Management of the potential pediatric organ donor following neurologic death

INTRODUCTION — The management of the potential donor following neurologic death is as complex as that of any other patient cared for in an intensive care unit. A major paradigm shift in strategy occurs after neurologic death. The goal of antemortem management is to maintain cerebral perfusion pressure, while the postmortem goal is to maintain the perfusion of all potential donor organs (table 1). Following neurologic death, circulatory collapse occurs if medical intervention to sustain circulation and respiration is not continued.

The pathophysiology of neurologic death and management of the potential pediatric organ donor are discussed here. The determination of neurologic death and assessment of the pediatric patient for potential organ donation are discussed separately. (See "Diagnosis of brain death" and "Assessment of the pediatric patient for potential organ donation".)

OVERVIEW

●Care team – Optimal management of the potential organ donor is a continuum of care that requires collaboration and coordination between the medical team in the intensive care unit including physicians, nurses, respiratory therapists, pharmacists, social workers, child life specialists, spiritual support, and the organ procurement organization (OPO) [1]. This team approach allows for early identification of a potential donor, timely determination of neurologic death, optimal support to grieving families surrounding end-of-life care, donation discussions with the family that are appropriately timed and sensitive to the family's emotional needs, medical interventions to preserve organ function, evaluation to determine donor potential and suitability, and successful recovery and placement of organs.

●Care setting – The process and timing of organ recovery is a complex task. In the absence of pediatric support, every effort should be made to transfer the donor to a local or regional pediatric critical care unit with expertise in medical management and support for the family. If this is not possible due to patient instability, the local pediatric critical care team can offer consultation or consider traveling to the referring unit to provide expertise in donor management.

●Timing – Organ recovery depends on the physiologic stability of the donor. An unstable donor may require early organ recovery to avoid losing potentially transplantable organs, whereas a stabilized donor with optimal management can be maintained for a longer period of time. In many instances, organizing appropriate laboratory and diagnostic testing, acceptance and placement of donor organs, coordination of organ recovery teams, and availability of an operating suite may require active medical management of the donor for 24 hours or longer. Prolonging the time interval between neurologic death and organ retrieval has not been associated with decreased organ procurement rates nor compromised quality of organ function [2,3].

PATHOPHYSIOLOGIC CONSEQUENCES OF NEUROLOGIC DEATH — Regardless of the initial cerebral insult, the end point of neurologic death is complete ischemia and irreversible loss of brainstem function due to loss of cerebral circulation. In many countries, the term and medicolegal definitions encompass whole "brain death" (brain and brainstem), while other jurisdictions (eg, the United Kingdom and India) use "brainstem death" to define death [4].

It is important to understand the pathophysiology of neurologic death so that appropriate supportive management strategies can be provided to the potential donor. Neurologic death unleashes a cascade of autonomic, endocrine, hematologic, inflammatory, and cardiorespiratory responses that threaten organ viability. Most, if not all, donors will develop this inflammatory cascade as neurologic death occurs.

In experimental models, neurologic death is characterized by an orderly rostrocaudal progression of ischemia and related autonomic symptoms [5]. Once the ischemic threshold of the brain is exceeded, death of the cerebrum is followed by progression to the brainstem. Widespread cerebral damage is associated with increased vagal activity manifested by signs of bradycardia, hypotension, and decreased cardiac output. Pontine ischemia leads to a combination of vagal and sympathetic signs. In an attempt to maintain cerebral perfusion, hypertension, bradycardia, and abnormal breathing patterns (known as Cushing's triad) are elicited. Finally, when the ischemic process extends into the brainstem, an outpouring of catecholamines known as an "autonomic storm" occurs.

In humans, the physiologic events associated with neurologic death are less predictable and depend in part upon the cause and rate of progression of the neurologic injury (see "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis" and "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis"). Nonetheless, many patients will display predictable pathophysiologic patterns in the minutes and hours leading up to and following neurologic death. Understanding and anticipating these events will allow for optimal management of the patient. The phases and key clinical characteristics associated with neurologic death are discussed in the following sections.

Autonomic storm — The final event in neurologic death is often necrosis of the parasympathetic nuclei in the medulla oblongata and unchallenged sympathetic activation, leading to an outpouring of catecholamines. This is known as an "autonomic storm," or "hyperdynamic phase," because of the associated tachycardia and hypertension. Increases of catecholamine levels of up to 1200-fold have been described; maximal levels are directly proportional to the rate of onset of neurologic death [5,6]. In animal models, this occurs within minutes after neurologic death [6].

During the autonomic storm, elevated levels of epinephrine, norepinephrine, and dopamine lead to increased heart rate, mean arterial pressure, cardiac output, and massive peripheral vasoconstriction [6]. Although cardiac contractility is increased, left ventricular output is functionally reduced because of the significantly increased systemic vascular resistance [7,8]. The massive outpouring of catecholamines results in ischemic changes to the myocardium and conductive tissue, further impairing cardiac output [5,6] and potentiating arrhythmias. Other causes of myocardial dysfunction include cytolysis [9], abnormal cardiac receptor function [10], and production of a myocardial inhibitory protein [11].

The autonomic storm is closely followed by a phase of hemodynamic compromise, which presents the greatest risk to donor organs. The autonomic storm is short-lived because the spinal cord becomes ischemic, which interrupts the sympathetic overdrive. In addition, destruction of the sympathetic spinal cord tracts leads to loss of autonomic regulation, resulting in peripheral vasodilation. As a result, heart rate, blood pressure, and myocardial contractility decrease [12]. Untreated hypotension results in coronary artery hypoperfusion and further myocardial tissue damage.

Hemodynamic instability due to myocardial dysfunction and loss of systemic vascular resistance results in hypotension with hypoperfusion of potential donor organs. Left untreated, this the greatest cause for organs becoming unsuitable for transplantation.

Pulmonary — The lungs are extremely susceptible to the physiologic changes that occur with progression to neurologic death.

Neurogenic pulmonary edema may occur during the autonomic storm (hyperdynamic phase of neurologic death), as a result of the systemic vasoconstriction resulting in pulmonary volume overload and leading to pulmonary edema [13,14].

Additionally, neurologic death predisposes patients to pulmonary infection for several reasons. First, neurologic death abolishes the cough reflex and most brain-dead individuals are in the supine position for days or have limited mobility, leading to suboptimal mucus clearance and associated atelectasis. Second, the ability to produce sigh breaths, which is present in normal health and is important in maintaining lung volume, is absent in neurologic death, increasing the chance of atelectasis [15]. Lastly, the larynx and pharynx are atonic and nonfunctional in the clinical context of neurologic death, which increases the likelihood of aspiration of pharyngeal contents into the tracheobronchial tree, without clinical symptoms of aspiration [16]. For this reason, a cuffed endotracheal tube (ETT) with high balloon pressures to minimize silent aspiration is recommended [16].

Endocrine abnormalities — Neurologic death leads to alteration and destruction of the hypothalamic-pituitary-adrenal axis. This can lead to the following endocrine abnormalities:

●Arginine vasopressin deficiency (AVP-D) – Levels of arginine vasopressin (also known as antidiuretic hormone), cortisol, and adrenocorticotropic hormone (ACTH) fall dramatically following brain death and are undetectable within hours [6,12]. AVP-D (previously called central diabetes insipidus) is the most common endocrine abnormality following brain death, occurring in up to 87 percent of adults [17,18] and approximately 40 percent of pediatric patients [19,20]. Although not pathognomonic nor required to make a determination of neurologic death, the onset of AVP-D in severely brain-injured patients should raise the consideration of midbrain dysfunction and neurologic death in comatose patients. Depletion of AVP and ACTH causes hypovolemia and further aggravates hemodynamic instability if left untreated. Treatment of AVP-D with intravenous vasopressin and hormone replacement therapy (HRT) may allow weaning of inotropic support required to maintain cardiac output in brain-dead patients [21-23]. Desmopressin is also used to pharmacologically treat AVP-D. (See 'Arginine vasopressin deficiency' below.)

●Thyroid dysfunction – Levels of triiodothyronine (T3) decline and become very low within hours of neurologic death. Thyroxine (T4) levels are typically normal or low and thyroid-stimulating hormone (TSH) does not rise in response to these low levels, because the hypothalamus and pituitary are no longer functional. This rapid decline of free T3 levels and peripheral conversion to inactive reverse T3 leads to a "sick euthyroid syndrome" [24]. It remains unclear whether this condition contributes to the myocardial depression often seen after neurologic death and whether thyroid hormone treatment is beneficial to the potential donor [23-27].

●Anaerobic metabolism – Neurologic death and the loss of hormonal regulation leads to changes in metabolism, most notably a shift from aerobic to anaerobic metabolism [28]. Impaired mitochondrial function results in a lactic acidosis, which is a marker of oxygen delivery to the tissues. Some of these metabolic changes may be caused by the deficit of thyroid hormone that is needed to promote aerobic cellular metabolism.

