EVOLUTION OF THE CONCEPT OF BRAIN DEATHThe concept of Brain Death is important for those involved in organtransplantation, however this condition was not invented for thebenefit of organ donation. The head injury due to road traffic accidentcan account for almost 50% of Brain Deaths. Organ donation is perhapsthe only positive outcome of this grave tragedy, provided the relativesagree to the process.

History: Two Frenchphysicians in 1959 first recognized Brain Deathon patients beingventilated in the intensive care units and called it coma depasse (astate beyond coma). In 1968, an Ad Hoc Committee of Harvard MedicalSchool defined brain death as irreversible coma with the patientbeing totally unreceptive and unresponsive with absence of all cranialreflexes and no spontaneous respiratory efforts during a 3 minutesperiod of disconnection from the ventilator. How much of brain needs tobe actually dead before death can be diagnosed has been debated overthe years. Experiments have shown that a few cubic centimeters oftissue called œbrainstem which is located beneath Aqueduct of Sylviusanteriorly and floor of fourth ventricle posteriorly is the vitalsection of the brain that determines consciousness and ability tobreathe spontaneously. Destruction of this tissues is what determinesbrain death. However, in certain countries, the whole brain includingthe brainstem needs to die to diagnose the state of 'irreversibledeath' and requires four vessels (carotid and vertebral) angiographyand Isotope studies of the cranium. This can be a cumbersome exerciseto undertake in an intrinsically unstable patient. In contrast, thetests that determine brainstem death are more clinical and over thelast 30 years have proven to be simple, clinical, foolproof and capableof confirmation. In 1988 the Irish working committee on Brain Death in its memorandum said, if the brainstem is irreversibly lost, whatgoes on elsewhere in the brain is immaterial and Life cannot return.

However, in this situation time is the essence in organizing bothprocurement of organs and transplant of various organs and tissues tovarious patients as all organs have a critical time limit beyond whichthey cannot be stored. In the last three decades, this concept evolvedand has had judicial approval in many parts of the world. 

India in 1994,accepted the concept of brainstem death and passed an actto this effect and called it the Transplantation of Human Organ Act(THO). The act also proposed to stop commercial dealing of organs bymaking regulatory authorities in each state to look into the wholeprocess of organ donation for both live related (or unrelated) andcadaver organ donation and transplantation. 

Patho-physiology: This situation of physiologicaldecapitation can be caused by any pathology that increases in thepressure within the confines of the cranium. Usually this happens as aresult of bleeding from rupture of a vessel or a tumor (Fig.1).Increase in the intra-cranial pressure usually results in coning of thebrainstem and ischemia leading to brainstem death. In the situation theheart can continue to beat and keep the circulation of some of theessential organs, provided the patient is kept adequately ventilatedand hemodynamic stable. However, this state can be only maintainedtemporarily and eventually cardiac asystole occurs in all the patients.

Legal Aspects in brain death certification: As per the Transplantation of Human Organ Act two clinicians who are experts inthe field (like neurologists or neuro-surgeons) are required for braindeath certification. The certifying clinicians must have no interest orbenefit in any way from transplantation of cadaver donor organs. Theyare expected to do two sets of tests six hours apart to certify braindeath. One of these two clinicians should be a nominated member fromthe panel of doctors listed by the State Government for this purpose.The legal time of death in these circumstances is taken as the secondset of brainstem death tests. The certification should be done on laidout forms as per the act. In a medico-legal case, a forensic expert isalso required for the certification. The medical director or medicalsuperintendent of the hospital should finally countercheck and sign theform (Table-I - Form 8. THO Act). It is only after these formalitieshave been completed, should ventilatory support be discontinued ororgans retrieved.

Establishing Brain Death Diagnosis

The aim is to establish that the patient has absent brainstem reflexes and is apnoeic. The testing itself is straightforward. There are certain preconditions that should have been fulfilled to make sure that the tests are performed on the right patients and at the right time. These are as follows:

Patient should be comatose and on ventilatory support.
The cause of irreversible structural brain damage should be known
Functional reversible causes of a non-functioning brain stem should have been ruled out. These causes include.

