Brain DeathBrain Death

Nawal Salahuddin MD, FCCPNawal Salahuddin MD, FCCPAssociate ProfessorAssociate Professor

Section of Pulmonary & Critical Care Section of Pulmonary & Critical Care MedicineMedicine

AKUHAKUH

► ICUs sometimes create an amalgam of ICUs sometimes create an amalgam of Life-in-Death,Life-in-Death,

►A state of being unable to participate A state of being unable to participate in human life but also unable to diein human life but also unable to die

Historical perspective (1)Historical perspective (1)

► The traditional concept of death emphasized The traditional concept of death emphasized cessation of respirationcessation of respiration

► In 1978, Sweet stated in the New England In 1978, Sweet stated in the New England Journal of Medicine;Journal of Medicine;

““It is clear that a person is not dead unless his It is clear that a person is not dead unless his brain is dead. The time honored criteria of brain is dead. The time honored criteria of

the stoppage of the heart beat and the stoppage of the heart beat and circulation are indicative of death only when circulation are indicative of death only when

they cause the brain to die”they cause the brain to die”

Historical perspective (2)Historical perspective (2)

►Death is a loss of Cellular Function that Death is a loss of Cellular Function that leads to putrefactionleads to putrefaction

►Death is an Irreversible cessation of Death is an Irreversible cessation of the integrated functioning of the the integrated functioning of the organization as a wholeorganization as a whole

Historical perspective (3)Historical perspective (3)

►With organ transplantation, resuscitative With organ transplantation, resuscitative techniques (artificial cardiopulmonary support, techniques (artificial cardiopulmonary support, cryopreservation) the diagnosis of Brain Death cryopreservation) the diagnosis of Brain Death has become especially importanthas become especially important

► In 1981, the Uniform Determination of Death In 1981, the Uniform Determination of Death Act asserted the definition of Death as;Act asserted the definition of Death as;

““1. Irreversible cessation of circulatory and 1. Irreversible cessation of circulatory and respiratory functionsrespiratory functions

OROR2. Irreversible cessation of all functions of the 2. Irreversible cessation of all functions of the

entire brain, including the Brain Stem”entire brain, including the Brain Stem”

Pathophysiology:Pathophysiology: Relevent brainstem Relevent brainstem anatomyanatomy

►The primary Ventilatory Centre is located The primary Ventilatory Centre is located in the reticular core of the medulla in the reticular core of the medulla oblongata. oblongata.

►The circulatory system is controlled by The circulatory system is controlled by central neurons diffused throughout the central neurons diffused throughout the reticular core of the pons and medullareticular core of the pons and medulla

Pathophysiology:Pathophysiology: Relevent brainstem Relevent brainstem anatomyanatomy

►The pupillary reflexes are mediated The pupillary reflexes are mediated through the nuclei of cranial nerves II, through the nuclei of cranial nerves II, III in the midbrainIII in the midbrain

►The Doll’s eye (oculocephalic) reflex & The Doll’s eye (oculocephalic) reflex & cold calorics (vestibulo-ocular) reflexes cold calorics (vestibulo-ocular) reflexes are mediated by cranial nerves VIII, are mediated by cranial nerves VIII, II ,VI and the pontine reticular II ,VI and the pontine reticular formationformation

Pathophysiology:Pathophysiology: Relevant brainstem Relevant brainstem anatomyanatomy

►Why are these reflex arcs important?Why are these reflex arcs important?

►These cranial nerve nuclei lie next to the These cranial nerve nuclei lie next to the RAS, which spans the midbrain & pons. RAS, which spans the midbrain & pons.

►The RAS is essential for consciousness The RAS is essential for consciousness and is not directly testable. If the and is not directly testable. If the adjacent nerve nuclei are not adjacent nerve nuclei are not functioning there is no significant functioning there is no significant possibility that the RAS is intactpossibility that the RAS is intact

Causes of Brain DeathCauses of Brain Death

2 mechanisms;2 mechanisms;

►Global injury of the entire CNSGlobal injury of the entire CNS

Circulatory failure (cardiac arrest)Circulatory failure (cardiac arrest)

Respiratory failure (anoxia from, CO Respiratory failure (anoxia from, CO poisoning)poisoning)

► Focal injury to the CNSFocal injury to the CNS

Primary Injury trauma, ischemia, IC Primary Injury trauma, ischemia, IC heamorrhageheamorrhage

Secondary injury (herniation of brain stem)Secondary injury (herniation of brain stem)

Definitions (1)Definitions (1)

