Brain Resuscitation and

Protection
Mutiara Lirendra
 BRAIN
• Protection : theraputic • Resuscitation refers to
intervention to improve therapeutic interventions
neurologic outcome initiated after an ischemic
(maintain of cerebral event.
perfusion, systemic
hemodynamics, maintain • The goal is treatment of
adequate oxygenation and ischaemia and
ventilation) in patiens who attenuation of neuronal
will be at risk for cerebral injury.
ischaemia.
• The primary objective is
prevention of the deleterious
effects of ischemia. (prevent
further cerebral damage)
MONRO KILLIE DOCTRINE
Cerebral ischemia. Cerebral ischemia is defined as perfusion insufficient to provide the
supply of oxygen and nutrients needed for maintenance of neuronal metabolic integrity
(40% to 45% of total cerebral metabolic rate for oxygen consumption [CMRo2]) and
function (55% to 60% of CMRo2). It is assumed that a hierarchy of ischemic damage exists
in which neuronal function is abolished before cellular integrity is lost.
Clinical ischemia

Of all body organs, the brain is the most vulnerable to ischemia. Loss of consciousness
occurs within 15 seconds of cardiac arrest. Brain PCr becomes negligible within 1 minute.
Glucose and ATP stores are exhausted within 4 to 5 minutes. Critical levels for cerebral blood
flow (CBF), cerebral perfusion pressure (CPP, the difference between the mean arterial
pressure [MAP] and the intracranial pressure [ICP]), and the partial pressure of arterial
oxygen (Pao2) have been determined below which cerebral ischemia occurs (Figure -1) with
characteristic EEG changes.
Critical CBF is 18 to 20 mL/100 g of brain/minute. The penumbra is a hypoperfused region
that may remain viable depending on timely reperfusion. The EEG becomes isoelectric at a
CBF of 15 mL/100 g/minute. Metabolic failure occurs at a CBF of 10 mL/100 g/minute.
Critical CPP is 50 mm Hg in the normal individual.
Critical Pao2 is 30 to 35 mm Hg in healthy awake patients.
Reperfusion injury refers to damage that occurs after the restoration of cerebral perfusion.
An initial phase of hyperperfusion occurs, followed by a gradual decline in CBF referred to as
the no-reflow phenomenon. Hypoperfusion results from thromboxane-induced
vasoconstriction and platelet aggregation, impaired red cell deformability, tissue edema, and
the persistence of abnormal Ca levels. In addition, intracellular acidosis, continued EAA,
neurotransmitter and catecholamine release, and free radical formation contribute to
delayed neuronal damage. This no-reflow phenomenon can last for up to 24 hours.
Brain Protection
Nonpharmacologic treatment

Hypothermia decreases both metabolic and functional activities of the brain.

Avoidance of hyperglycemia. The current recommendation is to keep the serum
glucose below 150 mg/dL. Serum glucose is monitored frequently, and hypoglycemia
(serum glucose below 60 mg/dL) is scrupulously avoided.

Avoidance of hypotension, hypoxia, and hypercapnia. The surgeon may request

induced hypertension to improve CPP during temporary proximal occlusion of the
parent vessel before definitive aneurysmal clip-ligation. Induced hypotension can be
detrimental in patients at risk for vasospasm.

Hemodilution to a hematocrit of 32% to 34% increases CBF by decreasing viscosity,

thereby improving oxygen delivery.
Normalization of increased ICP is achieved through moderate hyperventilation
(partial pressure of arterial carbon dioxide [Paco2] of 25 to 30 mm Hg), head
elevation to 30° in the neutral position, mannitol and/or furosemide diuresis,
cerebrospinal fluid (CSF) drainage via ventriculostomy, limited fluid restriction, and
barbiturate coma in patients unresponsive to these techniques.

Correction of acidosis and electrolyte imbalance including Na and K abnormalities

should be prompt.
Pharmacologic treatment

Barbiturates and erythropoietin remain the only drugs shown to be effective for
pharmacologic cerebral protection against ischemic damage in humans.

