Ebook Neurocritical care A guide to practical management Part 2

8

Seizures on the Adult Intensive Care Unit
Morgan Feely and Nicola Cooper

Key Points
1. Seizures are commonly encountered in the ICU.
They can be provoked by acute illness, medicines, or alcohol
2. The causes of seizures tend to differ in different
age groups
3. Tonic-clonic status epilepticus carries a significant mortality
4. Early and effective treatment is essential
5. EEG can distinguish between tonic-clonic status
and non-epileptic attack disorder (NEAD) and
diagnose nonconvulsive status
6. Long-term treatment of epilepsy depends on the
type of seizures and the characteristics of the
patient – involve an expert

Introduction
Seizures are commonly encountered in the critical care
setting, either as a primary event in epilepsy or as a
symptom of acute illness, for example, brain injury.
This chapter discusses the recognition and management of the different types of seizure disorders encountered in the intensive care unit (ICU), which are:
· Status epilepticus
· Seizures occurring as part of an acute illness or
following neurosurgery
· Incidental seizures in a patient with epilepsy
· Non-epileptic attack disorder (NEAD)
(“pseudostatus”)

A brief overview of seizures is essential before
discussing specific disorders. Viewed as a single
condition, epilepsy is the most common serious
neurological condition, affecting 1:130 people in
the United Kingdom. Epilepsy refers to a tendency
to have recurring, unprovoked seizures.

Types of Seizure
Seizures (as opposed to epilepsy) are far more
common in the general population and can be provoked by prescribed medication, benzodiazepine
or alcohol withdrawal, metabolic disturbances, and
brain injury.
Figure 8.1 outlines the different types of common
seizures that occur. When a physician sees a patient
who has had a seizure, three questions must be
considered:
1. Was this episode a seizure?
As many as 25% of patients diagnosed as having
epilepsy in the United Kingdom do not have the
condition at all. Seizures are diagnosed almost
entirely using a detailed eye-witness account,
and inexperienced doctors generally do not ask
the right questions, nor recognize important
clues.
2. Were there any obvious provoking factors?
Medicines and alcohol are the most common
factors that provoke seizures.



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M. Feely and N. Cooper
SEIZURES

Provoked (tonic clonic)

Due to acute illness
(tonic-clonic or partial seizures)
Part of epilepsy
(recognised or unrecognised)

GENERALISED EPILEPSY
(Mostly idiopathic; young people with structurally
normal brains )

•

LOCATION-RELATED EPILEPSY
(Mostly symptomatic; people with a focal
brain abnormalit y)

•

Absences (brief episodes of detachment,

easily missed)

Partial seizures +/- secondary
generalization (tonic-clonic seizures)

• Myoclonic jerks
• Tonic-clonic seizures

Simple partial seizures

Complex partial seizures

- Conscious

- Impaired consciousness

- Focal rigidity/jerking

- Unresponsive/glazed

- Abnormal sensations

- Automatisms
- Speech disturbance
- Focal rigidity or jerking

All seizure types can occur as status epilepticus

Figure 8.1.  Types of seizures.

3. Does this patient have previously unrecognized
epilepsy?
A tonic-clonic seizure can be the presenting symptom
in people with previously unrecognized epilepsy.
A detailed history should be taken to uncover previous myoclonic, absence or partial seizures. In one
study, 74% of patients presenting with a first tonicclonic seizure had experienced seizures before.

Types of Seizures
The main causes of seizures differ with age. In the
teens to early twenties, alcohol use commonly

triggers seizures in patients who have a common
form of idiopathic generalized epilepsy called
“juvenile myoclonic epilepsy.” The patient often
experiences myoclonic jerks, usually first thing in
the morning, and may think these are normal. The
condition is especially sensitive to triggers such as
sleep deprivation, alcohol, and stress.
Between the late twenties and the fifties, excessive alcohol is the commonest cause of first tonicclonic seizures in men. These patients do not have
epilepsy but are experiencing provoked seizures.
Although in many cases this occurs during withdrawal or after a binge, it is distinct from overt
alcohol-withdrawal syndrome. Other conditions


8.  Seizures on the Adult Intensive Care Unit

such as primary brain tumors and metabolic disorders should be excluded.
Over the age of fifty, cerebrovascular disease is
the commonest cause of epilepsy and the incidence
of epilepsy is now highest in the over-eighties. A

previous stroke or transient ischemic attack (TIA)
may cause “location-related” epilepsy and partial
seizures. Epilepsy is frequently unrecognized in the
elderly. Dementias, secondary brain tumors and
metabolic disorders are other causes of seizures in
this age group.
Location-related epilepsy is the commonest form of
epilepsy across all ages, which is why it is important
to ask about other seizure types when a patient
presents with tonic-clonic seizures. Causes include
mesial temporal sclerosis (following childhood
febrile convulsions), subarachnoid hemorrhage,
stroke, and traumatic brain injury.

Imaging and EEG
Imaging (CT or MRI) is carried out to find any
underlying cause for seizures. A focal lesion points
toward location-related epilepsy, even if there is no
clinical history to suggest focal seizures. Patients
suffering from refractory epilepsy, with a focal
abnormality on imaging and an anatomically corresponding abnormality on EEG during an attack,
may benefit from epilepsy surgery.
An MRI is superior to CT in detecting small
tumors, arteriovenous malformations, areas of sclerosis, and post-traumatic changes. Although young
people with idiopathic generalized epilepsy or obviously provoked seizures may not require imaging,
patients with location-related epilepsy, refractory epilepsy, or status epilepticus should always be scanned.
Patients with location-related epilepsy should go on
to have an MRI scan if their CT scan is normal.
The electroencephalogram (EEG) is used to help
classify an epilepsy syndrome, establish a suspected

clinical diagnosis, and distinguish between epilepsy
and NEAD. It is also of use in the diagnosis of
herpes simplex encephalitis. The EEG is affected by
the patient’s state of arousal, medication, and other
diseases.
Normal background EEG activity consists of alpha
and occasional beta waves, theta waves in light sleep
and delta waves in deep sleep. Generalized slow
waves are seen in drowsy or sedated patients and can
be caused by drugs, metabolic disturbances, stroke,

71

encephalitis, or a post-ictal state. Focal slow waves can
be a non-specific indicator of a focal brain abnormality such as stroke. Spikes (narrow upward deflections)
are caused by the simultaneous depolarization of a
large number of neurons and occur in seizures.
Half of patients with clinical epilepsy will have
a normal EEG between attacks. Serial EEGs or one
recorded in a condition of sleep deprivation
increase the chance of yielding abnormalities.
Twenty-four hour EEGs and video-EEG telemetry
are used in difficult cases.
In the critical care setting, the principle uses of the EEG are:
1. To distinguish between tonic-clonic status epilepticus and NEAD
2. To confirm or exclude a diagnosis of nonconvulsive status
epilepticus

An EEG during an attack is the gold standard in
the differentiation between tonic-clonic status

and NEAD. The absence of post-ictal slowing after
a prolonged attack adds weight to the diagnosis of
NEAD. Post-ictal slowing, however, can be caused by
benzodiazepines, and therefore does not necessarily
indicate a seizure.
Nonconvulsive status epilepticus should be considered in patients with
unexplained states of semiconsciousness or coma.

Anti-Epileptic Drugs
The choice of anti-epileptic drug (AED) depends
on the type of epilepsy and the characteristics of
the patient. Figure 8.2 shows the commonly used
first-line AEDs.
AEDs have several different mechanisms of
action, and some have more than one. Some AEDs
worsen one seizure type while benefiting another.
For example, lamotrigine is effective for tonicclonic seizures but can be ineffective or even exacerbate myoclonic jerks.
Checking drug levels may be of value in the
context of overdose or to assess a patient’s compliance with medication, but is rarely helpful when
adjusting dosages. The one exception is phenytoin, which has a narrow therapeutic index; levels
should be monitored in status epilepticus.

Status Epilepticus
The three commonest seizure types presenting as
status epilepticus are tonic-clonic status, focal


72

M. Feely and N. Cooper

Primary generalised epilepsy

Location-related epilepsy

Sodium valproate (Epilim) – IV/PO

Carbemazepine (Tegretol) PO/PR

Lamotrigine (Lamictal) – PO

Sodium valproate –IV/PO

Levetiracetam (Keppra)* – IV/PO

Lamotrigine
Levetiracetam (Keppra) – IV/PO
Phenytoin (Epanutin)** - IV/PO

*Although levetiracetam was not included as 1st line therapy in the 2004 NICE
guidelines (it did not have a monotherapy license at the time), many neurologists
are now using it as first choice.
**Different preparations of the same drug are not always equivalent and a change
may affect epilepsy control, particularly in the case of phenytoin.

Figure 8.2.  Commonly used first line AEDs and routes of dosing.

motor status (epilepsia partialis continua), and
non-convulsive status. Status epilepticus is defined
as a continuous seizure, or serial seizures without
recovery in between, lasting for 30  min or more.

