Ebook Neurocritical care A guide to practical management Part 2

(BQ) Part 2 book Neurocritical care A guide to practical management presentation of content: Seizures on the adult intensive care unit, acute weakness in intensive care, coma, confusion, and agitation in intensive care, imaging the brain injured patient, ethical dilemmas within intensive care,...

Key Points

1 Seizures are commonly encountered in the ICU

They can be provoked by acute illness,

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

manage-ment of the different types of seizure disorders

encoun-tered 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 SeizureSeizures (as opposed to epilepsy) are far more common in the general population and can be pro-voked 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

8

Seizures on the Adult Intensive Care Unit

Morgan Feely and Nicola Cooper

www.ebook3000.com

70 M Feely and N Cooper

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

previ-ous myoclonic, absence or partial seizures In one

study, 74% of patients presenting with a first

tonic-clonic 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, sive alcohol is the commonest cause of first tonic-clonic seizures in men These patients do not have epilepsy but are experiencing provoked seizures

exces-Although in many cases this occurs during drawal or after a binge, it is distinct from overt alcohol-withdrawal syndrome Other conditions

with-All seizure types can occur as status epilepticus

- Focal rigidity or jerking

Due to acute illness (tonic-clonic or partial seizures)

Part of epilepsy

(recognised or unrecognised)

Figure 8.1 Types of seizures.

8 Seizures on the Adult Intensive Care Unit

such as primary brain tumors and metabolic

dis-orders 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

cor-responding 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

scle-rosis, and post-traumatic changes Although young

people with idiopathic generalized epilepsy or

obvi-ously provoked seizures may not require imaging,

patients with location-related epilepsy, refractory

epi-lepsy, 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,

encephalitis, or a post-ictal state Focal slow waves can

be a non-specific indicator of a focal brain ity 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

abnormal-a normabnormal-al EEG between abnormal-attabnormal-acks Seriabnormal-al 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

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

Anti-Epileptic DrugsThe 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 tonic-clonic seizures but can be ineffective or even exac-erbate myoclonic jerks

Checking drug levels may be of value in the context of overdose or to assess a patient’s compli-ance with medication, but is rarely helpful when adjusting dosages The one exception is pheny-toin, 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

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

Nonconvulsive status epilepticus should be considered in patients with unexplained states of semiconsciousness or coma.

72 M Feely and N Cooper

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

epi-lepticus are the main determinants of outcome

Tonic-clonic status epilepticus occurs in stages

(Fig 8.3) During early status, the systemic and

cer-ebral metabolic consequences of status are still

con-tained 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 dehydra-tion, pyrexia, arrhythmias, hyperkalemia, and rhab-domyolysis (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 sei-zures, 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 thetic drugs in refractory status Aim for pheny-toin levels at the high end of the normal range, before adding another drug

anes-Primary generalised epilepsy Location-related epilepsy

Sodium valproate (Epilim) – IV/PO Lamotrigine (Lamictal) – PO Levetiracetam (Keppra)* – IV/PO

Carbemazepine (Tegretol) PO/PR Sodium valproate – 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.

8 Seizures on the Adult Intensive Care Unit

· 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

asso-ciated with a very poor prognosis Hui et al reported

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 diffi-cult to control Agents such clonazepam or sodium

• 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.

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

74 M Feely and N Cooper

valproate have been traditionally used, although

newer agents such as as levetiracetam have been

tried with some success Continued epileptic

sei-zures 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

exami-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

con-scious and signs may be subtle, for example,

twitch-ing 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

hypergly-cemia, and penicillin therapy in the presence of a

local breakdown in the blood–brain barrier (e.g.,

after neurosurgery) Treatment is essentially the same, except that oral clobazam is the preferred benzodiazepine as it is less likely to reduce the con-scious level or cause respiratory depression

Non-convulsive status epilepticus is

under-recognized

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 rela-tives had noticed jaw twitching and occasional jerking of his right arm throughout the day

An EEG confirmed nonconvulsive status

epilepticus, which was treated with intravenous lorazepam and phenytoin

Seizures Occurring as Part of an Acute Illness or Following NeurosurgerySeizures occur as part of many acute illnesses, especially metabolic disorders (e.g., hypoglyc-emia, hyponatremia) and brain diseases (e.g., meningo-encephalitis, subarachnoid hemor-rhage) Acutely ill patients presenting with sei-zures require careful evaluation, and consideration should be given to performing a lumbar punc-ture 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 Tonic-clonic seizures affect ventilation and some

Figure 8.4 Systemic complications of tonic-clonic status epilepticus.

Whenever seizure control is difficult, it is sensible to seek expert help

from a neurologist at an early stage

In a case of coma without an obvious cause, an EEG will exclude convulsive status.

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

prac-tice to give prophylactic AEDs to patients after

neu-rosurgery or following traumatic brain injury or

subarachnoid hemorrhage Early postoperative

sei-zures (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

struc-tural 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

adjust-ments, 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

precipi-tate 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

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 sions 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, hyperventi-lation with normal SpO2, and rapid recovery despite

admis-a prolonged seizure Proladmis-actin level is admis-an unreliadmis-able 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 lepsy Butterworth Heinemann, Boston, MA Hui A, Cheng C, Lam A et al (2005) Prognosis following postanoxic myoclonus status epilepticus Eur Neurol 54:10–13

epi-Manford M (2003) Practical guide to epilepsy worth Heinemann, Boston, MA

Butter-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

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

sys-temic 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

sub-arachnoid 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

sub-arachnoid 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 ing 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

life-threaten-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 tions, 19% to the primary bleed, 22% to re-bleeding,

complica-and 23% to vasospasm Eighty-three percent of those who died had a life-threatening complica-tion compared to 30% of the survivors Half of the

“medical” deaths were from pulmonary tions and a poor GCS at presentation, not surpris-ingly, seemed to correlate with a higher degree of respiratory dysfunction Table 9.1 outlines the relative frequencies of the medical complications

complica-in the study

In another series of 242 patients with SAH (Gruber et al 1999), medical complications were again commonplace with 81% of patients develop-ing dysfunction of at least one non-neurological

organ system, and 26% developing organ system

failure Non-neurological organ dysfunction

cor-related with severity of the SAH Mortality was 31% for SAH and single non-neurological organ

J.P Adams

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

dys-function was commonly implicated, occurring in

23% of patients Non-neurological organ

dysfunc-tion 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

associ-ated 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

Hypov-entilation and hypervHypov-entilation 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 tory 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)

respira-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 monary lymph flow (Pelosi et al 2005)

pul-Brain-injured patients are at particular risk for the development of Ventilator-Associated Pneu-monia (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 mismatchMany 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, pulmo-nary microembolisms leading to an increase in dead space, and depletion of surfactant (Pelosi

et al 2005; Schumacker et al 1979)

Table 9.1 Relative frequencies of medical complications in patients

with SAH (Solenski et al 1995)

9 Non-Neurological Complications of Brain Injury

3 Neurogenic Pulmonary Edema

In the 1960s, Simmons reported that 85% of combat

soldiers dying of isolated severe head injury

dem-onstrated alveolar edema, hemorrhage, and

con-gestion 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

cere-bral insult and 90% will have diffuse bilateral

infil-trates 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)

Etiology:

Neurogenic pulmonary edema has a different etiology to acute lung injury (ALI) following an inflammatory insult, although brain injury (espe-cially 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 pul-monary 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

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

pulmo-79

J.P Adams

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

disrup-tion of the basement membrane (West and

Mathieu-Costello 1992) or possibly by an increase in

pulmonary capillary permeability, secondary to

the release of brain cytokines or adhesion

mole-cules 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

com-ponents 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

pos-sibilities 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

radio-logical 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

pul-monary artery catheter or pulse contour analysis

device will help with the initial diagnosis and

sub-sequent resuscitation

Treatment:

Treatment is essentially supportive Usual

strate-gies for treating cardiac failure-induced

pulmo-nary edema include positive pressure ventilation

and diuretics, but systemic overload is not the

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 aug-mentation with inotropic agents such as dob-utamine or milrinone, and in severe cases, epine-phrine 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 hypo-tension, 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-adren-oceptor blockade with propranolol and phen-tolamine (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 InjuryThe 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)

80

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

circu-lation may induce or exacerbate ALI Additionally,

the need for sedation to facilitate ventilation

sig-nificantly complicates monitoring neurologically

injured patients Subtle alterations in cognition,

indicative of the onset of delayed ischemia

follow-ing 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

respira-tory failure without negative effects on cerebral

physiology (Wolf et al 2002) Although widely

dis-couraged, 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

pro-tocols appear to reduce the need for fluid as

com-pared 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

inci-dence of VAP One strategy to reduce VAP from

pooled secretions has been to perform 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 high-volume 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

conti-f) Standards of hygiene, for example, hand washing

3 Accelerated weaninga) Aggressive chest physiotherapy (caution with high ICP levels)

b) Positioning and regular turningc) Fiberoptic bronchoscopy to remove deep secretions (clinical data scanty)

d) Early tracheostomy

Cardiovascular SystemThe patient with acute brain injury frequently has evidence of cardiovascular impairment This may range from minor ECG changes through to malig-nant dysrhythmias and life-threatening ventricu-lar dysfunction

ECG ChangesECG changes are extremely common after brain injury and are almost universal in patients suf-fering 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) Sub-endocardial ischemia and focal myocardial necrosis are the usual pathological findings

81

J.P Adams

(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

asso-ciated 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

fol-lowing 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

abnormali-ties and the presence of raised serum cardiac

enzymes or mechanical hypokinesis on

echocar-diography (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

asso-ciated with raised cardiac enzymes or echo

hypokinesis, as the risk of malignant

dysrhyth-mias is high

Cardiac EnzymesSerum 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 ated with an increase risk of vasospasm

associ-HypertensionHypertension 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 com-mencing 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 Figure 9.2 Marked inferior and lateral ST segment changes in a patient following an acute aneurysmal SAH.

82

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

recep-tor down regulation Echocardiography is the usual

first-line investigation and the whole spectrum of

systolic and diastolic dysfunction may be

encoun-tered, including a relatively newly recognized

car-diomyopathy characterized by apical and mid-

segment stunning with preserved basal function

(Tako-tsubo cardiomyopathy) (Das et al 2009)

Hypokinesia, reduced ejection fraction, and

per-fusion abnormalities have also been demonstrated

by thallium scanning and nucleotide

ventriculogra-phy (Szabo et al 1993) Use of more advanced

moni-toring techniques such as a pulmonary artery

catheter are recommended as any combination of

ventricular disturbance and pulmonary artery

pres-sure 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

con-stantly changing Almost every combination and

vasopressor has been tried with varying degree of

success Many clinicians would favor dobutamine

as opposed to epinephrine in cases of hypotensive heart failure where LVSWI is reduced The phos-phodiesterase 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 pre-served (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., pulmo-nary artery catheter) is essential The initial catecho-lamine 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 ciency appears to be relatively common after brain injury (Bernard et al 2006); patients with hemo-dynamic 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 DisturbanceAbout 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)

83

J.P Adams

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

extracellu-lar 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

cer-ebral 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

mal-formations 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

antago-nize 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

HypernatremiaThe 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 Aggres-sive 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 intracra-nial 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)

84

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

iatro-genic sampling, hemodilution, and other associated

injuries In contrast to other groups of

intensive-care 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

hypercoagu-lable 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

addi-tion 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

impor-tant GI hemorrhage Splanchnic ischemia appears

to be common in brain injury and may have a role

in the development of stress ulceration (Venkatesh

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

ConclusionsNon-neurological organ dysfunction is common-place after brain injury and is associated with sig-nificant 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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87

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, thrombo­prophylaxis, 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

CausesAcute 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 com­plete 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 assess­ment of the cranial nerves Deficiencies in Nerves

II and III suggest an intracranial cause A partial ptosis (III) can occur in myasthenia, myotonic dys­trophy, and syphilis A swallowing assessment and testing of the gag and cough reflexes gives impor­tant 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

10

Acute Weakness in Intensive Care

Louise Barnes and Michael Vucevic

89

L Barnes and M Vucevic

of the arms being relatively spared Clinical signs

included brisk reflexes, clonus,“clasp­knife” 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 horn­cell 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 alve­olar 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 inef­ficient 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 respira­tory 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 mis­match (i.e., shunt) Hypoxic pulmonary vasocon­striction attempts to minimize the effects of shunting, but is incomplete At this point respira­tory failure becomes a consequence of both paren­chymal 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 pathol­ogy, 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

Table 10.1 Differential diagnosis of acute weakness

Epidural infection, neoplasm or hematoma

Acute transverse myelitis

Acute ischemia

Arnold-Chiari malformations

Poliomyelitis (anterior horn cells)

Neuropathies Guillain-Barré syndrome

Chronic inflammatory demyelinating polyneuropathy

Motor neurone disease

Metabolic polyneuropathy; diabetic, uremic

hypothyroid and porphyria Phrenic nerve injury

Poisons; organophosphates e.g., insecticides, sarin

Myopathies 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) 90

10 Acute Weakness in Intensive Care

· 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

Management

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

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

increasingly utilized as the patient improves Tra­cheostomy 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 facilitat­ing speech and communication

General Management Issues

· Prevention of venous thromboembolismBecause of immobilization, deep venous thrombo­sis 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

· NutritionThe 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 ControlPain control in acute weakness can be a complex problem and is often under­treated Both chronic and acute pain syndromes occur, and may pre­dominate 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 DisturbanceThis is common in the more generalized neuropa­thies, 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

91

L Barnes and M Vucevic

· Pressure Sores

Attention to frequent turns and the use of pressure­

relieving 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 long­term mechanical ventilation;

they are often sleep­deprived, 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 well­matured

tracheostomy, these are Level 2 high­dependency

type units which are often run by respiratory

physicians Different strategies of weaning (e.g.,

SIMV vs progressive ventilator free (T­piece)

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

Specific Acute WeaknessesGuillain–Barré syndrome is one of the common­est 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 demyeli­nating 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 infec­tion, 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 occur­ring 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 ventila­tion has improved, autonomic dysfunction is now the leading cause of death Some residual neuro­logical deficit occurs in a further 10–40%.Several distinct clinical pictures of GBS have been described

1 Acute inflammatory demyelinating polyradicu­lopathy (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

1 a portable device that alternately applies positive than

negative pressure to the patient’s airway to assist in clearing

retained bronchial secretions

92

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

system may be present Anti­ganglioside anti­bodies may be found; GMI antibodies are asso­ciated with a poorer prognosis GQ1b antibodies are present in the Miller–Fisher variant

2 Cerebrospinal fluid (CSF)Ninety percent of patients have raised CSF pro­tein (>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 ElectrocardiogramChanges may be indicative of autonomic dys­function and can include ST segment depression, T­wave inversion, a prolonged QT interval, and arrhythmias

5 Spirometry and arterial blood gasesUseful in determining the need for ventilatory support and assessing progress in the later stages

of the disease

6 Chest X­rayPulmonary infiltrates, atelectasis, and pleural effu­sion may be present and are also predictors of the need for ventilatory support

