Coma For Medical Finals (based On Newcastle University Learning Outcomes)

Hospital Based Practice – Coma Coma •

Presentation. o

Defined as a state of unrousable unresponsiveness. 





No evidence of arousal: •

No spontaneous eye opening

•

No comprehensible speech

•

No voluntary limb movements.

Unresponsive to external stimuli, however: •

Abnormal postures may be adopted.

•

Eyes may open to pain

•

Grunts may be elicited in response to pain.

Involuntary movements. •

o

Eg. seizure of myoclonic jerks may occur

GCS is a useful way of assessing and monitoring levels of consciousness.

Score

Eye opening

Voice

Movement in best limb

1

None

None

None

2

In response to pain

Grunting

Abnormal extension

3

In response to command

Inappropriate words

Abnormal flexion

4

Spontaneously

Confused

Withdraw from pain

Normal

Localises pain

5 6

To command o

Signs of brain shift may accompany decreasing level of consciousness. 

Signs. •

Raised ICP may produce a distinct progression of brainstem syndromes. 1.

Central herniation syndrome

2.

Lateral (uncal) herniation syndrome

3.

False localising signs

4.

Tonsillar herniation.



Central herniation syndrome. •

Vertical displacement of brainstem due to supratentorial mass. o

First signs are of diencephalic dysfunction.

o

Reduced alertness

o

Cheyne – Stokes breathing.

o

Paratonic reflexes in contralateral limbs. 

o

Up – going plantar reflexes.

o

Pupils small but reactive. 



Possibly due to hypothalamic sympathetic dysfunction.

o

May initially be unilateral hemiplegia due to supratentorial mass

o

Eventually development of decortate response to pain.

o

Abnormal flexion to pain

Mid – brain pontine dysfunction becomes evident with: •

Fluctuations in temperature.

•

Onset of central neurogenic hyperventilation

•

Apneustic or cluster breathing

•

Unreactive pupils

• 

Geganhalten

o

Mid – position

o

Often irregular in shape

o

Loss of vertical eye movements. 

Tested with “doll’s – head” movments.



Increased difficulty in eliciting horizontal oculocephalic and oculovestibular responses.

Progress from decorticate (flexor) to decerebrate (extensor) rigidity in response to pain.

Lower pontine – upper medulary compromise is revealed by: •

Ataxic breathing

•

Fixed mid – position pupils

•

Failure to elicit oculocephalic and oculovestibular responses.

•

Flaccidness at rest.

o



Medullary dysfunction is terminal. •

Breathing is ataxic or gasping.

•

Pulse rate may decrease and BP increase. o

•

•

Pain may not elicit any response apart from occasional flexor responses in the lower limbs.

Cushing’s response

After a few gasps. o

Breathing stops

o

Pupils dilate and become fixed.

Causes. o

o

o

Most usefully categorized as: 

Metabolic



Toxic



Infective



Structural lesions.

In addition, causes can be subdivided into those that cause 

Local brainstem signs



Lateralizing cerebral signs



Meningeal irritation

Generally, toxic and metabolic cuases usually don’t produce focal signs except, rarely, with 

Hypoglycaemia



Liver failure



Renal failure

o

Infections and structural lesions tend to cause focal signs.

o

Presence of meningism is a very useful clue into determining cause.

o

Coma without focal/ localising signs.



Anoxia/ hypoperfusion



Metabolic causes involve high or low: •

Glucose

•

pH

•

Sodium

•

Hypercalcaemia



o

•

Hepatic failure

•

Renal failure

Intoxications. •

Alcohol

•

Opiates

•

Benzodiazepines

•

Tricyclics

•

Neuroleptics

•

Lithium

•

Barbituates

•

Carbon monoxide



Hypothyroidism



Hypothermia/ hyperthermia



Epilepsy



Hypertensive encephalopathy.

Coma with focal/ lateralizing signs. 

Due to brainstem or cerebral dysfunction.



Vascular.



o

•

•

Cerebral haematoma

•

Infarction.

Supra – or infratentorialspace – occupying lesion. •

Only cause coma if within brainstem, or compressing thr brainstem to cause brain shift.

•

Tumour

•

Haematoma

•

Abscess

Coma with meningism. 

Subarachnoid haemorrhage



Meningitis



Encephalitis.

Severity is assessed on: o

GCS

o

Signs of brina shift

o

Signs of brainstem compromise.

•

Immediate management. o

o

o

o

Priorities. 1.

Stabalise paitient

2.

Consider giving thiamine/ glucose/ naloxone/ flumazenil

3.

Examine patien

4.

Plan for future investigations

5.

Observe for signs of deterioration, and try to reverse them.

Open airway by lying patient on their side. 

Note pattern of breathing.



If there is apnoea, laboured or disturbed breathing consider intubation and ventilation.



Measure ABGs.

Support circulation. 

Correct hypotension with colloids and/ or inotropes.



If prolonged therapy required, both require careful and frequent monitoring of central venous pressure and/ or pulmonary wedge pressure.



Search for any occult causes of bleeding, eg. abdominal cavity.

Treat seizures with usual drugs. 

Beware of over sedation and hypotension.



Benzodiazepines



•

Diazepam

•

Lorazepam

•

Phenytoin

•

Fosphenytoin

•

Paraldehyde

•

General anaesthetic.

Take blood for: •

FBC

•

U&Es

•

LFTs

•

Glucose

•

Calcium

•

Clotting screen

•

Toxicology

• o

o

Urgent paracetamol

o

Urgent salicylates

Urine toxicology screen.

Consider thiamine, dextrose, naloxone or flumazenil 

Check BM. •

Good argument for giving 50 ml of 50% glucose immediately in presumed hypoglycaemia, as it won’t do any harm and might rouse the patient if the diagnosis is hypoglycaemia. o







Naloxone should only be given if opiate intoxication is likely. •

Suggested by small pupils

•

In adults give 0.8 – 2.0 mg IV every 2 – 3 minutes, to a maximum of 10 mg.

Flumazenil should only be given if benzodiazepine intoxication is likely. •

Contraindicated in epileptics who are on prolonged benzodiazepine therapy.

•

In adults give. o

200 μg over 15 seconds

o

100 μg at 1 minute intervals.

o

Usual dose is 300 – 600 μg

o

Maximum dose outside ITU is 1 mg

Both naloxone and flumazenil can be repeated if drowsiness returns. •

o

Dextrose may precipitate Wernike’s encephalopathy, so give 100 – 200 mg IV thiamine first.

Better if this is done in an ITU setting.