Thiopental, a potent cerebrovasoconstrictor, decreases CMRo2, CBF, cerebral blood

volume (CBV), and ICP. CO2 reactivity is preserved.
(1) The primary mechanism of protection involves a reduction in CMRo2 of up to 55%
to 60% at which point the EEG becomes isoelectric. Further reduction in CMRo2
confers no additional protection. Thiopental's beneficial effects are thus limited to
preservation of neuronal function.
(2) Thiopental may cause an inverse steal phenomenon whereby vasoconstriction in
normal tissue improves perfusion of ischemic areas that are unable to vasoconstrict.
(3) Thiopental is an effective anticonvulsant.
(4) Other possible mechanisms include gamma-aminobutyric acid (GABA) agonism,
free radical scavenging, membrane stabilization, NMDA antagonism, Ca channel
blockade, and maintenance of protein synthesis.
(5) Thiopental does not improve outcome in global or complete ischemia after cardiac
arrest.
(6) The thiopental dose in focal ischemia is 3 to 5 mg/kg every 5 to 10 minutes titrated
to EEG burst suppression up to a total of 15 to 20 mg/kg. Maintenance of
cardiovascular stability could determine the rate of administration.
 Pentobarbital's cerebral effects are similar to those of thiopental. Pentobarbital is
longer acting (t1/2 = 30 hours). The current clinical indication for pentobarbital is
limited to barbiturate coma in patients who have increased ICP resistant to standard
therapy. A loading dose of 3 to 10 mg/kg over 0.5 to 3 hours is given, followed by a
maintenance infusion of 0.5 to 3 mg/kg/hour titrated to EEG burst suppression. The
currently accepted therapeutic plasma concentration of pentobarbital is 2.5 to 4 mg/dL.

Methohexital, a short-acting barbiturate, can precipitate seizures in individuals who

have epilepsy. Methohexital is useful for the induction of anesthesia for brief
procedures in which seizure activity is desired (e.g., electroconvulsive therapy [ECT] and
epilepsy surgery).
Etomidate is a short-acting imidazole compound which, like
barbiturates, causes cerebral vasoconstriction.
Electroencephalographic burst suppression occurs with higher
doses. Most studies have not shown beneficial effects after
cerebral ischemia. The administration of induction doses of
etomidate has been associated with cerebral desaturation.
(1) Etomidate reduces CMRo2 (by as much as 50%), CBF, and ICP
while maintaining cardiovascular stability and CPP. CO2 reactivity
is preserved.
(2) Etomidate can cause adrenocortical suppression for up to 24
hours after a single induction dose (inhibition of 11 beta-
hydroxylase). This may be of clinical concern when etomidate is
used as an infusion, especially in patients who are not
concomitantly receiving steroids.
(3) Myoclonic activity has been reported with etomidate, and
seizures may occur.
(4) Side effects of etomidate include nausea, vomiting, and pain
on injection.
Propofol (2, 6-diisopropylphenol), a short-acting induction drug also used to maintain
anesthesia, has a cerebrovascular profile similar to that of barbiturates. Beneficial effects
of propofol after brain ischemia have not been demonstrated.
(1) Propofol decreases CMRo2, ICP, and CBF (via cerebrovasoconstriction). Hemodynamic
depression decreases CPP more than with barbiturates.
(2) Burst suppression on EEG occurs with larger doses of propofol.
(3) Propofol may decrease postoperative nausea and vomiting.