7 CT BrainNecessary to exclude raised ICP prior to lumbar puncture and to exclude other diagnoses

8 Gadolinium­enhanced MRI of the spinal cord.This may show selective enhancement of anterior nerve roots (95% of cases)

9 Electrophysiological studiesVariable findings including low compound action potential (CMAP) and prolonged distal latencies (DL); may give prognostic information

TreatmentTreatment is supportive, but two specific therapies may decrease the duration of the disease Intrave­nous immunoglobulin and plasma exchange therapy

93

L Barnes and M Vucevic

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 anti­idiotypic antibodies and down­

regulation 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

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 Hypoten­sion is best treated with fluid boluses but refrac­tory cases may require a pressor agent for example, phenylephrine (Neo­Synephrine) 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 infec­tion, mechanical respiratory support, old age, absent or reduced CMAP, anti­GMI antibody, neuron­specific enolase, and S­100 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 presyn­aptic 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 embarrass­ment and limb weakness Autonomic disturbance manifests as ileus, unresponsive pupils, dry mouth, and urinary retention Sensory system and menta­tion are usually spared

94

10 Acute Weakness in Intensive Care

Treatment is supportive with the addition of anti­

toxin 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 auto­antibodies occupy the acetylcholine

receptor at the neuromuscular junction produc­

ing weakness and increased fatigability of skeletal

muscle Symptoms are usually well­controlled 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)

Treatment is supportive Pyridostigmine is given with neostigmine Immunosuppressive therapies are used including steroids, azathioprine, cyclo­phosphamide, and ciclosporin Plasma exchange and intravenous immunoglobulin have been used

in severe cases

TetanusRare 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 immuniza­tion Clinical features include trismus, facial muscle contraction (Risus sardonicus), and generalized muscle pain and spasm Muscle spasm may be pre­cipitated 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 self­limiting 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 GABA­agonist and sedative properties For severe cases, nonde­polarizing 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 meas­ures to control spasms (benzodiazepines, mus­cle paralysis) and autonomic disturbances (an­tiarrhythmic and antihypertensive drugs).(e) Environment – the patient should be nursed

in a quiet, calm environment in an attempt to prevent spasms

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)

L Barnes and M Vucevic

Wounds should be debrided to remove the toxin

source and benzylpenicillin 1.2g qds and metroni­

dazole 500 mg IV tds are given to prevent on­going

toxin production Human tetanus immunoglobulin

is sometimes given to neutralize the toxin and may

shorten the course of the disease

Tetanus patients without access to mechanical

ventilation die from respiratory failure whereas

the cause of death in ventilated patients is usually

autonomic dysfunction

Organophosphate Poisoning

Organophosphates irreversibly inhibit choline­ste­

rases including acetylcholinesterase (AchE) Symp­

toms usually occur within 3 h and may rapidly

progress to death Muscarinic symptoms reflect

AchE inhibition at autonomic synapses and include

miosis, bronchospasm, pulmonary edema, laryn­

gospasm, bradycardia, and hypotension Nicotinic

effects reflect AchE inhibition at the neuromuscular

junction, and include fasciculations and skeletal

muscle paralysis Severe intoxication leads to sei­

zures and coma Treatment consists of supportive

therapy including intubation and ventilation,

gastric lavage, decontamination of skin and mucous

membranes, and anticonvulsant therapy Atropine

is used to treat muscarinic side effects and may be

required in high doses, for example, 1–2 mg hourly

Pralidoxime, a cholinesterase reactivator, is some­

times used as an adjunct to atropine in severe cases

It must be given within 24 h of the poisoning to be

effective and repeated doses may be needed Assist­

ance from a Clinical Pharmacologist is advised in

the management of such cases

Neuromuscular Disorders in ICU

Neuromuscular disorders in the critically ill are

relatively common, especially in those who have

been ventilated The diagnosis is usually considered

when the patient fails to wean from ventilation or

when limb weakness is noted The cause is probably

multifactorial but disuse atrophy, catabolic states,

and drugs (e.g., steroids, muscle relaxants) have all

been implicated

(a) Critical Illness Neuropathy:

Usually present with a flaccid weakness follow­

ing prolonged ICU admission Nerve conduction

velocities are normal (excluding demyelination),

CSF is normal, and neurophysiological studies

suggest an acute idiopathic axonal degeneration The condition is self­limiting, but recovery may be very prolonged and can be incomplete Mortality

is higher than in unaffected controls, primarily as

a result of the prolonged time to wean

(b) Critical Illness MyopathyThe incidence of drug­induced myopathy is probably declining in the critically ill population, as the use

of high­dose steroids has reduced Muscle relax­ants may have prolonged effects and may be poten­tiated by drugs such as b2 agonists Accordingly, the use of muscle relaxant in the Intensive Care should

be for the shortest possible duration, and doses titrated with the aid of neuromuscular monitor­ing Histological studies have demonstrated mus­cle fiber atrophy, mitochondrial defects, myopathy, and necrosis Again the condition is self­limiting but with a prolonged recovery

ConclusionsAlthough a case of acute weakness generates a large differential diagnosis, a detailed history and exami­nation combined with targeted investigations should elucidate the cause Treatment is essentially supportive until a definite diagnosis is made and requires a coordinated effort from a multidiscipli­nary team Significant morbidity and mortality are still associated with these conditions

Suggested Reading

Bhardwaj A, Mirski M, Ulatowski J (eds) (2004) Hand­ book of neurocritical care Humana Press, New Jersey, USA, pp 199–212

Chan­Tack KM, Bartlett J (2004) Botulism E­Medicine Cheng BC, Chang WN et al (2004) Predictive factors and long­term outcome of respiratory failure after guil­ lain barre syndrome Am J Med Sci 327(6):336–340 Fanion D(2004) Guillain Barre Syndrome E­medicine Hughes RA, Raphael JC, Swan AV, Doorn PA (2004) Intra­ venous Immunoglobulin for Guillain Barre Syndrome

Cochrane Database of Reviews (1):CD002063 Kumar R (2002) Guillain barre syndrome JIACM 3(4):389–391 Richards K, Cohen A (2003) Guillain­Barre syndrome BJA, CEPD Reviews 3(2):46–49

Thwaites CL, Yen LM, Laon HT et al (2006) Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial Lancet 368(9545):1398–1399

Raphael J­C, Chevret S, Hughes RAC Plasma exchange for Guillain Barre syndrome Cochrane Review CD­

ROM Oxford, England 96

Key Points

1 Coma and delirium are very common in

criti-cally ill patients, and represent an independent

risk factor for poor outcome

2 Management of the comatose patient involves

rapid initial assessment and correction of easily

reversible causes, protecting the brain from

further injury, diagnosing and specifically

treating the underlying cause, plus good generic

multidisciplinary care

3 Management of delirium includes rapid

assess-ment, treatment of easily reversible causes

(pain, urinary retention, hypoxia, hypotension

etc.) and investigation of other causes

Non-pharmacological measures are as important as

drug therapy

4 Guidelines (and adherence to them) are useful

for both the assessment of delirium and

moni-toring of sedation scores

5 The ideal sedative agent does not exist Choice

of agent(s) should be patient-specific,

moni-tored closely to achieve the desired end-point

with the minimum of side effects and given for

the shortest time necessary

6 Inappropriate use of sedatives may actually

worsen or prolong delirium

IntroductionDisorders of consciousness are very common The

2005 NCEPOD report found that over 50% of patients had a Glasgow Coma Scale (GCS) <9 on admission to ICU The prevalence of confusion and agitation in ICU patients has been reported anywhere between 20 and 80% in cohort studies.Normal Consciousness