• Primary Hypothermia
• Alcohol intoxication
• Neuromuscular blockades (like use of muscle relaxants)
• Use of central nervous system depressant drugs like use of sedatives
• Severe metabolic or endocrinal disturbances.
• Patient should have no circulating therapeutic levels of any drug that could cause coma

Establishing loss of 'Brainstem reflexes' at the bedside: - Absence ofbrain stem function is essential for establishing the diagnosis ofBrain death (Fig -2). In a brain stem dead patient cranial nervereflexes (Table-II) are tested to observe their motor response to asensory input. The absence of brain stem function is documented byconducting the following five tests:

• Absence of Pupillary reflex response to light
• Absence of Corneal reflexes
• Absence of vestibulo-ocular reflex
• Absence of cranial nerve response to pain
• Absence of gag and cough reflexes

Pupillary Reflexes: To checkfor absent pupillary response to light, a bright pen torchlight shouldbe used in a darkened room. It should be made sure that no eye drops todilate the pupils have been used in the four hours previously. Thepupils may not be necessarily fixed and dilated in the brainstem deadpatients, however there should be no pupillary response to light.

Corneal Reflexes: A moist cotton tipped swab should be used and firm pressure should be applied to the cornea without damaging it.

Vestibulo-ocular Reflexes:testing involves instilling 20ml of ice-cold water into the externalauditory canal and looking at eyeball movements of either eye for abouta minute. No eyeball movement indicates absence of reflex. Presence ofruptured eardrums or discharge from the ear prevents this test frombeing performed.

Gag and Cough Reflexes Test: requires temporary disconnection from the ventilator. A cotton tippedswab can be used to stimulate the posterior pharynx to look for aresponse. Experienced ICU staff usually notice a progressive loss ofresponse during the evolution of brainstem death when performing theroutine suction of airways andoropharynx.

Grimacing of the face to a painful stimulation is a normal response and this is absent in brainstem death situation. Afirm supra-orbital pressure( trigeminal nerve) should be used to checkthis cranial reflex. Pin pricks should not be used to test thisresponse.

Dolls Head Eye Phenomenon: (testing for oculo-cephalic reflex) This is one test that can be done to know if the brainstem is still alive. If this test is positive than othertests to establish brain death can be postponed. One may need todisconnect the patient from the ventilator for 15 to 20 second toperform this test. To do this test the physician holds the patients head between his hands and moves the head from side to side through1800. The clinician should hold the head to one side for 3 to 4 seconds and look at the simultaneous eye movement to that side. A similar movement is done to the opposite side and eye movement is noticed. In a normal fully alert individual and in a cadaver the eyes move with thehead and there is only a very fractional delay. If the cerebral hemispheres are damaged but brain stem is still alive there will be aobvious deviation of the eyes to the opposite side for a second or two followed by a release phenomenon when the eyes will get realigned tothe side of the head. This test should not be done if cervical fracture is suspected. 

The plantar response: may continue to be present in brain death patients along with spinal reflexes and should not be tested. Thedecorticate and decerebrate posturing is absent, however on occasionsit may be difficult to differentiate these from complex spinal reflexes.

Apnoea Test: The aim of apnoea test is to establish death of the respiratory centre in the brainstem (Table III). This is the ultimate test to establish brainstem death. It demonstrates that thespontaneous respiratory response fails to occur even in the absence ofstimulatory drive from CO2. For this test the patient is disconnectedfrom the ventilator for 10 minutes. However, to avoid hypoxia to vitalorgans, 100% oxygen is given for 5 minutes before disconnection from the ventilator. Even during the test period, 100% oxygen is given through a tracheal catheter. In the patient who is brain dead the carbon dioxide tension increase at a rate of 2mm/min (0.3 kPa/min)during apnoea testing. If the initial CO2 tension before testing isabout 40mmHg (5.3 kPa) then arterial CO2 tension after 10 minutes islikely to be 60mmHg (8 kPa). However, a rise to 50mmHg in CO2 tensionis acceptable and should provide sufficient stimulatory drive forspontaneous respiration in an intact respiratory centre. In patients with chronic airway disease or severe chest trauma, the apnoea test maybe difficult to perform. 