Care givers of patients with epilepsy are advised to
give “rescue” medication, for example, buccal
midazolam, if a tonic-clonic seizure lasts for
5 minutes or more.
· Status epilepticus is the first presentation of
epilepsy in 12% of patients.
· The overall mortality of status epilepticus in
studies is around 23%, lower in younger patients,
and higher in the over sixties.
· The underlying cause and duration of status epilepticus are the main determinants of outcome.
Tonic-clonic status epilepticus occurs in stages
(Fig. 8.3). During early status, the systemic and cerebral metabolic consequences of status are still contained by homeostatic mechanisms. In established
status, the homeostatic mechanisms start to fail, the
patient decompensates in terms of vital signs, and
brain oxygenation and metabolism starts to fall. In
refractory status, there is a high risk of hypoxic
brain injury. The condition becomes progressively
harder to treat and motor activity declines so that
only subtle twitches around the eyes and mouth
may be visible. Subtle tonic-clonic status epilepticus,
commonly encountered in the elderly, carries a very
high mortality.
In established or refractory status, the task of
ICU staff is to:

· Provide supportive care
· Ensure appropriate treatment for seizures is given
· Ask if there is something more than status
epilepticus going on
Tonic-clonic status epilepticus causes significant

physiological compromise and supportive care starts
with the basic assessment and management of
Airway, Breathing, Circulation and Disability, whilst
treatment is initiated. Further supportive care on
ICU consists of ventilation, cardiovascular support,
and correction of metabolic abnormalities. Systemic
complications of status epilepticus include dehydration, pyrexia, arrhythmias, hyperkalemia, and rhabdomyolysis (see Fig. 8.4) and will require appropriate
intervention. IV thiamine should be given if alcohol
withdrawal is suspected. Muscle relaxants are usually
avoided so that seizures can be monitored. However,
if they are required to facilitate gas exchange or
control the lactic acidosis caused by recurrent seizures, then continuous EEG monitoring (e.g., CSA,
CFAM) should be used wherever possible.
Possible reasons for failure to terminate seizure
activity in status epilepticus include:
· If diazepam was used rather than lorazepam
(shorter duration of action)
· Failure to initiate additional therapy in early
status
· Using inadequate doses of phenytoin or anesthetic drugs in refractory status. Aim for phenytoin levels at the high end of the normal range,
before adding another drug


8.  Seizures on the Adult Intensive Care Unit
•
•
•

73

Airway, Breathing, Circulation, Disability
Check blood glucose
Give thiamine or pyridoxine if appropriate

Pre-status: A phase of escalating seizures lasting hours or days.
• Buccal

Midazolam (5-10mg) or oral Clobazam (10-20mg/day)

Early status: Seizure or serial seizures lasting up to 30 minutes.
Use one of the following IV benzodiazepines. 65% chance of terminating SE.
• Lorazepam (1st choice): 2-4mg; long duration of action, recurrent seizures
less likely.
• Midazolam: 0.05-0.2mg / kg; short action, rapid metabolism, best choice
for continuous benzodiazepine infusion.
NB. Doses may need to be reduced in the elderly. Additional therapy must be
started at this point to prevent further seizures.

Established status: 30-60 minutes
• Phenytoin 15-20mg / kg IV @ 50mg / min, or
• Fosphenytoin 15-20mg / kg IV / IM @ 150mg / min
NB Both require continuous ECG monitoring
If seizures continue, administer additional phenytoin or fosphenytoin 5-10mg/kg and
check levels.
Refractory status: Seizures lasting > 1 hour
Several options: ICU care required for ventilatory support and invasive
monitoring
Use continuous EEG monitoring if available
•
•

•
•

Propofol: 2mg / kg bolus, 150-200mcg / kg / min infusion, or
Thiopental: 5-10mg / kg bolus, 1-10mg / kg / hr infusion, or
Midazolam: 0.2mg / kg bolus, 0.1-0.2mg / kg / hr infusion
Valproate: 400-800mg / kg IV bolus may be added (if phenytoin levels ok)1

NB: deep sedation is recommended for at least 12 hours before reducing and
looking for evidence of seizure activity, ideally using an EEG for guidance. Ensure
adequate levels of anticonvulsants for chronic seizure control. Haemodialysis
may be helpful in cases of drug-induced status (especially antibiotics,
theophylline).
If seizures continue after a period of deep sedation despite adequate
anticonvulsant drug levels, additional agents such as Phenobarbital or levetiracetam may be
considered.

Figure 8.3.  Stages and treatment of tonic-clonic status epilepticus.

· Not using deep barbiturate or propofol sedation
for a minimum of 12  h (ideally with EEG
monitoring)
· Incorrect diagnosis (e.g., NEAD)
Continued seizures and myoclonic jerking occurring
early after a hypoxic brain injury are frequently associated with a very poor prognosis. Hui et al. reported

1

a series of 18 patients who developed postanoxic
myoclonic status following a cardiac arrest. The

myoclonus developed a mean of 11.7  h after the
arrest and lasted a mean of 60.5 h. Sixteen patients
died and the remainder were left vegetative or highly
dependant. As well as being distressing for the
patient’s family, myoclonic status can be very difficult to control. Agents such clonazepam or sodium

Levetiracetam is gaining popularity as adjunctive therapy and is available in both oral and IV preparations


74

M. Feely and N. Cooper
Metabolic
• Respiratory and metabolic acidosis
• Hypoglycemia
• Hyperkalemia
• Rhabdomyolysis

after neurosurgery). Treatment is essentially the
same, except that oral clobazam is the preferred
benzodiazepine as it is less likely to reduce the conscious level or cause respiratory depression.
Non-convulsive status epilepticus is underrecognized.

• Dehydration
• Increased ADH secretion
Autonomic
• Fever
• Hypertension or hypotension
• Cardiac arrhythmias
• Urinary retention

Others
• Leucocytosis
• Aspiration pneumonia
• Venous thromboembolism
• Trauma

Figure 8.4.  Systemic complications of tonic-clonic status epilepticus.

valproate have been traditionally used, although
newer agents such as as levetiracetam have been
tried with some success. Continued epileptic seizures following a hypoxic injury can also be difficult
to treat and are often associated with a bad outcome.
The seizures should be treated according to the
status epilepitcus algorithm, and serial EEG examiWhenever seizure control is difficult, it is sensible to seek expert help
from a neurologist at an early stage

nations may be required. Wherever possible, it is
sensible to render the patient seizure free for a period
of 24–48 h before making prognostic decisions.
In addition, status epilepticus can be a symptom
of another illness, and a thorough evaluation to
look for an underlying cause (e.g. infection) is
always required.
Focal motor status epilepticus (epilepsia partialis
continua) is manifested by a continuous jerking of
one side of the body. This patient is usually conscious and signs may be subtle, for example, twitching of the corner of the mouth. Focal seizures
can spread, leading to a reduced conscious level or
a tonic-clonic seizure. Causes include structural
brain lesions, hyperosmolar non-ketotic hyperglycemia, and penicillin therapy in the presence of a
local breakdown in the blood–brain barrier (e.g.,

Case Histories
1. A 30-year-old lady who was 32 weeks pregnant
was admitted to the delivery suite following a
tonic-clonic seizure. She was known to have
primary generalized epilepsy and was usually
fit and well, apart from a recent urinary tract
infection. Following her tonic-clonic seizure she
had an altered conscious level for 24 h. Her eyes
were open and she spontaneously moved all
four limbs, but she did not speak and appeared
“glazed.” An EEG confirmed absence status; she
was given intravenous lorazepam and she then
woke up, asking what had happened.
2. An 80-year-old man, known to have epilepsy
following a small stroke, was admitted with
severe sepsis. He was successfully resuscitated,
but 24  h later was still unconscious. His relatives had noticed jaw twitching and occasional
jerking of his right arm throughout the day.
An EEG confirmed nonconvulsive status
In a case of coma without an obvious cause, an EEG will exclude nonconvulsive status.

e­ pilepticus, which was treated with intravenous
lorazepam and phenytoin.

Seizures Occurring as Part of an Acute
Illness or Following Neurosurgery
Seizures occur as part of many acute illnesses,
especially metabolic disorders (e.g., hypoglycemia, hyponatremia) and brain diseases (e.g.,
meningo-encephalitis, subarachnoid hemorrhage). Acutely ill patients presenting with seizures require careful evaluation, and consideration

should be given to performing a lumbar puncture. Seizures can also be difficult to control in
patients with epilepsy if there is a concurrent
illness that reduces the seizure threshold, for
example, hypocalcemia or hypothyroidism. Tonicclonic seizures affect ventilation and some


8.  Seizures on the Adult Intensive Care Unit

patients with severe chronic lung disease may
develop acute respiratory failure and may require
mechanical ventilation.
The prevention and early treatment of seizures
is important following neurosurgery, because
seizures can precipitate serious complications,
including secondary intracranial bleeding, hypoxia,
aspiration and raised intracranial pressure. Seizures
can be provoked by hyponatremia, acidosis, alcohol
withdrawal, hypoxemia, sepsis, steroid therapy, or
a postoperative hematoma.
In the United Kingdom, it is not common practice to give prophylactic AEDs to patients after neurosurgery or following traumatic brain injury or
subarachnoid hemorrhage. Early postoperative seizures (within 24  h) may be considered provoked
seizures rather than a manifestation of epilepsy,
and do not necessarily require ongoing treatment.
Seizures occurring later than this indicate a structural brain lesion and may need treatment.Although
phenytoin is used acutely, patients should normally
be discharged on an alternative drug. Its narrow
therapeutic index and unpleasant long-term side
effects (e.g., gum hypertrophy and hirsutism) make
it an unsuitable first-line drug for most people.