These endocrine abnormalities are often addressed by HRT. (See 'Hormone therapy' below.)

Hematologic — The hematocrit may rise acutely within minutes after neurologic death [12]. This is most likely due to acute redistribution of vascular volume and transcapillary fluid shifts caused by acute increases in hydrostatic pressure. The hematocrit may fall later, most likely because of fluid redistribution, hemolysis, and the dilutional effect of aggressive fluid resuscitation.

Coagulation disturbances can occur during and after the progression to neurologic death as large amounts of prothrombotic agents are released into the circulation following the initial cerebral insult. The autonomic storm also causes the release of cerebral gangliosides and thromboplastin and can result in disseminated intravascular coagulopathy. (See "Disseminated intravascular coagulation in infants and children".)

Inflammatory changes — Neurologic death results in activation of platelets, leukocytes, and endothelial cells. Production of cytokines, chemokines, adhesion molecules, tumor necrosis factor, and interleukin 6 typically increases after neurologic death, as measured by messenger RNA expression. These cytokines, along with catecholamines released during the autonomic storm, are thought to cause decreased myocardial contractility and contribute to hemodynamic instability after neurologic death [29].

The organs of brain-dead donors are more immunogenic than living donors, possibly because of upregulation of the expression of major histocompatibility complex class I and II antigens. This may predispose to earlier and more severe rejection as compared with grafts from live donors [30].

Mobility — The concept of death has been synonymous with immobility. However, spinal reflexes resulting in abnormal movements can occur in brain-dead patients. The classic described movement is the "Lazarus sign." It consists of flexion at the elbows, shoulder adduction, lifting of the arms, dystonic hand posturing, and crossing of the hands [31]. These abnormal movements occur most often in the first 24 hours and do not exclude the determination of neurologic death [32]. Abnormal movements also have been described when pharmacologic agents, such as naloxone, were previously used as novel therapies to improve lung function in the potential donor. (See "Diagnosis of brain death", section on 'Neurologic examination'.)

MANAGEMENT OF THE PEDIATRIC DONOR

Donor management goals — Specific donor management goals (DMG) have been developed to guide clinical care, including minimizing inotropic use, normalization of blood pressure, oxygenation and ventilation parameters, correction of electrolyte disturbances, and controlling fluid balance (table 2) [33]. Studies in adults have demonstrated that meeting DMGs improves chances of organ recovery and graft function post-transplant [34]. Achieving DMGs in children has shown similar results. As an example, in a non-published study of 148 pediatric brain-dead donors reviewed over a five year period, when DMGs were met ≥80 percent of the time 4.39 organs were transplanted per donor, whereas only 3.37 organs were transplanted per donor when ≤80 percent of DMGs were met [35].

The following sections discuss important aspects about management of the pediatric donor.

Hemodynamic monitoring — In the first hour(s) following the autonomic storm and progression to neurologic death, hypotension becomes the overriding hemodynamic issue (table 3) [36]. Because of autonomic paralysis, the heart rate may not increase in response to hypovolemia. Unrecognized or untreated hypotension with continued hypoperfusion will render organs unsuitable for transplantation. Aggressive management to restore normal hemodynamics and maintain organ perfusion is essential for successful organ recovery.

An indwelling arterial catheter to continuously monitor arterial blood pressure and central venous access will assist the clinician and the organ-recovery coordinator in the management of the potential donor. Central access with a multilumen catheter is necessary for vasoactive and hormone replacement therapy (HRT) that is often needed to stabilize the donor and allow for allocation of organs for transplantation. Hemodynamic parameters vary with age and should be taken into account when monitoring and treating the potential pediatric organ donor (table 4). Serial measurements of lactate can help to assess the adequacy of oxygen delivery to the tissues. Monitoring of mixed venous oxygen saturation (SVO₂) also may be beneficial in determining adequate cardiac output. If lactate and SVO₂ are within normal ranges, the clinician may permit lower blood pressures and thus minimize use of vasopressors. There is increasing use of near-infrared spectroscopy (NIRS) as a noninvasive monitoring tool. NIRS may be beneficial to alert the medical team of changes in oxygen delivery and the need for intervention. Conversely, elevations in serum lactate and the development of a metabolic acidosis provide evidence of tissue ischemia and should prompt immediate attention and treatment [37,38]. Traditional indicators of cardiac output such as capillary refill and urine output may not be reliable following neurologic death, because of hypothermia and arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus). Nonetheless, catheterization of the bladder and meticulous measurement of fluid input and output is essential to assess response to therapies.

Pulmonary artery catheters are rarely used in children. Their potential benefits must be weighed against the potential risks for an individual patient. Consultation with the transplant surgeon, medical director of the organ procurement organization (OPO), and the pediatric intensivist can assist in making this determination.

A pulmonary artery catheter may provide information that can be used to guide treatment for older adolescents or adults with the following indications:

●Evaluation for thoracic organ donation

●Cardiac ejection fraction <45 percent by echocardiography

●CVP >15 mmHg

●Coexisting valvular disease, cardiomyopathy, severe lung disease, persistent hypotension

Inotropes and vasopressors — Progression to neurologic death is associated with increased blood pressure to maintain cerebral perfusion pressure prior to herniation. This is followed by profound vasodilation after herniation with resultant hypotension and hypoperfusion. This results in tremendous alterations in cardiac output, ultimately resulting in end-organ dysfunction. (See 'Autonomic storm' above.)

Hypotension is typically treated with a combination of fluids, inotropic, and vasopressor agents. This balanced approach helps prevent excessive volume administration which can result in pulmonary edema, making the lungs less suitable for transplantation. Commonly used drugs with inotropic and vasopressor agents are shown in the table (table 5).

The following are appropriate goals for systolic blood pressure (SBP) and diastolic blood pressure (DBP) for the pediatric organ donor (table 2) [33]:

●Neonate – SBP 60-90; DBP 35-60

●Infant – SBP 80-95; DBP 50-65

●Toddler – SBP 85-100; DBP 50-65

●School age – SBP 90-115; DBP 60-70

●Adolescent – SBP 110-130; DBP 65-80

A consensus conference recommended adjustment of fluids, inotropes, and vasopressors every 15 minutes based on serial hemodynamic measurements. Most centers attempt to meet the blood pressure parameters using a balanced approach to fluid administration and vasoactive agents. Minimizing the use of inotropic agents and alpha-agonists such as epinephrine and norepinephrine is recommended [39]. This is because the use of adrenergic agents has been associated with cardiac graft dysfunction [40,41], suggesting that use of these drugs may cause, or are a marker for, myocardial injury. The evidence for this effect is mixed and may not apply to renal or liver transplantation [42-44]. Despite these uncertainties, the use of pharmacologic agents to maintain adequate blood pressure and organ perfusion is generally well accepted, and these agents are routinely used by many centers to support cardiac output and oxygen delivery to the tissues. Specific considerations to guide the choice and dosing of inotropes and vasopressors are discussed in the following sections (see 'Vasoactive agents' below and 'Vasopressors' below). Serial echocardiograms can provide information about treatment response to improve cardiac function [45].

If a pulmonary artery catheter is placed, we suggest the following DMGs. Some of these criteria were suggested for adult patients and are also appropriate ranges for most older adolescents who are potential donors [39]:

●Mean arterial pressure >60 mm Hg.

●CVP 4 to 12 mm Hg.

●Pulmonary capillary wedge pressure 8 to 12 mm Hg.

●Systemic vascular resistance 800 to 1200 dynes × sec/cm⁵.

●Cardiac index >2.4 L/min/m².

●Minimize vasoactive and inotropic agents. Dopamine and dobutamine have fallen out of favor, and most centers are using epinephrine, norepinephrine, or vasopressin for hemodynamic support. (See 'Vasoactive agents' below.)

Vasoactive agents — In many instances, fluid resuscitation alone cannot achieve a reasonable blood pressure to meet DMGs for the potential pediatric donor. Importantly, fluid overload is a risk factor for pulmonary edema and may significantly impact the suitability of donor lungs for transplantation. Vasoactive agents are commonly used for hemodynamic support of the pediatric donor.

Pediatric donor management protocols recommend minimizing vasoactive or inotropic infusion rates [39]. If the combination of fluid alone is not sufficient to maintain blood pressure, vasopressor or inotropic support can be added to counteract the peripheral vasodilatation and improve cardiac performance that occurs after neurologic death. Inotropic support can be used to augment cardiac output.

Epinephrine, norepinephrine, and vasopressin have become the primary vasoactive agents for hemodynamic support. Vasopressin is increasingly being used as first-line therapy to achieve hemodynamic goals. It has a dual role, binding to G-protein-coupled V1 receptors on peripheral vascular smooth muscle, which increases intracellular calcium levels with resultant vasoconstriction. In addition, it acts on V2 receptors in the distal convoluted tubule of the kidney, resulting in water reabsorption. Vasopressin use for donor management has been associated with increased organ recovery and less overall graft refusal due to poor function [46,47]. Corticosteroids and thyroid hormone may be beneficial as adjunct agents to support cardiovascular function. (See 'Hormone therapy' below.)