Examine patient.



If a history is available it makes assessment much easier.



Even if history not extensive, a witness can give clues as to the cause. •

Sudden onset suggests vascular event

•

Is the patient suffering from any underlying disease



An examination of a comatose patient should be thorough and cover all relevant areas. •

•

Core temperature. o

Fever normally suggests fever, but can be cause by diencephalic lesions.

o

Hypothermia is often forgotten as a cause of coma.

o

Possibility of myxoedema should be considered.

Heart rate and rhythm. o

•

•

May indicate arrhythmias causing poor cerebral perfusion

Blood pressure. o

Prolonged hypotension causes anoxia and ischemia.

o

Apart from cardiac causes, consider: 

Occult bleeding



Sepsis



Drug intoxication

Respiratory pattern. o

Shallow, slow breathing suggests drug intoxication. 

•

Eg. opiates

o

Deep, rapid Kussmaul breathing suggests acidosis

o

Brainstem compromise can cause breathing that is: 

Apneustic



Ataxic



Gasping.

Breath. o

Alcohol

o

Ketones

o

Hepatic foetor

o

•

•

Skin. o

Signs of head trauma

o

Basal skull fracture suggested by: 

Bruising over scalp and mastoids



Blood in nostrils



Blood in ears,

o

Rash suggests meningococcal septicaemia

o

Look for. 

Signs of chronic liver failure.



Sallow discolouration of uraemia



Needle tracks of IV drug users.

Heart. o

•

Uraemic foetor.

Occasionally bacterial endocarditis or vasculitides associated with heart murmurs can present with coma.

Abdomen. o

Look for organomegaly. 

o

•

May suggest causes of coma.

Important not to miss acute intra – abdominal event. 

Perforation of viscus



Leaking AAA

Fundi. o

Papilloedema indicates raised ICP 

o

Absence of papilloedema doesn’t exclude raised ICP.

Subhyloid bleeds are pathognomonic of sub – arachnoid haemorrhage. 

Rare finding.

o

•

Meningism. o

Neck stiffness assessed on if there has definitely been no trauma to cervical spine.

o

Increased stiffness suggests meningeal irritation due to:

o

o •

•

Changes due to diabetes or hypertension suggest encephalopathy secondary to these conditions.



Inflammation



Infiltration



Presence of blood.

Meningism raises possibility of 

Meningitis



Encephalitis



Subarachnoid bleeding.

Start Abx as soon as meningitis is suspected.

Assess GCS. o

May reveal brainstem dysfunction or localizing signs.

o

Decorticate or decerebrate posturing may become clear on assessing motor function.

o

Changing signs may indicated brain shift.

Evidence of brain stem dysfunction. o

Test and observe. 

Pupillary responses



Corneal reflexes



Resting position of the eye



Spontaneous eye movements.



Oculocephalic response.

o

•

Doll’s head manoeuvre

•

Don’t perform if any risk of C – spine injury.



Oculovestibular/ calorific stimulation.



Swallowing



Respiratory problems.

Brainstem function occurs when there is 

Intrinsic lesion



Extrinsic compression



Metabolic causes. •

•

Eg. drug intoxication.

o

If there are focal signs, lesion is more likely to be intrinsic.

o

If there is retro – caudal progression of signs, this strongly suggests herniation syndrome.

o

If there appears to be brainstem dysfunction it may not be easy to distinguish between structural and metabolic cuases. 

In metabolic coma, pupils are responsive to light.



Only possibly not reactive to light I if patient is on. •

Atropine

•

Scopolamine

•

Glutethiamine intoxication.

Assessing lateralizing signs. o

o

General exam or GCS will detect patients with lateralizing sigsns. 

Differences in facial symmetry



Altered muscle tone



Altered reflexes.

As said above, lateralising signs point to presence of: 

Infection

 o

o

Structural lesions.

Focal signs can occasionally be found with metabolic causes.

Plans for future management. 

Diagnosis helped by history, examination and laboratory studies.



Often this takes time or only gives vague hints.



Most useful next step depends on whether brainstem function is intact or not.



Brainstem function intact. •

Urgent CT head will reveal one of the following. o

o

Operable lesions, which should be referred as appropriate. 

Subdural haematoma



Subarachnoid haemorrhage



Intracranial haemorrhage

Inoperable lesions, for which treatment is supportative. 

o •



Normal CT

If CT is normal, perform lumbar puncture. o

•

Eg. bilateral cortical infarcts.

CSF analysis may reveal an infective process. 

Meningitis



Encephalitis.

If CSF analysis normal, most probable cause is metabolic.

If brainstem function not intact. •

Consider if there are signs of brain shift.

•

If herniation syndrome appears to be progressing rapidly.

•

•

o

Give mannitol

o

Force patient to hyperventilate

o

Fast bleep neurosurgery.

If progression is not quite so rapid. o

Give mannitol

o

Send for urgent CT

Even if brainstem signs don’t appear to be progressing, send for CT to exclude operable posterior fossa mass. o

o

•

If CT is normal, send for lumbar puncture to look for infection.

•

If lumbar puncture also normal, likely diagnoses are: o

Intrinsic brinastem disease not visable on CT

o

Metabolic coma

o

Posible infection without leukocyte response

•

Consider MRI, as more sensitive than CT in detecting intrinsic brainstem disease.

•

Repeat lumbar puncture the next day if no improvement in condition.

•

Treatment is supportative.

Monitoring progress. 



Regular observation of vital signs, neurological state and electrolytes •

Including GCS.

•

Deterioration often due to: o

Electrolyte or metabolic changes.

o

Hypovolaemia or fluid overload.

Important cause of deterioration in structural lesions is brain shift and herniation. •

o

Eg. cerebellar haematoma.

Recognition and treatment of raised ICP to be discussed later.

Prognosis. 

When coma related to head injury, prognosis closely related to GCS score.

• 

In non – traumatic coma, GCS alone is not a very good indocator of prognosis. •



Very poor prognosis at GCS < 9.

Drug intoxication causes very low scores on admission, but has generally good outcomes.

Assessment of prognosis in non – traumatic coma is assisted by simple examination findings. •

For example, a patient at 24 hours who still has no papillary, corneal or oculovestibular response has a very poor chance of survival.

Raised ICP. •

Presentation. o

Normal ICP in adults is 0 – 10 mmHg at rest.

o

Treatment is required when ICP > 15 – 20 mmHg for > 5 minutes.

o

Signs and symptoms suggestive of raised ICP include. 