Case History
A 60-year-old man on the neurosurgical HDU had
had a very stormy postoperative course and was
making a slow recovery. He had a low albumin and
was receiving phenytoin via a nasogastric tube.
Despite several low levels and subsequent dose adjustments, he continued to have seizures. Low albumin
makes it difficult to interpret the levels of highly
protein-bound drugs such as phenytoin. The patient
was switched to valproate and his seizures stopped.

Incidental Seizures in a Patient with
Epilepsy
Since epilepsy is a common neurological condition,
many patients with epilepsy present for surgery or
to critical care. Almost any acute illness can precipitate seizures. Patients should be maintained on
their usual AED, by an alternative route if necessary,
at all times. If a seizure occurs because treatment
was omitted, the patient will not be allowed to drive
for one year. The other important consideration is

75

to avoid provoking factors, including commonly
prescribed medications, that lower the seizure
threshold, for example, ciprofloxacin, tramadol,
antipsychotics, antihistamines, antimalarials,
baclofen, bupropion (zyban), and theo-phyllines.

Non-epileptic Attack Disorder
(“pseudostatus”)

NEAD accounts for a significant number of admissions to ICU for “status epilepticus.” Distinguishing
true tonic-clonic status from NEAD can be difficult.
Features of NEAD include fluctuating thrashing
activity, back arching, eyes screwed shut, hyperventilation with normal SpO2, and rapid recovery despite
a prolonged seizure. Prolactin level is an unreliable
test to distinguish tonic-clonic seizures from NEAD.
In about one third of cases of NEAD, the patient
also has epilepsy. NEAD commonly occurs in
young adults with a history of psychological
trauma or social problems, and is rare in the
elderly. A normal EEG during the attack almost
always confirms the diagnosis. If in doubt, treat for
tonic-clonic status and get expert help.
Many patients with NEAD genuinely believe the
attacks are real. In our experience, explaining that
these attacks are a genuine illness, but not due to
epilepsy, and thus require different treatment, is the
best way to explain the diagnosis.

Further Reading
Guberman A, Bruni J (1999) Essentials of clinical epilepsy. Butterworth Heinemann, Boston, MA
Hui A, Cheng C, Lam A et al (2005) Prognosis following
postanoxic myoclonus status epilepticus. Eur Neurol
54:10–13
Manford M (2003) Practical guide to epilepsy. Butterworth Heinemann, Boston, MA
NICE 2004 guidelines: The diagnosis and management
of the epilepsies in adults and children in primary
and secondary care. www.nice.nhs.uk/nicemedia/
pdf/CG020fullguideline.pdf
Panayiotopoulos C (2002) A clinical guide to epileptic

syndromes and their treatment. Bladon Medical
Publishing, Oxfordshire, UK
Shorvon S (1994) Status epilepticus – its clinical features
and treatment in children and adults. Cambridge
University Press, UK
Walker M (2005) Clinical review. Status epilepticus: an
evidence based guide. BMJ 331:673–77


9

Non-Neurological Complications
of Brain Injury
John P. Adams

Key Points
1. Medical complications are now recognized as
significant contributors to patient outcome
after severe neurological injury
2. Respiratory complications may account for up
to 50% of deaths following brain injury
3. Neurogenic pulmonary edema (NPE) requires
aggressive management with positive pressure
ventilation and careful restoration of the systemic circulating volume
4. Patients with NPE and myocardial stunning
often appear moribund, but have a good chance
of rapid recovery if appropriately managed
5. Patients with severe cardiac dysfunction after
brain injury require invasive cardiovascular
monitoring (e.g., pulmonary artery catheter) to

accurately guide therapy
6. Cerebral salt wasting is common after subarachnoid hemorrhage (SAH), and must be
distinguished from SIADH.
Medical complications are now recognized as
significant contributors to patient outcome after
severe neurological injury. They may arise as a
direct effect of the injury or as a consequence of
its treatment. Early studies in patients with subarachnoid hemorrhage (SAH) focused on two
main complications: neurogenic pulmonary edema
(NPE) and “myocardial stunning.” It is now clear
that, individuals suffering from other types of
neurological insult, including traumatic brain



injury, are also susceptible to these life-threatening medical complications and indeed, many other
organ systems can be involved. The etiology of
these complications is still poorly understood and
the management of such conditions is often poorly
described in the literature. This chapter aims to
examine the current evidence base and suggests
some practical solutions for the management of
these problems.
One study of over 450 patients with SAH found
that nearly all the patients had one or more
medical complication, and classified this as severe
in 40%(Solenski et al. 1995). Twenty-three percent
of all deaths were attributed to medical complications, 19% to the primary bleed, 22% to re-bleeding,
and 23% to vasospasm. Eighty-three percent of
those who died had a life-threatening complication compared to 30% of the survivors. Half of the

“medical” deaths were from pulmonary complications and a poor GCS at presentation, not surprisingly, seemed to correlate with a higher degree of
respiratory dysfunction. Table  9.1 outlines the
relative frequencies of the medical complications
in the study.
In another series of 242 patients with SAH
(Gruber et  al. 1999), medical complications were
again commonplace with 81% of patients developing dysfunction of at least one non-neurological
organ system, and 26% developing organ system
failure. Non-neurological organ dysfunction correlated with severity of the SAH. Mortality was
31% for SAH and single non-neurological organ

77


J.P. Adams

78
Table 9.1.  Relative frequencies of medical complications in patients
with SAH (Solenski et al. 1995)
Complication

Frequency (%)

Anemia
Hypertension
Arrhythmia
Pulmonary oedema
Pneumonia
Hepatic dysfunction
Coagulopathy

Renal dysfunction
Thrombocytopenia
Electrolyte disturbance

37
36
35
23
22
24
 4
 7
 4
16

failure, 91% with two organ failure, and 100%
when three or more organs were involved.
Non-neurological organ system dysfunction is
also prevalent in traumatic brain injury (TBI).
Zygun et al. studied 209 patients with severe TBI
and found that 89% developed non-neurological
organ system dysfunction, with 35% having overt
organ failure (Zygun et al. 2005). Respiratory dysfunction was commonly implicated, occurring in
23% of patients. Non-neurological organ dysfunction was independently associated with mortality
and Glasgow Outcome Score, with mortality rising
sharply with each sequential organ failure.

Respiratory System
Respiratory dysfunction is the commonest medical
complication in the brain-injured patient, and may

account for up to 50% of deaths after brain injury.
The type of respiratory problem and its treatment
may be different between different categories of brain
injury. Respiratory failure is significantly associated with an increase in ICU stay and a higher risk
of vasospasm after SAH (Friedman et al. 2003).
There are three main causes of respiratory
dysfunction in the brain-injured patient (Pelosi
et al. 2005):
1. Structural parenchymal abnormalities
These are the commonest reason for respiratory
insufficiency in the brain-injured patient. Hypoventilation and hyperventilation are common after
brain injury and when associated with poor cough
and retention of secretions can lead to atelectasis
and consolidation. Pneumothorax or rib fractures

following direct trauma may also lead to respiratory embarrassment. Release of both brain and
systemic inflammatory mediators after brain
injury can lead to peripheral organ dysfunction.
Pulmonary aspiration can also cause a systemic
inflammatory response. Additionally, treatment of
impaired gas exchange with invasive ventilation
can cause barotrauma and volutrauma, which in
turn may trigger the release of pulmonary
cytokines (Pelosi et al. 2005).
Brain injury is usually followed by intense
sympathetic hyperactivity with high levels of
circulating catecholamines. Besides producing
hypertension and tachycardia, they may also have
effects on the pulmonary circulation with increases
in alveolar capillary barrier permeability and pulmonary lymph flow (Pelosi et al. 2005).

Brain-injured patients are at particular risk for
the development of Ventilator-Associated Pneumonia (VAP) (Sirvent et al. 2000; Ewig et al. 1999).
It is classified as “early” if it occurs within the first
four days of ICU admission and the usual responsible
organisms are Staphylococcal aureus, Hemophilus
influenzae and Streptococcus pneumoniae. After
4 days it is termed “late” and is usually caused by
Pseudomonas aeruginosa, Enterobacteriaceae and
Acinetobacter species (Pelosi et  al. 2005). Risk
factors are outlined in Table 9.2.
2. Ventilation–Perfusion mismatch
Many brain-injured patients have moderate to
severe hypoxemia without radiographic evidence
of interstitial or alveolar edema. It may be caused
by ventilation–perfusion mismatch with suggested
mechanisms including redistribution of pulmonary
blood flow mediated by the hypothalamus, pulmonary microembolisms leading to an increase in
dead space, and depletion of surfactant (Pelosi
et al. 2005; Schumacker et al. 1979).
Table 9.2.  Risk factors for Ventilator-Associated pneumonia
Risk factors for VAP in brain-injured patients
Altered GCS
Aspiration
Emergency intubation
IPPV >3 days
Re-intubation
Age >60 years
Supine position
Co-existing disease
Prior antibiotic use

9.  Non-Neurological Complications of Brain Injury

79

Figure 9.1.  Chest x-ray of a patient with acute aneurysmal SAH showing diffuse bilateral infiltrates consistent with neurogenic pulmonary edema (NPE).