Dopamine is no longer recommended as a first-line vasopressor, although historically it was used at a low dose (4 mg/kg/min) for this purpose. Although a lower rate of delayed graft function was observed in a randomized controlled trial [48], there has been no long-term, demonstrable graft survival benefit (most data are from donors with brief dopamine infusion times). Choice of vasoactive agents for hemodynamic support will be dictated by local intensive care unit and OPO practices [49].

Many transplant programs are reluctant to recover and transplant a heart from a donor requiring significant vasoactive or inotropic support. Ideally, the donor heart should have reasonable function on minimal inotropic support. There are a few reports of acceptable outcomes for heart transplantation from donors treated with higher doses of vasoactive agents [50,51]. Retrospective studies demonstrate that HRT may increase the functional resuscitation of organs in donors treated with vasoactive agents at doses that are higher than this threshold [26,52]. In addition, replacement of thyroid hormone is helpful if dopamine is used because dopamine inhibits TSH, thus exacerbating an altered hypothalamic pituitary-adrenal axis in the patient who is progressing towards or has completed neurologic death. Evidence supporting HRT in the potential donor remains controversial. However, HRT is routinely used by many OPOs during donor management (see 'Hormone therapy' below). Epinephrine and norepinephrine are being used more frequently in critically ill children to support blood pressure and improve cardiac performance. The superiority of one inotropic regimen over the other on graft outcomes has not been established in any randomized controlled trials. (See 'Vasopressors' below.)

Vasopressors — If peripheral vasodilatation is the main concern, epinephrine or norepinephrine infusions can be used to improve mean arterial pressure. The commonly used alpha-agonists include norepinephrine, or phenylephrine. These agents are more commonly used in older children; however, their use is not restricted to this population of patients. The concern with these alpha-agonists is the possible occurrence of excessive peripheral and splanchnic vasoconstriction. This may compromise perfusion of the donor organs, specifically the splanchnic bed, limiting the potential for transplantation. Epinephrine is commonly used in smaller children for both alpha and beta agonist effects. Additionally, vasopressin is used in many centers to control AVP-D while also augmenting blood pressure.

In patients with AVP-D and associated hemodynamic instability, intravenous vasopressin should be the primary agent used to control the central vasopressin deficiency. For this indication, doses of 0.5 to 1 milliunits/kg/hour are used and titrated to decrease urine output to 2 to 4 cc/kg/hour. Vasopressin increases systemic vascular resistance and circulating volume, thus improving hemodynamic stability; this may allow weaning of other inotropic agents. (See 'Arginine vasopressin deficiency' below.)

If excessive doses of norepinephrine or epinephrine are required (eg, norepinephrine in excess of 0.05 mcg/kg/min), vasopressin may be considered in patients without AVP-D as a second-line agent for hemodynamic support. For this purpose, vasopressin is used in doses similar to those used to treat shock, ie, up to 2 milliunits/kg/minute [53]. The use of vasopressin may allow other vasoactive agents to be weaned. The use of norepinephrine has been associated with a reduced one-year survival in heart transplant recipients [54], while vasopressin use has increased rate of organ recovery [46]. Hormone replacement therapy should be considered if hypotension persists despite appropriate support with volume administration, inotropes, and vasopressors.

The hypertensive crisis that occurs during the autonomic storm can result in serious ischemic injury to the end organs. Opinions are divided as to whether antihypertensive management should be instituted. Many experts feel that the catecholamine surge is relatively short lived and does not require aggressive management. Additionally, reducing blood pressure when the body is compensating for increased intracranial pressure (ICP) can be detrimental to the patient. Many of the commonly used antihypertensive agents have longer half-lives, and determining when to start these agents can be problematic. Short acting and titratable intravenous medications such as sodium nitroprusside or esmolol may be suitable agents [55-57] but can rapidly decrease blood pressure with resultant hypotension, affecting end-organ perfusion and function. These agents should be used with extreme caution in this patient population. Intermittent doses of hydralazine can be considered in some cases in which treatment of hypertension might be warranted. Dihydropyridine calcium channel blockers such as nicardipine are being used more frequently to treat hypertension in the donor. This agent is easily titratable and has a short half-life.

Although hypotension is the most common hemodynamic problem in brain-dead patients, hypertension can occur intraoperatively during organ recovery. This phenomenon occurs because of a sympathetic spinal reflex to the stimulus of surgery [58,59]. Inhalational anesthetic agents, opiates, and neuromuscular blocking agents have been used to blunt the sympathetic response, resultant hypertension, and spinal mediated reflexes [60].

Arrhythmias — A baseline 12-lead electrocardiogram (ECG) should be performed to assess the intrinsic conduction of the donor's heart, followed by continuous ECG monitoring (telemetry) to detect subsequent arrhythmias.

A variety of atrial and ventricular arrhythmias can occur during and after neurologic death. Hypovolemia, hypothermia, electrolyte abnormalities, increased intracranial pressure (ICP), myocardial ischemia, oxygenation issues, acid base disturbances, and myocardial contusion may contribute to the development of these arrhythmias. The use of inotropes and vasopressors can also predispose to or exacerbate arrhythmias, especially in the presence of an ischemic myocardium.

To prevent arrhythmias, maintenance of normal body temperature and fluid and electrolyte balance is important. Any electrolyte abnormalities should be aggressively treated and corrected. Hypokalemia commonly occurs in this patient population secondary to excessive diuresis caused by AVP-D and/or hyperglycemia. Overventilation following neurologic death may cause a respiratory alkalosis and exacerbate hypokalemia. Hypomagnesemia can occur with profound diuresis. Magnesium should be aggressively replaced and levels maintained in a normal range if ventricular arrhythmias are noted. Hypothermia is a potent proarrhythmic stimulus and should be prevented. Respiratory alkalosis (induced by over-ventilating the donor) may be desirable as it can reduce arrhythmias, especially ventricular arrhythmias [18]. However, excessive alkalosis may reduce oxygen delivery to tissues by shifting the hemoglobin oxygen dissociation curve to the left (figure 1). Therefore, most providers try to maintain the pH between 7.3 and 7.45 as outlined in the pediatric DMGs. Careful interpretation of the ECG is required as ST-segment change and J-waves are commonly seen in brain-dead patients with electrolyte abnormalities and hypothermia.

Bradycardia is the most common arrhythmia in the brain-dead donor and only requires treatment if it is associated with hypotension or evidence of poor oxygen delivery to tissues. Atropine is ineffective in treating bradycardia in brain-dead patients because the inhibitory effect that is normally exhibited on the vagus nerve is lost. In patients who require treatment for bradycardia, epinephrine is the agent of choice. If epinephrine is not effective, isoproterenol might be added to the regimen [61]. However, isoproterenol can induce hypotension (because of vasodilation) or paradoxical bradycardia [62]. Therefore, transthoracic or transvenous pacing may be a better alternative in this instance.

Tachyarrhythmias and ventricular arrhythmias may be symptoms of electrolyte imbalances, hypotension, or may be caused by inotropic drugs. If epinephrine is the presumptive causes of the dysrhythmia, stopping this drug and changing to norepinephrine may be helpful to reduce beta receptor stimulation. Body temperature below 28°C may cause resistant ventricular arrhythmias. If ventricular arrhythmias occur, lidocaine or amiodarone can be used. Correction of temperature, electrolyte and acid base disturbances, and hypoxia may reduce arrhythmias as well.

Potential donors are at risk for cardiac arrest, especially those with persistent or untreated hypotension. In fact, up to 25 percent of potential donors are lost due to hemodynamic instability or cardiac arrest following neurologic death [63]. A cardiac arrest does not preclude a patient from successfully donating organs if adequate organ perfusion is maintained [17]. Preexisting "do not resuscitate" (DNR) orders are invalidated following neurologic death unless otherwise specified by the family or the OPO coordinator. DNR orders pertain only to living individuals. Resuscitation procedures for a donor are similar to protocols used for other patients. The idea of "resuscitating" an already dead child may be extremely distressing to parents and family members who are coming to terms with recent loss. This situation is commonly discussed with the family during authorization for donation by the OPO. Occasionally, the family may oppose the continuation of aggressive donor management even after explanation, and their wishes should be respected. Medical staff may also have difficulty understanding the need to resuscitate a dead child who is a donor as a means to maintain circulation so organs can be recovered for transplantation. It is important to emphasize that resuscitation continues to honor the wishes of the family for their child to become a donor [64,65].

In extreme cases, extracorporeal membrane oxygen (ECMO) support has been used in an effort to recover organs from a deteriorating donor [66,67]. Although no studies are reported in children, it could be used as part of aggressive management of the donor, which honors the wish of families to have their child become an organ donor. Additionally, use of continuous renal replacement therapy (CRRT) has been used to manage fluid and electrolyte disturbances in donors [68].