Headache & vomiting. •

Worse in morning. o

• 



•

Normally occur in presence of a space occupying lesion

•

May occur with medical conditions, eg. liver failure.

•

May be false localising signs, eg. VIth nerve palsy

Seizures. May occur with: o

Space occupying lesions

o

CNS infections

o

Metabolic encephalopathies

Papiolloedema. •



Exacerbated by bending over.

Focal neurological signs.

•



Morning occipital headache could be raised ICP, or cervical spondylosis

Only present in CSF obstruction.

Impaired consciousness.

• 

Signs of brain shift. •



•

May accompany decreasiung consciousness levels.

Bradycardia with hypertension. •

Late sign

•

Known as Cushing’s response.

•

Probably due to direct medullary compression

•

Clinical value is probably overemphasised in comparison with other signs of brain shift.

Causes. o

Head injury. 

Leads to subdural haematoma/ brain swelling/ contusion.

o

Stroke.

o

Metabolic.

o

•

Ranges from mild confusion to coma.



Liver failure



Renal failure



DKA



Hyponatraemia



Etc.

CNS infection. 

Abscess



Encephalitis



Meningitis



Malaria.

o

CNS tumour

o

Status epilepticus

o

Hydrocephalus

o

“Benign “ intercranial hyp[ertension.

Assessment of severity. o

GCS

o

Signs of brain shift

o •

•

Signs of brainstem compromise.;

Management. o

Stabalise the patient.

o

Consider active measures to reduce ICP

o

Attempt to make a diagnosis

o

Treat factors which may exacerbate raised ICP

o

Observe for signs of deterioration, and try to treat them.

o

Consider specific therapies.

Stabalise the patient. o

Open airway by lying patient on their side.

o

Give oxygen

o

Check ABGs.

o

Consider need for intubation and ventilation.

o Hyperventilate the patient to keep PaCO2 = 3.3 – 4.0 kPa o

o

Correct hypotension. 

Ensure frequent and careful monitoring of CVP and pulmonary wedge pressure so as to not overload patient and worsen ICP.



Generally, patients with raised ICP should be fluid restricted to 1.5 – 2.0 L/day.



Volume expand with colloids or inotropes as little as possible to maintain a good BP.

Treat seizures. 

o

o

See later section on status epilepticus.

Examine rapidly for signs of head injury. 

If patient is hypotensive, examine carefully for any occult blood loss.



If there is a rash, consider meningococcal meningitis. •

Take blood cultures.

•

Give antibiotics.

Check venous blood glucose. 

Raised in DKA and HONK.

 o

Check U&Es. 

Biochemical assessment for dehydration & renal function



Potassium for suscepitibility to dysrrhythmias



Hyponatraemia in inappropriate ADH secretion.



Hypernatraemia in over aggressive diuretic – induced dehydration.

o

LFTs.

o

Albumin

o

Clotting studies

o

Ammonium. 

•

May be low in liver failure

To assess liver function

o

FBC

o

Blood cultures.

Measures to reduce ICP. o

Value of ICP monitotring is controversial.

o

Regardless of whether ICP is being actively monitored or not, consider following interventions.

o Elevate head of bed to 30o. 

Once C – spine injury has been ruled out.



Promoted venous drainage.

o Hyperventilate to blow off CO2. 

Promoted cerebral vasoconstriction



Lowers cerebral blood volume



Requires intubation and paralysis.



Will also lower BP. •

o

May compromise cerebral circulation.



Discuss with ITU.



No longer indicated in patients with liver failure.

Mannitol. 

0.5 – 1 g/kg over 10 – 15 minutes. •

About 250 ml of 20% solution for an average adult.



Reduces ICP within 20 minutes



Effects last for 2 – 6 hours



Potentiated with 20 – 40 mg IV Frusemide.



If required, boluses of 0.25 – 0.5 g/kg can be given every few hours.



Monitor U&E and serum osmolality carefully as profound diuresis may occur. •

o

o

Do not allow serum osmolality to rise > 320 mOsm/kg.

Corticosteroids. 

Benefit in reducing oedema around space occupying lesion.



Not useful in treating stroke or head injury.



Dextramethasone. •

Loading dose of 10 mg IV

•

Followed by 4 – 6 mg QDS PO or via NG tube.

Fluid restrict. 

1.5 – 2.0 L/day



Check U&E regularly.

o Cool to 35 oC  o

Avoid/ treat hypoglycaemia. 

•

Reduces cerebral ischemia.

Exacerbates ischemia

Attempt to make a diagnosis. o

Often history makes diagnosis obvious, and raised ICP is a secondary diagnosis.

o

If history not available, focal neurological signs or seizures suggest an underlying structural lesion. 

May also occur with hepatic or renal failure.

o

Meningism should lead to a suspicion of SAH, meningitis or encephalitis.

o

CT should be performed in all patients with suspected raised ICP prior to lumbar puncture being performed. 

o

Lubar puncture should be discussed with a senior colleague or neurologist.

Blood sent for analysis on admission may assist in diagnosing metabolic causes.

o

Benign intra – cranial hypertension. 

Syndrome of raised ICP in absence of intercranial mass or hydrocephalus.



Rarely life threatening



Can cause permanent visual loss, secondary to optic nerve damage.



Affects 1 in 100000 of population overall.



•

Rises to 1:5000 in obese women of child bearing age.

•

Predominance of women over men of 4:1 in age range 17 – 45.

Presentation. •

Constant, but variable, headache.

•

Visual disturbances. o

Diplopia

o

Visual obscurations

o

Scotoma

•

Nausea

•

Problems with balance

•

Problems with memory

•

Tinnitus

•

Neck and back pain

•

Papilloedema. o

•

May be unilateral

BIH can be distinguished from other cause of raised ICP as there are: o

No focal signs

o

No Epilepsy

o

No loss of cerebral function. 

Compare with bacterial meningitis



•

•

Associations. o

Obesity is present in 90%

o

Menstrual problems

o

Drugs. 

Tetracycline



Isoretinoin



Etretinate



Malidixic acid



Nitrofruantoin



Lithium

o

Oral contraceptive pills

o

Steroid withdrawl

o

Recurrent miscarriage

Investigations o

CT head and MRI generally normal.

o

Lumbar puncture reveals CSF pressure increased by > 20 cm. 

•

Compare with viral encephalitis.

May increase in obesity anyway.

Management. o

Seek expert advice.

o

Lose weight

o

Therapeutic lumbar puncture every 2 – 5 days.

o

Prednisolone. 

40 – 60 mg/day.