3. Neurogenic Pulmonary Edema

Etiology:

In the 1960s, Simmons reported that 85% of combat
soldiers dying of isolated severe head injury demonstrated alveolar edema, hemorrhage, and congestion which were not seen in those with chest
trauma (Simmons et al. 1969). Rogers subsequently
showed that 32% of patients dying at the scene of
an accident with head injury had NPE (Rogers
et al. 1995).
Onset is commonly within 4 h of the initial cerebral insult and 90% will have diffuse bilateral infiltrates on the CXR (see Fig. 9.1). Mortality is high
(up to 10%) but survivors usually recover very
quickly with appropriate intervention. In SAH,
NPE is associated with increasing age and poor
WFNS grade (Solenski et al. 1995). It is commonly
seen at presentation or at the time of intervention
but can be seen up to 14 days after the initial insult.
It is not significantly associated with triple H therapy
(aggressive fluid loading), cerebral angiography,
ECG changes or pre-existing cardiorespiratory
disease (Solenski et al. 1995; Macmillan et al. 2002).

Neurogenic pulmonary edema has a different
etiology to acute lung injury (ALI) following an
inflammatory insult, although brain injury (especially SAH) can trigger a systemic response, which
in turn leads to ALI (Macmillan et  al. 2002).
Neurogenic pulmonary edema requires a normal
circulating volume to occur, as blood is shunted
from the systemic circulation to increase the pulmonary vascular volume. It seems that a massive
catecholamine surge leads to a and b adrenoceptor
activation and cardiac injury resulting in increased
transpulmonary pressures and pulmonary edema
(Macmillan et  al. 2002; Davidson and Charuzi
1973). A massive, but not necessarily prolonged
surge in pulmonary artery pressure (PAP) leads
to an increase in extra vascular lung water
(EVLW), which causes a reduction in compliance
and an increase in the alveolar–arterial (A–a)
oxygen difference (Davidson and Charuzi 1973;
Touho et al. 1989). Although hydrostatic mechanisms
appear to be the common pathophysiological


80

pathway in the development of NPE, some patients
exhibit permeability edema with high protein
content edema fluid (Smith and Matthay 1997).
This may result from an increase in pulmonary
capillary volume and pressure causing a disruption of the basement membrane (West and MathieuCostello 1992) or possibly by an increase in
pulmonary capillary permeability, secondary to
the release of brain cytokines or adhesion molecules. After SAH, concentrations of epinephrine,

norepinephrine, and dopamine can reach 1200,
145, and 35 times the normal limits and can remain
at increased levels in the circulation for up to 10
days (Graf and Rossi 1978; Naredi et al. 2000).
Diagnosis:
A recent study of 16 patients with SAH and NPE
showed that the typical cardiovascular profile was
that of normal blood pressure, reduced cardiac
output and left ventricular stroke work index
(LVSWI), variable pulmonary capillary wedge
pressure (PCWP), bilateral diffuse infiltrates on
CXR, hypoxemia, and markedly elevated pulmonary
vascular resistance(Deehan and Grant 1996). These
findings imply both cardiac and pulmonary components. In brain injury, EVLW appears to have
little correlation with PCWP (Touho et  al. 1989).
Diagnosis of NPE can be difficult and is essentially
clinical together with the exclusion of other possibilities such as ALI (e.g., following aspiration at
the time of injury). Onset is usually shortly after
the initial insult, or on the day of surgical or radiological intervention (Macmillan et al. 2002). Rapidly
progressive hypoxemia is accompanied by diffuse
bilateral infiltrates on the CXR together with the
typical physiological abnormalities described
earlier. It tends to resolve quickly with positive
pressure ventilation with high PEEP and careful
restoration of the systemic volume, but those cases
with protein-rich edema fluid may resolve more
slowly or progress to an ARDS-like picture. A pulmonary artery catheter or pulse contour analysis
device will help with the initial diagnosis and subsequent resuscitation.
Treatment:
Treatment is essentially supportive. Usual strategies for treating cardiac failure-induced pulmonary edema include positive pressure ventilation

and diuretics, but systemic overload is not the

J.P. Adams

cause of NPE. Blood has been shunted from the
systemic to the pulmonary circulation, rendering
the patient acutely hypovolaemic. Therefore,
careful volume resuscitation with colloid boluses
against a measurable end point such as PCWP
may be required. The brain-injured patient with
NPE will almost always need intubation with IPPV,
and high levels of oxygen and PEEP are often
required. The cardiac output may require augmentation with inotropic agents such as dobutamine or milrinone, and in severe cases, epinephrine. Pressor agents such as norepinephrine or
phenylephrine are also frequently used in an
attempt to maintain an adequate blood pressure.
Although these patients often appear moribund with
critical oxygenation and seemingly intractable hypotension, it is vital that they are managed aggressively
by appropriately trained staff, as the physiological
abnormalities are often short-lived with a good
chance of a favorable outcome (Parr et al. 1996).
Prevention:
In theory, some protection from pulmonary and
cardiac complications following brain injury may be
possible if the patient could be shielded from the
catecholamine storm (Macmillan et al. 2002).Animal
studies have shown that pulmonary edema does not
occur when the cervical cord is transected and that
a-adrenoceptor blockade with phenoxybenzamine
prevents death and NPE in rabbits infused with
epinephrine (Siwadlowski et al. 1970). One human

study demonstrated a reduction in cardiac injury in
patients with SAH who had received a- and b-adrenoceptor blockade with propranolol and phentolamine (Neil-Dwyer et al. 1978).
Magnesium also merits further investigation
and research as it inhibits catecholamine release
and reduces vasospasm (Macmillan et  al. 2002).
However, it may reduce MAP and hence CPP.

Ventilating the Patient with Brain Injury
The ventilatory management of patients with
acute severe brain injury remains a significant
challenge. Because respiratory dysfunction plays
such an important role in outcome of brain injury,
prevention is extremely important. The main goals
are to prevent collapse and consolidation, prevent
lung infections, and to accelerate weaning from
IPPV as soon as possible (Pelosi et  al. 2005).


9.  Non-Neurological Complications of Brain Injury

However, this must be balanced against the need
to optimize cerebral hemodynamics by improving
oxygenation and maintaining normocapnia, whilst
minimizing intrathoracic pressure. Unfortunately,
the high tidal volumes and low levels of PEEP
required to match the needs of the cerebral circulation may induce or exacerbate ALI. Additionally,
the need for sedation to facilitate ventilation significantly complicates monitoring neurologically
injured patients. Subtle alterations in cognition,
indicative of the onset of delayed ischemia following a SAH, will be inevitably missed in sedated
and ventilated patients. Sedation may also have an

adverse effect upon blood pressure in such
patients. Therefore, one option for the provision
of advanced respiratory care, especially in SAH
patients, is early tracheostomy removing any need
for sedation.
1. Prevention of collapse and consolidation:
Progressive collapse can be reduced by the application
of IPPV with moderate levels of PEEP and early
use of recruitment maneuvers. A recent study on
the use of an open-lung approach in neurosurgical
patients showed improvement in severe respiratory failure without negative effects on cerebral
physiology (Wolf et al. 2002). Although widely discouraged, the prone position has been found to
improve oxygenation with minimal effects on ICP
and CBF (Reinprecht et al. 2003).
Careful fluid balance is essential. ICP-targeted protocols appear to reduce the need for fluid as compared to CPP-driven regimes, and are associated with
less respiratory dysfunction and better neurological
outcomes (York et al. 2000; Contant et al. 2001).
Interestingly, the use of antisympathetic drugs
(clonidine) and selective b1 adrenergic blocking
agents have been associated with better respiratory
and neurological outcome (Asgeirsson et al. 1995).
2. Prevention of lung infection
a) Prophylactic antibiotics cannot be currently
recommended
b) Selective decontamination of the digestive tract
is controversial and not widely practiced.
c) The patient should be nursed 30° upright
whenever possible.
d) Regular oropharyngeal suction reduces upper
airway contamination and reduces the incidence of VAP. One strategy to reduce VAP from

81

pooled secretions has been to perform conti­
uous aspiration of subglottic secretions (CASS)
using a specially designed endotracheal tube.
The tube contains a separate dorsal lumen
ending in the subglottic space just above highvolume low-pressure cuff. Fluid can be drained
along this channel with suction. In clincial
studies the incidence of VAP fell from 29 to
13% with intermittent drainage and 32 to 18%
with continuous drainage (Valles et  al. 1995;
Kollef et al. 1999; Shorr and O’Malley 2001).
e) Early use of enteral nutrition
f) Standards of hygiene, for example, hand
washing
3. Accelerated weaning
a) Aggressive chest physiotherapy (caution
with high ICP levels)
b) Positioning and regular turning
c) Fiberoptic bronchoscopy to remove deep
secretions (clinical data scanty)
d) Early tracheostomy

Cardiovascular System
The patient with acute brain injury frequently has
evidence of cardiovascular impairment. This may
range from minor ECG changes through to malignant dysrhythmias and life-threatening ventricular dysfunction.

ECG Changes

ECG changes are extremely common after brain
injury and are almost universal in patients suffering SAH (Brouwers et  al. 1989) (see Fig.  9.2).
Almost any disturbance is possible, but common
findings are ST depression, T wave inversion,
prominent U waves, and prolonged QT interval
(Cropp and Manning 1960; Shuster 1960; Galloon
et  al. 1972). The changes may mimic an acute
myocardial infarction (Cropp and Manning 1960)
and may be accompanied by rises in cardiac
enzymes, although post-mortem studies suggest
that the coronary arteries are usually normal
(Hammermeister and Reichenbach 1969). Subendocardial ischemia and focal myocardial
necrosis are the usual pathological findings


82

J.P. Adams

Figure 9.2.  Marked inferior and lateral ST segment changes in a patient following an acute aneurysmal SAH.