For donors following donation after circulatory death, abdominal and thoracic normothermic regional perfusion (NRP) are being used more frequently to limit warm ischemic time and enhance organ viability.

Respiratory — The lungs are the most likely organ to be compromised after neurologic death, preventing successful recovery for transplantation. Meticulous care of the donor is required to maximize potential for lung recovery. The inflammatory response and neurogenic pulmonary edema associated with increased ICP contributes to the pathology affecting lung recovery for transplantation. Close collaboration with the pediatric intensivist and respiratory therapist to manage respiratory issues of a potential donor is highly recommended. Importantly, standardized management of the younger donor is inconsistent and may limit the number of organs recovered for pediatric lung transplant candidates [69].

Potential pediatric organ donors should be intubated with a cuffed endotracheal tube (ETT) rather than the uncuffed type of ETT that is often used for some pediatric patients. For donors with an uncuffed ETT in place, changing to a cuffed ETT is recommended to minimize aspiration risk and protect the lower airway. The balloon of the cuffed ETT should be inflated to a high cuff pressure (inflated until no air leak is observed, often >25 cm H₂O), to protect the lungs and minimize any chance of aspiration. Diligent pulmonary toilet is important to protect the lungs, including regular suctioning of the hypopharynx for accumulation of debris, elevating the head of the bed, turning of the patient to avoid atelectasis, and appropriate oral care [16].

Ventilatory settings — Ventilatory settings for the brain-dead patient should be carefully adjusted to maintain a relatively normal physiologic state. The main goals are to prevent hypoxemia, atelectasis, ventilator-induced lung damage, and restore normal oxygenation and ventilation. The ventilation strategy differs from that used prior to neurologic death, in which the most important goal of mechanical ventilation was to maintain adequate oxygenation and assist with reduction of cerebral edema. With the onset of neurologic death, oxygen consumption and CO₂ production is greatly decreased. Such ante mortem strategies to reduce CO₂ can exacerbate a significant respiratory alkalosis after death, as respiratory drive ceases and CO₂ production declines. Alkalosis can affect donor organs because a lower PaCO₂ can cause peripheral vasoconstriction and alter oxygen delivery to tissues by shifting the hemoglobin/oxygen dissociation curve to the left. The leftward shift impairs oxygen delivery to the tissues, and the anaerobic metabolism following neurologic death can result in a worsening lactic acidosis. Thus, ventilator management to normalize the CO₂ and pH is essential to the care of the potential donor.

Volume-limited mechanical ventilation is a commonly used mode of ventilation in most circumstances. Pressure ventilation is used if the peak and plateau airway pressures are very high due to poor compliance or elevated mean airway pressure [70,71]. Decelerating flows should be set on the ventilator because the flow is more laminar at the end of inspiration; this approach decreases mean airway pressure and resistance [72]. Intensivists are increasingly employing lung protective strategies prior to neurologic death, using lower tidal volumes and higher positive end-expiratory pressure (PEEP). This type of ventilation strategy may be beneficial to the potential donor to ensure adequate lung recruitment and protect the lungs from overinflation. The antiinflammatory effects of higher PEEP may also be beneficial to the potential donor [73].

The initial setting of PEEP should be a minimum of 5 cm H₂O [74], to maintain a reasonable functional residual capacity (FRC) and prevent atelectasis. The fraction of inspired oxygen (FiO₂) should be kept <0.5 as long as oxygen saturations (SaO₂) are above 95 percent. A PaO₂ near or above 100 mmHg (9.3 and 13.3 kPa) is desirable [75]. The PaCO₂ should be kept within the normal range (35 to 45 mmHg), which corresponds to a pH 7.35 to 7.45. This range corresponds to a pH that is optimal for unloading of oxygen at the tissue level.

Every effort should be made to prevent further exacerbation of pre-existing lung injury [76,77]. Use of lower tidal volumes and increased PEEP can provide adequate oxygenation and ventilation and maintain alveolar recruitment to overcome atelectasis and maintain FRC [71]. Advanced ventilation techniques to manage atelectasis are safe and effective, especially if atelectasis persists on initial settings; these include airway pressure release ventilation (APRV) utilizing higher inspiratory pressures and longer inspiratory times, and lung recruitment strategies using higher PEEP. In some cases, high ventilator settings (especially high PEEP) that increase mean airway pressure may decrease venous return and exacerbate hypotension, thereby requiring volume loading to maintain adequate cardiac output.

To determine whether the patient's lungs are suitable for organ donation, an oxygen challenge is performed with lower PEEP. The potential donor is preoxygenated by providing a FiO₂ of 1.0, and the PaO₂ is measured by arterial blood gas analysis. If the PaO₂ is >300 mmHg, the lungs are considered suitable for donation in many centers.

Lung recruitment maneuvers may be needed when the chest radiograph shows atelectasis or under-inflation. There are many different strategies to improve lung recruitment. Sustained inflation with manual ventilation and a pressure gauge is one option. Another approach is use of the San Antonio Lung Transplant (SALT) protocol, which includes pressure-cycled ventilation for two hours, with inspiratory pressure of 25 cm H₂O and PEEP of 15 cm H₂O, followed by a return to conventional volume-controlled ventilation [78]. Using airway pressure release ventilation (APRV) mode of ventilation for lung recruitment has shown promise in adults [79,80]. Experience with APRV in children is limited. One protocol suggests an initial setting of 20 cm H₂O as inspiratory pressure, with a PEEP of 5 cm H₂O and an inspiratory to expiratory ratio of 5:1 [16]. This inevitably leads to a high mean airway pressure; discontinuation of APRV can be considered if there is decline in cardiac output. Successful ventilatory management with resuscitation of the lungs may require several hours.

Complications — Once ventilatory settings are established and pH, PaCO₂, and PaO₂ have been normalized, an acute increase in ventilatory requirements suggests pulmonary edema, atelectasis, mucous plugging, aspiration, barotrauma, or infection.

●Pulmonary edema – Pulmonary edema can be cardiogenic, pulmonary, or neurogenic in origin. If pulmonary edema interferes with oxygenation and ventilation, PEEP can be increased to improve oxygenation. Importantly, increased PEEP may impair venous return and ultimately affect cardiac output. If increased PEEP is required and hemodynamic compromise is noted, volume loading with crystalloid or colloids or adjustment in inotropic medication may be required to improve cardiac output. Pulmonary edema of cardiac origin should be treated with appropriate inotropic agents, adjustment in fluid management, and/or diuretics.

●Hypoxemia – If hypoxemia occurs, the cause must be identified and treated to ensure continued oxygen delivery to tissues. Possible causes include pneumonic processes (eg, aspiration pneumonia), barotrauma, atelectasis, pulmonary edema or pleural fluid collections, elevation in pulmonary vascular resistance, ventilator and circuit malfunction. The following strategies may be helpful to maximize functioning lung zones and recruit alveoli [72] (see "Modes of mechanical ventilation"):

•Convert to pressure-cycled strategies for ventilation if PIP are excessively high [78]

•Increase PEEP

•Increase the inspiratory time

•Patient positioning – Placing the patient in a prone position (may be difficult to perform in a patient who is large and/or hemodynamically unstable)

•Use advanced ventilation strategies, such as APRV, or, in rare circumstances, high-frequency oscillation ventilation, which may improve FRC

Additional measures to improve oxygenation include:

•Maintain adequate hemoglobin concentration to improve oxygen carrying capacity

•Maximize cardiac output

•Correction of acidosis

•Treatment with inhaled nitric oxide for pulmonary hypertension associated with acute lung injury

●Aspiration – Neurologic death increases the risk for aspiration of material from the hypopharynx because swallowing and laryngeal protective reflexes are extinguished. Measures to prevent aspiration include use of a cuffed ETT with high cuff pressure, and regular chest physiotherapy with tracheal suctioning to clear and keep secretions to a minimum (see 'Respiratory' above). The use of manual chest physiotherapy (CPT) or a CPT vest may be required to mobilize secretions. [81]. Periodic reassessment of the lungs with chest radiograph is recommended and should be performed earlier if oxygenation or ventilation is worsening.

Bronchoscopy — In most centers, flexible bronchoscopy is performed to evaluate the lungs of potential donors. Bronchoscopy should be performed safely and can be used for diagnostic and therapeutic purposes. Early bronchoscopy is a valuable addition to the initial assessment of the potential organ donor, may identify potential pathogens to guide antibiotic therapy, and provides therapeutic bronchial toilet [16,39,82]. Repeated bronchoscopies may be indicated in some individuals. In some instances, a bronchoscopy may not be indicated if the lungs will not be transplanted, because the potential donor is too small, too unstable, or will not tolerate the procedure because the lungs are too damaged. Moreover, the smallest pediatric bronchoscopes may not have a suction channel and only allow visual inspection of the airways. Discussion with the donation coordinator and OPO medical director is essential to determine whether a bronchoscopy is indicated and can be performed safely.