Role of Cerebral Angiography & EEG for brain death testing: Four-vessel angiography is used to show absence of cerebral blood flowand confirm death of whole brain. However, this test is not doneroutinely as it is a cumbersome investigation to undertake in anunstable patient. Nor is it necessary to use EEG to diagnose thecondition. If there is, any doubt in the diagnosis of brain death oneshould not proceed for a request for organ donation and ventilatorysupport should be continued. In case of severe facial trauma orpresence of paralyses or severe chest trauma, routine tests may not be possible and one may require to do special tests like isotope scanningor colour flow duplex scanning of the cranium to confirm brain death.All these tests can have limitations and can sometimes be inconclusive.In these inconclusive situations, if organ donation is being contemplated, the patients relatives should be told about it and theventilator should only be disconnected in the operation theatre andorgan retrieval started only after cardiac standstill. The Transplantation of Human Organ act does not require investigations like cerebral angiography or EEG for brain death certification.

In children, there remains uncertainty about the reliability of clinical brainstem testing. In neonates especially, organs for transplantation should not be removed in the first seven days of life with beating hearts. Radioisotope brain scanning has been recommended under the age of one year when brain stem death certification is required.

REQUEST FOR ORGAN DONATION

Brain death is relatively a newconcept and making request for organ donation in these circumstancescan be an extremely difficult task for a doctor or a nurse toundertake. If the decreased carries, a Donor Card (a card the size ofa credit card expressing their desire about organ donation) the task ofasking for organ donation becomes easier.

A large survey of 5008 members of the Indian public was undertaken in1995 to find out their attitude towards organ donation. Seventy twopercent of the people surveyed were willing to donate eyes. Less than50% were agreeable for solid organ donation ( heart, liver, lungs,kidney, Pancreas). Based on this survey a simple protocol was devisedcalled Ramachandra Protocol when asking for organs. In this protocol Eyes ' were first requested for and only if the relatives agreed,other organs were asked for.. In the tragic circumstance it was feltthat by asking for the eyes first the relatives were less likely toget upset with a request for organ donation (Table-IV).

Usually the organ donation request is made in the time interval between the diagnosis of brain death and discontinuation of the ventilator. Ifthe relatives are agreeable the process of organ donation is under taken and vital organ like heart, lunge, liver, pancreas and kidneys are removed for transplantation. Corneas should be kept moist and eyelids should be closed and retrieval surgery can be done for up to 12 hours after cardiac standstill. Other tissues like heart valves, skin, bone and cartilages can be removed for up to 48 hrs after death. The processof organ donation and transplantation requires co-ordination (Table-V)between different teams operating almost simultaneously and sometimes in different locations. It may require getting surgeons from differentspecialties together for both donor and recipient surgery.
Generally, there is no bar to organ donation and one or the other organor tissues can be donated at any age (Table.VI). However, it isimportant to do some essential virology screening before accepting thedonor. All potential donors will require a virology screen to preventpossible transmission of disease from donor to the recipient(Table.VII). The next of kin should be made aware that this isnecessary, if there are any objections these should be respected.However, it does mean that donation cannot then take place. 

Support of the Brain Dead Organ Donor

Oncethere is confirmation of brainstem death, the clinicians should switchthe focus of the management of the cadaver from therapy for elevatedintracranial pressure and brain protection, to preservation of organfunction and optimization of tissue oxygen delivery.

This will keep the organs in optimum condition so that the recipienthas the best chance of recovery after transplant. Supportive treatmentshould start early as soon as brain death has been recognizedirrespective of the consent; otherwise, there can be rapiddeterioration of initially suitable donors. In a poorly managedcadaver, the exercise of organ donation would yield organs that willresult in poor graft outcomes. 

Contraindications to organ donation : The absolute contraindications to organ donation are:

• Malignancy (except primary brain tumors, low grade skin malignancies and carcinoma in situ of the cervix), 
• Uncontrolled sepsis, 
• Active viral infections-hepatitis A and B, cytomegalovirus, herpes simplex virus and AIDS. 

Specific criteria and contraindications exist for individual organs: There have been instances where kidneys from positive hepatitis statusdonors have been transplanted into positive hepatitis status recipient.Given the severe shortage of donor organs, the criteria for donoracceptance have been expanded. This has led to the concept of marginaldonors as against ideal donors. Marginal donors may be elderlypatients, patients with hypertension or poisoned victims(organophosphrous poisoning) with significant complications of brainstem death. When there is concern about the suitability of organs, thismay have to be resolved during the organ procurement procedure, bydirect inspection and in some cases by open biopsy and frozen sectionhistopathology examination.