(Hammermeister and Reichenbach 1969; Doshi
and Neil-Dwyer 1980). Atrial and ventricular
dysrhythmias are seen in over 30% of SAH
patients, and are said to be clinically important
in about 5% (Frontera et al. 2008). They are associated with a worse outcome and an increase in
the length of hospital stay. ECG changes may
persist for up to six weeks after the initial brain
injury, but usually resolve completely.
The ECG changes are thought to occur as a

result of an increase in sympathetic activity following posterior hypothalamic stress at the time
of brain injury (Macmillan et al. 2002). A massive
surge in catecholamines occurs and is thought to
cause damage to the heart by either a direct toxic
effect or by increasing afterload. There appears
to be little consistency between ECG abnormalities and the presence of raised serum cardiac
enzymes or mechanical hypokinesis on echocardiography (Rudehill et al. 1982). The presence of
minor ECG changes alone should not delay
definitive treatment, but surgery should be
delayed when major ECG abnormalities are associated with raised cardiac enzymes or echo
hypokinesis, as the risk of malignant dysrhythmias is high.

Cardiac Enzymes
Serum markers of cardiac injury are often raised
after brain injury, especially SAH. Troponin I may
be elevated in more than 20% of cases, but not all
of these will have a wall motion abnormality on
echocardiography (Horowitz et al. 1998). CK-MB
is raised in an even greater number of patients but
does not correlate with ECG changes (Rudehill
et al. 1982), although its presence may be associated with an increase risk of vasospasm.

Hypertension
Hypertension is common after brain injury, and
should not be treated unless severe. Indeed, it may
be required for therapeutic purposes in patients
with symptomatic vasospasm or those at a high
risk of vasospasm (e.g., after aneurysm clipping
in SAH). Simple interventions such as providing
adequate analgesia should be tried before commencing antihypertensive treatment. If the systolic

blood pressure is consistently raised above
180 mmHg and the patient’s usual antihypertensive
regime has been recommenced, treatment may be
warranted. Labetalol has the advantage of lowering


9.  Non-Neurological Complications of Brain Injury

BP whilst having little effect on cerebral blood flow
(CBF) or ICP, whereas hydralazine and sodium
nitroprusside may increase both CBF and ICP.
Check with the Regional Neurosurgical Center for
advice on acceptable BP parameters.

Ventricular Dysfunction
The concept of the “stunned myocardium” after
brain injury is well-recognized but its etiology is still
poorly understood and its treatment has received
little clinical focus in the literature. Sudden onset of
(usually) hypotensive ventricular failure with or
without pulmonary edema has been frequently
reported after brain injury, and again a massive
surge in catecholamine is thought to be responsible
(Macmillan et  al. 2002). It is difficult to know why
catecholamines cause the initial disturbance in cardiac
function yet are often required in its subsequent
treatment. It is probably a consequence of the initial
huge catecholamine surge and the subsequent receptor down regulation. Echocardiography is the usual
first-line investigation and the whole spectrum of
systolic and diastolic dysfunction may be encountered, including a relatively newly recognized cardiomyopathy characterized by apical and midsegment stunning with preserved basal function

(Tako-tsubo cardiomyopathy) (Das et  al. 2009).
Hypokinesia, reduced ejection fraction, and perfusion abnormalities have also been demonstrated
by thallium scanning and nucleotide ventriculography (Szabo et al. 1993). Use of more advanced monitoring techniques such as a pulmonary artery
catheter are recommended as any combination of
ventricular disturbance and pulmonary artery pressure abnormalities are possible and can change
markedly with time. Esophageal doppler monitoring
is often employed, although this will not give any
information about the pulmonary circulation. Newer
monitoring modalities such as pulse contour analysis
can provide additional information such as estimates
of extravascular lung water, and may prove useful.
Recommendations for treatment of ventricular
dysfunction in acute brain injury are difficult to
make because of the wide spectrum of pathophy­
siological events that may be occurring and constantly changing. Almost every combination and
vasopressor has been tried with varying degree of
success. Many clinicians would favor dobutamine

83

as opposed to epinephrine in cases of hypotensive
heart failure where LVSWI is reduced. The phosphodiesterase inhibitor milrinone is becoming
increasingly popular and it seems to be useful in
cases where systolic function is severely depressed
but blood pressure and vascular resistance are preserved (Naidech et  al. 2005). In addition, where
severe myocardial “stunning” has occurred the
combination of milrinone and vasopressin seems
to be particularly effective (Yeh et al. 2003). When
NPE is also present, accurate assessment of systemic
volume status with invasive monitoring (e.g., pulmonary artery catheter) is essential. The initial catecholamine surge forces blood from the systemic to

the pulmonary circulation rendering the patient
acutely hypovolemic. Carefully administered fluid
boluses may be more appropriate than the usually
prescribed diuretics in this instance (Macmillan
et al. 2002).
Despite the fact the patient may appear moribund,
aggressive treatment strategies should be adopted,
as myocardial dysfunction is often short-lived and
normal pre-morbid cardiac function is usually
restored. The clinical picture may change rapidly,
and the attending physician must be ready to adapt
their treatment strategy to match the individual’s
unique requirements.
On a separate note, functional adrenal insufficiency appears to be relatively common after brain
injury (Bernard et al. 2006); patients with hemodynamic instability (in particular, increasing
vasopressor requirements) should have a short
synacthen test, with physiological replacement of
steroids if the response is poor.

Water and Electrolyte Disturbance
About 60% of patients in a comatose state for more
than 24 h will develop some degree of electrolyte
disturbance, secondary to the disease process itself
or its treatment (Arango and Andrews 2001).
Hyponatremia
This is the commonest electrolyte abnormality in
brain injury. The stress response leads to an increased
secretion of ADH and aldosterone, which increase
water reabsorption to produce a relative excess in
total body water(Arango and Andrews 2001).

J.P. Adams

84

The syndrome of inappropriate antidiuretic
hormone secretion (SIADH) is probably the best
recognized cause of significant hyponatremia. Its
many causes include raised ICP, IPPV, pneumonia,
and basal skull fractures. It is characterized by
hyponatremia, plasma hypotonicity, high urine
Na+ concentration (>20 mmol/L) and extracellular volume expansion. It is treated with fluid
restriction (typically 1–1.5l/day) and sometimes
demeclocycline (an ADH antagonist). Hypertonic
saline solutions should only be used for severe
symptomatic hyponatremia. The plasma [Na+]
should only rise by 0.5 mmol/h.
More recently, it has been recognized that cerebral salt wasting syndrome (CSWS) is a more
common cause of hyponatraemia in brain injury
than SIADH. The two conditions can be difficult
to distinguish. CSWS is characterized by severe
renal salt wasting, hyponatremia, severe serum
hypo-osmolality, high urine osmolality and crucially,
extracellular volume contraction. Other clinical
markers that support a diagnosis of CWSW include
orthostatic changes in pulse and BP, dry mucous
membranes, and negative fluid balance on the flow
charts. CSWS is commonly associated with SAH,
TBI, cerebral tumors, CNS infections, and AV malformations. It is probably caused by the release of

brain natruiretic peptide (BNP) which generates a
failure of sodium transport at the renal tubules,
leading to the loss of serum sodium and vascular
volume. A reduction in intravascular volume is a
powerful stimulus for ADH secretion, so in these
circumstances ADH is secreted appropriately and
a hyponatremic state is maintained (Arango and
Andrews 2001). BNP may be released in response
to the massive sympathetic outflow that is seen in
conditions such as SAH as it is known to antagonize the adrenergic effects on both the systemic
and pulmonary circulations. It may help to protect
against NPE and cardiac stunning, but at the risk
of hyponatremia and volume contraction, and the
consequent risk of cerebral infarction. CSWS is
managed by sodium and volume replacement and
occasionally fludrocortisone (controversial).
Calculation of Na+ replacement in a cerebral salt
wasting state
For example, 80 kg patient, plasma Na+ 125 mmol/L,
urine Na+ 40 mmol/L, urine output 6000 mL/day
AIM: Increase plasma Na+ from 125 to 135 mmol/L
over 24h

1. Calculate Na+ deficit:
0.6 × weight × ([Na] goal (mmol/L)−[Na] actual
(mmol/L)) = 0.6 × 80 × (135–125) = 480 mmol
2. Calculate on-going Na+ losses:
Urine output = 6  L/day with 40  mmol Na+/L
∴240 mmol Na+ being lost in the urine/day.
Normal daily Na+ requirements: Approximately

100mmol (0.7–1.4mmol/kg/day)
Replacement over 24h: 480 + 240 + 100 = 820 mmol
Na±
This is equivalent to 2733 mL of hypertonic 1.8%
NaCl = 113 mL/h
(1000 mL 1.8% NaCl contains 300 mmol Na+)
Clearly, renal sodium loss may change over time,
and it is therefore vital that plasma and urine
sodium concentrations are regularly measured,
and new calculations performed to avoid overly
rapid correction of the deficit (this can lead to
central pontine demyelination which is irreversible!).
In particular, fludrocortisone may dramatically
reduce renal Na+ loss, thereby reducing the amount
needed to be replaced hourly.
Hypernatremia
The frequent use of osmotic and loop diuretics in
the brain-inured patient makes hypernatremia a
relatively common finding. It can be exaggerated
by high caloric enteral feeds, the use of phenytoin
(ADH inhibition), and inadequate use of IV fluids
because of concerns about raised ICP (Arango
and Andrews 2001). Mild elevations in plasma
Na+ are often left untreated since they may help to
minimize vasogenic edema and hence ICP. Aggressive reduction of plasma Na+ may lead to cerebral
edema.
Of particular interest is diabetes insipidus which
can occur following pituitary surgery and in many
other neurosurgical conditions such as intracranial hypertension, SAH, and brainstem death.
A relative or complete lack of ADH results in loss

of large volumes of dilute urine with the rapid
development of hypernatremia, hypovolemia, and
plasma hyperosmolality. Diagnosis is made by the
detection of high plasma osmolality coupled with
low urinary osmolality. Treatment is with arginine
vasopressin (DDAVP, 0.5–1mcg IV boluses repeated
as necessary) and hypotonic fluids (e.g., 0.45%
NaCl + colloid boluses).