The goal of bronchoscopy is to assess the airways; identify anatomic variations; evaluate for airway trauma; obtain airway cultures; and locate, characterize, and remove secretions. The bronchoscopists should pay special attention to the re-pooling of purulent secretions after initial removal. Lower respiratory tract samples are collected in small aliquots (<20 cc and <5 cc in infants) via limited bronchoalveolar lavage for immediate microbiologic examination and culture. The amount of fluid used for lavage should be kept to a minimum because extensive lavage will lead to new infiltrates and transient worsening of oxygenation, which may confuse the clinical picture for the evaluating transplant team.

Fluids and electrolytes — Adequate organ perfusion to maintain oxygen delivery to viable tissue is essential to preserve organ function for transplantation. Fluid resuscitation may be necessary to restore intravascular volume and maintain atrial filling pressures, but this benefit should be balanced against the potential risks of worsening lung function or exacerbating pulmonary edema and fluid overload [83]. Excessive fluid resuscitation can lead to volume overload and pulmonary edema, with impaired gas exchange, hypoxemia, and end organ ischemia. In extreme cases of volume overload, dialysis for fluid removal and electrolyte correction has been used [1]. Many centers have adopted a balanced approach using fluids, inotropic and vasoactive support, and HRT to restore normal circulating volume and maintain acceptable hemodynamics in the potential donor (table 6).

Judicious use of crystalloid or colloid boluses is one of the first steps to replenish or maintain adequate vascular volume and sustain blood pressure. Although CVP may not be the best measure for intravascular volume, many OPOs have a goal to maintain CVP around 8 to 10 mmHg. There are now several alternative dynamic parameters used for predicting cardiovascular response to fluid challenge. These include studying noninvasive methods such as pulse pressure variation, passive leg raising, and systolic pressure variation. Doppler devices such as ultrasonic cardiac output monitor (USCOM) are increasingly used, although their performance is inconsistent [77,84]. Bedside ultrasound can also provide information about volume status as well.

Glucose-containing fluids should never be used for volume resuscitation because these fluids may induce an osmotic diuresis, further complicating fluid and electrolyte disturbances. Use of synthetic colloids should be avoided since these agents may precipitate or exacerbate renal insufficiency and hypoglycemia [85]. The US Food and Drug Administration issued a labeling change in prescribing information for hydroxyethyl starch to warn about the risk of mortality, kidney injury, and excess bleeding. After the potential donor has been resuscitated, the serum sodium and glucose levels guide the choice of maintenance fluid. Excessive administration of normal saline may lead to hyperchloremic acidosis. Lactated Ringer solution or Plasma-Lyte A may be better alternatives [86]. This fluid management resuscitation strategy is consistent with the management of septic shock and sepsis-associated organ dysfunction in children [87]. The "hemodynamic profiling" of a potential donor with meticulous measurement of fluid input, output and vital signs, and invasive monitoring techniques including measurement of CVP and cardiac function, will help in directing the therapy required to maintain a normal blood pressure [88]. End organ function, which is commonly used to determine cardiac output, may not be reliable in the brain-dead patient. For example, urine output is not a reliable indicator of renal function following neurologic death, because of AVP-D. Hypothermia may make capillary refill a poor indicator of peripheral perfusion.

Hypernatremia — Sodium levels may be elevated due to antemortem practices to reduce ICP (eg, fluid restriction, mannitol, hypertonic saline, and diuretic therapy). If hypernatremia occurs in conjunction with increased urine output, the possibility of AVP-D should be considered. (See 'Arginine vasopressin deficiency' below.)

If hypernatremia is present, every effort should be made to restore serum sodium levels to a normal range. This is because sodium levels in excess of 160 mmol/L may contribute to cellular edema, dysfunction, apoptosis and necrosis, and these factors may contribute to primary graft failure and decreased graft function after orthotopic liver transplant [89]. However, one study showed no difference in hepatic graft failure rates in children receiving livers from hypernatremic donors, suggesting that hypernatremia does not appear to have negative effects on mortality or graft failure in pediatric liver transplant recipients [90]. In practice, many liver transplant programs may not accept organs from donors with hypernatremia. Attention to serum sodium early in the course of donor management is therefore strongly recommended.

To avoid or correct hypernatremia, the fluid status should be evaluated and AVP-D corrected if present. Isotonic solutions should be used to restore circulating volume until the patient has achieved a euvolemic state. AVP-D is managed by replacing urine output with hypotonic fluids and by titrating pharmacologic agents to reduce but not stop urine output. (See 'Arginine vasopressin deficiency' below.)

Arginine vasopressin deficiency — AVP-D (previously called central diabetes insipidus) occurs in approximately 40 percent of pediatric organ donors following neurologic death. AVP-D is characterized by hypernatremia and high output of dilute urine (table 7) (see 'Endocrine abnormalities' above). The high urine output leads to intravascular fluid depletion if left uncorrected. It also produces biochemical and electrolyte abnormalities, including hypokalemia, hypomagnesemia, hypocalcemia and hypophosphatemia; these abnormalities should be treated aggressively to prevent arrhythmias. (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)

The management goal for AVP-D is to achieve a euvolemic and normonatremic state while reducing, but not completely stopping, urine output. The first step of management is fluid replacement to restore a normal circulating volume and support blood pressure and tissue perfusion. In a hypotensive patient, fluid resuscitation should be performed with isotonic or colloid solutions. Once euvolemia has been established, the fluid requirement consists of the usual maintenance needs plus replacement of urine output. The appropriate solute content of the maintenance fluid depends on serum sodium and glucose levels. Hypernatremia is common in the setting of AVP-D and may also be compounded by treatment of cerebral edema prior to death. Maintenance and replacement fluids should be low in sodium (see "Arginine vasopressin deficiency (central diabetes insipidus): Treatment"). In most cases, urine output should be replaced with quarter-normal or half-normal saline. Additionally, free water can be administered through a nasogastric (NG) tube when necessary to correct the hypernatremia. Rapid changes in serum osmolarity are of no concern, since neurologic death has occurred. Most donors have high glucose levels and little or no exogenous glucose is required. If glucose levels fall, dextrose should be added to replacement fluids to maintain normal glucose levels. (See 'Hyperglycemia' below.)

Pharmacologic treatment with vasopressin analogs should be contemplated early if polyuria persists despite fluid therapy (eg, urine output greater than 5 to 7 mL/kg/hour). Despite reports suggesting that vasopressin was associated with poor outcomes for kidney transplantation [91], a large randomized controlled trial showed no detrimental effect on early or late kidney graft function [92].

The two available vasopressin analogs are the naturally occurring AVP or the synthetic desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]). Both analogs have antidiuretic activity, but only vasopressin has vasopressor action. Vasopressin has the benefit of increasing blood pressure and can decrease vasopressor requirements [23,83,93]. In one study, vasopressin helped to maintain cardiac output and improved serum osmolality. A separate small retrospective study showed that vasopressin exerted a pressor effect at time of organ recovery; children treated with vasopressin were more likely to tolerate weaning off of alpha-agonists than a control group [93]. Desmopressin has a theoretical advantage over vasopressin because it is not a splanchnic vasoconstrictor and does not negatively affect hepatic, renal, and pancreatic blood flow. Nonetheless, clinical outcomes are similar for the two drugs [94]. A small number of children may be resistant to vasopressin; desmopressin can be used alone or in combination with vasopressin in these patients [95]. If urine output cannot be controlled with these two agents, urine sodium should be checked. If the urine sodium is elevated, this may be consistent with cerebral salt wasting, requiring administration of a fluorinated corticosteroid. Desmopressin also may be useful in the donor with an ongoing coagulopathy because of its effects on platelets. Many donor management protocols favor vasopressin to pharmacologically treat AVP-D because of its shorter half-life as compared with desmopressin. When desmopressin is used, it can be discontinued two to three hours prior to going to the operating room, to allow metabolism of this agent prior to organ transplant. In this case, urine output of more than 3 to 4 cc/kg/hour should be replaced to maintain a euvolemic state in the donor.

Drug dosing for patients with AVP-D is adjusted according to the clinical response. The dosing and duration of action of these two agents differ slightly:

●Vasopressin – Vasopressin is administered by continuous IV infusion, in doses of 0.5 to 1 milliunit/kg/hour and titrated to reduce urine output to 2 to 4 cc/kg/hour [33,96]. This agent has a half-life of 10 to 35 minutes. Note that this is a lower dose than when vasopressin is used to treat hypotension. (See 'Vasopressors' above.)

●Desmopressin (DDAVP) – DDAVP is preferably administered by continuous IV infusion starting at doses of 0.5 mcg/hour and titrated to reduce urine output to 2 to 4 cc/kg/hour. This agent has a half-life of 75 to 120 minutes. Subcutaneous and intramuscular injections should be avoided because of a depot effect in the tissues and the possibility of diminished absorption from the tissues in this patient population. Intranasal DDAVP is not recommended.