The neuroanatomy and neurophysiology of normal consciousness is not completely understood Vir-tually all areas of the brain play a role, but of par-ticular importance is the interaction between the cerebral cortex and the reticular activating system The reticular formation is a diffuse collection of nuclei located in the upper brainstem These nuclei receive input from most of the body’s sensory systems, as well as the cerebellum and cerebral hemispheres Descending neurons project from the reticular formation to the spinal cord, where they synapse with motor neurons The ascending neurons, which project into most of the rest of the brain, are known as the reticular activating system, and are responsible for normal wakefulness and awareness Although the main area coordinating

M Clark and J McKinlay

consciousness is located in the brainstem, a

func-tioning cortex is also required Alteration in

con-sciousness can therefore occur due to lesions within

the brainstem itself, brainstem compression by

lesions elsewhere, or by global disruption of normal

neuronal metabolic and electrical activity

Coma

Definition

Coma can be described as a state of prolonged,

deep unconsciousness in which the patient is

totally unaware of both self and external

sur-roundings, and is unable to respond meaningfully

to external stimuli In coma, the patient’s normal

sleep–wake cycle is disrupted, which differentiates

it from other conditions with low conscious level

such as persistent vegetative state

The Glasgow Coma Scale (GCS) records the patient’s

response to verbal and physical stimuli (see later)

A score of eight or less can be described as coma

Management of the Comatose Patient

The important principles are:

· Rapid initial assessment and correction of

easily reversible causes

· Protecting the brain from further injury

· Diagnosing the underlying cause

· Management of the specific cause

· General care of the comatose patient

Initial Assessment of the Comatose Patient

· Obtain a brief history (from third parties)

· Airway–assess patency and any potential

intu-bation difficulties Be alert to potential injury of cervical spine

· Breathing–color, respiratory rate and pattern,

pulse oximetry, chest auscultation

· Circulation–pulse, blood pressure, capillary

refill time, heart sounds

· Assess conscious level (GCS)

· Assess pupillary responses and eye movements

· Observe limb movements, reflexes, posture, and

localizing signs

· Be aware of signs of meningism/ raised ICP

· Brief general examination–breath odor, skin (color, rashes, needle marks), abdomen, external signs of injury (especially around the head)

· Temperature

· Capillary glucose level

· Venous blood sample (glucose, electrolytes, calcium, osmolality, liver function tests, full blood count, paracetamol (acetaminophen) and salicylate levels, blood alcohol)

· Consider urinary catheter Send urine for toxicology

· ECG, Chest x-ray

· Consider CT brain

During and after the immediate assessment, it is important to correct any easily reversible abnor-malities and begin treatment of any obvious causes

of reduced conscious level This is outlined in the following section

· Ensure adequate airway and oxygenation Indications for intubation and ventilation are failure to maintain and protect the airway, inad-equate oxygenation, hyperventilation, expected clinical deterioration and to allow diagnostic/therapeutic procedures or transfer

· Aim for normocapnia

· Obtain reliable intravenous access Support culation with fluid and/or vasoactive drugs

cir-· Correct hypoglycemia

· Control seizures

· Avoid hyperthermia or excessive hypothermia

· Correct electrolytes/acid-base disturbance

Glasgow Coma Scale

11 Coma, Confusion, and Agitation in Intensive Care

· Give antibiotics if infection suspected

(espe-cially meningitis)

· Give mannitol if raised intracranial pressure present

· Consider specific antidotes for overdose or

poisoning (e.g., naloxone for opioids)

· Give thiamine if history of alcohol abuse

Protecting the Brain from Further Injury

The injured brain is susceptible to further secondary

physiological insults that may worsen outcome

(hypoxia, hyper- and hypocapnia, hypotension,

aci-dosis, glucose abnormalities, hyperthermia, seizures)

and these must be avoided For the management of

raised intracranial pressure refer to Chap 3

Diagnosis of the Cause of Coma

Etiology of coma may be multifactorial, for

example, drugs and trauma Generally, focal

central nervous system (CNS) abnormalities on

examination imply there is a structural CNS

pathology, although a normal CNS examination

does not exclude a mass lesion Sometimes

clini-cal signs may suggest the location of a lesion

within the CNS; for example, bilateral periorbital

hematomas (Battle’s sign) is suggestive of a base

of skull fracture False localizing signs such as

the third and sixth cranial nerve palsies may be

secondary to raised ICP Other tests to consider

are MRI (for lesions not visible on CT plus lesions

within the brainstem and spinal cord), lumbar

puncture, electroencephalography (EEG), and

carotid duplex scans if there is a suggestion of

carotid injury

Differential Diagnosis (see Appendix)

1 Trauma (e.g., Subdural hematoma, diffuse axonal

injury, cerebral contusions)

2 Vascular (e.g., subarachnoid hemorrhage,

ischemic stroke)

3 Infective (e.g., abscess, encephalitis, sepsis)

4 Metabolic (e.g., hyponatremia, hypoglycemia,

hypocalcemia, liver failure)

5 Endocrine (e.g., myxedema, hypopituitarism)

6 Pharmacological (e.g., opiates, alcohol, carbon

monoxide, substance withdrawal)

7 Neoplastic (e.g., brain tumor)

8 Neurological (e.g., seizures)

General Care of the Comatose PatientGeneral principles of ICU management are very important: Establishing early nutrition, gastric pro-tection, thrombembolic prophylaxis, pressure-area monitoring and bowel/ bladder care require atten-tion GCS, pupillary reaction and limb movement should be regularly assessed, as they may provide the first indication of deterioration in the patient’s condition With primary neurosurgical pathologies, specific cerebral monitoring (e.g., ICP, processed EEG, and cerebral oxygenation monitoring) can be used to assist monitoring of the sedated patients.Sedation of the Comatose Patient

A small subgroup of comatose ICU patients require no sedation In other patients, sedation is

to be withheld to assess wakening from coma The majority (mainly those with intermediate con-scious levels) require some degree of sedation to assist with treatment of their condition, or with general supportive ICU care The indications for sedation on ICU and the properties of an ideal sedative are listed below

Indications for Sedation on ICU

· Facilitate mechanical ventilation

· Reduce oxygen extraction/utilization in ARDS and sepsis

· Brain protection (seizure control, decrease cerebral metabolism, control ICP)

· Provide hemodynamic stability

· Amnesia during paralysis with muscle relaxants

· During interventions (line insertion, stomy)

tracheo-· To prevent movement (during imaging) and to permit transfer of the patient

· Relieve anxiety and fear

· Facilitate sleepWhich Agent?

The ideal sedative agent does not exist, and a bination of sedative and analgesic drugs, each titrated to specific end points, is commonly given Propofol or benzodiazepines such as midazolam are the most commonly used sedative drugs Alfentanil, fentanyl, morphine, and remifentanil

com-99

M Clark and J McKinlay

are the most popular opioids for infusion They

are all equally effective at equipotent doses, offer

a degree of sedation, and only really differ in speed

of onset/offset and cost The use of a sedation

protocol with episodes of intermittent sedation

withdrawal is probably more important than the

differences between individual agents Some ICUs,

with facility to scavenge exhaust gases have also

successfully employed anesthetic agents to sedate

· Does not accumulate in renal or hepatic failure

· Inactive or nonharmful metabolites

· Cardiovascular stability

· Controllable respiratory side effects

· No interactions with other drugs

· No tolerance over time

· Cost-effective

Confusion and Agitation

Definitions

Confusion: Disturbed orientation with regard to

time, place, or person and sometimes accompanied

by disordered consciousness

Agitation: A state of anxiety accompanied by

motor restlessness

Delirium: An acute organic cerebral syndrome

in which there is fluctuating disturbance of

con-sciousness, cognition, and behavior There are

hyperactive, hypoactive, and mixed types An ICU

psychosis, encephalopathy of critical illness, and

an acute confused state are other terms used to

imply delirium

Introduction

The term delirium will be used hereafter since it

encompasses both the confused and agitated

patient Up to 80% of patients in the ICU develop

delirium although it often goes unrecognized,

especially in the elderly

Delirium is an independent predictor of length of

ICU stay, total hospital stay, and six-month mortality

It is also associated with an increase in medical complications, it can significantly hamper effec-tive medical therapy, and long- term neuropsy-chological problems are more common Agitated patients have increased levels of physiological stress with resultant tachycardia, hypertension, increased oxygen demands, and higher calorific requirement Besides being an end-organ effect

of multiple organ dysfunction syndrome, ium may augment the systemic inflammatory cascade by inducing the production of periph-eral cytokines

delir-Causes of DeliriumIncreasing age, preexisting co-morbidity, a history

of substance abuse, or neuropsychological ment are all predisposing factors to delirium in the ICU patient

impair-Common causes include pain, occult infection, metabolic derangement, hypoxia, substance with-drawal, and drug effects/interactions Environ-mental risk factors such as sleep disturbance, high levels of ambient noise and light, lack of verbal/ cognitive interaction, and immobilization are also important factors

