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The optimal anesthetic strategy during organ procurement in brain-dead donors remains unknown. The administration of anesthetic drugs in this setting aims to preserve hemodynamic stability in the face of reflex responses mediated by preserved spinal activity. Volatile anesthetics may blunt these reflexes, but their potential benefits in this context have never been investigated.
This randomized trial evaluates the effects of volatile anesthesia (sevoflurane), opioid administration (sufentanil), or no anesthetic drugs on intraoperative hemodynamic stability during organ procurement in brain-dead donors. The primary outcome is the proportion of operative time within a predefined arterial blood pressure range.
Brain-dead donors (BDD) remain the primary source of grafts for organ transplantation in France and worldwide. The main objective of BDD management, from the diagnosis of brain death in the intensive care unit (ICU) to organ procurement (OP) in the operating room, is to restore or maintain physiological homeostasis in order to preserve graft viability and improve long-term recipient outcomes. ICU management of potential BDD-particularly through donor management goals-has been shown to increase both the number and the quality of transplanted organs.
In contrast, anesthetic management of BDD during OP is less standardized, although surgical manipulation may jeopardize donor homeostasis. Hemodynamic responses to surgical stimuli (e.g., incision and visceral manipulation), such as tachycardia and marked increases in arterial blood pressure, are well described and result from preserved spinal reflexes. These reflexes, and the vasoactive drugs administered to counteract them, may cause intraoperative hemodynamic instability potentially detrimental to grafts.
Opioids have been proposed to attenuate these responses, but they have proven ineffective in suppressing catecholamine release induced by nociceptive surgical stimulation. Volatile anesthetics (in addition to potential protective effects against ischemia-reperfusion injury) may more effectively blunt these reflex responses. However, their benefits during OP in BDD have not been demonstrated. In the absence of evidence, retrospective studies and surveys in the USA and France report wide heterogeneity in anesthetic strategies used during graft harvesting. Volatile anesthetics and opioids remain the most common agents despite the lack of proven benefit compared with no anesthetic use.
This randomized controlled trial is designed to evaluate whether volatile anesthetics (sevoflurane) improve intraoperative hemodynamic stability during OP in BDD, compared with either no anesthetic use or opioid (sufentanil) administration. The hypothesis is that halogenated agents, by blunting spinally mediated hemodynamic responses to surgical stimuli, will provide greater intraoperative hemodynamic stability than no anesthetic or an opioid-based strategy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Volatile anesthetic group | Experimental | Sevoflurane administration during the organ procurement procedure |
|
| Opioid anesthetic group | Active Comparator | Sufentanil administration during the organ procurement procedure |
|
| No anesthetic drug group | Active Comparator | No hypnotic (volatil anesthetics or intravenous anesthetics) or analgesic (opioid agents) drug administration during the organ procurement procedure |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Volatile anesthetic | Drug | In the volatile anesthetic group, sevoflurane will be administrated during the organ procurement procedure. Administration will be initiated progressively after moving in the operating room and will be pursued until aortic clamping (targeted end-expiratory concentration suggested between 1 and 2%). No opioid agent (or intravenous hypnotic agent) will be allowed in this group. |
| Measure | Description | Time Frame |
|---|---|---|
| A hierarchical endpoint of hemodynamic stability during the organ procurement procedure | Proportion of intraoperative time (between initial skin incision and aortic clamping) with a mean arterial blood pressure between 65 and 75 mmHg, between the volatile anesthetic group of brain-dead donors and :
| Operative time |
| Measure | Description | Time Frame |
|---|---|---|
| Comparaison of the hemodynamic stability during the organ procurement procedure between the no anesthetic drug group and the opioid anesthetic group of brain-dead donors | Proportion of intraoperative time (between initial skin incision and aortic clamping) with a mean arterial blood pressure between 65 and 75 mmHg. | Operative time |
| Measure | Description | Time Frame |
|---|---|---|
| Comparaison the 1-year graft survival | The aim of the TREATED (grafT suRvival aftEr Anesthesia sTrategy in brain dEath Donors) ancillary observational study will be to compare the 1-year graft survival of the solid organ transplanted (kidney, liver, heart, lungs) according to the randomization group of the brain-death donor included in the ATROPINE trial, adjusted on the main known risks factors for 1-year graft survival for each category of solid organ. |
Inclusion Criteria:
Eligible adult brain-dead donor hospitalized in intensive care unit in one of the participating center:
Information of the patient's next of kin by the investigator and absence of opposition to research confirmed by the testimony of the next of kin according to French public health code.
Exclusion Criteria:
Age < 18 years.
DCD (donation after circulatory death) donors.
Ongoing extracorporeal circulation at the time of death.
Hemodynamic instability at the screening visit defined by a noradrenalin dose > 1 µg/kg/min.