Hyperglycemia — Neurologic death frequently leads to hyperglycemia, most likely caused by catecholamine release during the autonomic storm, decreased metabolic rate of the brain during and after neurologic death, and the use of exogenous inotropes and steroids. Hyperglycemia has been reported in 48 percent of pediatric donors under 5 years of age and 28 percent in donors between 5 to 12 years [97]. Catecholamines cause glucose release and decrease tissue sensitivity to insulin. Pancreatic endocrine function is generally preserved after neurologic death [98]. Hyperglycemia may be exacerbated by administration of dextrose in intravenous fluids, which can result in further volume losses from an osmotic diuresis.

In some cases, hyperglycemia is associated with AVP-D and low CO₂ production. This association has been described as a pathognomonic sign for the onset of neurologic death and is known as "Turner's triad." Hyperglycemia occurs most frequently, and the full triad is not always present [20].

Hyperglycemia raises the serum osmolality and can exacerbate fluid loss through an osmotic diuresis. Glycemic control is important with a goal of maintaining blood glucose levels between 60 and 150 mg/dL (3.3 to 8.3 mmol/L). Higher glucose levels may be acceptable if the transplant surgeon intends to keep the islet cells active for pancreas transplantation. Higher intraoperative glucose values are associated with increased ischemic injury and worse donor renal function [99]. If the blood glucose levels remain persistently above 200 mg/dL (11.1 mmol/L), intravenous insulin should be commenced as a continuous infusion at doses of 0.05 to 0.1 units/kg and titrated to the desired glucose levels. Insulin also may be dosed on a sliding scale; however, it may be more difficult to achieve tight glucose control with a sliding scale. Subcutaneous administration of insulin is discouraged because this may lead to erratic and unpredictable absorption (a "depot effect"). Glucose levels should be checked frequently to avoid hypoglycemia, especially in infants. It is important to monitor potassium levels, as insulin infusions can promote hypokalemia.

Hormone therapy — For potential donors who fail to respond to conventional medical management for hemodynamic stabilization, HRT is suggested. HRT can help reduce the need for vasoactive agents and improve chances of organ recovery. HRT is recommended by the United Network for Organ Sharing (UNOS) for organ donors unresponsive to conventional resuscitation measures as manifested by poor cardiac output, inadequate organ perfusion pressures, and increasing lactic acidosis [57,100,101]. This practice is also applicable to pediatric organ donors. Because of preliminary data suggesting that aggressive medical treatment incorporating HRT improves recovery of organs and leads to a higher incidence of organs transplanted in adults and children, many centers now routinely use HRT for all potential donors [33]. In these centers, HRT is an important component of support for hemodynamically stable donors. Those donors who are hemodynamically unstable will require additional support with fluid resuscitation and inotropic/vasopressor support in addition to HRT (table 6).

Commonly used agents and doses for hormonal resuscitation in pediatric donors include (table 8):

●Methylprednisolone – Methylprednisolone dose is 20 to 30 mg/kg bolus IV (maximum dose 2 g), repeated thereafter at 8- to 12-hour intervals, depending on the duration of donor management. Hydrocortisone (Solucortef) is administered by some OPOs in a continuous infusion of 1 to 2 mg/kg/hour, not to exceed 100 mg/hour. The use of a hydrocortisone infusion may require a dedicated IV line.

●Levothyroxine – Levothyroxine dose is 0.8 to 1.4 mcg/kg/hour IV (maximum dose 20 mcg/hour). In the hemodynamically unstable child, treatment may be initiated with a bolus dose of 1 to 5 mcg/kg. Infants and small children may require a larger bolus and infusion doses [23]. For hemodynamically stable donors, no bolus dose is required and a continuous infusion of levothyroxine can be initiated. Some centers prefer to use triiodothyronine (T3) instead of levothyroxine (T4) [39]. The dosing range of T3 for pediatric patients is 0.05 to 0.2 mcg/kg/hour [39]. Both T3 and T4 can be titrated to effect. T4 is a prohormone and is converted to active T3, but this process may be inhibited by conversion of T4 to inactive reverse T3 during the catecholamine storm [26]. T3 is more potent and has a shorter half-life and onset of action, and therefore a more predictable action. However, T3 is seldom used in the United States because of its expense. If the donor becomes hypertensive or tachycardic with levothyroxine, the dose can be reduced or discontinued.

●Vasopressin – Vasopressin is given to patients with high urine output caused by AVP-D, at a dose of 0.5 to 1 milliunits/kg/hour, titrated to decrease urine output to 3 to 4 cc/kg/hour [33,96,102] (see 'Arginine vasopressin deficiency' above). Desmopressin may be used as an alternative. Vasopressin also may be considered in patients without AVP-D as a second-line agent for hemodynamic support (eg, for patients requiring norepinephrine in excess of 0.05 mcg/kg/min). In this case, vasopressin doses of up to 2 milliunits/kg/hour may be used. Vasopressin and desmopressin should be used in conjunction with fluid administration to maintain a euvolemic state. (See 'Vasopressors' above.)

●Insulin – Insulin is given to patients with hyperglycemia; the infusion is titrated to maintain blood glucose 60 to 150 mg/dL (3.3 to 8.3 mmol/L). (See 'Hyperglycemia' above.)

HRT seeks to correct the hormonal changes and deficiencies that are commonly seen after neurologic death [103]. These include depletion of antidiuretic hormone (ADH), triiodothyronine (T3), thyroxine (T4), cortisol, and insulin [28]. The depletion of thyroid hormone contributes to mitochondrial dysfunction, anaerobic metabolism (lactic acidosis), and organ dysfunction after neurologic death. There is some evidence that this process can be reversed by thyroid hormone replacement [28]. Corticosteroids are believed to attenuate proinflammatory cytokines, decrease the upregulation of cytokines, and prevent leukocyte migration into the new allograft. Other potential benefits of steroids may lie in their ability to alter adrenergic receptors and regulate vascular tone by increasing sensitivity to catecholamines. Steroids also have been shown to stabilize pulmonary function, reduce lung water accumulation, and increase lung recovery from donors [38]. Intravenous methylprednisolone can improve oxygenation leading to a progressive increase in PaO₂ and decrease in FiO₂ requirements [104].

The role of HRT for donor management remains controversial. Studies in adults suggest that HRT, consisting of the combination of thyroxine, cortisol, vasopressin and insulin, may restore aerobic metabolism, normothermia, organ stability, and cardiac function, replenish ATP, and diminish requirements for inotropes and bicarbonate replacement [28,103,105-107]. In a large study in the United States, donor resuscitation with a combination of corticosteroids, thyroid hormones, and vasopressin reduced the odds of early transplant recipient death by 46 percent, and graft dysfunction by 48 percent [108]. There was an increase in 22.5 percent of total organs transplanted per donor when systematic combination hormonal replacement program was used [26,109,110]. In addition, there is increasing evidence that HRT, along with optimization of CVP and myocardial performance, significantly increases heart and lungs for transplantation and improves graft function for the transplant recipient [111,112]. A meta-analysis of thyroid hormone administration in brain-dead donors failed to support a routine role for thyroid hormone administration in the brain-dead donor [27].

Less information is available regarding the use of HRT for pediatric donors, and there are no controlled trials. However, in a retrospective review of 1903 pediatric donors published in abstract form, HRT was associated with significantly increased odds of having the liver and at least one kidney and lung transplanted [113]. There was no significant increase in the odds of the heart being transplanted. Importantly, HRT may lead to improvement in meeting donor management goals, which has been shown to improve organ function and to increase the number of organs recovered for transplantation [34,35]. In a registry-based study in pediatrics, HRT was associated with improved recipient survival (with no significant adverse effects reported in potential donors) [114].

Thermal regulation — After neurologic death, the donor often becomes hypothermic and requires active measures to maintain normal body temperature. The demise of the thermoregulatory center following neurologic death leads to failure of thermoregulatory mechanisms. Heat loss occurs via convection and radiation. The vasodilation that occurs after neurologic death results in further heat loss, exacerbating thermoregulatory instability. The administration of excessive amounts of room-temperature resuscitation fluids can easily contribute to hypothermia as well.

Hypothermia causes a variety of problems that affect donor management and organ viability. Hypothermia is a direct myocardial depressant and will lead to bradycardia and hypotension. As body temperature drops, the kidney's ability to maintain tubular concentration gradients is lost, resulting in a cold-induced diuresis. Temperatures below 32°C adversely affect coagulation. The oxyhemoglobin dissociation curve is shifted to the left decreasing oxygen delivery to the tissues further exacerbating tissue acidosis and contributing to organ deterioration.

All efforts should be made to keep the patient's temperature above 35°C [76,115]. If possible, all potential donors should be managed in private rooms within the intensive care unit, not only for privacy but also for more effective environmental temperature manipulation. The ambient temperature in the room should be increased. Passive heating methods such as the use of warmed blankets and space blankets (such as the Bair Hugger) are easy to use and valuable in reducing radiant heat loss. If these measures are inadequate, active rewarming may be needed. Warmed intravenous fluids and warmed gastric and bladder lavage may be effective. All ventilator gases should be humidified and heated to 38.5°C.