Assessment and Diagnosis of the ICU Patient with Delirium

The 2002 SCCM guidelines for sedation in ICU suggest that all patients should be monitored for delirium and level of sedation The Richmond Agitation Sedation Scale, the Sedation Agitation Scale, the Intensive Care Delirium Screening Checklist, the Motor Activity-Assessment scale and the Confusion Assessment Method for the ICU have all been validated or shown to have diag-nostic reliability None are universally used within the United Kingdom

Management of the ICU Patient with Delirium

The principles of management of the confused or agitated patient on ICU are:

11 Coma, Confusion, and Agitation in Intensive Care

· Non-pharmacological treatment

· Pharmacological treatment

Nonpharmacological Treatment of Delirium

These include reorientation, provision of

cogni-tively stimulating activities, early mobilization,

protocols to establish normal sleep–wake cycles

and reduction in unnecessary ambient noise and

light Correction of visual and auditory

impair-ment with the patient’s normal aids (glasses and

hearing devices) is also recommended

Involve-ment of the relatives may be useful as part of the

orientation process Physical restraints, whilst

commonly used in other countries, should be

avoided unless absolutely necessary to prevent

the patient harming themselves

Pharmacological Treatment of Delirium

Inappropriate use of sedatives may actually

worsen or prolong delirium Pharmacological

intervention should only be considered for

extreme cases of agitation where the patient is

either not complying with essential therapies, or

endangering themselves, other patients, and the

staff looking after them The underlying cause of

the agitation must be treated wherever possible

In general, when sedation is deemed necessary, it

should be given in the smallest dose and for the

shortest time possible If a patient has received

multiple sedative medications with little effect,

the best solution is often to stop them all and

reas-sess Nicotine patches should be considered in

heavy smokers

There is very little evidence in the literature to

support the use of one drug over another in the

management of delirium

Major Tranquilizers

Neuroleptic Agents

Examples are haloperidol and chlorpromazine,

which act by antagonizing dopamine-mediated

neurotransmission at the cerebral synapses and

basal ganglia Haloperidol is the neuroleptic agent

of choice due to its greater efficacy and favorable

side-effect profile (e.g., lack of respiratory

depres-sion) It can be given orally or by injection (IV or

IM) The optimal dose is not widely agreed upon,

but an initial loading dose of 2–10 mg is usually effective Its relatively long half-life means that maintenance doses need only be given every 12 h

A total daily dose of 10–20 mg is adequate for most patients once they are under control Doses can be gradually tapered after 3–5 days Haloperidol can

be given by IV infusion, but its long half-life makes this unnecessary and it may cause lactic acidosis.Adverse effects of these drugs include hypotension, extrapyramidal effects, malignant hyperthermia, anticholinergic effects (dry mouth, urinary retention), and seizures The most significant risk

is torsades de pointes, and these drugs should not

be given to patients with a prolonged QT interval

Atypical Antipsychotics

Newer “atypical” antipsychotics (e.g., risperidone, olanzapine) may also be useful for delirium They affect not only dopamine, but also other key neu-rotransmitters such as serotonin, acetylcholine, and norepinephrine Although gaining popularity, there

is currently little evidence to suggest their use over more traditional treatments for delirium

Tetracyclic Antidepressants

Trazadone and mianserin are antidepressant drugs which antagonize the action of serotonin at the 5-HT2 receptor They cause a reduction in the non-cognitive symptoms of agitation that is independent

of their mood-affecting effects

Benzodiazepines

Commonly used examples are midazolam, lorazepam, diazepam, and chlordiazepoxide They act by modulating gamma-aminobutyric acid- (GABA) mediated neurotransmission within the CNS, and are very effective in the treatment of anxiety and agitation They also have excellent anticonvulsive properties and are particularly useful in the treatment of agitation due to alcohol withdrawal There is less evidence for their use in delirium of other causes and over sedation and respiratory depression are potential problems Benzodiazepines potentiate the tranquillizing effects of haloperidol As with haloperidol, the drug dose must be gradually tapered after a few days, since abrupt cessation may result in benzo-diazepine withdrawal symptoms

101

M Clark and J McKinlay

Midazolam is a rapid onset, short-acting

(half-life 2–3 h) drug It is given as a loading dose in

increments of 1–2 mg (IV) Maintenance is

usu-ally by IV infusion of approximately 0.1–0.2 mg/

kg/h Accumulation may occur with high doses or

prolonged infusions

Lorazepam has a rapid onset with an

interme-diate half-life (10–20 h) It is longer acting than

midazolam, but has no active metabolites and

accumulates to a lesser extent than other

benzo-diazepines It is the benzodiazepine of choice in

the non-ventilated patient with agitation Loading

doses are 1–2 mg (IV) Maintenance can be given

by intermittent IV or oral boluses, or by IV

infu-sion

Diazepam has a short duration of action but a

long elimination, making it unsuitable for use in

the agitated ICU patient

Chlordiazepoxide is an intermediate duration

drug that is commonly used in the treatment of

agitation due to alcohol withdrawal Oral loading

dose is 50–100 mg Maintenance doses of 20–50 mg

every 4–6 h (max 300 mg/day), with a reduction

of the dose starting on Day 3 Treatment for more

than one week is not usually required

All benzodiazepines have been shown to be

equally effective in treating problems

associ-ated with alcohol withdrawal The choice of

agent depends on the desired duration of action,

presence of hepatic disease, and available route

of administration Some debate exists as to

whether regular or “as required” dosing is more

effective

a 2 -Adrenoceptor Agonists

Clonidine is an a2-adrenoceptor agonist that has

sedative and analgesic properties A

sympatho-lytic effect on heart rate and blood pressure may

also be beneficial, but can limit its usefulness It is

increasingly used in ICU for sedation and

analge-sia, although trial evidence for its use is lacking It

is thought to be of some use in the patient with

delirium and agitation, particularly in the context

of alcohol withdrawal Intravenous loading dose is

in the order of 0.5–2.0 mcg/kg Maintenance doses

are approximately 0.1–2.0 mcg/kg/h, although

higher doses have been safely used

Dexmedetomidine, an even more potent a

2-agonist than clonidine, is also gaining popularity

as a sedative and analgesic agent on ICU It is not currently available in the United Kingdom, but has been approved in the United States for short-term sedation(less than 24 h) in ICU In major tri-als comparing it with placebo, patients required less supplemental sedation and analgesia An IV loading dose is usually 1–2.5 mcg/kg over 10 min Maintenance doses are 0.2–0.7 mcg/kg/h The drug causes minimal respiratory depression, allowing useful sedation in the extubated patient As with clonidine, the major limiting side effects are hypo-tension, bradycardia, and nausea Dexmedeto-midine is thought to be less amnesic than other sedative agents