Effective in relieving headache and visual obscuration papilloedema.



Steroids shouldn’t be used long – term.

o

Acetazolamide ± Frusemide.

o

Surgical shunting.

 •

Treat factors that exacerbate raised ICP. o

Hypoxia/ hypercapnia. 

o

ABGs need to be measured regularly.

Inadequate analgesia, sedation or muscle relaxation. 

Pain causes hypertension.



Hypertension shouldn’t be treated aggressively. •

o

o

Can lead to border zone cerebral infarcts.

Seizures. 

•

Eg. lumboperitoneal shunt.

May be difficult to identify in paralysed patients.

Pyrexia. 

Increases cerebral metabolism, and conquently cerebral vasodilatation.



Also appears to increase cerebral oedema



Cause of pyrexia should be sought.



Give PR/IV paracetamol.



Actively cool patients.

o

Hypovolaemia

o

Hyponatraemia. 

Usually result of fluid overload



May be caused by a SIADH secretion.



Treat with DDAVP 1 – 4 μg IV daily

Consider specific therapies. o

Once diagnosis is established, may be appropriate to consider surgery. 

Decompression of brain



Insert ventricular shunt to drain CSF.

o Intracranial infections should be treated with most appropriate antibiotics. o

o

Many metabolic causes have their own specific treatments: 

Hyperglycaemia



Liver failure



Renal faliure

Often there is not a specific intervention that is appropriate. 

Eg. Contusion following head injury.



Management is a case of optimising patient’s condition whilst awaiting recovery.

Epidemiology poisoning. •

•

Poisoning can be: o Acute (eg. overdose). o Chronic o Acute on Chronic. It can also be catagorised into: o Deliberate:  Self harm.  Homocidal o Accidental

•

Each year in England. o 135,000 cases of poisoning/overdose presents to A&E. o 100,000 of these are admitted. o 300 of these die in hospital. o 3000 die out of hospital or before they get to hospital.

•

Exposure to poisoning can be: o Oral (eg. drug overdose) o Inhlaed (eg. smoke inhalation). o Percutaneous (eg. cyanide, organophosphates). o Occular (eg. industrial chemicals) o Chemical burns. As a rule of thumb, most poisonings are: o Deliberate. o Self – harm. o Using drugs. o Taken orally. The two groups of patients who commonly present with poisoning are: o Young children.  1 – 5 years.  Males more frequently than females.  Due to accidental ingestion.  Presents during the day. o Adolescents and young adults.  Equal gender split.  Due to deliberate self harm.  Presents evening and night time.  Increased episodes at weekends.

•

•

•

•

Trends in deliberate drug overdoses. o Non – opioid analgesics account for about 55% of overdoses, and is steadily increasing. o Paracetamol accounts for about 40% of overdoses, but is very rapidly increasing. o Tranquilizers and sedatives account for about 15% of overdoses, but is steadily decreasing. o Antidepressants are fairly stable at about 15% of overdoses  But now tend to be SSRIs rather than tricyclics, so much fewer deaths. In males in the Scottish borders from 1983 – 1991. o The most common route of successful suicide between 25 – 65 was overdose. o Below, and above, these ages it was hanging.

•

It is very important to practice social medicine in the follow up of patients who present with deliberate self – poisoning. o Without interventions, 35% will be dead within 10 years. o Natural causes accounts for 30% of these (10% of all patients). o Suicide accounts for only 22% of these (8% of all patients). o This suggests that the patients who present with deliberate self poisoning have social factors that put them at an increased risk of death.

•

Most common poisons causing death: o Paracetamol. o Tricyclic antidepressants. o Opiates.  IV heroin.  Co – proxamol • Arrythmias. • Loss of consciousness • Acidosis • Plus paracetamol effects. o Carbon monoxide, in smoke from housefires.

•

Interval between poisoning and presentation at hospital is very important in terms of prognosis. People are quite good at presenting early, but wee need to get even more to present early.

• 45 40 35 30 25 20 15 10 5 0

<1 hr

1 - 2hr

2 - 4hr

4 - 8hr

> 15 hr

•

Immediate management: o Airway:  Ensure adequate airway and gag reflex.  ? Intubate.  Coma position. o Breathing:  Respiratory rate.  Oxygen Sats.  Blood Gases. o Circulation.  Assess pulse, BP, perfusion.  Obtain IV access.  Consider IV fluids for hypotension.

•

Immediate history. o Likely to be collateral. o When did the overdose take place? o What poisons were involved?  Bottles?  Tablets?

o o

•

 Prescription drugs?  Alcohol? Mode and duration of exposure?  Eg. smoke inhalation. Symptoms?  Especially vomiting. • Good sign: Evacuates tablets. • Bad sign: Shows that the patient is toxic.  Convulsions: • Tricyclics. • Theophylline • Opiods • Mefenamic acid • Isoniazid • Amphetamines  Delerium and hallucinations. • Anticholinergics. • Amphetamines • Cannabis (allegedly) • Recovery from tricyclic overdose  Blindness: • Methanol. • Quinine  Tinnitus and deafness. • Salicylates. • Quinine.

Later history. o Not collateral. o Why was the overdose taken? o Past history of self harm? o Attempt at concealment?  Timing.  Precautions against discovery.  Medical help sort? • Did patient seek help, or were they found and brought in?  Final acts performed? • Will • Life insurance.  Suicide note?  Overdose expected to be fatal?  Wanted to die?  Premeditation?  Symptoms of psychiatric illness?

o •

 Isolation? Perform quantative Bede’s suicide risk test.

On Examination look particularly for: o Skin colour.  Cyanotic?  Hyperperfused? o Temperature.  Hypothermia • Phenothiazines. • Barbituates.  Pyrexia • Amphetamines. • MAOIs • Cocaine • MDMA o Pulse rate and rhythm.  Fast and/ or irregular. • Salbutamol. • Antimuscarinics. • Tricyclics. • Quinine • Phenothiazine o Blood pressure. o Coma scale  Benzodiazepines.  Alcohols  Opiates  Tricyclics  Barbituates

Motor 6 – Obeys commands. 5 – Localises to pain. 4 – Withdrawl from pain. 3 – Abnormal flexion 2 – Abnormal extension 1 – No movement

Voice 5 – Coherent speech 4 – Confused conversation 3 – Inappropriate with no conversation 2 – Grunting 1 – No speech