Targeted temperature management and controlled hypothermia are being used by some organ recovery organizations to enhance organ function and recovery. In a study in adults, organ donors were randomized to two targeted temperatures ranges: either 34 to 35°C (mild hypothermia) or 36.5 to 37.5°C (normothermia) [116]. Paradoxically, mild hypothermia was shown to significantly reduce delayed graft function in kidney recipients. There are no pediatric studies in donors supporting use of controlled hypothermia.

In the unlikely event that elevated body temperature of the donor occurs from active warming measures, all blankets should be removed, intravenous fluids should not be warmed, and a cooling blanket should be used if needed. Antipyretics can be administered via nasogastric (NG) tube or by suppository every four to six hours, although the effect of antipyretics in the brain-dead donor are unclear and are unlikely to be effective since the thermoregulatory center has been destroyed.

Infection — Although severe overwhelming sepsis and active infection such as meningococcemia with multisystem organ failure may rule out donation, the majority of patients with bacteremia can be suitable candidates after adequate treatment with antibiotics [1]. Organs transplanted from bacteremic donors do not transmit bacterial infection nor result in poorer outcomes [117,118]. There are reports of successful transplantation from donors with bacterial meningitis following antibiotic therapy for at least 24 hours [119,120]. Transmission of infections, many times viral, to immunosuppressed recipients may lead to severe life-threatening or even fatal illness, even if the infection is unusual or of modest virulence. The risk of transmitting such infections can be reduced by a careful medical and travel history from the donor's family. A Donor Risk Assessment Interview (DRAI) is routinely performed for any donor, including children. Transplant centers must have sophisticated molecular and antigen detection facilities to permit early diagnosis if an unusual infection is suspected [121-123]. Criteria for excluding a potential donor because of infection are determined by the transplant coordinator and the medical director of the organ procurement organization [1].

Once the donor status is confirmed, blood cultures should be obtained and repeated after 24 hours, if necessary. A tracheal aspirate, urine sample, and blood should be cultured. Any infection must be appropriately treated with antibiotics. Broad-spectrum antibiotics should be initiated when infection is suspected or proven. The duration of treatment is typically determined by the transplant and infectious disease teams. Routine treatment of the potential donor with broad-spectrum antibiotics for prophylactic purposes is not universally practiced [57]. However, because of evidence that the lungs of organ donors are particularly susceptible to infection, prophylactic antibiotic therapy is frequently utilized by many centers in the United States [124,125]. The choice of antibiotic varies between centers, but the use of antibiotics should provide broad-spectrum coverage to treat common respiratory pathogens or ventilator-associated pneumonia (eg, vancomycin with piperacillin-tazobactam). End-organ function should be considered when using nephrotoxic antimicrobial agents. This should also be a consideration if contrast agents are utilized for organ assessment. Consultation with the transplant coordinator, OPO medical director, infectious disease specialists, and transplant clinicians and surgeons is recommended for all potential donors. Many OPOs routinely give antibiotics at the time of organ recovery.

Issues related to the coronavirus disease 2019 (COVID-19) pandemic are discussed separately:

●Donor testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and related contraindications for organ donation (see "Assessment of the pediatric patient for potential organ donation", section on 'Candidates for donation' and "COVID-19: Issues related to solid organ transplantation", section on 'Pretransplantation screening')

●Reduced supply of organs from deceased or living donors during the pandemic (see "Assessment of the pediatric patient for potential organ donation", section on 'Inadequate supply of organs for transplant')

●Outcomes for solid organ transplants during the pandemic (see "COVID-19: Issues related to solid organ transplantation", section on 'Active COVID-19 in solid organ transplant recipients')

Hematology — Coagulation abnormalities are common after neurologic death due to the release of tissue thromboplastin and cerebral gangliosides during the autonomic storm (see 'Hematologic' above). Disseminated intravascular coagulation can be seen in the pediatric donor and requires aggressive treatment to preserve organ function. In trauma patients with large transfusion requirements, the procoagulant factors may become diluted and contribute to the coagulopathy. Donors with hepatic dysfunction or failure may have impaired synthetic function, resulting in coagulation abnormalities.

Hematologic parameters should be monitored and maintained near the normal range. If a coagulopathy develops, clotting factors should be transfused as needed, platelet levels should be kept above 50,000/microliter (50 × 10⁹/L), and anticoagulant medications (if being administered) should be discontinued. Many drugs can promote thrombocytopenia and should be discontinued if thrombocytopenia is identified. Beta blockers, calcium channel blockers, antibiotics, histamine 2 receptor blockers, and heparin are common drugs that can induce or exacerbate thrombocytopenia. Treatment of hematologic abnormalities may also be determined if the patient is symptomatic with ongoing bleeding or if there are coagulation disturbances that require correction prior to or during surgical recovery of donor organs.

Sites for potential ongoing loss of blood should be assessed regularly. The hemoglobin should be kept close to the normal range (eg, hemoglobin >10 g/dL or hematocrit >30 percent), to optimize oxygen carrying capacity and oxygen delivery to the tissues.

Supportive care

Coordination of care — Many centers in the United States with a high volume of potential donors are staffed with on-site coordinators from the OPO. These coordinators are available to work with staff and families in all end-of-life care and organ donation stages, even before the formal declaration of neurologic death occurs [126,127]. Staff from the OPO are trained to approach families for donor authorization and should be included in donation discussions to ensure the best outcomes. (See "Assessment of the pediatric patient for potential organ donation", section on 'When to consult an organ procurement organization'.)

A team approach has been adopted by many institutions when discussing donation with families of potential pediatric organ donors, in which the bedside nurses and intensivists work in concert with the OPO personnel. This practice is encouraged by the United States Department of Health and Human Services (HHS) Organ Donation Collaborative's report on best practices [128]. Coordinated efforts between OPO coordinators and medical professionals have improved authorization rates while assisting families with end-of-life care issues [1]. Authorization rates are increased when the OPO is involved with approaching families [129]. There are family-specific or cultural reasons that organ donation may be declined [130]. In some instances, coordinators and staff are matched to the donor family culture, language and religion to provide the most sensitive and effective interface for the grieving family and to improve organ donation rates. Involvement of palliative care teams also has been identified as another resource to assist the intensive care unit team, parents, and families facing end-of-life issues with their child [131].

Organ donation is a process that begins when a critically ill or injured patient is identified as a potential donor. Early recognition of potential death and a timely referral to the OPO is valuable because it prevents a rushed approach to donation and is considered a best practice to increase donation potential and recover more organs for transplantation [132]. A successful process incorporates clinical triggers that alert the OPO of a possible donor. Appropriate time is required to determine donor potential, perform extensive testing, and determine suitability and placement of organs recovered for transplantation. This time period may exceed 24 hours or more in some instances. The patient must be continually monitored and medically supported until death has been declared or until medical therapies are withdrawn. Determination of death must be made in a timely and efficient manner to allow for procurement of organs as soon as possible following determination of neurologic death. However, there may be delay due to logistic issues. Delays from time of neurologic death to recovery of organs has been associated with poorer outcomes in organ function post-transplant or loss of potential donors in one study that focused primarily on adult donors [133], although another review concluded that an increase in time interval between neurologic death and organ procurement was not associated with reduced organ procurement rates nor salvageable organs [2]. Most importantly, the donor should continue to be aggressively managed to maintain a normal physiologic status to ensure optimal organ function until organ recovery.

Supportive care of the potential organ donor is a multidisciplinary endeavor and requires inter-agency cooperation and management strategies. The pediatric intensive care specialist and critical care team is instrumental in the success and quality of organs recovered from donors. The medical management of the potential organ donor requires knowledge of the unique physiologic derangements that occur in this patient population. Care of the organ donor should be viewed as a continuum of care with ongoing emotional support for the family during the most difficult time in their lives as they endure the loss of their child [1]. Social workers, chaplains, child life specialists, and family support personnel from the OPO are important components of an effective support team. Thus, the donation process relies on all caregivers working to support the potential donor and family through end-of-life issues. This process is essential to maximize organ recovery from a limited population of patients.

Nursing — The role of the intensive care nurse is vital in the successful management of a potential organ donor. Due to the intensive contact with the patient, the nurse in the pediatric intensive care unit may be the first health care practitioner to identify a potential donor. Nurses in the pediatric intensive care unit are an important resource to access in discussions with the donor's family.

Intensive nursing care is critical to maintain homeostasis and preserve organ viability. In addition to the management issues discussed above, routine care of the potential donor includes:

●Repeated turning to prevent pressure sores

●Lubrication and protection of eyes

●Nasogastric (NG) tube insertion to provide drainage of secretions and to reduce or prevent aspiration

Respiratory care is vital to maintain the integrity of the potential lung donor. Chest physiotherapy and pulmonary toilet to maintain lung volume is required. In some centers in the United States, chest physiotherapy vest devices are used for continuous mucus clearance therapy. (See 'Respiratory' above.)

