NEUROSURGICAL ANAESTHESIA
Clinical neuroprotection Learning objectives
and secondary neuronal After reading this article, you should be able to:
injury mechanisms C outline the pathophysiology of secondary brain injury
C list the strategies for physiological neuroprotection
C list the drugs used and their mechanism of action for pharmaco-
Manni Waraich logical neuroprotection
Neeraja Ajayan
that can modify the cascade of events which would otherwise lead
to permanent tissue damage.1 This article focuses on the patho-
Abstract
physiological mechanism of secondary brain injury, various cere-
Acute brain injury triggers the ischaemic cascade, a series of
bral protection strategies, the current evidence-based guidelines
biochemical events at the cellular level, which leads to a loss of
pertinent to each strategy, and future directions.
integrity and function of the neurons, consequently decreasing the
chance of functional recovery. Neuroprotection refers to therapies
capable of mitigating the detrimental effects of secondary brain injury Secondary brain injury
by antagonizing and reversing the pathophysiological mechanism at
The most common factors leading to secondary brain injury are
multiple points, which would otherwise lead to irreversible brain
hypoxia and hypoperfusion, which lead to ischaemia, tissue
injury. Though several experimental pharmaceutical trials have
oedema and bloodebrain barrier (BBB) disruption (Table 1). All
been conducted with drugs acting at several focal points in the
these factors lead to increased intracranial pressure (ICP), further
ischaemic cascade, the results have been discouraging. Despite
reducing cerebral perfusion and setting up a vicious cycle of
this, in the last few decades, the implementation of guidelines
ischaemic insults. The biochemical and cellular events initiated
focusing on bedside practice of neuroprotective strategies saw sub-
during primary insult can progress to delayed secondary injury
stantial improvement in the outcomes of patients with acute cerebral
with long-lasting sequelae. The pathophysiological mechanisms
injury. This article delves into these strategies focusing on their
of secondary brain injury are shown in Figure 1.
mechanism of action, evidence-based practice and guidelines, and
also summarizes the novel therapies currently being evaluated.
Cerebral protection
Keywords Acute brain injury; ischaemic cascade; neuroprotection;
secondary brain injury; stroke; traumatic brain injury The primary treatment goal after an ABI is to prevent and treat
cerebral ischaemia, to prevent or minimize the degree of sec-
Royal College of Anaesthetists CPD Skills Framework: Neurology ondary cerebral damage and maximize the potential for neuro-
logical recovery. Cerebral protection involves providing the most
favourable internal milieu for the brain to ensure maximal
neurological recovery and optimal functioning as a long-term
Introduction objective. The therapeutic measures to achieve this goal may
Acute brain injury (ABI) is a leading cause of severe morbidity, be divided into physiological, pharmacological and surgical
disability and mortality with significant social and economic ram- treatments (Table 2).
ifications. Common conditions resulting in ABI are traumatic brain
injury (TBI), acute ischaemic stroke (AIS), haemorrhagic stroke, Physiological strategies for neuroprotection
which includes subarachnoid haemorrhage (SAH) and intracere-
Maintenance of oxygenation
bral haemorrhage (ICH), epilepsy and post-cardiac arrest. Primary
Oxygen is an essential substrate for mitochondrial respiration and
brain injury refers to the sudden and profound injury to the brain
energy production in the brain. A low local brain tissue oxygen
that is considered more or less complete at the time of the event and
tension (PbtO2) often indicates ongoing cerebral ischaemia.
is not amenable to therapeutic measures. Secondary brain injury
Hyperoxia can increase PbtO2, restore mitochondrial redox po-
refers to the pathological processes initiated at the time of injury but
tential, decrease ICP, restore aerobic metabolism, and improve
has delayed detrimental functional and structural sequelae. Early
pressure autoregulation. In the TBI patient cohort, PaO2 values of
neuroprotective strategies limit the progression to secondary brain
150e200 mmHg are associated with better 6-month functional
injury. Neuroprotection involves physiological, pharmacological
and cognitive outcome. However, excessive oxygen can result in
and surgical interventions initiated before the onset of ischaemia
the formation of reactive oxygen species, which consequently
activate inflammatory responses resulting in cerebral damage.
Though no specific value for oxygen tension is suggested as a
Manni Waraich FRCA EDIC FFICM is a Consultant in Neurocritical Care neurotoxic oxygen threshold, a study found that PaO2 >200 mmHg
at the National Hospital for Neurology and Neurosurgery, London, in patients with TBI was associated with 6-month mortality.
UK. Conflicts of interest: none declared.
Recommendations:
Neeraja Ajayan MD DM is a Senior Clinical Fellow in
Neuroanaesthesia at the National Hospital for Neurology and TBI: Hypoxaemia (PaO2 <8 kPa) is associated with a significant
Neurosurgery, London, UK. Conflicts of interest: none declared. increase in mortality in patients with severe TBI. Current
ANAESTHESIA AND INTENSIVE CARE MEDICINE 25:1 16 Ó 2023 Published by Elsevier Ltd.
, NEUROSURGICAL ANAESTHESIA
AIS: Though routine supplemental oxygen is not recommended for
Causes of secondary brain injury non-hypoxic patients with AIS, it should be provided to maintain
Extracranial causes Intracranial causes oxygen saturation >94%. Hyperbaric oxygen (HBO) is not recom-
mended unless the stroke was caused by air embolization.3
Hypoxia Haemorrhage
Hypotension C Extradural Arterial carbon dioxide control
Metabolic C Subdural The partial pressure of CO2 in arterial blood (PaCO2) is the most
C Hyponatraemia C Intracerebral potent vasomodulatory determinants of cerebral blood flow
C Hyperthermia C Intraventricular (CBF); between the range of 2.5e10 kPa, CBF changes propor-
C Hypoglycaemia/ C Subarachnoid tionately and linearly to PaCO2. In hypercapnia, a 1 kPa increase
hyperglycaemia in PaCO2 increases CBF by 25e35%, whereas in hypocapnia, a
Swelling 1 kPa decrease causes a concurrent decrease of CBF by 15%.
C Venous congestion/ While the response to changes in PaCO2 is prompt, this response
hyperaemia is not sustained long-term, wearing off after 6e12 hours of
C Oedema hypocapnia. Hypocapnia can induce cerebral ischaemia by ce-
Vasogenic rebral vasoconstriction, whereas hypercapnia, by vasodilation,
Cytotoxic can produce hyperaemia and thus increase ICP. Thus maintain-
Interstitial ing an optimum CO2 level is advised, and hypocapnia is only
Infection suggested as a temporizing measure for managing intracranial
C Meningitis hypertension.
C Brain abscess
Recommendations:
Infarction
TBI: Prolonged prophylactic hyperventilation with PaCO2 of
Table 1 <3.3 kPa is not recommended.4
guidelines suggest that a PaO2 >13 kPa should be targeted for AIS: Use of brief moderate hyperventilation (PaCO2 of 4e4.5 kPa)
TBI patients. Maintenance of a PaO2 target of 11e16 kPa is is suggested as a reasonable bridging treatment prior to definitive
currently recommended in the acute phase of ABI.2 management in patients with threatening brain swelling.3
Figure 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 25:1 17 Ó 2023 Published by Elsevier Ltd.