Brain Death is defined as “ the complete & Brain Death is defined as “ the complete & irreversible absence of all brain function”irreversible absence of all brain function”

Definitions (2)Definitions (2)

Important distinctions;Important distinctions;► ComaComa: Impaired consciousness either due to : Impaired consciousness either due to

impairment of the RAS or cortex. Reversibleimpairment of the RAS or cortex. Reversible► Persistent Vegetative statePersistent Vegetative state: Cortices failed, : Cortices failed,

brainstem functionsbrainstem functions► Locked in SyndromeLocked in Syndrome: Preserved upper : Preserved upper

brainstem functions (consciousness) preserved, brainstem functions (consciousness) preserved, lower brainstem impaired (respiration, lower brainstem impaired (respiration, circulation)circulation)

► Profound HypothermiaProfound Hypothermia: can have clinical : can have clinical manifestations similar to brain death. So brain manifestations similar to brain death. So brain death cannot be diagnosed unless the core death cannot be diagnosed unless the core temperature is temperature is ≥≥ 32 32ºº C C

►Brain Death implies failure of the Brain Brain Death implies failure of the Brain stem. stem.

►There may also be associated failure There may also be associated failure of cortical functioning that leads to of cortical functioning that leads to loss of integrative activity and loss of integrative activity and brainstem reflexesbrainstem reflexes

PrognosisPrognosis

Patients who fulfill criteria for brain death have;Patients who fulfill criteria for brain death have;

► NO PROSPECT OF SURVIVAL independent of NO PROSPECT OF SURVIVAL independent of artificial respiratory & circulatory support, artificial respiratory & circulatory support,

►NO PROSPECT OF RECOVERY of brain functionNO PROSPECT OF RECOVERY of brain function

►NO PROSPECT OF IMPROVEMENT even to a NO PROSPECT OF IMPROVEMENT even to a persistent vegetative state or comapersistent vegetative state or coma

Diagnosis of brain deathDiagnosis of brain death

►Clinical CriteriaClinical Criteria

►Confirmatory testingConfirmatory testing

EEGEEG Evoked responsesEvoked responses Measurement of blood flowMeasurement of blood flow

►CT/ MRICT/ MRI►AngiographyAngiography►Transcranial doppler ultrasoundTranscranial doppler ultrasound

Diagnosis of brain death:Diagnosis of brain death: Clinical Criteria Clinical Criteria (1)(1)

Two preconditions must be met ;

1. The cause of injury is known: there must be clear evidence of an acute, catastrophic, irreversible brain injury.

2. Reversible conditions that may obfuscate the clinical diagnosis of brain death must be excluded.

3. Body temperature must be greater than 32C, to rule out hypothermia.

4. There is no chance of drug intoxication or neuromuscular blockade.

5. The patient is not in shock.

Diagnosis of brain death:Diagnosis of brain death: Clinical Criteria Clinical Criteria (2)(2)

1. The patient does not respond to verbal or visual command.

2. The patient makes no movements, no spontaneous movements, or any movement induced by painful reflex.

3. The pupils are fixed and nonreactive.

4. The patient has no oculocephalic reflex. When the patient’s eyes are opened and the head is turned from side to side, the eyes remain fixed in their position. Alternatively, the oculovestibular reflex may be tested. The patient’s ear canal is inspected to ensure an intact tympanic membrane. While the eyes are held open, ice water is injected into the ear canal.

The eyes of a brain-dead patient remain fixed in their position.

Diagnosis of brain death:Diagnosis of brain death: Clinical Criteria Clinical Criteria (3)(3)

5. The patient has no corneal reflexes when a cotton swab is dragged across the cornea while the eye is held open.

6. The patient has no gag reflex. The movement of the breathing tube (in and out) or insertion of a smaller tube down the breathing tube does not elicit a reflex.

7. The patient has no spontaneous ventilation. The patient is temporarily removed from life support (the ventilator). With the cessation of breathing by the machine, the body immediately starts to build up metabolic waste of CO2 in the blood. When the CO2 level reaches 55 mm Hg, an active brain causes the patient to breathe spontaneously. A dead brain gives no response.

Diagnosis of brain death:Diagnosis of brain death:Clinical Criteria (4)Clinical Criteria (4)

If, after this extensive clinical examination, the patient shows no sign of neurologic function and the cause of the injury is known, the patient can be pronounced brain-dead.

more than one physician is required to make this pronouncement for brain death to become legal death.