Contraindication to the implementation of the anesthetic interventions evaluated in the trial:
Opposition to the research expressed by the patient during his or her lifetime and documented by the next of kin.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Benoit CHAMPIGNEULLE, MD, PhD | Contact | +33476766879 | BChampigneulle@chu-grenoble.fr | |
| Anaïs ADOLLE | Contact | +33476766879 | aadolle@chu-grenoble.fr |
| Name | Affiliation | Role |
|---|---|---|
| Benoit CHAMPIGNEULLE, MD, PhD | University Hospital, Grenoble | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU Grenoble Alpes | Recruiting | Grenoble | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7793540 | Background | Fitzgerald RD, Dechtyar I, Templ E, Fridrich P, Lackner FX. Cardiovascular and catecholamine response to surgery in brain-dead organ donors. Anaesthesia. 1995 May;50(5):388-92. doi: 10.1111/j.1365-2044.1995.tb05989.x. | |
| 3525756 | Background | Conci F, Procaccio F, Arosio M, Boselli L. Viscero-somatic and viscero-visceral reflexes in brain death. J Neurol Neurosurg Psychiatry. 1986 Jun;49(6):695-8. doi: 10.1136/jnnp.49.6.695. |
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|
| Opioid Anesthesia | Drug | In the opioid anesthetic group, intravenous sufentanil will be administrated during the organ procurement procedure. Continuous administration will be initiated after moving in the operating room (suggested dosage : 0,3 µg/kg/h) with supplemental dose if needed (at the discretion of the anesthesia team) and will be pursued until aortic clamping. No hypnotic drug administration will be allowed in this group. |
|
| Intraoperative brain-dead donor management | Other | In all groups (experimental and control groups), neuromuscular blocking agents will be administered during the entire procedure, according to national guidelines. In all groups, hemodynamic management (use of vasoactive agents as vasopressors or anti-hypertensive drugs) will be done according to the discretion of the anesthesia team. In all groups, all the others aspects of the donor management will be not modified by the study protocol. |
|
| Between-group comparaison of the proportion of intraoperative time spent in hypotention |
Relative duration of intraoperative time (from initial skin incision to aortic clamping) spent with a mean arterial pressure < 60 mmHg. |
| Operative time |
| Between-group comparaison of the proportion of brain-dead donors with a hemodynamic response at initial surgical incision | Occurrence of an increase in systolic blood pressure ≥ 20%, within 5 minutes of the initial surgical incision, compared with the mean systolic blood pressure registered in the 1 to 5 min preceding the initial surgical incision. | Operative time |
| Between-group comparaison of the proportion of brain-dead donors with a hemodynamic response to sternotomy | Occurrence of an increase in systolic blood pressure ≥ 20%, in the 5 minutes following sternotomy, compared with the mean systolic blood pressure measured in the 1 to 5 min preceding sternotomy, in the subgroup of brain-death donors who underwent an intra-thoracic organ harvesting. | Operative time |
| Between-group comparaison of the mean arterial blood pressure variability during the organ procurement procedure | Intraoperative variability of the mean arterial pressure measuring using the average real variability (ARV) index of mean arterial pressure. | Operative time |
| Between-group comparaison of the mean arterial blood pressure variability during the organ procurement procedure | Intraoperative variability of the mean arterial pressure measuring using the intra-individual standard deviation of mean arterial pressure measurements (SD-MAP). | Operative time |
| Between-group comparaison of the mean dose of catecholamines administered during the organ procurement procedure | Intraoperative mean dose (µg/kg/min or U/min) of each catecholamine administered (noradrenaline, adrenaline, dobutamine, vasopressin) and intraoperative mean norepinephrine equivalent score. | Operative time |
| Between-group comparaison of the total intraoperative volume of vascular filling | Volume by type of feeling solution during the organ procurement procedure | Operative time |
| Between-group comparaison of the total intraoperative volume of labile blood products | Volume of labile blood products by type during the organ procurement procedure | Operative time |
| Between-group comparaison of the number of organs harvested and transplanted | Number of solid organs (heart, lungs, liver, kidneys) harvested and effectivelly transplanted by brain-dead donors. | 24 hours |
| Between-group comparison of the rate of delayed graft function of the kidney | Delayed graft function of the kidney in the recipient defined as the need for dialysis within 7 days post-transplant. | 7 days post-transplant |
