Optimal management of brain-dead organ donor

Abstract

Maintaining a brain stem–dead (BSD) donor is specialized science. It is a daunting task as they are fragile patients who need to be handled with utmost care owing to extreme haemodynamically instability and need the best of monitoring for maintenance of organs. To ensure a successful transplant, a BSD donor first needs to be identified on time. This requires scrupulous monitoring of neurologically compromised patients who tend to be the most frequent organ donors. Once the donor is identified, an all-out effort should be made to legally obtain consent for the donation. This may require numerous sessions of counselling of the relatives. It needs to be performed tactfully, displaying the best of intentions. It is important to understand the physiology of a brain-dead individual. A cascade of changes occurs in BSD donor which result in a catastrophic plummeting of the clinical condition of the donor. All organ systems are involved in this clinical chaos, and best possible clinical support of all organ systems should be available and extended to the donor. Organ support includes cardiovascular, pulmonary, temperature, glycaemic, metabolic and hormonal. This article has been written as a follow-up article of previously published article on identifying an organ donor. It intends to give the reader a concept of what the BSD donor undergoes after brain death and as to how to maintain and preserve various organs for donation for successful transplantation of maximum organs.

Introduction

Management of the brain stem–dead (BSD) donor has been a challenge for clinicians ever since organ harvesting became a valid method of transplanting organs in the ever increasing wait list of patients with end-stage organ failure. In view of rapid deterioration of a BSD donor, it is vital that such an individual is optimally managed. This has been recognized and now the management of a BSD donor has been considered a highly specialized science.

The science of BSD donor management is based on physiological considerations. Such aggressive and optimal management increases the donor organ pool by converting marginal donors to certain donors and sustaining them till successful organ harvest.

Identifying an organ donor

A typical organ donor is a young patient with irreversible brain damage. Morning round is the most frequent and convenient time when a brain dead donor is identified whereas the fact would be that the patient had stopped triggering ventilator much earlier which goes unnoticed. This could lead to delay in recognition and potentially missing a BSD donor which in real terms plummets chance of organ harvesting. Identification of BSD leads to a flurry of activity to optimize the donor and hurry up with the first brain stem death testing and a race against lost time which in many cases becomes impossible. A patient with poor Glasgow Coma Scale (GCS) should be kept under close observation and cessation of triggering should be picked up early. This should be followed up immediately by the organ harvesting protocol notwithstanding the time of the day that it occurs.

The identification of brain stem death has already been elaborated elsewhere.¹ Indian Society of Critical Care Medicine came out with a position statement on the same topic which can be referred to² in a similar article by Kumar.³

Identifying BSD donor is important as the waiting list for organ transplant is never ending and compounded by decreased donor donation rate which is dismal 0.8 per million in India, whereas it is 46.9 per million in Spain, 32 per million in USA and 23.1 per million in UK.⁴ Few countries in Europe such as Spain, Austria and Belgium have ‘presumed consent’ wherein there is an opt-out mechanism, thereby hugely increasing the donor pool. Many other countries too have such a legislation, but their donation rates are way lower than the aforementioned countries. In our country, cultural and social beliefs along with awareness results in extremely poor rate of organ donation.

Physiological alterations in brain-dead donor

Profound physiological changes cause rapid physiological deterioration in the body after brain death which has to be countered with strategies to maintain organs in optimal condition for harvesting. The commonest cause of brain death is increase in intracranial pressure owing to a mass effect; whatever may be the offending cause. This mass effect incites a vicious cycle owing to worsening cerebral ischaemia, herniation of the brain through foramen magnum and increasing cerebral oedema. This increases until the intracerebral circulation ceases. Ischaemia of different areas of the brain leads to typical systemic response. Pontine ischaemia causes mixed vagal and sympathetic stimulation leading to Cushing's response with bradycardia and hypertension. Medullary ischaemia causes aggravated sympathetic response. Slowly, there is loss of this sympathetic stimulation, loss of hormonal control of pituitary and loss of temperature regulation owing to hypothalamic ischaemia. Classic changes as described may not be present in all brain-dead patients as it depends upon aetiology, time course of events and medical management administered to the patient during the time.

The classic cardiovascular response is the ‘catecholamine storm’ owing to profound rise of circulating dopamine, epinephrine and norepinephrine.⁸ It is characterised by systemic vasoconstriction including coronary vasoconstriction. Reduction of coronary blood supply with decreased myocardial oxygen delivery results in subendocardial ischaemia. These patients require inotropic support to maintain BP if their heart is harvested.

