Physiologic changes during brain stem death—lessons for management of the organ donor

doi:10.1016/j.healun.2004.06.017

The Journal of Heart and Lung Transplantation

Volume 23, Issue 9, Supplement, September 2004, Pages S217-S222

https://doi.org/10.1016/j.healun.2004.06.017 Get rights and content

The widespread physiologic changes that follow brain stem death lead to a high incidence of complications in the donor and jeopardize vital organ function. Strategies for the management of organ donors exist whereby the rapid physiologic decline seen after brain stem death can be stabilized by active donor resuscitation so that the functional integrity of potentially transplantable organs is maintained. Understanding the complex physiologic changes that occur after brain stem death is crucial to the development of effective donor management strategies. This article reviews the pathophysiologic changes that occur after brain stem death and discusses controversies in donor management.

Section snippets

Intracranial events leading to brain stem death

In most clinical situations, a patient suffers brain stem death owing to a sudden or gradual rise in intracranial pressure (ICP) after an acute intracranial hemorrhage or head injury. Progressive mass effect in the brain and worsening cerebral ischemia produces venous engorgement and brain swelling. The brain stem is forced through the foramen magnum, causing arterial compression and subsequent tissue ischemia and infarction. This in turn leads to further brain swelling and an increase in ICP

Cardiovascular changes

The intense sympathetic outflow that accompanies brain stem death leads to a substantial rise in circulating catecholamine levels. In an animal model of brain stem death, circulating dopamine, epinephrine, and norepinephrine concentrations were increased by 800%, 700%, and 100%, respectively,⁵ and these levels are similar to those seen in the clinical situation.⁶ This “sympathetic storm” causes intense vasoconstriction that leads to hypertension, tachycardia, and a secondary increase in

Resuscitation and maintenance of the organ donor

After a diagnosis of brain stem death, there must be a change in emphasis of patient care. Therapy has previously been aimed at preserving residual brain function, but after brain stem death has been confirmed, the emphasis of care switches to optimizing organ function for subsequent transplantation. Although adequate time must be allowed for the proper confirmation of brain stem death, unnecessary delays should be avoided because the incidence of complications increases progressively with time.

The future

Hormone resuscitation replacement strategies are now widely used, and a recent study has demonstrated that 3-hormone donor support (steroids, T3/T4, and vasopressin) is necessary for optimal recipient results.¹³ However, this study was based on retrospective analysis, and potential clinical benefits should be confirmed in prospective, randomized studies.

Heat shock proteins can protect against ischemia-reperfusion injury and animal evidence suggests that donor hyperthermic pre-conditioning can