Although the patient has a dead brain and dead brainstem, spinal cord reflexes (eg, a knee jerk) can sometimes be elicited. In some brain-dead patients, a short reflex movement may occur when the hand or foot is touched

Diagnosis of brain death: Diagnosis of brain death: Confirmatory testing (1)

All these tests measure cortical activity in some way.

Confirmatory tests are not generally required in the United States, but in several European, Central American, South American, and Asian countries, confirmatory testing is mandatory

Confirmatory testing(2): Electroencephalographic

recording

► Loss of bioelectrical brain activity as shown on the EEG (ie, isoelectric EEG) is a reliable confirmation of whole-brain death. Total electrical silence is not required for brain death.

► It is important to note that an isoelectric EEG can be obtained after drug intoxication, such as intoxication with barbiturates and residual electrical activity may persist after BSD

►Electrocerebral inactivity or electrocerebral silence is defined as no EEG activity above 2 mV/mm.

Confirmatory testing (3): Evoked responses

Brainstem auditory evoked potentials are signals generated at the level of the auditory nerves and brainstem in response to an acoustic stimulus.

Brainstem auditory evoked potentials consist of five identifiable waves. Wave I represents the vestibular nerve action potential; wave II, the vestibular and cochlear nerves; wave III, the lower pons; and waves IV and V, the upper pons and the midbrain The loss of waves III to V or II to V, or no reproducible brainstem auditory evoked potentials on both sides, is usually regarded as indicating BSD

Somatosensory evoked potentials are waves of neural activity generated from the neural structures along the afferent somatosensory pathways, which are generated after electrical stimulation of a peripheral nerve. The pathway starts at a peripheral nerve, then ascends by the brachial plexus, upper cervical cord, dorsal column nuclei, ventroposterior thalamus, and sensory cortex. Bilateral absence of specific waves following median nerve stimulation is consistent with brain death confirmatory laboratory finding

Confirmatory testing (4): Measurement of blood flow

Absent intracranial circulation indicates irreversible cerebral damage

Measurement of blood flowMeasurement of blood flow►AngiographyAngiography►CT/ MRICT/ MRI►Transcranial doppler ultrasoundTranscranial doppler ultrasound

1. Angiography.

• Absence of blood flow to the brain leads to destruction of brain tissue. The greatest advantage of angiography for the determination of brain death is that it is influenced neither by central nervous system– depressant drugs nor by hypothermia.

2. CT. Various CT techniques may be used, including CT angiography, CT perfusion,

and xenon-CT perfusion, to demonstrate absent or nonviable cortical blood flow

3. MRI. MRI and magnetic resonance angiography should be used with caution in

confirming brain death.

4. Tran cranial Doppler sonography. Transcranial Doppler sonography uses a 2-MHz ultrasonic probe affixed to

the temporal area, and the flow velocity of each of the major intracranial arteries may be measured.

In brain death, cerebral perfusion pressure approaches zero, and transcranial Doppler demonstrates systolic spikes; undetectable flow (i.e., no signal); or reversal of blood flow in diastole (i.e., to-and-fro or oscillating waveform) .These patterns were highly specific for brain death

Sedation & Analgesia Sedation & Analgesia in the ICUin the ICU

Nawal Salahuddin MD, FCCPNawal Salahuddin MD, FCCPAssociate ProfessorAssociate Professor

Section of Pulmonary & Critical Care Section of Pulmonary & Critical Care MedicineMedicine

AKUHAKUH

PAIN Control PAIN Control

►A sedated patient is not necessarily a A sedated patient is not necessarily a pain-free patientpain-free patient

►Sources of pain;Sources of pain;►Surgical incisions, traumaSurgical incisions, trauma► Intravenous lines, bed sores, endotracheal suctioningIntravenous lines, bed sores, endotracheal suctioning►Vertebral body fractures, arthritis, prolonged Vertebral body fractures, arthritis, prolonged

immobility immobility

►Pain is misinterpreted as agitationPain is misinterpreted as agitation

Adverse physiological effects of Adverse physiological effects of PAINPAIN

► Increased endogenous catecholaminesIncreased endogenous catecholamines

►Myocardial ischemiaMyocardial ischemia

►Hyper metabolic statesHyper metabolic states

►Sleep deprivation, agitation, anxiety, Sleep deprivation, agitation, anxiety, deliriumdelirium

Analgesic StrategiesAnalgesic Strategies

►Opiate receptors are found in the CNS & Opiate receptors are found in the CNS & PNS.PNS.