| Between-group comparison of the rate of primary lung graft dysfunction | Primary lung graft dysfunction in the recipient, as defined by the French Biomedicine Agency: Existence within 72 hours post-transplant of diffuse pulmonary opacities, the severity of which is graded from 1 to 3, depending on the PaO2/FiO2 ratio (< 200, 200-300, >300) or the need for extracorporeal oxygenation (grade 3). | 72 hours |
| Between-group comparison of the rate of primary heart graft dysfunction | Primary heart graft dysfunction in the recipient, as defined by the French Biomedicine Agency: left ventricular ejection fraction < 30% (ultrasound), and/or need for mechanical circulatory assistance, re-transplantation or death of the recipient within 24 hours post-transplant. | 24 hours |
| Between-group comparison of the rate of primary liver graft dysfunction | Primary liver graft dysfunction in the recipient, as defined by the French Biomedicine Agency: bilirubin ≥ 10mg/dL on day 7, international normalized ratio ≥ 1.6 on day 7, and alanine or aspartate aminotransferases >2000 IU/L within the first 7 days | 7 days post-transplant |
| Describe the number of donor management goals achieved in the 12 hours prior and during the organ procurement procedure | Describe the number of donor management goals achieved in the 12 hours prior and during the organ procurement procedure, including the following:
| 24 hours |
| 1 year |
| Compare the number and type of rejection episodes that occurred for each type of transplanted organ | The secondary objective of the TREATED ancillary trial will be to compare the number and type of rejection episodes that occurred for each category of transplant (kidney, liver, heart, lung) in the recipients (censored at 1 year) according to the randomization group of anesthetic strategy | 1 year |
| 3882020 | Background | Wetzel RC, Setzer N, Stiff JL, Rogers MC. Hemodynamic responses in brain dead organ donor patients. Anesth Analg. 1985 Feb;64(2):125-8. |
| 14690096 | Background | Fitzgerald RD, Hieber C, Schweitzer E, Luo A, Oczenski W, Lackner FX. Intraoperative catecholamine release in brain-dead organ donors is not suppressed by administration of fentanyl. Eur J Anaesthesiol. 2003 Dec;20(12):952-6. doi: 10.1017/s0265021503001534. |
| 20879630 | Background | Elkins LJ. Inhalational anesthesia for organ procurement: potential indications for administering inhalational anesthesia in the brain-dead organ donor. AANA J. 2010 Aug;78(4):293-9. |
| 29276852 | Background | Souter MJ, Eidbo E, Findlay JY, Lebovitz DJ, Moguilevitch M, Neidlinger NA, Wagener G, Paramesh AS, Niemann CU, Roberts PR, Pretto EA Jr. Organ Donor Management: Part 1. Toward a Consensus to Guide Anesthesia Services During Donation After Brain Death. Semin Cardiothorac Vasc Anesth. 2018 Jun;22(2):211-222. doi: 10.1177/1089253217749053. Epub 2017 Dec 24. |
| 22541983 | Background | Boutin C, Vachiery-Lahaye F, Alonso S, Louart G, Bouju A, Lazarovici S, Perrigault PF, Capdevila X, Jaber S, Colson P, Jonquet O, Ripart J, Lefrant JY, Muller L; pour le groupe AzuRea. [Anaesthetic management of brain-dead for organ donation: impact on delayed graft function after kidney transplantation]. Ann Fr Anesth Reanim. 2012 May;31(5):427-36. doi: 10.1016/j.annfar.2011.11.027. Epub 2012 Apr 26. French. |
| 29519220 | Background | Perez-Protto S, Nazemian R, Matta M, Patel P, Wagner KJ, Latifi SQ, Lebovitz DJ, Reynolds JD. The effect of inhalational anaesthesia during deceased donor organ procurement on post-transplantation graft survival. Anaesth Intensive Care. 2018 Mar;46(2):178-184. doi: 10.1177/0310057X1804600206. |
| 39167559 | Background | Lele AV, Vail EA, O'Reilly-Shah VN, DeGraw X, Domino KB, Walters AM, Fong CT, Gomez C, Naik BI, Mori M, Schonberger R, Deshpande R, Souter MJ; MPOG Perioperative Clinical Research Committee. Identifying Variation in Intraoperative Management of Brain-Dead Organ Donors and Opportunities for Improvement: A Multicenter Perioperative Outcomes Group Analysis. Anesth Analg. 2025 Jan 1;140(1):41-50. doi: 10.1213/ANE.0000000000007001. Epub 2024 Jul 25. |
| 32149890 | Background | Lele AV, Nair BG, Fong C, Walters AM, Souter MJ. Anesthetic Management of Brain-dead Adult and Pediatric Organ Donors: The Harborview Medical Center Experience. J Neurosurg Anesthesiol. 2022 Jan 1;34(1):e34-e39. doi: 10.1097/ANA.0000000000000683. |
| 31202272 | Background | Champigneulle B, Neuschwander A, Bronchard R, Fave G, Josserand J, Lebas B, Bastien O, Pirracchio R; SFAR research network. Intraoperative management of brain-dead organ donors by anesthesiologists during an organ procurement procedure: results from a French survey. BMC Anesthesiol. 2019 Jun 15;19(1):108. doi: 10.1186/s12871-019-0766-y. |