Propofol

Propofol is widely used for sedation in intensive care It is easily titratable and accumulates to a lesser extent than other drugs for example, benzo-diazepines It is also gaining popularity as a seda-tive agent outside the ICU It is not licensed for the treatment of delirium or agitation within the ICU, but may have a role in refractory cases Case reports suggest it may be useful in patients with alcohol withdrawal symptoms

Remifentanil

Sedation using remifentanil is becoming ingly common in ICU Its pharmacokinetic profile allows easy and rapid titratability, whilst offering better awakening after cessation of infusion There is much evidence to suggest its safe use in all types of ventilated patients, either alone, or in combination with a hypnotic agent Remifentanil has also been used as a component of anesthesia

increas-in a spontaneously ventilatincreas-ing patient There is virtually no published evidence for its use as a single agent for treatment of the agitated, nonin-tubated patient in ICU

Remifentanil’s unique pharmacokinetics (i.e., a context insensitive half-time) means that it does not accumulate, irrespective of duration of use Therefore it can be a useful agent in situations where multiple drugs have been used to calm agi-tation, and where polypharmacy is now contrib-uting to the condition Remifentanil can be used to

“cover” clearance of such agents without any risk

of its own accumulation

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11 Coma, Confusion, and Agitation in Intensive Care

Nicotine

Nicotine withdrawal in heavy smokers can cause

anxiety, irritability, altered cognition, and sleep

dis-ruption Symptoms peak in the first week and may be

exaggerated in a critically ill patient with

neurocogni-tive impairment due to other factors Nicotine

replace-ment therapy (15–21 mg transdermal patch daily) can

dramatically reduce delirium in heavy smokers in

ICU, and should be considered for all such patients

Carbamazepine

Carbamazepine has been used successfully as

mon-otherapy and in combination with other sedatives

for the treatment of alcohol withdrawal-associated

delirium Its use for treatment of delirium of other

etiologies cannot be recommended

Other Drugs

The hormones melatonin and cortisol have shown

limited ability in re-establishing normal circadian

rhythm and day–night cycles, and have been used

in ICU patients

Conclusions

Altered conscious level is a common finding in

ICU patients The most important principles are

rapid assessment of the patient, immediate

inter-vention to treat potentially reversible problems,

investigation of the underlying cause, and general

supportive care of the patient Sedating drugs may

be a cause of morbidity and must be used rationally

Coma, confusion, and agitation are often due to

multiple etiologies, and demand a

multidiscipli-nary approach for effective management

Suggested Reading

Journal Articles

Cohen IL, Gallagher TJ, Pohlman AS et al (2002)

Man-agement of the agitated intensive care unit patient

Crit Care Med 30:S97–S123

Ely EW, Shintani A, Truman B et al (2004) Delirium

as a predictor of mortality in mechanically tilated patients in the intensive care unit JAMA 291:1753–1762

ven-Jacobi J, Fraser GL, Coursin DB et al (2002) Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult Crit Care Med 30:119–141

Kress JP, Pohlman AS, Hall JB (2002) Sedation and gesia in the intensive care unit Am J Respir Crit Care Med 166(8):1024–1028

anal-Mayer SA, Chong JY, Ridgway E et al (2001) Delirium from nicotine withdrawal in neuro-ICU patients Neurology 57:551–553

Osterman ME, Keenan SP, Seiferling RA et al (2000) Sedation in the intensive care unit: a systematic review JAMA 283:1451–1459

Pandharipande P, Jackson J, Ely EW (2005) Delirium: acute cognitive dysfunction in the critically ill Curr Opin Crit Care 11:360–368

Books

Diagnostic and Statistical Manual of Mental ders 4th edition (1994) American Psychiatric Association

Disor-Fink M, Abraham E, Vincent J-L, Kochanek P (2005) Textbook of Critical Care 5th edn Saunders WB, Oxford

Oh TE, Bersten AD, Soni N (eds) (2003) Intensive care manual, 5th edn Butterworth-Heinemann, Phila- delphia

Webb AJ, Shapiro MJ, Singer M, Suter P (eds) (1999) Oxford textbook of critical care Oxford University Press, Oxford

Yentis SM, Hirsch NP, Smith GB (2004) Anaesthesia and intensive care A-Z Butterworth-Heinemann, Oxford

Other Publications

An Acute Problem? National Confidential Enquiry into Patient Outcome and Death London 2005 www.nce- pod.org.uk

103

Key Points

1 In the United Kingdom, brainstem death

test-ing can, in the majority of circumstances, be

performed at the bedside

2 Brainstem death testing cannot be

contemplat-ed unless drug intoxication, hypothermia, and

metabolic and electrolyte disturbances have

been excluded

3 Four vessel cerebral angiography may be

help-ful in cases of brainstem death testing, where

drug intoxication or metabolic disturbance is

confusing the clinical picture

4 Management of the potential heart-beating

or-gan donor requires high-quality critical care,

support of the cardiovascular, respiratory, and

renal systems, and early commencement of

hormonal therapy

5 In cases of potential controlled donation after

cardiac death, analgesia and anxiolysis must

not be given simply to accelerate asystole, and

thereby facilitate donation

Background

The natural history of a fatal intracranial catastrophe

such as a spontaneous intracerebral hematoma is

one of coma (caused by compression of the

mid-brain, together with a massive reduction in cerebral

perfusion pressure), apnea (resulting from

com-pression of the pons and the medulla oblongata) and an agonal hypoxic cardiac arrest (Fig 12.1) Furthermore, although the precise sequence of events differs from other examples of cardiac death (for instance, following a myocardial infarction), the constellation of clinical signs traditionally used

to diagnose death by cardiorespiratory criteria, that is, irreversible and simultaneous coma, apnea, and the absence of circulation remain the same However, the development of cardiorespiratory resuscitation and critical care facilities in the 1950s provided clinicians with the means to interrupt the hitherto inexorable progression from intra-cranial catastrophe and irreversible apnea to cardiac death, thereby generating a clinical state in which pro-found apneic coma is associated with a preserva-tion of somatic function for as long as artificial ventilatory support is continued (Fig 12.1).The landmark description of this hitherto unrecognized complication of intensive care appeared in 1959, and was initially described as

“le coma depassé” (literally the state beyond coma) (Mollaret and Goulon 1959) The following decade saw health-care professionals across the world debate the implications of this state of irreversible neurological oblivion, its relationship with the traditional form of cardiorespiratory death, and the criteria by which it might be diagnosed with sufficient confidence to reassure both the medical profession and society at large, particularly as its close association with cadaveric solid organ dona-tion developed Criteria in North America focused

12

Death and Donation in Critical Care:

The Diagnosis of Brainstem Death

Paul G Murphy

105

P.G Murphy

on death of the brain as a whole (Wijdicks 2001),

and placed some reliance upon confirmatory

tests such as electro-encephalography or cerebral

angiography In contrast, the UK criteria, published

in their original format almost 30 years ago

(Medical royal colleges and their faculties in the

United Kingdom 1976), concentrated upon death

of the brainstem The UK code, last reissued

in 1998 (dh.gov.uk/en/Publicationsandstatistics/

Lettersandcirculars/Healthservicecirculars), states

that the irreversible loss of brainstem functions

such as maintenance of consciousness along with

the capacity to breathe is as much a state of death

as that of irreversible cardiac asystole, both being

heralds of death of the body as a whole (Conference

of Medical Royal Colleges and their Faculties in the

UK 1995) A further key feature of the UK code is

the principle that, in the majority of circumstances

at least, death of the brainstem can be determined

clinically at the bedside without recourse to specialist

imaging or other investigations through the cation of a process with three key stages (Table 12.1):

appli-1 The fulfillment of essential preconditions

2 The satisfactory exclusion of potentially reversible causes of coma

3 A clinical examination of the integrity of the brainstem

The Intensive Care Society (ICS) has recently produced up-to-date guidelines for the diagnosis

of death by neurological criteria*, which has been recently followed by the Academy of Medical Royal Colleges’ review of the UK Code for the diagnosis of brainstem death (Danzl and Pozos

1994; http://www.aomrc.org.uk/)

Figure 12.1 Death by cardio-respiratory and neurological criteria.