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Brain death (BD) compromises the viability of the lung for donation. Hypertonic saline solution (HSS) induces rapid intravascular volume expansion and immunomodulatory action. We investigated its role in ventilatory mechanics (VMs) and in the inflammatory activity of the lungs of rats subjected to BD.
Wistar rats were divided into four groups: control, n = 10: intact rats subjected to extraction of the heart–lung block; BD, n = 8 (BD): rats treated with isotonic saline solution (4 mL/kg) immediately after BD; hypertonic saline 0 h, n = 9 (Hip.0′): rats treated with HSS (4 mL/kg) immediately after BD; and hypertonic saline 1 h, n = 9 (Hip.60′), rats treated with HSS (4 mL/kg) 60 min after BD. The hemodynamic characteristics, gas exchange, VMs, inflammatory mediators, and histopathological evaluation of the lung were evaluated over 240 min of BD.
In VMs, we observed increased airway resistance, tissue resistance, tissue elastance, and respiratory system compliance in the BD group (P < 0.037), while the treated groups showed no impairment over time (P > 0.05). In the histological analysis, the BD group showed a greater area of perivascular edema and a higher neutrophil count than the control group and the Hip.60′ group (P < 0.05).
Treatment with HSS was effective in preventing changes in the elastic and resistive pulmonary components, keeping them at baseline levels. Late treatment reduced perivascular and neutrophilic edema in lung tissue.
Suspected Malignant Hyperthermia in a Brain-Dead Donor During Anesthesia for Organ Procurement Surgery: A Case Report
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We report an unusual case of highly suspected malignant hyperthermia after inducing anesthesia in a brain-dead 18-year-old male patient undergoing organ procurement surgery. The patient was administered desflurane (3 vol%) and rocuronium bromide (50 mg) to induce and maintain general anesthesia. He experienced hypercapnia and tachycardia within 5 minutes of anesthesia induction; however, his body temperature rapidly rose only after 15 minutes. The volatile anesthetic was discontinued, and dantrolene was administered at a low dose (1 mg/kg) to avert possible hepatotoxic effects on the donor liver. Fortunately, the clinical course of the brain-dead donor until the organs were harvested and the liver transplantation outcome of the recipient was favorable. A comprehensive understanding of the pathophysiology of brain death, organ transplantation, and malignant hyperthermia is essential to respond promptly and appropriately. Based on our experience, low-dose dantrolene may be clinically used in brain-dead donors while accounting for its potential hepatotoxic effects.
Alpha-1-Antitrypsin Protects Vascular Grafts of Brain-Dead Rats Against Ischemia/Reperfusion Injury
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Endothelial dysfunction is a potential side effect of brain death (BD). Ischemia/reperfusion (IR) injury during heart transplantation may lead to further endothelial damage. Protective effects of alpha-1-antitrypsin (AAT), a human neutrophil serine protease inhibitor, have been demonstrated against IR injury. We hypothesized that AAT protects brain-dead rats’ vascular grafts from IR injury.
Donor rats were subjected to BD by inflation of a subdural balloon. After 5.5 h, aortic rings were immediately mounted in organ baths (BD, n = 6 rats) or preserved in saline, supplemented either with vehicle (BD-IR, n = 8 rats) or AAT (BD-IR + AAT, n = 14 rats) for 24 h. During organ bath experiment, rings from both IR groups were exposed to hypochlorite to simulate warm reperfusion-associated endothelial injury. Endothelial function was measured ex vivo. Immunohistochemical staining for caspases was carried out and DNA-strand breaks were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Data are presented as median (interquartile range).
AAT improved IR-induced decreased maximum endothelium-dependent vasorelaxation to acetylcholine in the BD-IR + AAT aortas compared to the BD-IR group (BD: 83 (9-28) % versus BD-IR: 49 (39-60) % versus BD-IR + AAT: 64 (24-42) %, P < 0.05). Additionally, an increase in the rings’ sensitivity to acetylcholine was noted after AAT (pD₂-value: BD-IR + AAT: 7.35 (7.06-7.89) versus BD-IR: 6.96 (6.65-7.21), P < 0.05). Caspase-3, -8, -9, and -12 immunoreactivity and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were significantly decreased by AAT.
AAT alleviates endothelial dysfunction, prevents increased caspase-3, -8, -9, and -12 levels, and decreases apoptotic DNA breakage due to BD and IR injury. This suggests that AAT treatment may be therapeutically beneficial to reduce IR-induced vascular damage.
Emerging treatments in graft reconditioning beyond machine perfusion
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Extended criteria donors are increasingly used to expand the pool of available donor livers for transplantation. These suboptimal grafts are more susceptible to ischemia-reperfusion injury (IRI), which increases the incidence of posttransplant complications. Machine perfusion (MP) improves the quality of donor livers and allows for extended preservation times and functional assessment. MP also paves the way for the delivery of therapeutic interventions to repair marginal grafts that are declined after viability assessment to make them suitable for transplantation. In this chapter, we discuss the current literature on the application of therapeutic strategies during ex vivo MP to mitigate IRI and regenerate injured livers before transplantation. These strategies include the incorporation of hemoabsorption and the administration of inflammasome inhibitors, stem cell-based therapies, defatting agents, and RNA-interference therapy. Defatting agents are currently explored in clinical trials, whereas the other therapeutic approaches require further research or optimization before proceeding to clinical studies.
Endocrine Management and Hormone Replacement Therapy in Cardiac Donor Management: A Retrospective Observational Study
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Pituitary dysfunction after brainstem death can cause various hormone deficiencies in potential heart donors. The aim of this study was to evaluate the relationship between hormone replacement therapy (HRT; including antidiuretic hormone analog, thyroid hormone, and methylprednisolone) in heart donors and the recipients’ outcomes after heart transplantation (HTx).
We retrospectively analyzed HTxs performed between January 2012 and October 2018. Donor and recipient characteristics were retrieved with a focus on endocrine parameters and HRT. The primary outcome was primary graft dysfunction (PGD). Secondary outcomes were the 30-day and 2-year mortality of the recipients. Univariate and multivariate Cox regression analyses were applied.
The study included 297 HTxs. PGD occurred in 56 recipients (18.9%). In the multivariable Cox analysis, methylprednisolone and thyroxine treatment in donors were associated with a lower odds for PGD (odds ratio [OR], 0.43; 95% CI, 0.19-1.01; P = .052; and OR,: 0.34; 95% CI, 0.15-0.76; P = .009, respectively). In multivariate analysis, thyroxine treatment in donors was associated with a lower odds of PGD (OR, 0.38; 95% CI, 0.17-0.86; P = .020). Donor thyroxine supplementation also had a beneficial effect on recipients’ 2-year survival (OR, 0.53; 95% CI, 0.29-0.96; P = .036).
Combined thyroxine and methylprednisolone treatment could be a protective factor against PGD. Thyroxine administration was associated with better 2-year survival in recipients.
Inflammatory responses in lungs from donation after brain death: Mechanisms and potential therapeutic targets
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The vast majority of lungs used in clinical transplantation are donated after brain death (DBD). The utilization of DBD lungs is low due to brain death-induced lung injury. Moreover, inflammatory responses in DBD lungs used for transplantation contribute to ischemia-reperfusion injury and primary graft dysfunction. Work from human observational studies has demonstrated overexpression of cytokines, activation of endothelial cells, and cell death in DBD lungs, are associated with the activation of signaling pathways. Animal models have characterized the pulmonary injury induced by brain death and identified potential strategies to improve donor management. Interestingly, transcriptomic studies comparing DBD and donated after circulatory death (DCD) lungs have found that inflammatory responses are elevated in DBD lungs, while cell death pathways are elevated in DCD lungs. Development of the ex vivo lung perfusion technique, has made it possible to assess donor lungs using inflammation and cell death biomarkers. In the future, identification of potential therapeutic targets and development of novel treatments strategies may allow for lung repair during EVLP prior to transplantation.

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Physiologic changes during brain stem death—lessons for management of the organ donor

Section snippets

Intracranial events leading to brain stem death

Cardiovascular changes

Resuscitation and maintenance of the organ donor

The future

Transplant Proc

J Thorac Cardiovasc Surg

Metabolism

J Am Coll Cardiol

Am J Transplant

Hepatology

Kidney Int

Aggressive donor management

Curr Opin Organ Transplant

Management of the multiple organ donor

Surgery

Aggressive pharmacological donor management results in more transplanted organs

Transplantation

Hormonal and hemodynamic changes in a validated model of brain death

Crit Care Med

Changes in serum catecholamine levels in patients who are brain dead

J Heart Lung Transplant

Increase in myocardial interstitial adenosine and net lactate production in brain-dead pigsan in vivo microdialysis study

Transplant Proc

Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function

Circulation

Type and extent of myocardial injury related to brain damage and its significance in heart transplantationa morphometric study

J Heart Lung Transplant