Hemodynamic instability occurring during coning or brain herniation is the result of an autonomic storm.This is the result of massive increase in systemic catecholamine levelsand increase in sympathetic activity. This phase occurs unheralded andis of variable duration. During brain, herniation major metabolicstress and impairment of organ perfusion occur which affects posttransplant organ function. This is of critical significance inchemo-sensitive organs like the heart and liver where immediate graftfunction is essential. Following the autonomic storm there is aprofound reduction in sympathetic outflow and catecholamine levelsdecreases to below baseline values. The resting vagal tone is abolishedbecause of destruction of the nucleus ambiguus. The subsequent chronicmaintenance phase of brain stem dead donors is frequently characterizedby hypotension.

There is evidence that brainstem deatheventually leads to cardiac arrest, even when cardio-respiratorysupport is maintained. Complications related to the profoundphysiological disturbances consequent on brain stem death includehypotension arrhythmias, pulmonary edema, hypoxia, diabetes insipidus,metabolic acidosis, Disseminated intravascular coagulation andinfections. The incidence of complications increases progressivelyafter brainstem death and may affect organ function. The common anduncommon problems usually encountered in these patients are enlisted inTable VIII. While optimizing the function of different organs, it isnecessary to pay attention to the details. For instance, large volumefluid resuscitation is important for maintaining kidney function, butmay result in pulmonary edema rendering the lungs unsuitable fortransplantation.

Cardio-respiratory support: As indicated earlier theoverall management goal is to ensure adequate tissue oxygen delivery.Parameters that suggest this, in the absence of lactic acidosis areindicated in the Table.IX.. The usual problems encountered in a braindeath patient are related to

• Hypotension 
• Arrhythmias and cardiac arrest 
• Hypoxemia 
• Ventilatory support.

Hypotension: This is most common problem seen inbrainstem dead organ donors. This is commonly multifactorial, mainlydue to volume depletion and to a lesser extent impaired myocardialcontractility. The volume depletion is both 1) absolute, related totherapy for raised intracranial pressure; and 2) relative, related tothe loss of sympathetic tone. The latter is due to complete vasomotorcollapse with significant peripheral venous pooling.
Thedifferential diagnosis includes, hypovolemia, cardiac dysfunction,electrolyte abnormalities, and hypothermia and drug effect.

Invasive monitoring of arterial and central venous pressure should beinstituted. In the management of hypotension, it is important toremember that proper fluid management is the cornerstone of therapy. Ifpossible, the use of vaso-pressors should be minimized because of theirsplanchic vaso constrictive effects. All inotropes and vasopressorshave been used. The first choice is usually Dopamine, preferably at adose below 10mcg/kg/min. Dobutamine should be used for impairedmyocardial contractility; and Norepinephrine or Epinephrine for severesystemic vasodilation. If the patient has tachycardia, dopamine willcause further tachycardia and in these situations dobutamine is usefulas this will not increase the heart rate. Norepinephrine can be used inshort bursts to maintain the blood pressure. Sometimes all the threedrugs are used simultaneously to maintain an adequate pressure. Ifheart retrieval is contemplated for transplant, these ionotropes shouldbe controlled carefully and monitored.

Fluid resuscitation may require several liters of fluid. A combinationof crystalloids and colloids is used. Relying on urine output alone todetermine adequacy of fluid resuscitation is misleading because ofpolyuria due to diabetes insipidus. In donors who remain unstabledespite routine management, pulmonary artery catheterization may helpin determining the problem.

Arrhythmias: Hemodynamic instability can be pronouncedafter brainstem death with a spectrum of bradyarrhythmias andtachyarrhythmias Bradyarrhythmias occurring as part of the Cushingreflex, during coning, do not require treatment . Correctable factorslike acidosis, electrolyte abnormalities and inotrope- relatedarrhythmias should be treated. Thereafter, medications that possessrapid reversibility and a short half-life should be used. Atropine isineffective for bradyarrhythmias after brain death has occurred.