►Clinically important receptors are Clinically important receptors are designated designated µ & ĸµ & ĸ

►µ1 receptors mediate analgesia, µ2 µ1 receptors mediate analgesia, µ2 receptors mediate respiratory receptors mediate respiratory depression, nausea, vomiting, depression, nausea, vomiting, constipation, euphoriaconstipation, euphoria

Analgesics(3)Analgesics(3)

All opiates induce respiratory depression All opiates induce respiratory depression

►centrally mediated & dose dependentcentrally mediated & dose dependent

►Response to hypercapnia is reducedResponse to hypercapnia is reduced

►Ventilatory response to hypoxia is Ventilatory response to hypoxia is obliteratedobliterated

►These respiratory depressive effects are These respiratory depressive effects are used in the ICU to treat ventilator-patient used in the ICU to treat ventilator-patient dyssynchrony, dyspnea , coughingdyssynchrony, dyspnea , coughing

Analgesics(4)Analgesics(4)

Opiates have minimal heamodynamic Opiates have minimal heamodynamic effects in euvolemic patientseffects in euvolemic patients

Hypotension is seen in patients whose BP Hypotension is seen in patients whose BP is maintained by sympathetic is maintained by sympathetic compensationcompensation

Analgesics(5)Analgesics(5)

►Morphine-induced histamine release is Morphine-induced histamine release is rarely clinically important in the ICUrarely clinically important in the ICU

►Dependence & Withdrawal can be Dependence & Withdrawal can be seen with prolonged infusions seen with prolonged infusions

Analgesics (6)Analgesics (6)

►Drugs most commonly used;Drugs most commonly used;

►MorphineMorphine►FentanylFentanyl►RemifentanilRemifentanil►KetorolacKetorolac

Recommendations for analgesic Recommendations for analgesic use in the ICU (1)use in the ICU (1)

1. All critically ill patients should have the right to adequate analgesia and management of their pain.

2. Pain assessment and response to therapy should be performed regularly by using a scale appropriate to the patient population and systematically documented.

3. Patients who cannot communicate should be assessed through subjective observation of pain-related behaviors (movement, facial expression, and posturing) and physiological indicators (heart rate, blood pressure, and respiratory rate) and the change in these parameters following analgesic therapy.

Recommendations for analgesic Recommendations for analgesic use in the ICU (2)use in the ICU (2)

4. A therapeutic plan and goal of analgesia should be established for each patient and communicated to all caregivers to ensure consistent analgesic therapy.

5. If intravenous doses of an opioid analgesic are required, fentanyl, hydromorphone, and morphine are the recommended agents.

Recommendations for analgesic Recommendations for analgesic use in the ICU (3)use in the ICU (3)

6. Scheduled opioid doses or a continuous infusion is preferred over an “as needed” regimen to ensure consistent analgesia.

7. Fentanyl is preferred for a rapid onset of analgesia in acutely distressed patients.

8. Fentanyl or hydromorphone are preferred for patients with hemodynamic instability or renal insufficiency.

9. Morphine and hydromorphone are preferred for intermittent therapy because of their longer duration of effect.

Recommendations for analgesic Recommendations for analgesic use in the ICU (4)use in the ICU (4)

10. NSAIDs or acetaminophen may be used as adjuncts to opioids in selected patients.

11. Ketorolac therapy should be limited to a maximum of five days, with close monitoring for the development of renal insufficiency or gastrointestinal bleeding. Other NSAIDs may be used via the enteral route in appropriate patients.

Sedation:Sedation: Indications Indications

►AnxietyAnxiety

►facilitate nursing carefacilitate nursing care

►reduce Oxygen consumption & CO2 reduce Oxygen consumption & CO2 productionproduction

►When neuromuscular blockade is usedWhen neuromuscular blockade is used

Sedation:Sedation: Goals Goals

► Should be individualizedShould be individualized

► Sedation ScoresSedation Scores

Ramsay scaleRamsay scale

Sedation – Agitation scaleSedation – Agitation scale

Adaptation to ICU environment scaleAdaptation to ICU environment scale

Sedation:Sedation: Drugs (1) Drugs (1)

►Benzodiazepines act by potentiating the Benzodiazepines act by potentiating the GABA receptor mediated inhibition of the GABA receptor mediated inhibition of the CNSCNS

►GABA receptors act by regulating a GABA receptors act by regulating a chloride channel on the cell membranechloride channel on the cell membrane

►By increasing the intracellular flow of ClBy increasing the intracellular flow of Cl- -

neurons become hyperpolarized with a neurons become hyperpolarized with a higher threshold for excitabilityhigher threshold for excitability