Benzodiazepines, sedative-hypnotic drugs most commonly used as anesthetic adjuncts,

stimulate the inhibitory neurotransmitter GABA and decrease CMRo2 and CBF while
preserving CO2 reactivity. ICP may be decreased slightly. Benzodiazepines are potent
anticonvulsants. They also produce amnesia and anxiolysis.
(1) Diazepam is used as an oral premedicant at a dose of 0.1 to 0.25 mg/kg.
(2) Midazolam has a t1/2 of 1 to 4 hours. The intravenous dose of midazolam for
premedication is 0.5 to 2.5 mg up to 0.1 mg/kg. Excessive sedation and the possibility
of hypoventilation-induced hypercapnia should be avoided in patients at risk for
increased ICP. Midazolam in larger doses may have beneficial effects after brain
ischemia.
(3) Lorazepam is also an effective premedicant in doses of either 0.5 to 4 mg by mouth or
2 to 4 mg intravenously (i.v.) or intramuscularly (i.m.). Like diazepam, its use is limited in
neurosurgery by a t1/2 of 10 to 20 hours.
Opioids produce sedation and analgesia and cause a reduction in neurotransmitter release
while preserving autoregulation, CO2 reactivity, and cardiovascular stability. CBF, CMRo2, and
ICP are unchanged or slightly decreased. Delta waves are seen on EEG; burst suppression does
not occur.
(1) Morphine is a potent analgesic with relatively poor central nervous system (CNS)
penetration. Commonly used for postoperative analgesia in neurosurgical patients, morphine
can cause hypotension secondary to histamine release.
(2) Meperidine may increase the heart rate because of its atropine-like structure and effect.
Normeperidine is a metabolite of meperidine that can cause CNS excitation and seizures.
(3) Fentanyl is 100 times more potent than morphine. Fentanyl does not cause histamine
release, is shorter acting than morphine, and decreases ICP and CBV slightly while maintaining
CPP.
(4) Sufentanil is more potent than fentanyl and may increase ICP (via vasodilatation) in patients
who have severe head trauma. The use of another opioid should be considered in such
instances.
(5) Remifentanil is a very short-acting (t1/2 = 3 to 10 minutes) esterase-metabolized opioid that
compared favorably to fentanyl in reduction of ICP and CBV and maintenance of CPP in a recent
clinical trial.
Ca channel-blocking drugs should theoretically provide cerebral protection by vasodilatation
and diminution of the consequences of Ca influx.
(1) Nimodipine decreases vasospasm after aneurysmal subarachnoid hemorrhage (SAH).
Nimodipine may increase CBF to underperfused areas by redistribution through an
inverse steal effect. The dose of nimodipine, presently available only in oral form, is 60
mg every 4 hours for 21 days after SAH. Hypotension may occur with the administration
of nimodipine.
(2) Nicardipine, available for intravenous administration, has decreased ischemic
damage in animal studies, but clinical trials have not shown improved neurologic
outcome after ischemia.
Ketamine, a phencyclidine derivative, produces dissociative anesthesia.
(1) Ketamine markedly increases ICP and CBF (60%) via cerebrovasodilatation. The
CMRo2 is unchanged or slightly increased. Autoregulation is abolished.
(2) Seizures can occur.
(3) Although it is a noncompetitive NMDA antagonist, ketamine is not recommended for
patients who have intracranial pathology.
Local anesthetics are commonly used as adjuvants in neuroanesthesia.
(1) Lidocaine's clinical effects are determined by the dose. When administered after EEG
isoelectricity induced by pentobarbital, lidocaine may decrease CMRo2 by an additional
15% to 20%. At clinically recommended doses (1.5 mg/kg), lidocaine may reduce
ischemic damage. Lidocaine also blunts the hemodynamic response to intubation by
increasing anesthetic depth. At lower doses, lidocaine possesses anticonvulsant activity
and can be used as ancillary therapy for status epilepticus. At toxic doses, lidocaine
causes seizures.
Brain Resuscitation
 Brain Resuscitation
1. Head of bed elevation : The treatment of any patient with TBI should
begin with elevation of the head 30 degrees in an attempt to reduce
cerebral edema and augment venous drainage. Elevating the head from
0 to 30 degrees has been shown to significantly lower mean ICP from 20
to 14 mmHg with no significant change in the CPP or CBF (2). In patients
with suspected or documented spine injury, this is best achieved by
placing the patient’s bed in the Reverse Trendelenburg position.
2. Hypertonic vs isotonic resuscitation
Resuscitation using hypertonic saline solutions (HSS) results in a restoration of
intravascular volume, improving tissue perfusion, while producing
extravascular dehydration, decreasing tissue edema and vasospasm in critical
areas such as the brain. This allows restoration of MAP and resultant
improvement in CPP without worsening in cerebral edema (a problem
associated with hypotonic and isotonic solutions). The exact mechanism by
which HSS acts on the injured brain has yet to be fully elucidated. In a meta-
analysis of 6 prospective, randomized trials evaluating HSS for the
resuscitation of hypotensive TBI patient, patients who received HSS were
twice as likely to survive as those who received saline (p< 90 mmHg) TBI
patients 1) the use of HSS was safe; there were no cases of intracranial
bleeding or central pontine myelinolysis 2) hypotensive trauma patients with
a GCS ≤ 8 had significant improvement in survival to discharge with HSS as
compared with NS or LR; and 3) dextran had no additional benefit of HSS
alone (6-9).
3. Mannitol
Mannitol at a dose of 0.25-1 g/kg body weight has been shown to be effective for control of
raised intracranial pressure in TBI patients. Maximal effect was seen 40 minutes after the
start of the 20 minute infusion, and effects lasted up to 100 minutes