Hypoxia: This may be related to infections, collapse orpulmonary edema. The etiology of pulmonary edema may be cardiogenic,fluid overload, neurogenic or Adult Respiratory Distress Reproduction..This is treated by titrating the fractional inspired oxygenconcentrations (FiO2) and positive and expiratory pressure (PEEP).While high FiO2, greater than 0.6, increases the risk of oxygentoxicity; high PEEP>15cmH2O reduces cardiac output.

Ventilatory support: This is an essential part of thesupport of brainstem dead organ donors as they are apneic. Discontinuehyperventilation , which is likely to have been employed for control ofraised intracranial pressure. The partial pressure of CO2 should bemaintained in the normal range. This may require a considerablereduction in minute volume. Routine use of PEEP at 5 cm H2O inbrainstem dead organ donors is recommended to prevent microatelectosis.Airway pressures, i.e. the plateau pressures should be below 35cmH2O toreduce the risk barotrauma.

Renal support: If the urine output is less than1ml/kg/hr, despite adequate filling pressures and blood pressure, loopdiuretics or osmotic diuretics should be used to initiate diuresis.Polyuria, a frequent finding in brainstem dead organ donors, is due todiabetes insipidus. Other causes include osmotic diuersis due tomannitol or hyperglycemia and physiologic diuersis due to massive fluidresuscitation. Electrolyte abnormalities observed during diabetesinsipidus include hypernatremia, hypokalemia, hypocalcemia andhypomagnesemia.

Endocrine changes: Diabetes insipidus - Thisshould be suspected when urine volumes exceed 300ml/hr (or 7ml/kg/hr)in association with hypernatremia (Serum Sodium greater than 150mEq/l),elevated serum osmolality (>310mOsm/L) and a low urinary sodiumconcentration. Desmopressin (dDAVP) should be used in preference toVasopressin. The latter has undesirable splanchnic and renalvasoconstrictive effects. The dose is titrated to maintain urineoutputs of 1-2ml/kg/hr. usual dosages are Desmopressin 1-4 mcg every 8to 12 hours or Vasopressin 1-4 units/hr. One there is hyernatremia thereplacement intravenous fluids should contain free water, i.e. Dextroseand / or half strength (0.45) Normal saline.

Hyperglycemia - This is due to the administration ofglucose containing fluids, reduced insulin secretion and increasedlevels of catecholamines. Hyperglycemia results in an osmotic diuresisand electrolyte disturbances. Blood glucose levels should be controlledwith intravenous insulin infusion.
Other hormones - The use ofhormonal therapy, Thyroxine, tri-iodothyronine(T3), corticosteriods andinsulin, has been advocated to improve cardiovascular stability. Atpresent, such therapy is regarded as experimental.

MISCELLANEOUS PROBLEMS Infection -Systemicinfection is a relative contraindication to organ donation. Allunnecessary indwelling devices should be removed. All lines andcatheters must be inserted aseptically and meticulous care of dressingsand wounds is vital. Tracheal suction should be done with sterileprecautions. Appropriate samples from suspected sources of infectionshould be sent for culture and sensitivity. Treatment should beinitiated based on culture reports. Prophylactic antibiotics areindicated only immediately before organ retrieval.

Coagulopathy - Disseminated intravascularcoagulation is common in patients with traumatic head injuries. This isdue to the release of thromboplastin from the injured brain. If itresults in clinically significant mucocutaneous bleeding, treatmentwith appropriate blood components is required.

Hypothermia - Core temperature should be monitored usingrectal thermometers. The core temperature should be maintained above350C. After brain death, the body becomes poikilothermic because of theloss of central temperature control mechanisms. Treatment includes useof humidified and warmed ventilator gases ; warmed intravenous fluidsand blood products ; and heating blankets. Sometimes a hot blower next to the patient is the best solution to maintain the bodytemperature.

CONCLUSION:
A severe shortage of organs theworld over has led to increased pressure on the intensive care stafffor early identification of the brain dead donor and optimum managementof this condition. The diagnosis of brain death as per theTransplantation Human Organ Act is based as simple clinical bedsidetests. The passing of this Act in 1994 and its subsequent adaptation bymany Indian States has made it possible in India to use this pool ofpatients for organ retrieval and transplantation.