Nutrition — Following neurologic death, high concentrations of catecholamines and inflammatory cytokines will have deleterious effect on transplanted organs associated with reduced function and outcome [134,135]. Maintaining nutrition may reduce those effects, although metabolic rate is extremely low following neurologic death. Concerns about aspiration and metabolic complications of parenteral nutrition have usually precluded feeding in donors awaiting surgery. However, one study demonstrated that enteral feeding was safe and approximately 30 percent of donors absorbed and metabolized enteral nutrition [136]. Discussion with the OPO medical director and abdominal transplant surgeons should occur to determine the need for nutritional support.

Emerging technology and therapies to support donor organs

●Ischemia-reperfusion injury (IRI) is inevitable during organ transplantation and has deleterious effects on the transplanted organ. Ischemic-perfusion conditioning has been attempted to prepare organ for subsequent IRI. One review that pooled data from meta-analyses demonstrated short-term benefit [137]. Larger studies powered for survival need to be conducted.

●Antioxidants – Neurologic death and IRI lead to production of reactive oxygen species (ROS), which play a major role in oxidative damage to tissue. Antioxidants have been evaluated to study their effects on ROS and grafts. In one study, preconditioning with alpha-lipoic acid, a potent antioxidant, reduced inflammatory markers, diminishing early kidney dysfunction and clinical post-transplant pancreatitis [138]. More studies are needed to determine whether antioxidants have a role in donor management.

●Ex situ machine perfusion – Ex situ (ex vivo) machine perfusion to maintain organ function and potentially condition organs for transplantation continues to evolve and may increase organ availability for transplantation. Organs that have reduced function such as heart, lungs, and liver are being recovered and supported with ex situ machine perfusion [139-141]. Ex situ machine perfusion for heart, lung, and liver can improve organ performance for previously marginal organs that could not be transplanted.

NRP is used specifically for donation after circulatory death. A discussion about NRP is beyond the scope of this topic review and encompasses the donation after circulatory death donor and not donation after neurologic death. (See "Assessment of the pediatric patient for potential organ donation", section on 'Candidates for donation'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of potential deceased organ donors".)

SUMMARY AND RECOMMENDATIONS

●Goals – Meeting donor management goals (DMGs) (table 2) increases successful organ recovery and results in more organs transplanted in children. (See 'Donor management goals' above.)

●Cardiovascular – The cardiovascular events following neurologic death frequently include a hyperdynamic phase (autonomic storm), followed by severe hypotension. Maintaining organ perfusion after neurologic death is critical to organ preservation.

•Hemodynamic monitoring – We suggest continuous use of invasive central venous and arterial pressure monitors in all potential organ donors, regardless of age (Grade 2C). Fluid intake and output should be monitored and recorded. Children under the age 10 years are commonly managed without pulmonary artery catheters. In older children, pulmonary artery catheters may, on rare occasion, be used at the discretion of the clinicians. (See 'Hemodynamic monitoring' above.)

•Hypotension

-Hypotension is almost universal after neurologic death and is typically managed with a combination of judicious fluid administration to restore circulating volume, and drugs with inotropic and vasopressor effects. Appropriate management goals include maintaining the central venous pressure (CVP) at 8 to 10 mmHg (if measured) and maintaining urine output of >1 mL/kg/hour for the older child and 2 cc/kg/hour for the younger child (table 2). Arginine vasopressin deficiency (AVP-D) commonly contributes to hypovolemia and should be treated. (See 'Fluids and electrolytes' above and 'Arginine vasopressin deficiency' above.)

-Management of hypotension includes judicious use of crystalloid and colloid administration to restore normal circulating volume, in conjunction with use of inotropic agents for blood pressure support. Use of synthetic colloids is not recommended, as they can potentiate renal failure. Glucose-containing fluids should not be used for volume expansion, because these may promote osmotic diuresis. Excessive fluid administration can increase the risk of pulmonary edema. (See 'Fluids and electrolytes' above.)

-If judicious fluid administration does not achieve these goals, vasopressor agents can be used to support blood pressure and perfusion (table 5). We suggest using vasoactive agents at the lowest rates possible to support blood pressure and organ perfusion (Grade 2C). (See 'Vasoactive agents' above.)

-Vasopressors with alpha agonist effects (epinephrine, norepinephrine, or phenylephrine) may be added for additional hemodynamic support (table 5). Vasopressin is often used to treat concomitant AVP-D and has the added benefit of increasing systemic vascular resistance. (See 'Vasopressors' above.)

•Arrhythmias – Arrhythmias are common and may be caused or exacerbated by electrolyte disturbances, inotropes, hypovolemia, hypothermia, hypoxia, acid base disturbances, and myocardial ischemia or damage. Bradyarrhythmias should be treated only if they are associated with hypotension. Bradyarrhythmias will not respond to atropine in patients who have progressed to neurologic death. In patients who require treatment for bradycardia, epinephrine is the preferred agent. Isoproterenol may be considered for this use but can cause a drop in blood pressure. (See 'Arrhythmias' above.)

•Other tests – Serial measurements of lactate can help to assess the adequacy of oxygen delivery to the tissues. Monitoring of mixed venous oxygen saturation (SVO₂) also may be beneficial in determining adequate cardiac output. Near-infrared spectroscopy (NIRS) is being more frequently used and can assist with determination of tissue oxygenation through a noninvasive method. If lactate, NIRS, and SVO₂ are within normal ranges, the clinician may permit lower blood pressures and thus minimize use of vasopressors. Serial echocardiograms can provide information about treatment response to improve cardiac function. (See 'Hemodynamic monitoring' above.)

●Electrolytes and glucose – Patients frequently develop hypernatremia following neurologic death. This may be caused by AVP-D and/or sodium administration for treatment of increased intracranial pressure (ICP) during cerebral resuscitation, rendered prior to neurologic death in the pediatric intensive care unit.

•AVP-D – AVP-D (previously called central diabetes insipidus) is characterized by dilute urine production and intravascular volume depletion (table 7). Treatment includes restoration of normal circulating volume using isotonic fluids, followed by administration of hypotonic fluid for urine output replacement and maintenance fluids, in conjunction with vasopressin or desmopressin. The goal of treatment is to decrease, but not completely stop, urine output. (See 'Arginine vasopressin deficiency' above and "Arginine vasopressin deficiency (central diabetes insipidus): Treatment".)

•Hyperglycemia – Hyperglycemia may be caused by catecholamine release and/or exogenous inotropes, steroids, or decreased or absent cerebral metabolism of glucose. Hyperglycemia can contribute to osmotic diuresis. Blood glucose concentrations should be monitored and maintained between 60 and 150 mg/dL. In some cases, this can be accomplished by minimizing the use of exogenous glucose. If blood glucose levels are consistently greater than 180 to 200 mg/dL (10 to 11.1 mmol/L), we suggest treatment with insulin (Grade 2B), administered as a continuous intravenous infusion. (See 'Hyperglycemia' above.)

●Ventilation – All potential organ donors will require mechanical ventilation to maintain appropriate ventilation and oxygenation. A cuffed endotracheal tube (ETT), with high cuff pressure, should be used to minimize the risk of aspiration in children, regardless of age. Ventilator settings should be tailored to maintain adequate oxygenation, normalize ventilation, and prevent atelectasis. (See 'Respiratory' above.)

●Hormone replacement therapy (HRT) – Hormonal resuscitation therapy with a combination of corticosteroids, thyroid hormone, vasopressin, and insulin is commonly used in the United States. HRT appears to increase rates of successful organ recovery from adult organ donors that are unresponsive to or failing conventional resuscitation measures, as manifested by poor cardiac output, inadequate organ perfusion pressures, and increasing lactic acidosis. (See 'Hormone therapy' above.)

HRT should be considered early in the course of managing the potential pediatric organ donor. Glucocorticoids and thyroid hormone are routinely used as a part of donor management in many centers (table 8). When the donor is unresponsive to or failing conventional hemodynamic resuscitation measures, we suggest treatment with vasopressin to assist in blood pressure control and also as a treatment for AVP-D, if present.

●Antibiotics – Evidence of infection should be rigorously sought and treated in the potential organ donor. Prophylactic or preemptive antibiotics are commonly used in many centers in the United States for this select population following declaration of neurologic death. (See 'Infection' above.)

●Hypothermia prevention – Thermoregulatory mechanisms fail during the progression and upon completion of neurologic death. Hypothermia can promote arrhythmias, cold diuresis, decreased organ perfusion, and exacerbate an ongoing coagulopathy.

The temperature of the potential organ donor should be monitored and maintained in a normal range through passive measures (blankets, ambient heat, and warmed ventilator gases) and active measures (warmed intravenous fluids, gastric and/or bladder lavage). (See 'Thermal regulation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Shaun Wilson, MD, who contributed to earlier versions of this topic review.