Eyes. 4 – Open spontaneously 3 – Open to voice 2 – Open to pain 1 – Don’t open

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o o o o

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Pupils.  Constricted pupils. • Opioids. • Organophosphates. • Nerve agents  Dilated pupils. • Tricyclic antidepressants • Amphetamines • Cocaine • Anticholinergics • Quinine Muscle tone.  Hypertonia. • Tricyclics. • Anticholinergics. Tendon reflexes.  Hypereflexia. • Tricyclics. • Anticholinergics. Respiratory rate.  Hyperventilation. • Salicylates. • Phenoxyacetate herbicides. • Theophylline. • Hyperthermia • MDMA  Respiratory depression. • Opiates. • Benzodiazepam • Alcohols Needle marks Blisters/ Bullae.  Pressure  Kerosene  Barbiturates  Carbon monoxide. Pressure sores.  Risk in prolonged coma. Mucosal ulceration.  Sign of paraquat poisoning. Skin lacerations.  Old or new trauma? Dystonia (spasms)  Metoclopramide  Phenothiazines Divergent strabismus (divergent squint)  Tricyclic antidepressants. Papilloedema.  Carbon monoxide.  Methanol

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Nystagmus.  Phenytoin  Carbamezapine

Investigations in the poisoned patient. o FBC. o U&E  Hyponatraemia in MDMA.  Hypokalaemia in theophylline.  Hyperkalaemia in digoxin. o Creatinine.  Low urine creatinine compared to blood creatinine suggests renal failure. o BM  Hyperglycaemia. • Organophosphates. • Theophyllines • MAOIs  Hypoglycaemia. • Insulin. • Oral hypoglycaemics. • Alcohols. • Salicylates o ABG  Metabolic acidosis in: • Carbon monoxide. • Cocaine. • Ethanol. • Ethylene glycol • Methanol • Iron • Paracetamol • Salicylates • Tricyclics o ECG  Anything causing renal failure or other sources of hyperkalaemia can cause VF/VT.  Renal failure: • Salicylates. • Paracetamol • Ethylene glycol o Routine tests for specific poisons.  Paracetamol.  Salicylates. • ?Query as to whether it is cost effective.  CarboxyHb for carbon monoxide o Tests for specific poisons based on clinical suspicion.  Lithium. • Don’t use lithium- heparin tube.  Paraquat.  Iron  Methanol

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LFTs. Toxicology screen of urine.  No use in acute management, as takes a week to come back.  Useful for if patient still hasn’t recovered in a weeks time.  Need to do it for medicolegal reasons.

Gastric decontamination techniques •

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Methods available. o Activated charcoal. o Gastric aspiration/ lavage. o Induced emesis with Ipecacuanha. Theory. o Aim to reduce absorption of oral poisons. o Only required when ingested poison carries significant risk. o Little evidence for benefit unless used within 1 hour (depends on poison). o Cannot be used in patient with reduced LOC unless airway is protected.

Induced emesis. • Uses syrup of ipecacuanha. • Two doses produced vomiting in > 90% of people. • However. o Probably least effective way of removing poisons. o Induced vomiting may mask the fact that patient is still vomiting due to being toxic. • Complications o Persistent vomiting. o Diarrhoea. o Lethargy. o Aspiration. o Mallory – Weiss tear of stomach/ oesophageal mucosa. o Gastric herniation o Foetal abortion. • Contraindications. o Adults. o Patients with reduced LOC and poor gag reflex. • Rarely, if ever, appropriate. Gastric aspiration/ lavage. • AKA stomach pumping. • Suitable for: o Very large and life threatening overdoses. o Poisons not absorbed by activated charcoal. • More difficult in children. • In patients with reduced LOC and poor gag reflex, protect airway with cuffed endotracheal tube. • Complications. o Gut perforation. o Aspiration. o Laryngospasm. o Water intoxication (in children) o Dysrhythmias o Pneumothorax.

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o Enhanced early drug absorption. Contraindications. o Poisons where there is risk of aspiration pneumonitis and performation.  Hydrocarbon ingestion.  Caustic substance injection.

Activated charcoal. • Charcoal activated by heating in steam/ air/ carbon dioxide at 600 – 900 oC. • Adsorbs poison onto surface from GI tracts by direct contact. • Required charcoal:drug ratio is variable: o In rats, an 8:1 ratio needed for>80% reduction in concentration. o Normally use a 10:1 ratio in humans, up to 50g in one dose. • Good for: o Phenobarbitone. o Chloroquine. o Isoniazid. • Preferred method of evacuation due to simplicity. • Unpalatable, so often suspended in flat cola. • Can be delivered by NG tube in unconscious patients. o Airway should be protected by cuffed endotracheal tube if gag reflex poor.absent. • Should be given as early as possible to increase efficacy: o 56% concentration reduction from control if given at 1 hour. o 22% concentration reduction from control if given at 2 hours. o 8% concentration reduction from control if given at 4 hours. • Complications: o Aspiration pneumonitis. o Reduced absorption of therapeutic agents (eg. methionine in paracetamol poisoning). o Briquette formation, causing bowel obstruction. • Contraindications. o Poor bowel motility (particularly if bowel sounds absent). o Impaired gag reflex. o Inability to swallow. • Ineffective in: o Elemental metals/salts.  Lithium.  Iron  Boron o Insecticides:  Malathion  DDT  N – methyl carbamate o Cyanide o Strog acids/ alkalis. o Alcohols o Hydrocarbons.

Methods for increasing drug elimination • Methods used: o Multiple dose activated charcoal (MDAC). o Haemodialysis. o Haemoperfusion. o Haemofiltration o Combined methods.  Haemodiafiltration.  MARS MDAC • 50g activated charcoal, followed by 25 g every two hours. o Give laculose or magnesium sulphate to prevent constipation. • Reduced elimination half life by: o ‘Gastrointestinal dialysis’. o Interfering with enterohepatic circulation.  Bile salts (containing poison) circulate from gut to liver.  Having a gut full of charcoal will mean that poison will be adsorbed by the charcoal every time it passes through the gut. • Good evidence of efficacy in: o Carbemazipine. o Dapsone. o Phenobarbitone. o Quinine. o Theophylline. • Sometimes used for: o Alicylates. o Phenytoin. • Can lead to intestinal obstruction. Haemodialysis/ Haemoperfusion. • Useful when: o Poison has a small volume of distribution. o Has low clearance rate. o Is sufficiently toxic. o Is either:  Small enough to cross dialysis membrane (HD).  Bound to activated charcoal (HP). • Haemodyalisis. o Consider in life – threatening overdoses of:

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 Methanol  Ethylene glycol.  Isopropanol.  Salicylate  Sodium valproate.  Lithium Charcoal haemoperfusion. o Consider in life – threatening overdoses of:  Theophylline.  Aminophylline.  Phenytoin.  Carbemazepine.  Phenobarbitone.  Amylobarbitone.