In lungs, intense pulmonary vasoconstriction may cause endothelial damage; ventilatory management may result in pneumonia, aspiration, volutrauma and barotrauma. Catecholamine surge can directly lead to lung injury and pulmonary capillary permeability in the donor which aggravates pulmonary oedema.⁵

Endocrine system is rendered ineffective by the loss of hormonal control from hypothalamus and pituitary — both anterior and posterior. Depletion of antidiuretic hormone leads to diabetes insipidus (DI) in almost 80% of brain-dead donors.⁵ Management of DI is challenging as it causes hypernatraemia, fluid overload and consequent deterioration of all organs. Owing to absent thyroid stimulating hormone (TSH), there is rapid decline of T3 and T4 resulting in poor cardiac contractility, increasing anaerobic metabolism and lactic acidosis.⁶ Insulin levels fall leading to decreased intracellular concentration of glucose augmenting anaerobic metabolism and systemic hyperglycemia which is further aggravated by infusing salt-poor glucose-containing crystalloids. Inadequate stress response occurs owing to decreased adrenocorticotropic hormone (ACTH) and subsequent cortisol levels, leading to cardiovascular instability.⁶ Hepatic dysfunction occurs with depletion of glycogen and hepatic sinusoidal perfusion. Activation of coagulation pathways occur owing to release of tissue thromboplastin from dead brain tissue. Diffuse intravascular coagulation occurs in about 28% dead donors. Loss of hypothalamic temperature regulation, profound peripheral vasodilation, reduced metabolic rate and muscular activity lead to hypothermia. Immunogenic response is enhanced with proinflammatory mediators replete in the dead donor causing chances of acute rejection.⁷

Medical management of brain-dead donor

On admission of a neurological case to an intensive care unit (ICU), the aim of the treating team is to minimize damage to the brain but after declaration of brain death, the focus changes to preservation of organs for possible harvesting.⁹ Once the family wishes that their patient should donate organs for larger benefit of society, it becomes the duty of ICU team to provide organs in pristine condition.¹⁰ The management of a brain-dead donor is a challenging task fraught with chances of cardiac arrest lurking at all times. The management is at best compared with a video game with requirement of quick reflexes as the brain-dead donor goes along the roller coaster. Haemodynamics of these patients require intensivist sitting on a chair next to patient bed for prompt management. Pandit et al.² gave a “Rule of 100” which is paramount aim for these patients which is mentioned in Table 1.

Table 1.

Rule of 100.

•SBP >100

•Urine output >100 ml/h

•PaO2 > 100 mmHg

•Hb > 100 gm/lt

•Blood glucose 100 mg/dl

Management of dead donor is elucidated in the following paragraphs.

Monitoring

Owing to rapidly changing scenarios, optimal monitoring is required to manage a dead donor. The following monitoring should be established as soon as feasible:

• a.Invasive blood pressure: This should be established in either of the radial arteries. Femoral artery should not be cannulated because during retrieval process aorta is clamped much before total retrieval of organs and BP monitoring is lost midway. Highest quality arterial catheter should be used and the cost-saving practise of 20G IV cannula in radial artery should be avoided.
• b.Temperature Probe: Oesophageal temperature probe should be inserted the moment brain death is suspected. Please note that this monitoring is frequently overlooked. Temperature should be maintained as close to 37 °C as possible. The temperature can be measured in the nasopharynx or the middle one-third of oesophagus. Skin probes should not be used to quantify temperature in brain-dead donors as it is not accurate.¹⁰
• c.Central venous catheter: Central venous catheter should be inserted urgently in the right superior vena cava or subclavian vein on either side. Femoral route is not the natural choice as during harvesting, access is lost owing to clamping of Inferior Vena Cava (IVC) and vasoactive drug administration becomes erratic.
• d.Dynamic indices of fluid responsiveness. Invasive monitoring should include pulse pressure variation or systolic pressure variation and cardiac output. Importance of these is due to rapid fluctuations in the volume status of patient owing to unpredictable urine output.
• e.Nasogastric tube should be inserted to administer fluids, feed and preserve gut function.