Table 12.1 The UK code for the diagnosis of brainstem death

Preconditions • The patient must be deeply unconscious and apneic, on a mechanical ventilator

• The patient must be suffering from defined and irremediable brain injury of a type recognized as a cause brainstem death

Exclusion criteria The diagnosis of BSD cannot be contemplated as a possible cause of , or contributor to the state of, coma unless

• Drug intoxication

• Hypothermia

• Metabolic or endocrine disturbances are excluded Evaluation of brainstem

integrity • Brainstem areflexia• Apnea on disconnection from mechanical ventilator despite a suitably elevated arterial carbon dioxide tension

& heart sounds

fixed & dilated pupils; coma

fixed & dilated

pupils; coma

fixed & dilated pupils; coma

absent breath sounds

resuscitation

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12 Death and Donation in Critical Care: The Diagnosis of Brainstem Death

Preconditions and the Causes

of Brainstem Death

The diagnosis of brainstem death (BSD) in an

indi-vidual who is deeply unconscious and on a

ventila-tor cannot be considered until a firm diagnosis of

irremediable structural brain injury has been made,

the nature and severity of which must be able to

explain the patient’s clinical condition Such

assess-ments can only be made by clinicians with

experi-ence in the management of patients with severe

brain injury Although not specifically required by

the UK code, it is increasingly unlikely that any

clinician would consider the diagnosis of BSD

without having first commissioned a radiological

examination of the intracranial contents, usually

computerized tomography (CT) The commonest

cause of BSD is malignant intra-cranial

hyperten-sion which can be a consequence of a variety of

diffuse or focal pathologies (Table 12.2), and which

results in axial descent of brainstem through the

foramen magnum, disruption of pontomedullary

blood supply, and direct compression of the

brain-stem by the cerebellar tonsils – so-called “coning”

Less commonly, BSD results from direct damage to

the medulla oblongata, pons, and mesencephalon,

and is usually a result of trauma or spontaneous

hemorrhage

Exclusions and Irreversibility

A diagnosis of BSD cannot be made whilst there remains a possibility that a patient’s comatose state

is a consequence, in whole or in part, of potentially reversible influences such as hypothermia, intoxicating drugs, and metabolic/endocrine disturbances A careful history and evaluation of

a patient’s observation and drug charts are a crucial element of this phase of the process, with the required approach depending heavily upon the particular clinical circumstances

HypothermiaProfound hypothermia induces a reversible coma-tose state that mimics BSD (Danzl and Pozos 1994) Although clinical confusion between this state and true BSD is unlikely, the contributory effects of lesser degrees of hypothermia to the badly injured brain are less clear Furthermore, BSD is associated with hypothalamic failure and the inability to main-tain a normal body temperature (poikilothermia), and it is common for such patients to be mildly hypothermic as a result Recent guidance from the Association of Medical Royal Colleges now stipulates a minimum core body temperature of 34°C for BSD testing (www.aomrc.org.uk)

Circulatory, Metabolic, and Endocrine DisturbanceThe diagnosis of BSD should not be considered

in patients who are hemodynamically unstable

or whilst there are significant acute circulatory instability or biochemical disturbances such as hyponatremia, hypoglycemia, and acidosis Hemo-dynamic instability at this stage is usually a reflec-tion of the autonomic storm that is associated with profound brainstem ischemia (Figure 12.2), and may be exacerbated by the hypovolemia of uncorrected diabetes insipidus (DI) and diuretic therapy Correction is usually easily achieved through a combination of aggressive fluid admin-istration and vasopressor therapy, although it can occasionally be challenging when there is signifi-cant neurogenic pulmonary edema and cardiac injury (for further information on the etiology

Table 12.2 Causes of brainstem death

○ Ischemic stroke

○ Malignancy

○ Cerebral abscess

• Diffuse brain injury (cerebral edema)

○ Spontaneous subarachnoid hemorrhage

○ Diffuse axonal injury following trauma

○ Hypoxic/ischemic brain injury

○ Meningitis/encephalitis Direct brainstem injury • Trauma

• Malignancy

• Stroke

107

P.G Murphy

and management of the hemodynamic instability

of brainstem death, see Chap 13)

Although a variety of chronic metabolic and

endocrine conditions can cause coma, their onset is

usually an insidious one that will be apparent on

careful review of the clinical presentation Although

BSD is frequently associated with failure of the

pitu-itary gland, the only acute endocrine disturbance of

relevance to the diagnosis of BSD is the hypovolemia

and hypernatremia that results from uncorrected DI

Furthermore, although some clinicians would

con-sider it essential to correct such hypernatremia with

hypotonic solutions such as 5% dextrose or 0.45%

NaCl, others would only do so if it was suspected that

the disturbance in serum sodium predated the patient’s deterioration into a state of apneic coma.Drug Intoxication

Drug intoxication represents a clinically significant cause of reversible cause of coma, and may result both from substances taken by the taken prior to the onset of coma (Yang and Dantzker 1991), as well

as those administered to the patient during their treatment (Grattan-Smith and Butt 1993) Sug-gested approaches to specific clinical circumstances are given in Table 12.3, the most problematic of which are circumstances where the identity of the intoxicating agent is unknown, or when long-act-ing sedative drugs are believed to be contributing

to the functional consequences of an underlying structural brain injury (Wijdicks 2001) Although the

UK approach in these circumstances is generally a conservative one (Pallis and Harley 1996), if there

is substantial reason to believe that the patient is brainstem dead (e.g., on the basis of the CT head scan or a prolonged period of malignant intracra-nial hypertension), then possible options include:

To wait until such time as the effects of the

sed-·ative agents can be excluded either by plasma assay or by allowing an interval of at least four times the context sensitive elimination half life

of the agent to elapse (Wijdicks 2001) This may

Evolving cerebral edema on serial

CT head scans Unreactive pupils Plasma assay not available.

Severe traumatic brain injury

Spontaneous subarachnoid

hemorrhage

Signs of BSD develop during several hours after admission to ICU, during which the patient has been sedated with continuous infusions

of propofol and alfentanil

Stop drug infusions Verify that no other longer acting sedative agents have been administered.

Confirm absence of neuromuscular blockade.

Complicated sedative regimen including continuous infusion of midazolam followed

by induction of barbiturate coma.

