, Zsolt Bodnar, Arda Isik, Edoardo Picetti, Morad Hameed, Naisan R Garraway, Lisa Julien, Sandy Widder, Norie L Bradley, Paul T Engels, W Robert Leeper, Andrew Beckett, Christopher J Doig, Stacey A Page, Jessica L McKee, Ernest E Moore, Fikri M Abu-Zidan, Rosemary Carroll, John C Marshall, Peter D Faris, Matti Tolonen, Fausto Catena, Federico Cocolini, Massimo Sartelli, Luca Ansaloni, Sam F Minor, Bruno M Peirera, Jose J Diaz, Andrew W Kirkpatrick, Closed Or Open after Laparotomy (COOL) after Source Control for Severe Complicated Intra-Abdominal Sepsis Investigators, Derek J Roberts, Ari Leppaniemi, Craig N Jenne, Osvaldo Chiara, Paul Kubes, Braden Manns, Yoram Kluger, Gustavo P Fraga, Bruno M Pereira, Michael Sugrue, Teresa Holm, Jianan Ren, Chad G Ball, Raul Coimbra, Zsolt J Balogh, Elijah Dixon, Walter Biffl, Anthony MacLean, Ian Ball, John W Drover, Paul B McBeth, Juan G Posadas-Calleja, Neil G Parry, Salomone Di Saverio, Carlos A Ordonez, Cino Bendinelli, Bradeon MacDonald, Michael Dunham, Artan Reso, Kelly N Vogt, Annika Reintam Blaser, Manu Malbrain, Dario Tartaglia, Jan De Waele, Vincent Dubuisson, Hanna Lampela, Zsolt Bodnar, Arda Isik, Edoardo Picetti, Morad Hameed, Naisan R Garraway, Lisa Julien, Sandy Widder, Norie L Bradley, Paul T Engels, W Robert Leeper, Andrew Beckett

Abstract

Background: Severe complicated intra-abdominal sepsis (SCIAS) has high mortality, thought due in part to progressive bio-mediator generation, systemic inflammation, and multiple organ failure. Treatment includes early antibiotics and operative source control. At surgery, open abdomen management with negative-peritoneal-pressure therapy (NPPT) has been hypothesized to mitigate MOF and death, although clinical equipoise for this operative approach exists. The Closed or Open after Laparotomy (COOL) study (https://ichgcp.net/clinical-trials-registry/NCT03163095) will prospectively randomize eligible patients intra-operatively to formal abdominal closure or OA with NPTT. We review the ethical basis for conducting research in SCIAS.

Main body: Research in critically ill incapacitated patients is important to advance care. Conducting research among SCIAS is complicated due to the severity of illness including delirium, need for emergent interventions, diagnostic criteria confirmed only at laparotomy, and obtundation from anaesthesia. In other circumstances involving critically ill patients, clinical experts have worked closely with ethicists to apply principles that balance the rights of patients whilst simultaneously permitting inclusion in research. In Canada, the Tri-Council Policy Statement-2 (TCPS-2) describes six criteria that permit study enrollment and randomization in such situations: (a) serious threat to the prospective participant requires immediate intervention; (b) either no standard efficacious care exists or the research offers realistic possibility of direct benefit; (c) risks are not greater than that involved in standard care or are clearly justified by prospect for direct benefits; (d) prospective participant is unconscious or lacks capacity to understand the complexities of the research; (e) third-party authorization cannot be secured in sufficient time; and (f) no relevant prior directives are known to exist that preclude participation. TCPS-2 criteria are in principle not dissimilar to other (inter)national criteria. The COOL study will use waiver of consent to initiate enrollment and randomization, followed by surrogate or proxy consent, and finally delayed informed consent in subjects that survive and regain capacity.

Conclusions: A delayed consent mechanism is a practical and ethical solution to challenges in research in SCIAS. The ultimate goal of consent is to balance respect for patient participants and to permit participation in new trials with a reasonable opportunity for improved outcome and minimal risk of harm.

Keywords: Consent; Intra-peritoneal sepsis; Multiple organ dysfunction; Open-abdomen; Randomized controlled trial; Waiver.

Conflict of interest statement

Competing interestsJLM is the Clinical Research Director for Innovative Trauma Care, San Antonio, Texas, and has consulted for the Canadian Forces, Acesco Company, Acelity Corporation, and SAM Medical Corporation. EEM reported consulting for Haemonetics, Instrumentation Laboratory, Stago, Humacyte, and Prytime, with all proceeds paid to the University of Colorado. AWK serves in the Canadian Forces Medical Services and has consulted for the Innovative Trauma Care and Acelity Corporations. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Operationalization of the COOL Trial Informed Consent Process

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