Cardiovascular support

The aim of Cardiovascular System (CVS) support is to preserve heart without significant ischaemia while maintaining its primary function of perfusing all organs. A young patient without any cardiac abnormality whatsoever may become an unsuitable heart donor owing to endocardial ischaemia unleashed by the sympathetic storm associated with brain death. This sympathetic storm is short-lived and can be countered with short-acting β-blockers such as esmolol, titrated to effect. This sympathetic storm transforms into terminal sympathoplegia manifesting as vasoplegia leading to profound hypotension. To counteract hypotension, fluid resuscitation is required.¹¹ Volume resuscitation is double edge sword—along with stabilizing BP—owing to increased pulmonary capillary permeability. It leads to increased extravascular lung water and consequent V-Q mismatch. Hence volume resuscitation should be carried out by regularly checking the Inferior Vena Cava (IVC) diameter and maintaining the IVC Collapsibility Index around 18%.¹¹ Fluid of choice is crystalloids—balanced salt solution or Ringer lactate is most frequently used— the caveat is Ringer's acetate as lactate interferes with lactate measurement as a downstream manifestation of tissue perfusion. In case Na levels are very high, dextrose 5% can also be used as short-term measure, but it has its own problems of high blood glucose and poor retention in IV compartment.¹¹ Acceptable BP is mean of >60 mmHg and CVP of 6–10 mmHg. If heart is not considered for harvesting, a higher mean can be targeted.

Choice of inotropes takes a dramatic turn after brain death. Before brain death, noradrenaline, adrenaline and dopamine are the choice to maintain haemodynamics. But after brain death, myocardial ATP is rapidly depleted, and adrenergic receptor agonists have little positive effect; in fact, their administration leads to even faster ATP depletion.¹² Vasopressin is the drug of choice for hypotension in these subjects. First it improves haemodynamics by increasing diastolic BP and consequent improved organ perfusion, specially liver and kidneys. Second, it treats DI and decreases urine output to normal range, leading to physiological Na levels and better quality liver and kidney harvest.¹³ Third it reduces the dose of adrenergic agonists. Vasopressin should be given at a dose of not less than 1 IU/hr for DI, and the maximum dose should be 2.5 IU/hr above which adverse effect changes on heart and kidneys can be seen. Other inotropes which can be used are dopamine and adrenaline in prescribed doses.

Pulmonary Support

The aim of pulmonary support is to maximize oxygen delivery to transplantable organs. Pulmonary compromise occurs on various counts—sympathetic storm, overzealous IV administration, endothelial damage, pulmonary capillary leakage, pulmonary oedema, ventilator-associated oedema, systemic inflammatory response syndrome and unmasking of pulmonary contusion owing to polytrauma. The ventilatory strategy should be lung protective with tidal volume of 6–8 ml/kg, optimal PEEP and FiO2 should be kept to maintain PaO2 of about 100 mmHg.¹⁴ If lung transplantation is considered, frugal fluid administration has to be carried out with close observation of cardiac filling pressures.

Temperature management

Cadaveric temperature has to be maintained as close to normal as possible. Oesophageal temperature probe is to be inserted, all fluids should be warmed, forced air warmers should be used, room temperature should be increased to about 25–27 °C. Hypothermia is the norm in these brain dead patients which causes anaerobic metabolism and further deterioration of haemodynamics, as well as organ function.¹⁰

Metabolic parameters

Interior milieu undergoes massive changes with uncontrolled metabolic processes breaking loose owing to loss of neuro-hormonal control. Few of them are as follows:

• a.Hypernatraemia: Eighty percent of cadaveric donors have DI leading to abnormally high Na levels.¹⁰ In fact, rate of rise of Na may surprise everyone and hypernatraemia has adverse effect on both liver and kidney graft function. Very close watch must be maintained on urine output and hourly charting is the key. Critical care nurse should be briefed that any sudden increase of urine output must be brought to the knowledge of intensivist urgently. The method to counter DI is to administer salt-free fluids—best way is to give free water by NG tube but it may not be possible to give larger amounts by this route and supplementation can be carried out with dextrose 5% by IV. Rule of thumb is to maintain intake equal to last-hour output plus insensible loss of about 50 ml/h. In spite of this, intravascular volume and cardiac filling could be compromised, hence regular IVC diameter monitoring as frequently as required should be carried out. If close observation and tight control over these parameters is kept, DI may not develop and Na levels are likely to be in physiological range. It's a practise in our Institute to keep Na level around 135–140 mEq/l for optimal outcome.
• b.Potassium levels decrease rapidly owing to urinary loss, high blood glucose levels, administration of insulin and poor intake. Tachyarrhythmias and cardiac arrest is known if K levels are not kept in normal range. K replacement has to be carried out by central IV route by infusion pump. Rate of administration depends on K level and urgency of correction. The maximum rate is 40 mEq/hr; however, a slower administration of 20 mEq/hr frequently is acceptable coupled with efforts to maintain normal urine output.
• c.Blood glucose levels should be monitored frequently as hyperglycemia is the norm. Current guidelines recommend target blood glucose of 180 mg/dl.¹⁵ This hyperglycemia requires Insulin administration by way of insulin infusion rather than sliding scale bolus dose.¹⁵ The rate of insulin infusion should be blood glucose divided by 100.
• d.Metabolic acidosis: Metabolic acidosis occurs in about one-third of brain-dead donors and is mostly owing to large strong ion gap.16, 17 Hyperlactatemia, hypoalbuminemia and hypernatraemia too contribute to acidosis. Correction of acidosis by sodium bicarbonate leads to hypernatraemia and may not be effective. Normothermia and eucarbia should be achieved to lessen impact of metabolic acidosis. Correction of hypoalbuminemia is not mentioned in the literature, but it could also help in improving acidosis.