Signs of brainstem areflexia and apnea

Consider cerebral angiography if blocked cerebral circulation

Autonomic storm Myocardial ischemia

Hypotension

Massive systemic vasoconstriction

Acute mitral regurgitation Transient arterialhypertensionNeurogenic

pulmonary edema

Down-regulation of

catecholeamine receptors

and systemic vasoparalysis

108

12 Death and Donation in Critical Care: The Diagnosis of Brainstem Death

involve a period of many days in the case of

longer-acting sedative agents such as

thiopen-tone (thiopental), phenobarbithiopen-tone

(phenobar-bital), and certain benzodiazepines

Withdrawal of further cardiorespiratory

sup-·

port on the grounds of futility

To consider 4-vessel cerebral angiography or

·

trans-cranial Doppler to demonstrate the absence

of any intracranial circulation, thereby rendering

any issue regarding residual drug intoxication

or any other reversible contribution to the

com-atose state irrelevant Although such

confirma-tory tests are not currently recognized by the

existing UK Code (Bell et al 2004), experience

from elsewhere in the world suggest that they

can be invaluable in situations where there are

serious concerns regarding drug intoxication,

when access to the various brainstem reflexes is

limited, or when there is an associated high

cer-vical cord injury that may confound

interpreta-tion of the apnea test (Wijdicks 2001)

Clinical Testing for Brainstem Death

The definition of BSD according to the UK code

requires a simultaneous demonstration that the

patient has irreversibly lost the capacity for

consciousness, and the capacity to breathe, both

of which are dependent upon an intact brainstem

The clinical assessment of the integrity of the

brainstem as laid down in the UK code has two components – interrogation of a number of brain-stem-mediated cranial nerve reflexes, and the apnea test Whilst the conduct of testing overall is inevitably focused upon this final stage of the

process, it is vital to understand that the nation of brainstem areflexia and apnea can only be interpreted as indicative of BSD if the essential preconditions have been met and the various potentially reversible influences robustly excluded Furthermore, errors in the diagnosis of

combi-BSD using the UK Code, whilst being extremely rare, have invariably been the result of failures to exclude patients from testing or to identify poten-tially reversible influences, rather than errors in the performance of the tests themselves

Brainstem ReflexesDetails of the brainstem reflexes incorporated into the UK code are given in Table 12.4 The reflexes are mediated by cranial nerves whose nuclei run from the mid-brain, through the pons to the medulla oblongata, and thereby offer the opportu-nity to interrogate the integrity of the brainstem along much of its entire length (Figure 12.3) The anatomical proximity of the nuclei of the second and third cranial nerves in the midbrain to the reticular formation that maintains consciousness

Table 12.4 Cranial nerve reflexes in BSD testing

Pupillary light reflex II, III Use bright light source (not ophthalmoscope) in a dimmed environment Look for both

direct and consensual reaction Important reflex that interrogates at level of midbrain Corneal reflex V, VII Stroke cornea with gauze, whilst gently holding eyes open; avoid trauma to cornea

The various nuclei of V are found throughout the whole length of the brainstem, whilst that of VII (facial nerve) is in the upper medulla.

Central response to deep somatic

stimulation

V, VII Apply deep pressure stimulation centrally (e.g supra-orbital ridge) and peripherally

(e.g nail bed) Look for central motor response in the distribution of the facial nerve Peripheral stimulation may illicit peripheral spinal reflexes.

Cold caloric vestibule-ocular reflex III, IV, VI, VIII Check patency of external auditory canal with auroscope Flex head to 30 o (or apply 30 o

head up tilt if cervical spine injury is suspected) Slowly irrigate canal with 50 mL ice-cold water over 60 s Observe for nystagmus for a further 30 s Contra-indicated in trauma-related otorrhea The nuclei of III and IV lie within the midbrain, whilst those

of VI and VIII are in the medulla.

Gag reflex IX, X Stimulate uvula under direct vision with throat spatula, observing for contraction of soft

palate The nuclei of IX and X lie in the medulla.

Tracheal cough reflex X Expose patient to umbilicus Stimulate trachea to level of carina by introduction of

sterile suction catheter down endotracheal tube Observe for cough response.

109

P.G Murphy

indicates the importance of being able to

inter-rogate the pupillary light reflex, at least on one

side, particularly since no other reflex test

inter-rogates the midbrain function at such a high level

Similar importance can be allocated to the cough

and gag reflexes, given the proximity of the nuclei

of the glossopharyngeal and vagal nerves to the

caudal-most centers that control respiration,

although in this case difficult access to the gag

reflex test may be accommodated for by always

being able to perform the cough reflex test The

intervening reflex tests, that is, the corneal reflex,

deep central pain reflex, and the cold caloric

ves-tibulo-ocular reflex, are all mediated by cranial

nerve nuclei in the pons Such overlap allow

clini-cians to proceed with testing even on occasions where trauma might render one of the external auditory canals inaccessible, or make corneal stimulation difficult

Apnea TestingDeath of the brainstem results in the irreversible loss of the capacity to breathe The aim of the apnea test is to demonstrate the absence of respi-ration in a patient who has been disconnected from mechanical ventilation, and who has an arte-rial carbon dioxide (CO2) concentration that is above the level necessary to stimulate respiration Figure 12.3 Clinical anatomy of the brainstem.

110

12 Death and Donation in Critical Care: The Diagnosis of Brainstem Death

This level is normally set at 6.72 kPa (50 mmHg),

but should be higher in patients with chronic

(CO2) retention, the target here being acute

respi-ratory acidosis Again it is emphasized that the

irreversibility of the condition is determined by

the prior evaluation of the patient, rather than by

the test itself New UK guidelines (http://www

aomrc.org.uk/) stipulate that apnea testing should

be the last brainstem reflex to be tested, and should

not be carried out if any of the preceding tests

confirm the presence of brainstem reflexes This

avoids exposing a patient with residual brainstem

reflex activity to potentially harmful rises in

sys-temic arterial and intracranial pressure that are

sometimes observed as the arterial CO2 tension

rises during the apneic period The patient should

be preoxygenated in order to prevent hypoxia

during the period of apnea, and this can be

con-veniently done whilst examining the cranial nerve

reflexes Similarly, it may also be appropriate to

modestly reduce minute ventilation at this stage

so as to allow a gradual and controlled rise in the

arterial CO2 tension to the upper limit of normal

prior to disconnection During disconnection

oxygen should be delivered to the

tracheobron-chial tree by bulk flow, either via a suction catheter

placed into the trachea through the endotracheal

tube, or preferably with a Mapleson C type

re-breathing circuit It is important that the patient

is physically disconnected from the mechanical

ventilator during the apnea testing, since the

cardiac pulsation is frequently sufficient to trigger

ventilator-supported breaths if the ventilator is

simply set to a spontaneous breathing mode

Whilst disconnected from mechanical ventilation,

the patient should be exposed down to the

umbili-cus and their abdomen, chest, and neck

continu-ously observed for evidence of respiratory effort,

with clinical observation being supplemented by

in-line capnography, if available Although in

practice the arterial CO2 level is usually in excess

of 7 kPa after 5 min of apnea, the new UK Code

nevertheless recommends a period of observation

of no less than 5 min Patients with significant

intra-thoracic co-morbidities such as pulmonary

contusion or neurogenic pulmonary edema may

develop significant hypoxia during the apneic

interval, and it may be necessary to apply

continu-ous positive airway pressure or even the

occa-sional manual breath during testing in such

opportu-in a specialty with recognized experience and traopportu-in-ing in the diagnosis of brain death It is customary, but not mandatory, for the two doctors to perform the tests together Repetition of the tests is recom-mended but is only mandatory if organ donation is

train-to follow Whether or not a second set of tests is performed, the time of death is the time when the first set of tests was completed

Implications of Brainstem DeathThe brainstem dead patient is dead, not dying It is important that the patient’s family clearly under-stand that the declaration of BSD is not a prognosis

of future (albeit inevitable) death, but an actual current diagnosis of death that is as valid as that related to diagnosis by cardiorespiratory criteria Inevitably, the persistence of the circulation may occasionally prove a challenge for some families that may sometimes lead to conflict when the abject futil-ity of further ventilatory support is discussed The overwhelming evidence from instances where cardi-orespiratory support has been continued despite a diagnosis of brain death is that asystole almost always occurs within in a few days, and that even in those rare circumstances where somatic function is maintained for longer periods of time, no element of neurological recovery has ever been observed In our experience, giving relatives time to understand and accept the implications of the clinical diagnosis and prognosis is all that is usually required

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