Antidotes. Poison Paracetamol Opiates Benzodiazepines Ethylene glycol Methanol Iron Heavy metals Cyanide

Dapsone Organophosphates Digoxin Snake bites Oral anticoagulants. Beta – blockers Carbon monoxide

Antidote • N – acetylcysteine. • Methionine • Nalaxone • Flumazenil • Ethanol • Fomepizole • Desferrioxamine. (Fe) • Dimercaprol • Dicobalt edetate (CN) • Sodium Calcium edetate (Pb) • Dimercaptosuccinic acid (DMSA/ Succimer) (Pb, As) • Dimercaprol (Mercury) • Dimercaptopropanesulphonat e (DMPS/ Unithiol) (Mercury) • Sodium nitrate (CN) • Sodium thiosuplhate (CN) • Hydroxycobalamin (CN) • Methylene blue (CN) • Penicillamine (Mercury) • Prussian Blue (Thallium) • Methylene blue • Pralidoxime • Atropine • Digibind • • • • • •

Zagreb antivenom Vitamin K Atropine Glucagon Oxygen Methylene blue

Mechanism Glutathione repletors. Specific antagonist Alcohol dehydrogenase inhibitors. Chelating or fixing agents

Reducing agent Cholinesterase reactivator Muscarinic antagonist. Anti – digoxin antibody fragments. Antivenom

Reducing agent.

Management of specific poisons. Paracetamol. • Most popular analgesic in Britain. • Accounts for half of all overdoses presenting to hospital. • One of the leading causes of mortality from poisoning. o 100 – 200 deaths per year. o However, mortality from paracetamol OD < 1%. Mechanism of toxicity. • Most paracetamol conjugated with glucuronide or sulphate. • Small amount metabolised to reactive species N – acetyl – para – benzo – quinoneimine (NAPQI). • NAPQI then detoxified by conjugation with glutathione to form mercapturic acid. • In overdose, the major pathway is saturated; so lots of paracetamol goes down the minor pathway producing large amounts of NAPQI. • The liver’s stores of glutathione become exhausted, meaning that much of the NAPQI produced does not become detoxified, and so causes heapatocyte cell death by oxidation damage. • Induction of hepatic enzymes increases toxicity by pushing more paracetamol down the minor pathway. o Alcohol. o Phenytoin. o Rifampicin o Short term under – nutrition, due to decreased glutathione stores. Clinical Features. • Early: o Non – specific. o Nausea/ vomiting/ Abdo pain. o NO IMPAIRMENT OF CONCIOUSNESS • Delayed: o Hepatic necrosis after 2 – 3 days.  Jaundice.  Liver pain.  Encephalopathy.

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 Fulminant hepatic failure.  Death (3 – 6 days after overdose). Renal failure.  Less common.  Presents 2 – 7 days after OD.  Oliguria  Loin pain. Hypoglycaemia Metabolic acidosis.

Investigations. • Paracetamol levels. o Best early predictor of prognosis. o Determines need for antidotes.  In normal patients, treat if blood paracetamol > 200 at 4 hours.  In high risk patients treat if blood paracetamol > 125 at 4 hours.  Always be aware of the staggered dose overdose. • Will cause blood paracetamol to continue increasing over a longer period so, for example, blood levels could be 150 at 4 hours, but 250 at 6 hours. • Clotting studies. o Especially INR or PT.  Increased due to reduced production of clotting factors II, V and VII. • U&E and Creatinine. o Creatinine elevated in renal failure. o Urea may be artificially low in severe hepatic failure as the liver will stop producing it. • Blood gases. o Metabolic acidosis in severe poisoning. • LFTs. o Elevated transaminases are common.  Poor prognostic indicator. o Raised bilirubin indicates significant hepatic necrosis.  Not as sensitive or specific as clotting studies. Poor prognostic factors. • PT or INR rising after day 3. • PT > 180 at any time. • Bilirubin > 70 umol/l • Metabolic acidosis. Treatment

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Prevention of absorption. o Activated charcoal is dose was large. o Gastric lavage ± activated charcoal if dose was very large (>50g) o Only indicated if less than 1 hour post OD. Antidotes. o Provide glutathione for detoxification of NAPQI. o Value of antidotes decreases with time.

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N – Acetylecysteine. o Given IV over 20 hours in the UK. o Given orally over 72 hours in the US. o Very effective up to 8 hours post OD. o Some effect up to 24 hours post OD, but value decreases with time. o Current thinking is to treat at any point in severe poisoning. o Beneficial in patients with fulminant hepatic failure. o Complications.  Anaphylactoid reaction. • Urticaria. • Wheezing. • Hypotensions.  Not true allergy, but dose – related histamine release.  Reduce infusion rate and give antihistamines.

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Methionine. o Given orally in 4 doses. o Probably less effective than NAC. o Much less effective after 10 hours. o Rarely used in the UK. Supportative therapies. o Vitamin K.  Discussion as to appropriateness, as will artificially lower PT/INR, and so these will not be able to be used as markers of hepatic damage. o Fresh frozen plasma.  Only in active bleeding. o Hepatic intensive care.  Fluid balance.  Inotropic support.  Intercranial pressure monitoring. o Dyalysis for renal failure. o Orthotopic liver transplantation.

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Aspirin. • •

Now less common than paracetamol poisoning in the UK. Clinical features. o Dizziness. o Sweating. o Tinnitus. o Vomiting. o Vasodilatation.

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Hyperventilation. Agitation. Delerium. Coma.  Especially in children. Metabolic aicdosis.  Especially in children.  Due to acidifying effect of salicylate and poor tissue perfusion producing lactic acid. Respiratory alkalosis.  Especially in adults.  Due to direct respiratory stimulation. *** The two deranged Acid – Base states can occur simulataneously, to give an apparently normal pH ***.  Take into account the anion gap, which will be increased in a metabolic acidosis. Hypoglycaemia. Hypokalaemia.

Investigations. • Plasma salicylate concentration. • U&E • Bicarbonate. • BM • ABG. Treatment. • Gastric decontamination. o 50g activated charcoal. o ? gastric lavage + activated charcoal if very large OD (rarely used) o Within 1 hour of OD. • Enhanced elimination. o Repeated doses of activated charcoal. • No longer use forced alkaline diuresis as is dangerous and ineffective. •

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Opiates.