9.  Non-Neurological Complications of Brain Injury

Hypokalemia
Factors such as iatrogenic hyperventilation, use of
osmotic and loop diuretics, therapeutic hyothermia
and increased levels of aldosterone make this a
common finding in the setting of acute brain injury.
Hyperkalemia is rare, and nearly always associated
with renal failure (Arango and Andrews 2001).

Anemia and Coagulation Disorders
Anemia is common after brain injury (Solenski
et  al. 1995), with causes including repeated iatrogenic sampling, hemodilution, and other associated
injuries. In contrast to other groups of intensivecare patients, recent work suggests that patients
with SAH may benefit from higher hemoglobin
levels as this may be associated with better outcomes
(Naidech et al. 2007).
Severe head injury often produces a hypercoagulable state that is frequently followed by enhanced
fibrinolytic activity. One study demonstrated mild
coagulopathy in 41% and established disseminated

intravascular coagulopathy (DIC) in 5% (Hulka
et al. 1996; Owings and Gosselin 1997). Fibrinolytic
activity shortly after injury appears to correlate
with severity of brain injury, and hence may be
useful as a prognostic marker.
Patients with head injury and DIC appear to have
a different hematological profile when compared to
patients with DIC and sepsis. In brain injury, levels
of a2-plasmin inhibitor-plasmin complex and
D-Dimer are significantly higher, fibrinogen levels
significantly lower, and platelet counts are often
normal (Arango and Andrews 2001).
Secondary thrombocytosis (>750,000 platelets/
mm (Zygun et  al. 2005)), however, is relatively
common following head injury, particularly when
associated with more extensive bony trauma, and
it should be factored into any assessment of risk
for thromboprophylaxis. Low dose aspirin (75 mg
daily) is usually sufficient in this regard, in addition to routine low molecular weight heparin
therapy.

Gastrointestinal System
Most patients with TBI have some degree of gastric
erosion, but few go on to develop clinically important GI hemorrhage. Splanchnic ischemia appears
to be common in brain injury and may have a role
in the development of stress ulceration (Venkatesh

85

et  al. 1999). Gastro-protective agents such as H2

receptor blockers, proton pump inhibitors, or
sucralfate should be given as prophylaxis until full
enteral feeding has been established.

Conclusions
Non-neurological organ dysfunction is commonplace after brain injury and is associated with significant morbidity and mortality. A sound
understanding of the relevant pathophysiology,
coupled with vigilant monitoring and aggressive
treatment is required to ensure optimal outcome
for this challenging patient group.

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23(6):1007–1017
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Y (1989) Neurogenic pulmonary edema in the acute

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10

Acute Weakness in Intensive Care
Louise Barnes and Michael Vucevic

Key Points
1. Acute weakness may directly lead to a require­
ment for critical care or may occur during an
episode of critical illness (critical care neuro­
pathy).
2. Treatment requires a multidisciplinary ap­
proach. Pain control, nutrition, pressure area
care, thrombo-prophylaxis, physiotherapy, and
psychological care must all be addressed for
the best outcome to be achieved.
3. Guillain–Barré syndrome is one of the com­
monest causes of acute weakness seen on the
ICU.
4. Serial assessments of the respiratory system,
including spirometry help to evaluate the
progress of the disease, and the need for criti­
cal care support.
5. Bulbar palsy and swallowing difficulties must
be recognized early, otherwise aspiration and
subsequent pneumonia may occur.
Acute weakness as a cause for admission to Intensive
Care is common and is typified by:
1. Impaired respiratory muscle function requiring
ventilatory support
2. Inability to cough or clear secretions
3. Secondary complications of the disease process,
for example, sepsis, myocardial infarction (MI)
These conditions may herald the beginning of a
chronic illness and it is important that this is taken



into consideration when formulating a treatment
package.

Causes
Acute weakness can occur either before or after
admission to the ICU. Weakness can occur due to
pathology of the brain, spinal cord, muscles,
nerves or neuromuscular junction (see Table 10.1).
Treatment is often essentially supportive until
the results of specific investigations are known.

Neurological Assessment
The condition of the patient may preclude a com­
plete neurological assessment prior to admission
to the ICU. It is important to obtain detailed
information about the presenting complaint,
recent viral illnesses or immunizations, and any
chronic conditions.
A detailed examination should include assess­
ment of the cranial nerves. Deficiencies in Nerves
II and III suggest an intracranial cause. A partial
ptosis (III) can occur in myasthenia, myotonic dys­
trophy, and syphilis. A swallowing assessment and
testing of the gag and cough reflexes gives impor­
tant information about the safety of the airway.
Upper motor neuron disorders are the result of
lesions in the brain or spinal cord. Weakness begins

distally and spreads proximally, flexor muscles

89


90

L. Barnes and M. Vucevic

Table 10.1.  Differential diagnosis of acute weakness
Brain

Spinal cord
disorders

Neuropathies

Neuromuscular
junction

Myopathies

Trauma
Intracerebral hemorrhage
Subarachnoid hemorrhage
Cerebral infarction
Cerebral infections
Demyelinating disorders e.g., multiple sclerosis
Drugs
Traumatic myelopathy

Epidural infection, neoplasm or hematoma
Acute transverse myelitis
Acute ischemia
Arnold-Chiari malformations
Poliomyelitis (anterior horn cells)
Guillain-Barré syndrome
Chronic inflammatory demyelinating polyneuropathy
Motor neurone disease
Metabolic polyneuropathy; diabetic, uremic
hypothyroid and porphyria
Phrenic nerve injury
Myasthenia gravis
Lambert-Eaton myasthenic syndrome
Botulism
Poisons; organophosphates e.g., insecticides, sarin
Muscular dystrophy
Periodic paralysis
Sarcoidosis, SLE,
Alcoholic myopathy
Infections: HIV, Lyme disease, Coxsackie
Endocrine: Addison’s, Cushing’s and thyroid disease
Drugs; steroids, AZT
Acute necrotizing myopathy
Excessive liquorice ingestion
Polymyositis, dermatomyositis (inflammatory,
atuo-immune)
Disuse atrophy (e.g., after prolonged mechanical
ventilation)

of the arms being relatively spared. Clinical signs

included brisk reflexes, clonus,“clasp-knife” rigid­
ity, and an extensor plantar response. Muscle wast­
ing is usually a late feature.
Lesions of lower motor neurons can occur any­
where along the nerve. In anterior horn-cell disease
(e.g., poliomyelitis, spinal muscular atrophy and
motor neuron disease) weakness and wasting may
be patchy, reflexes reduced or absent, and muscle
fasciculation evident.
In disorders of the peripheral nerves, weakness is
often predominantly symmetrical and distal. Reflexes
are absent and the tone is greatly reduced with wasting
dependent on the duration of the neuropathy.
In primary myopathies, weakness is usually proximal
and symmetrical and can be painless. Reflexes are
preserved unless wasting is severe.

Pathophysiology of Respiratory
Failure
The hallmarks of respiratory failure are tachypnea
and a variable respiratory pattern with actual alve­
olar hypoventilation and carbon dioxide retention.
There is generally an insidious loss of the ability to
increase minute ventilation, often at a time of
increased demand. Impaired forced exhalation
results in accumulation of secretions and an inef­
ficient cough. Tachypnea increases the proportion
of dead space ventilation to tidal volume. Also, the
amount of time in inspiration increases, which may
exacerbate any energy deficit of the failing respira­

tory muscles as inspiratory muscles gain more of
their blood supply during relaxation (expiration).
Alternating periods of fast and slow breathing may
be seen in an attempt to rest fatiguing muscle
groups, but this may in itself exacerbate the rise in
CO2. In due course, the ventilatory muscle response
to CO2 becomes blunted, although frank ventilatory
failure may have occurred prior to this in the acute
setting. Retention of secretions often precipitates
segmental collapse and ventilation perfusion mis­
match (i.e., shunt). Hypoxic pulmonary vasocon­
striction attempts to minimize the effects of
shunting, but is incomplete. At this point respira­
tory failure becomes a consequence of both paren­
chymal pathology and pure ventilatory insufficiency.
In addition, retained secretions provide a fertile
media for superimposed secondary infection.