Hormonal support

Brain death leads to cessation of function of hypothalamus and pituitary leading to loss of TSH and ACTH. Replacement of pituitary hormones improves cardiorespiratory function and vasoactive drug requirement reduces. Triiodothyronine or l-thyroxine has been shown to be of immense benefit¹⁸ with increase of cardiac output and chances of successful organ harvesting. The dose of thyroxine to be given is 300–400 mcg every 8 h. Loss of ACTH leads to decrease of endogenous cortisol levels soon after brain death. Administration of methylprednisolone as replacement of cortisol could not be conclusively proven to improve renal graft function after transplantation. Large study carried out few years back did not recommended methylprednisolone for improved kidney graft function.¹⁹ However, methylprednisolone improves donor stabilization and has been shown to be beneficial in liver and lung transplantation.²⁰ Because it improves donor stability and increases yield of transplantable organs per donor, Inj methylprednisolone in dose of 15 mg/kg or 1000 mg IV per day should be administered to dead donor on priority. Lot of literature is available on dopamine administration as a hormone to brain dead donor and the conclusion is that dopamine at 4 mcg/kg/min is beneficial for renal harvesting without adversely affecting donor stability.²¹

Nutritional support

It is common perception that because donor is required to be maintained for a day or two, nutrition can be substituted by free water as is highly required. However, studies have shown that continued nutrition of the dead donor plays a role in improved graft function.²² Infusion of large quantities of dextrose repletes hepatic glycogen reserves and improves liver graft function.²² Proteins and fat increases protein synthesis, ATP content, and hepatic energy. Glutamine, propofol, free fatty acids improve heart and kidney graft function.²³

Identifying organs WHICH can be harvested

Age plays a major role in acceptability of organs which can be transplanted. Table 2 shows² a rough guideline for age criteria to accept organs. In all patients, we should aim for heart, liver, kidneys, and cornea to be harvested and transplanted. Other organs which can be harvested but are not common in India are pancreas, intestine, lungs, sclera, skin, bone, cartilage, tendon, meniscus, muscle fascia, heart valves, pericardium, and blood vessels.

Table 2.

Age limit for deceased organ donor.

Organ	Age limit
Kidneys	Upto 60 yrs
Liver	Upto 60 yrs
Kidney—pancreas	18–45 yrs
Pancreas	7 days—50 yrs
Heart	Upto 45 yrs
Lungs	Upto 65 yrs

Conclusion

A brain-dead donor programme with outstanding results would have to essentially target all concerned areas.²⁴ This would start from awareness and acceptability of brain death. There would also be a need for timely recognition of brain death. The need for early identification needs to be highlighted as marginal organs would be lost if there is any delay. Then there would be the intensive monitoring and sustenance of the potential brain-dead donor by the intensivist. This can be achieved only with an in-depth knowledge of the physiological alterations. The management would have to be multipronged and supporting all facets such as cardiovascular, pulmonary, temperature, metabolic, hormonal, and nutritional. Although there are not very many controlled trials on the topic but there is considerable agreement on the management goals. In addition is the requirement of identifying the organ to be harvested. Needless to say that a well-established brain-dead donor program²⁵ requires a team effort involving the intensivist, neurophysician, transplant co-ordinator, and counsellor.²⁶ One has to be aware of the fact that maintenance of the organ systems has to be of the highest standards so that the end-user recipient stands to gain an optimal organ.

Conflicts of interest

The authors have none to declare.