4.Post Traumatic seizure prophylaxis

Several studies have shown that TBI patients with no history of seizure disorder or witnessed
posttraumatic seizure activity are still at increased risk of developing post-traumatic seizures
if they have one or more of the following risk factors: GCS < 10, cortical confusion, depressed
skull fracture. SDH EDH, intracerebral hematoma, penetrating head wound, seizure within 24
hours of injury. Seizure prophylaxis reduce risk of seizure in the early period (up to 7 days
after injury). Should be discontinue after 7 days in the absence of seizure activity.

5.No Steroid : Multiple prospective, randomized studies have demonstrated no benefit to ICP
lowering or improvement in outcome with the use of steroids in TBI patients

6. ICP Monitor
ICP monitoring should be performed for patients who, after resuscitation, have a GCS ≤ 8 in
the following scenarios: • Abnormal admission computed tomography (CT) scan of the head •
Normal admission CT scan of the head AND one of the following: o Age > 40 years o
Unilateral or bilateral motor posturing o Systemic hypotension (systolic blood pressure < 90
mmHg)
7
. Sedation : The goal of sedative therapy in patients with TBI is to prevent secondary
neuronal damage due to increases in ICP or inadequate CPP.
Propofol is a sedative-hypnotic agent that has a favorable pharmacokinetic profile and
beneficial effects on cerebral metabolic rate, making it an effective drug for routine sedation
as well as controlling intracranial hypertension following brain injury. Its short half-life not
only allows for ease of titration, but also for rapid awakening when neurological evaluation
is necessary. Propofol is eliminated by hepatic conjugation to inactive metabolites and its
pharmacokinetics are not altered in the presence of renal or hepatic disease. Its beneficial
effects on the cerebrovasculature are mediated via dose-dependant decreases in cerebral
blood flow and metabolic rate

8. CT Scan
CT scan abnormalities are infrequently found in patients with minor head injuries (GCS = 15)
and a loss of consciousness (6-9%). However, in patients with TBI (GCS ≤ 8) they are much
more common (68- 94%) (23,26). The absence of abnormalities on CT scan at admission
does not preclude the occurrence of raised ICP and significant new lesions may develop in
40% of patients (23). The presence on CT scan of one or more of the following has been
associated with an 84-100% chance of having an unfavorable outcome: compressed cisterns,
midline shift > 5mm, multiple unilateral or bilateral contusions, and extracerebral hematoma
with swelling (23,26)
 References
• Neuroanesthesia cerebral protection and
resuscitation. Elias S 2009-CNS Clinic
• ATLS Ninth Edition 2014
• Brain Injury Resuscitation. 2009. Orlando
University
• NEUROMONITORING &CEREBRAL
PROTECTION STRATEGIES By; Dr Noor Raihan
bt Hasbullah Moderator; Dr Wan Mohd
Nazaruddin Wan Hassan. 2009