Specific Investigations
Investigations are guided by the history and clinical
findings
· Radiological imaging: If a central nervous
system lesion is suspected, then a CT scan with
and without contrast should be obtained. It also
helps in excluding raised intracranial pressure
prior to lumbar puncture. MRI may be useful in
cases of suspected demyelination.
· Electromyography: Helps to differentiate whether weakness is due to nerve or muscle pathol­
ogy, and if a neuropathy is generalized or local.
Demyelinating conditions result in decreased

nerve conduction velocity whereas axonal loss
leads to a reduction in the action potential.


10.  Acute Weakness in Intensive Care

91

· Cerebral spinal fluid: May be helpful in Guil­
lain–Barré Syndrome (GBS) or when infectious
processes are suspected
· Spirometry: Regular measurement of vital
capacity (VC) and peak flow when determining
the need for ventilation.
· Muscle biopsy: Indicated in the diagnosis of
myopathies and neuropathies.

increasingly utilized as the patient improves. Tra­
cheostomy is often required as ventilation may be
prolonged. It also allows less sedatives to be used,
and more active involvement with physiotherapy
whilst preventing laryngeal damage and facilitat­
ing speech and communication.

General Management Issues
Management

· Prevention of venous thromboembolism

Treatment requires a multidisciplinary approach.

Initial treatment is essentially supportive with
specific therapies being introduced once more
diagnostic information is available.
· Airway
Cranial nerve involvement can lead to bulbar palsy,
dysarthria, dysphonia, dysphagia, and a poor cough.
Acute aspiration may lead to sudden respiratory
arrest whereas a more insidious pattern of aspira­
tion will lead to pneumonia and gradual respira­
tory decompensation. Succinylcholine should be
avoided when intubating these patients as it can
cause hyperkalaemia and sudden cardiac arrest.
· Respiratory support
Bedside tests and clinical assessment determine
the need for respiratory support.
Test

Measured value

Significance

Vital capacity
(mL/kg)

  70
<30
<20

Normal
Inadequate cough

Inability to sigh,
atelectasis
Inadequate ventilation

<10

Urgent referral to ICU is indicated when VC <1  L
or less than 50% of predicted value, respiratory
rate >30, or when the patient is unable to cough
and clear secretions. Arterial blood gases should
be monitored regularly. However, pulse oximetry is
not particularly useful as desaturation is a very late
sign. Noninvasive methods of ventilation are rarely
of use due to poor cough, impaired ability to clear
secretions, and the prolonged duration that support
is often required for.
Initially, positive pressure ventilation will be
required to maintain oxygenation and normo­
carbia with pressure support ventilation being

Because of immobilization, deep venous thrombo­
sis and pulmonary embolism are a major risk.
Low molecular weight heparin should be given,
gradient compression stockings worn and passive
leg exercises encouraged. In those with illnesses of
a particularly long duration, anticoagulation with
warfarin may be considered.
· Nutrition
The gut usually remains functional and enteral
nutrition is usually achieved initially via the NG

route. Prokinetics such as metoclopramide and
erythromycin are often required in the early
stages. In severe cases of ileus, after appropriate
surgical review, intravenous neostigmine may
be useful. Oral feeding may be possible in some
patients with a tracheostomy. A percutaneous
endoscopic gastrostomy tube may be required in
the longer term. Stress ulcer prophylaxis may be
discontinued after full enteral feeding has been
established.
· Pain Control
Pain control in acute weakness can be a complex
problem and is often under-treated. Both chronic
and acute pain syndromes occur, and may pre­
dominate during different phases of a disease.
Opioids may be required in addition to simple
analgesics, and anticonvulsants or antidepressants
may be employed for neuropathic pain. Input from
a dedicated Pain Team may be useful.
· Autonomic Disturbance
This is common in the more generalized neuropa­
thies, and can be very difficult to manage; anticholinergic medication or cardiac pacing may
be required. It is a major cause of fatality in this
patient population.


92

· Pressure Sores
Attention to frequent turns and the use of pressurerelieving mattresses will help to prevent sores.

· Physiotherapy and occupational therapy
Physiotherapy plays a major part in the both the
initial treatment of these patients and their reha­
bilitation. Help with clearing secretions and cough
assist devices1 are used. Exercises to prevent con­
tractures and subsequent peripheral nerve palsies
are necessary. Splints may be required to further
aid mobilization. Prism spectacles may allow
supine patients to see what is going on around
them.
· Psychological care
Many of these patients are young, totally dependent,
awake, requiring long-term mechanical ventilation;
they are often sleep-deprived, may or may not have
a diagnosis, with an illness of unknown duration.
They may suffer from depression, anxiety, psychosis,
and delirium during their illness. A compassionate
multidisciplinary team approach is required. The
effect on relatives and caregivers should also be con­
sidered, and there are many support organizations
that can help.

Long-Term Weaning Management
Patients with neuromuscular weakness and venti­
latory insufficiency are best weaned in specialized
units with protocolized weaning strategies. Provided
their airways are supported by a well-matured
tracheostomy, these are Level 2 high-dependency
type units which are often run by respiratory
physicians. Different strategies of weaning (e.g.,

SIMV vs. progressive ventilator free (T-piece)
weaning) have their own advocates; what does
appear important, however, is adherence to
protocols and input from experienced physio­
therapy staff.
Some patients may only achieve daytime or
even shorter ventilator independence and will
ultimately require domicillary ventilation.

1
 a portable device that alternately applies positive than
negative pressure to the patient’s airway to assist in clearing
retained bronchial secretions

L. Barnes and M. Vucevic

Specific Acute Weaknesses
Guillain–Barré syndrome is one of the common­
est causes of acute weakness encountered in the
ICU. Myasthenic crises are occasionally seen and
weakness due to botulinum toxin is increasing in
the intravenous drug abusing population. Spinal
cord injury is considered in Chap. 6.

Guillain–Barré Syndrome (GBS)
Otherwise known as acute inflammatory demyeli­
nating polyradiculoneuropathy, GBS was first
described by Guillain, Barré and Strohl, in 1916, in
First World War soldiers with motor weakness,
areflexia, and CSF abnormality.

This disease has an autoimmune etiology and
often follows a respiratory or gastrointestinal infec­
tion, usually about two weeks before the onset of
symptoms. Many organisms have been implicated
including Campylobacter jejuni, cytomegalovirus,
Epstein–Barr, Mycoplasma and HIV. Vaccinations,
drugs, pregnancy surgery, epidural anesthesia,
and other autoimmune diseases have all been
implicated as precipitating GBS.
One to three cases per 100,000 occur per annum
with a male: female ratio of 1.5:1. It can occur at
any age with a bimodal distribution, peaks occur­
ring between 15–35 years and 50–75 years of age.
In the Western world it is the most common cause
of acute neuromuscular paralytic syndrome with
15–20% requiring ventilatory support and an
overall mortality of 5–10%. As mechanical ventila­
tion has improved, autonomic dysfunction is now
the leading cause of death. Some residual neuro­
logical deficit occurs in a further 10–40%.
Several distinct clinical pictures of GBS have been
described.
1. Acute inflammatory demyelinating polyradicu­
lopathy (AIDP) accounts for 85–90% of cases.
2. Acute motor axonal neuropathy (AMAN) – less
severe axonal form, most often described in
children and young adults in Northern China.
3. Acute motor sensory axonal neuropathy
(AMSAN) – more severe form of GBS presenting
with severe paralysis after a prodromal illness.

4. Miller–Fisher syndrome – characterized by
ataxia, areflexia, and ophthalmoplegia and asso­


10.  Acute Weakness in Intensive Care

ciated with the presence of antibodies to GQ1b
ganglioside.

Features
Usually an ascending pattern of progressive,
symmetrical weakness. Paresthesia begins in the
fingers and toes and spreads proximally. Cranial
nerves are involved in 45–75% of cases leading
to dysphagia, dysarthria, and facial weakness.
Hypotonia and sensory loss may be elicited.
Reflexes are decreased or absent even where
there is no weakness. The weakness tends to be
maximal 2 weeks after onset and stops progressing
after 5 weeks.
Vital signs may be labile with autonomic deficits
such as bradycardia, tachycardia, arrhythmias,
hypertension, and postural hypotension present.
Other signs of autonomic dysfunction include
hypothermia, hyperthermia, anhidrosis, paralytic
ileus, and urinary hesitancy.