Sedation:Sedation: Drugs (2) Drugs (2)

►All benzos are lipid soluble with a large All benzos are lipid soluble with a large volume of distributionvolume of distribution

►Duration of action after a bolus is Duration of action after a bolus is determined by the rate of determined by the rate of redistribution to the adipose tissuesredistribution to the adipose tissues

Sedation:Sedation: Propofol(1) Propofol(1)

►Propofol acts on the GABA receptor, Propofol acts on the GABA receptor, although the site of action on the although the site of action on the receptor is different from benzosreceptor is different from benzos

►Hydrophobic with high lipid solubility that Hydrophobic with high lipid solubility that allows for rapid crossing of the BBB and allows for rapid crossing of the BBB and redistribution to peripheral tissues…. redistribution to peripheral tissues…. Rapid onset and short duration of actionRapid onset and short duration of action

Sedation:Sedation: Propofol(2) Propofol(2)

► It causes depressed responsiveness, anxiolysis and It causes depressed responsiveness, anxiolysis and amnesiaamnesia

► Ventilatory depression & apnea. NOT an analgesicVentilatory depression & apnea. NOT an analgesic

► Profound hypotension due to dilation of venous Profound hypotension due to dilation of venous capacitance vessels & mild myocardial depressioncapacitance vessels & mild myocardial depression

► Hypertriglyceridemia; pancreatitisHypertriglyceridemia; pancreatitis

► ‘‘Propofol Infusion Syndrome’ : dysrhytmias, heart failure, Propofol Infusion Syndrome’ : dysrhytmias, heart failure, metabolic acidosis, hyperkalemia & rhabdomyolysis. metabolic acidosis, hyperkalemia & rhabdomyolysis. Associated with higher doses (> 80 mcg/kg/min.) or Associated with higher doses (> 80 mcg/kg/min.) or higher concentrations (2%)higher concentrations (2%)

► Not recommended in childrenNot recommended in children

Sedation:Sedation: Haloperidol Haloperidol

► Induce tranquility without respiratory depressionInduce tranquility without respiratory depression

► Antagonize basal ganglia dopamineAntagonize basal ganglia dopamine

►Doses of 1 – 10 mg. are used titrated to desired Doses of 1 – 10 mg. are used titrated to desired end – point. Onset 2 -5 min. , half life 2 hoursend – point. Onset 2 -5 min. , half life 2 hours

► Can prolong the QT interval on EKG, Neuroleptic Can prolong the QT interval on EKG, Neuroleptic Malignant Syndrome (lead-pipe rigidity, fever, Malignant Syndrome (lead-pipe rigidity, fever, mental status changes)mental status changes)

Recommendations for Sedative Recommendations for Sedative use in the ICU (1)use in the ICU (1)

1. Sedation of agitated critically ill patients should be started only after providing adequate analgesia and treating reversible physiological causes.

Recommendations for Sedative Recommendations for Sedative use in the ICU (2)use in the ICU (2)

2. A sedation goal or endpoint should be established and regularly redefined for each patient.

3. The use of a validated sedation assessment scale is recommended.

4. The titration of the sedative dose to a defined endpoint is recommended with systematic tapering of the dose or daily interruption with retitration to minimize prolonged sedative effects.

Recommendations for Sedative Recommendations for Sedative use in the ICU (3)use in the ICU (3)

5. Midazolam or diazepam should be used for rapid sedation of acutely agitated patients.

6. Midazolam is recommended for short-term use only, as it produces unpredictable awakening and time to extubation when infusions continue longer than 48–72 hours.

Recommendations for Sedative Recommendations for Sedative use in the ICU (4)use in the ICU (4)

7. Propofol is the preferred sedative when rapid awakening (e.g., for neurologic assessment or extubation) is important.

8. Triglyceride concentrations should be

monitored after two days of propofol infusion, and total caloric intake from lipids should be included in the nutrition support prescription.

Recommendations for Sedative Recommendations for Sedative use in the ICU (5)use in the ICU (5)

9. The potential for opioid, benzodiazepine, and propofol withdrawal should be considered after high doses or more than approximately seven days of continuous therapy.

Doses should be tapered systematically to prevent withdrawal symptoms.

Recommendations for Sedative Recommendations for Sedative use in the ICU (6)use in the ICU (6)

10. Haloperidol is the preferred agent for the treatment of delirium in critically ill patients.

11. Patients should be monitored for electrocardiographic changes (QT interval prolongation and arrhythmias) when receiving haloperidol.