Haemodyalisis. o Highly effective at removing salicylate. o Also corrects metabolic abnormalities. o Consider when:  pH < 7.3  Salicylate > 750 mg/l • Salicylate > 600 mg/l in children.  Presence of renal failure. Supportative treatment. o Airway. o IV fluids. o Ventilation. o Glucose for hypoglycaemia. o KCl for hypokalaemia. o IV bicarbonate for less aggressive alkaline diuresis.

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The common opiates used in overdose are: o Heroin. o Morphine. o Methadone. o Dihydrocodiene. o Codiene. o Pathidine. o Dipipanone o Dextropropoxyphene They are normally taken: o Orally. o Smoked. o IV. Effects: o CNS and respiratory depression. o Pin point pupils. o Hypotension with tachycardia. o Hallucinations. o Rhabdomyolysis. o Non – cardiac pulmonary oedema. Management: o Naloxone. o Supportative care. o IPPV + PEEP o Blood bourn virus precautions in IV drug users.

Naloxone: o Use in suspected opiate intoxication.  Diagnosis.  Treatment. o Aim is to rouse the patient enough to maintain their own airway and breathing. o Use adequate doses.  Adults: 2.4 mg or more.  Children: Titrate up from 0.01 mg/kg. o Repeat as necessary or use infusion.  IV infusion dose per hour is 2/3 of bolus dose required for rousing. o Dangers:  Pain due to antagonism of analgesics.  Acute withdrawl symptoms. • Muscle aches. • Diarrhoea • Palpatations. • Rhinorrhoea. • Yawning • Irritability • Nausea • Fever • Tremor

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• Cramps. Self discharge due to waking from coma. • Leads to coma and death outside hospital when naloxone wears off. Hypertension. Behavioural disturbances. • At high doses. Rarely: • Fits. • Arrythmias. • Pulmonary oedema.

Tricylcic Antidepressants. • • •

Account for about 10% of overdoses. High fatality rate. 100 – 200 deaths per year in the UK (similar to paracetamol).

Clinical features. • Hot, dry skin. • Dilated pupils. • Tachycardia • Urinary retention. • Cardiac arrythmias. o VT o VF o Wide QRS complexes on ECG due to delaying of Na channels, due to acidosis. • Agitation. • Delerium. • Fits. • Coma. • Hypertonia • Hypereflexia. Investigations. • U&E. • BM • ABG • ECG o QRS duration < 160 ms (4 squares) suggests a high risk of arrythmias. o ECG should be regularly monitored in CCU or ITU if overdose large, or initial ECG abnormal. o Initial ECG is often normal, so repeat regularly whatever the initial result. Ttreatment. • General o Activated charcoal, if within 1 hour of overdose. o Further doses of activated charcoal every two hours may enhance elimination of some drugs.  Amitryptiline.  Nortryptiline. • Arrythmias. o Arrythmias more likely if pH < 7.4

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Give sodium bicarbonate in presence of:  Acidosis.  Wide QRS complex.  Arrythmias.  Works by reducing acidosis and providing sodium load. Correct disorders of potassium concentration. If bicarbonate fails to correct acidosis and arrythmias, consider:  DC cardioversion.  Overdrive pacing DO NOT give antiarrythmics, as they will actually make the arrythmias worse.

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Diazepam. Lorazepam If drugs fail, consider paralysis and artificial ventilation.

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Fits.

Benzodiazepines.. • Deliberate overdose is very common. •

Effects are generally mild. o

•

Unless combined with other sedatives, eg. 

Alcohol



Tricyclics

Presentation o

Drowsiness

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Slurred speech

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Nystagmus

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Mild hypotension

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Ataxia

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Coma

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Respiratory depression

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Cardiopulmonary arrest. 

If administered intravenously.

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Elderly are most at risk of developing this sypmotom.

Management. o

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If patients present within an hour of ingestion. 

50 g activated charcoal

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Ensure patient can protect airway

Flumazenil. 

Benzodiazepine antagonist.



May be used to revers significant cardiorespiratory depression in severe overdose.

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Given as IV bolus of 0.2 mg.

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If no response, give 0.3 mg IV.

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If still no response, give 0.5 mg IV every 30 seconds.

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Maximum 3 mg.

Most benzodiazepines have a longed half life than flumezanil. •



Should not be used as diagnostic test in comatose patients where benzodiazepine overdose is not very likely. •

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To maintain effects of antagonist, start IV infusion at 0.1 – 0.4 mg/h

Can cause fits or death.

Avoid excessive doses to completely antagonise benzodiazepines. •

Can cause. o

Marked agitation in chronic benzodiazepine use.

o

Convulsions in patients who have also taken pro – convulsant drugs.

Selective Serotonin Reuptake Inhibitors.

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Dextropropoxyphene

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Theophyilline

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Tricyclics.

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Main problem with overdose is the risk of Serotonin syndrome.

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Serotonin syndrome. o Potentially life – threatening ADR due to.  Therapeutic drug use.  Drug interactions  Drug overdose  Recreational drug use. o More accurate term is serotonin toxicity of hyperserotonaemia. o Consequence of excessive serotonin activity at CNS and peripheral serotonin receptors.  Produces spectrum of specific symptoms, ranging from mild to near fatal, including. • Cognitive effects o Confusion o Hypomania o Hallucinations o Agitation o Headache o Coma • Autonomic effects o Shivering o Sweating o Pyrexia o Hypertension o Tachycardia o Nausea o Diarrhoea • Somatic effects. o Myoclonus o Hyperreflexia o Tremor

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Epidemiology o Unclear, as syndrome is often not recognised o Incidence may be increasing due to larger numbers of serotonergic drugs available o Thought that 14 – 16% of SSRI overdoses lead to serotonin syndrome.

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Presentation o Characteristic picture, but may be mistaken for other problems. o o

 Eg. neuroleptic malignant syndrome. Often rapid onset within minutes. Mild symptoms may include.  Tachycardia  Shivering  Sweating  Dilated pupils  Myoclonus. • Intermittent tremor or twitching.  Brisk reflexes.