Recommendations for ICU Admission
1. Rapid progression of motor weakness including
respiratory muscles

2. Presence of bulbar dysfunction and bilateral
facial palsy
3. Autonomic dysfunction
4. Medical complications (e.g., myocardial infarction
sepsis, pulmonary embolism)

Investigations
Guillain–Barré Syndrome is a clinical diagnosis
and investigations are more useful in ruling out
other diagnoses and assessing functional status
and prognosis.
1. Blood tests
· Full blood count, CRP, and blood cultures to
exclude intercurrent infection
· Liver enzymes are raised in up to a third of
patients
· Electrolytes – hyponatremia may be present.
Plasma and urine osmolality should be
measured if inappropriate antidiuretic
hormone secretion is suspected
· Antibody screen for causative organisms; anti­
bodies to the peripheral and central nervous

93

system may be present. Anti-ganglioside anti­
bodies may be found; GMI antibodies are asso­
ciated with a poorer prognosis.GQ1b antibodies
are present in the Miller–Fisher variant
2. Cerebrospinal fluid (CSF)

Ninety percent of patients have raised CSF pro­
tein (>400  mg/L), but absen ce does not exclude
the diagnosis. Elevation in CSF protein may not
occur until 1–2  weeks after onset of symptoms.
GBS associated with HIV infection features a CSF
leucocytosis.
3. Stool cultures
Campylobacter jejuni is a frequent cause of GBS.
4. Electrocardiogram
Changes may be indicative of autonomic dys­
function and can include ST segment depression,
T-wave inversion, a prolonged QT interval, and
arrhythmias.
5. Spirometry and arterial blood gases
Useful in determining the need for ventilatory
support and assessing progress in the later stages
of the disease.
6. Chest X-ray
Pulmonary infiltrates, atelectasis, and pleural effu­
sion may be present and are also predictors of the
need for ventilatory support.
7. CT Brain
Necessary to exclude raised ICP prior to lumbar
puncture and to exclude other diagnoses.
8. Gadolinium-enhanced MRI of the spinal cord.
This may show selective enhancement of anterior
nerve roots (95% of cases)
9. Electrophysiological studies
Variable findings including low compound action
potential (CMAP) and prolonged distal latencies

(DL); may give prognostic information.

Treatment
Treatment is supportive, but two specific therapies
may decrease the duration of the disease. Intrave­
nous immunoglobulin and plasma exchange therapy


94

have both been shown to reduce the duration of GBS
by up to 50%, no significant difference being found
between the two. The cost is similar.
(a) Plasma exchange (plasmapheresis) involves sub­
stituting 250 mL/kg of plasma with 4.5% human
albumin, typically five times at a specialist cent­
er. Treatment must commence within 2 weeks
of the onset of the disease. The mechanism of
action is thought to be by removal of cyto­
toxic constituents of the serum. Although albu­
min is traditionally used, there is no evidence
that it is better than any other colloid or crystal­
loid. Contraindications include hemodynamic
instability, recent myocardial infarction, severe
sepsis, renal insufficiency, and active bleeding.
Side effects include hypotension, coagulopathy,
hypocalcemia and sepsis, and those related to
vascular access.
(b) Immunoglobulin therapy (IVIG) has the ad­
vantage of being easily administered in a dose

of 400 mg/kg for 5 days. It is thought to work
by neutralizing circulating myelin antibodies
through anti-idiotypic antibodies and downregulation of proinflammatory cytokines. It
may also block the complement cascade and
promote remyelination.
Contraindications include IgA deficiency
(levels must be checked prior to treatment),
and previous anaphylaxis. Relative contraindi­
cations include congestive cardiac failure and
renal impairment (may cause deterioration in
renal function, especially in the elderly).
Side effects are generally mild and include
nausea, fever, headache, pruritis, petechiae, urti­
caria, and a transient rise in hepatic enzymes.
Migraine, aseptic meningitis and anaphylaxis
have also been reported. IVIG may increase
serum viscosity and increase the likelihood of
thromboembolic complications.
Corticosteroid therapy has been shown in several
trials to be of no benefit as a single therapy in GBS,
and there is no advantage in steroids being given
with immunoglobulin therapy. It is has been postu­
lated that steroids may be of benefit if given during
plasma exchange, owing to the enhanced antibody
production that can occur during the treatment.
CSF filtration is another therapy that has been
used in resistant cases but is not currently recom­
mended in the United Kingdom.

L. Barnes and M. Vucevic

Autonomic Dysfunction
This accounts for many of the deaths associated
with GBS and is most commonly seen in patients
with tetraplegia, respiratory failure or bulbar
involvement. Heart rate and blood pressure may
be extremely labile with frequent, unpredictable
changes. Severe bradycardia may require the
insertion of a temporary pacing wire. Hypoten­
sion is best treated with fluid boluses but refrac­
tory cases may require a pressor agent for example,
phenylephrine (Neo-Synephrine). Hypertension
does not usually require specific intervention
unless it is excessive (i.e., MAP >130 mmHg), or
if there is evidence of end- organ damage.

Prognosis
Mortality is 5–10%, the major cause of death
being cardiac secondary to autonomic instability,
pneumonia, ARDS, respiratory failure, sepsis,
and pulmonary embolism. Weakness commonly
peaks at 10–14 days and recovery takes weeks to
months. Without treatment the average time on
a ventilator is 50 days. Poor prognostic indicators
are upper limb paralysis, Campylobacter infec­
tion, mechanical respiratory support, old age,
absent or reduced CMAP, anti-GMI antibody,
neuron-specific enolase, and S-100 proteins in
the CSF.
Recurrence of acute symptoms occurs in 2–5%

of cases and is often not detected on the ICU.

Botulism
This condition is caused by the neurotoxin of the
bacterium Clostridium botulinum which blocks
neuromuscular transmission in cholinergic nerves
by inhibiting acetylcholine release at the presyn­
aptic cleft and binding to acetylcholine itself. It is
now most commonly seen in IV drug abusers.
Symptoms occur in 12–72  h, beginning with
nausea and vomiting. A descending symmetrical
paralysis ensues, initially affecting cranial nerves
with diplopia, facial weakness, dysphagia, and
dysarthria, followed by respiratory embarrass­
ment and limb weakness. Autonomic disturbance
manifests as ileus, unresponsive pupils, dry mouth,
and urinary retention. Sensory system and menta­
tion are usually spared.


95

10.  Acute Weakness in Intensive Care

Treatment is supportive with the addition of antitoxin and penicillin to destroy any live bacteria.
Mortality is 25%, less in those <25 years old and
recovery may be prolonged.

Myasthenia Gravis
Myasthenia gravis has an incidence of 50–100

per million. It is an autoimmune disease where
IgG auto-antibodies occupy the acetylcholine
receptor at the neuromuscular junction produc­
ing weakness and increased fatigability of skeletal
muscle. Symptoms are usually well-controlled on
pyridostigmine, an acetylcholinesterase inhibitor.
Patients with myasthenia are likely to need ICU
input in the presence of developing respiratory
failure or for perioperative management (e.g.,
after thymectomy). Complications of the disease
include respiratory muscle weakness and the ina­
bility to cough or clear secretions. Vocal cord
weakness or weakness of the oropharyngeal
muscles may add an obstructive component. Dete­
rioration may be provoked by infection, stress,
electrolyte disturbances, thyroid dysfunction, and
a large number of drugs (see Table 10.2).
Two types of crisis are recognized. A myasthenic
crisis can be precipitated by infection, medica­
tion changes (especially steroids), pregnancy,
and surgery and is more frequent in patients who
have thymoma. A cholinergic crisis occurs with
an increase of anticholinergic medication and is
characterized by signs of excessive cholinergic
activity (i.e. miosis, diarrhea, excessive saliva­
tion, bradycardia). Only a myasthenic crisis will
improve with a Tensilon test (2 mg edrophonium
test dose followed by a further 8 mg if no cholin­
ergic side effects are seen).
Table 10.2.  Drugs that may exacerbate a myasthenic crisis (N.B.

This list is not exhaustive!)
Drugs that may exacerbate a Myasthenic crisis
Antibiotics (e.g., aminoglycosides, penicillins, tetracyclines)
Cardiovascular drugs (e.g., b blockers, lidocaine, verapamil,
procainamide)
Neuromuscular blocking drugs
Anticonvulsants (e.g., phenytoin, carbamazepine)
Phenothiazines
Antidepressants
Antihistamines
Opiates

Treatment is supportive. Pyridostigmine is given
with neostigmine. Immunosuppressive therapies
are used including steroids, azathioprine, cyclo­
phosphamide, and ciclosporin. Plasma exchange
and intravenous immunoglobulin have been used
in severe cases.

Tetanus
Rare in the United Kingdom but may be up to one
million cases worldwide each year. The clinical
syndrome is caused by the exotoxin tetanospasmin
from the anaerobe Clostridium tetani. Tetanospasmin
ascends in motor and autonomic fibers blocking
the release of inhibitory neurotransmitters. The
disease may be modified by previous immuniza­
tion. Clinical features include trismus, facial muscle
contraction (Risus sardonicus), and generalized
muscle pain and spasm. Muscle spasm may be pre­

cipitated my minor disturbance (e.g. laryngospasm
provoked by swallowing). Mental state is not
affected. Risk factors include lacerations, diabetes
and IV drug abuse. The disease is self-limiting but
supportive measures are required including:
(a) Ventilatory support – early tracheostomy is
favored to avoid precipitation of laryngeal
spasm by the endotracheal tube
(b) Treatment of autonomic instability – dysrhythmias
and MI are the most common fatal events.
Labetalol may be used for hypertension and
tachycardia
(c) Control of muscle spasms – benzodiazepines
are used because of their GABA-agonist and
sedative properties. For severe cases, nonde­
polarizing neuromuscular blockers such as
vecuronium may be required. Succinylcholine
should be avoided.
(d) Magnesium sulfate – case reports have suggested
that magnesium sulfate (MgSO4) infusions can
prevent the need for mechanical ventilation in
some patients. In a larger series, however, MgSO4
did not reduce the need for respiratory support
but did reduce the requirement for rescue meas­
ures to control spasms (benzodiazepines, mus­
cle paralysis) and autonomic disturbances (an­
tiarrhythmic and antihypertensive drugs).
(e) Environment – the patient should be nursed
in a quiet, calm environment in an attempt to
prevent spasms