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Moderate symptoms.  All the mild symptoms.  Hyperactive bowel  Hypertension  Pyrexia. • Temperature > 40 oC is common.  Reflexes and clonus may be more severe in lower than upper limbs.  Mental state changes. • Hypervigilance • Agitation Severe symptoms.  Severe hypertension  Severe tachycardia.  Shock  Delerium  Muscular rigidity  Very tense muscles.  Pyrexia > 41 oC. • Metabolic acidosis • Rhabdomyolysis • Seizures • Renal failure • DIC

Pathophysiology. o Serotonin is a neurotransmittter involved in many states, including:  Aggression  Pain  Sleep  Appetite  Anxiety  Depression  Migraine  Vomiting

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Serotonin excess was first noticed in humans in 1960, due to increased levels in the CNS.  Was originally thought that agonism of 5 – HT1a receptors in central grey nuclei and medulla was responsible for development of the syndrome  Further study suggests that overstimulation of 5 – HT2a receptors have a significant contribution.  5 – HT1a receptors may contribute through a pharmacodynamic interaction • Increased synaptic concentrations or serotonin agonist saturate all receptor subtypes.  Additionally, noradrenergic CNS hyperactivity may play a role. • CNS noradrenaline concentration increased in serotonin syndrome. • Levels appear to correlate with the clinical outcome.  Other neurotransmitters may also play a role in development of the syndrome. • NMDA • GABA  Serotonin toxicity is more pronounced in supra – therapeutic doses and overdose • Mereg in continuum with toxic effects of overdose.  5 – HT1a receptors may contribute through a pharmacodynamic interaction

Causes o Many drugs and drug combinations have been reported to produce serotonin syndrome.  Antidepressants • Monoamine oxidase inhibitors • Tricyclic antidepressants • SSRIs • SNRIs • Bupropion  Opioids.

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• Tramadol • Pethidine • Fentanyl • Pentazocine • Buprenorphine CNS stimulants. • Phentermine • Diethylpropion • Amphetamines • Sibutramine • Methylphenidate 5 – HT1 agonists. • Triptans Psychedelics. • MDMA • MDA • MDEA • PMA • Psilocybin • LSD Herbs • St. John’s Wort • Yohimbe • Boswellia • Panax ginseng • Ginkgo bilba Others. • Tryptohan • Valproate • Montelukast • Buspirone • Kanna • Lithium • Linezolid • Dextomethorphan • 5 - Hydroxtryptophan • Chlorpheniramine • Risperidone • Olanzapine • Ondansetron • Granisetron • Metoclopramide

Many cases of serotonin toxicity occur in patients who have taken drug combinations  Combination of MAOIs with other serotonin agonists or precursors may be particularly dangerous.  Many MAOI irreversibly inhibit monoamine oxidase, so will take at least 4 weeks for the enzyme levels to return to normal.

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May also occur in patients who overdose on a single serotonergic agent. Was formerly thought that atypical antipsychotics could cause serotonin syndrome, but this is not believed any more.

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Spectrum concept. o Suggested spectrum concept of serotonin toxicity emphasises the fact that increasing serotonin levels cause a progressively worse clinical pictures. o Dose effect relationship between drugs may produce large elevation in serotonin levels.

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Risk and severity o Relative risk and severity of serotonin side effects and toxicity is complex. o Serotonin syndrome has been reported in patients of all ages. o Serotonergic toxicity of SSRIs increases with dose.  Even in overdose, would be rare to cause death in a healthy adult.  Usually only potentially fatal when combined with drugs which increase serotoinin levels via a different mechanism • Eg. with MAOIs o Other drugs which are associated with a severe syndrome include.  Tramadol  Amphetamines  MDMA

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Diagnosis o No test for serotonin syndrome o Diagnosis on history and examination. o Most important symptoms which suggest serotonin syndrome are  Tremor  Akathisia  Clonus • Spntanous • Inducible • Ocular o Examination should include assessment of  Reflexes  Muscle rigidity  Oral mucosal dryness  Size and reactivity of pupils  Intensity of bowel sounds  Skin colour  Sweating

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Hunter Serotonin toxicity Criteria may be useful in diagnosing serotonin syndrome



Suggests serotonin syndrome if patient has taken a serotoninergic agent and has symptoms of • Spontaneous clonus • Inducible clonus/ ocular clonus with agitation or diaphoresis • Tremor and hypereflexia

• •

Hypertonic and pyrexia > 38 oC with clonus.

Differential diagnosis o Gives a classical picture, so hard to confuse with anything else. o Occasionally mistaken for  Neuroleptic malignant syndrome • Most commonly confused diagnosis due to them both causing features of o Altered mental state o Autonomic dysfunction • Can be distinguished by: Serotonin syndrome Neuroleptic malignant syndrome

Cause

Serotonin excess

Dopamine blockade

Onset

Rapid onset after ingestion of serotonergic drugs Chlopromazine Cyproheptadine Hyperkinesia Clonus

Onset over several days after ingestion of neuroleptics Bromocriptine

Responds to Clinical features

     •

Bradykinesia “Lead pipe” rigidity.

Viral illness Anxiety Acute neurological disorder Anticholinergic poisoning Worsening psychiatric conditions

Management. o No antidote to condition itself. o Management involves  Removal of precipitating drug  Supportative care

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Supportative care.  Control of agitation  Administration of serotonin antagonists. • Cyproheptadine • Methysergide  Control of autonomic instability  Control of hyperthermia 

Intensity of therapy depends on severity of symptoms. • Mild symptoms may only require o Discontinuation of offending medications o Benzodiazepines for myoclonus

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o Waiting for symptoms to resolve. Moderate symptoms o Correct pyrexia o Correct cardiorespiratory abnormalities o Give serotonin antagonists Critically ill patients. o All above therapies o Sedation or neuromuscular paralysis

Specific symptomatic treatments may be required, regardless of severity • Benzodiazipines for agitation o Will also reduce the pyrexia, which is due to muscle over – activity. o Anti – pyretics will be ineffective as problem is due to over – activity, not hypothalamus function. o Severe cases may require intubation and paralysis with vecuronium. o Physical restraints are not recommended for agitation or delerium  May contribute to mortality by enforcing isometric muscle contractions  This can lead to profound lactic acidosis and death • Direct – acting sympathomimetics for hypotension o Adrenaline o Noradrenaline o Phenylephrine • Short – acting antihypertensives for hypertension or tachycardia. o Nitroprusside o Esmolol o Avoid longer acting drugs like propanolol  May lead to hypotension and shock.

Once therapy is started, and serotonergic drugs stopped, most cases of serotonin syndrome resolve within 24 hours.  Delerium may persist for several days.  Symptoms may persist if syndrome is due to drugs which have: • Long half life. • Active metabolites • Protracted duration of action  Muscle pain may persist for months, but this may be due to the effect of discontinuing antidepressants. Following appropriate medical management, prognosis is good