Recognition

• Penetrating extremity injury (e.g. stab or gunshot) or severe blunt trauma (e.g. arterial injury due to associated fracture)
• Cold, pale and pulseless distal extremity or a rapidly expanding hematoma suggests arterial compromise — look for ‘hard signs’ (Q7 below) and ‘soft signs’ (Q8 below)
• Check arterial pressure index (API) (Q9 below).
• Assess for hemorrhagic shock
• Angiography can be performed only if the patient is hemodynamically stable

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Management

• Immediate surgical consult
• Apply direct pressure and elevation
• Consider applying adrenaline soaked gauze or hemostatic dressings if available
• Tourniquets may be life saving
• Reduce and splint long bone fractures, apply a pelvic binder for pelvic fractures
• Correct coagulopathy and commence hemostatic resuscitation as required
• Do not clamp or tie off a vessel in a bleeding wound, unless it is superficial and clearly visible. Blindly clamping an artery may damage a nerve that often runs alongside the artery.

Learn more:

• Broome Docs — Clinical Case 018: Life and limb (not life OR limb)

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Direct digital pressure is the best method initially

• Take universal precautions (wear sterile gloves, goggles and gown)
• Ensure there are no hazardous objects in the wound
• Use one finger, with interposed gauze, to press directly on the bleeding vessel just proximal to the bleeding point
• Maintain this for 10 minutes

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I like the ‘nugget method‘ described by Shokrollahi et al (2008) as follows:

• The occluding finger should be substituted with a dental roll or tightly folded “nugget” of gauze.A tourniquet may be temporarily applied proximally to facilitate this.
• Once the positioning is correct and no further bleeding is occurring, slightly larger or less folded pieces of gauze can be placed one on top of the other, creating an inverted pyramid of gauze.
• The layers of gauze are secured with a loose bandage. Only very light pressure need be applied to the top layer of gauze to maintain hemostasis, as the pressure is “focused” onto the bleeding point. This technique is based on the equation: Pressure=Force/Area
• The tightness of the bandage can be judged from the amount of pressure needed to maintain hemostasis when applying the top layer of gauze.

From Shokrollahi et al (2008) — click image to enlarge

Hat tip to Scott Weingart for this one. I’ve used it on a few bleeding AV fistulae and it works like a charm.

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The easiest way in the ED is to apply a blood pressure cuff proximal to the bleeding point.

• Inflate the cuff above systolic blood pressure
• Clamp the tubing with a hemostat to prevent leakage and loss of pressure

An alternative is to use a pneumatic cuff, like that used for Bier’s blocks.

When applying a tourniquet ensure the following:

• Record the time of application
• Perform a neurological exam at the time of application
• Do not leave the tourniquet on for more than 120 minutes

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These are the two transition points

• Femoral artery at the inguinal ligament
• Axillary artery as it emerges from under the clavicle

Bleeding points proximal to these sites cannot be controlled by externally applied direct pressure or tourniquets. Call a surgeon!

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Hard signs

• Absent pulses
• Bruit or thrill
• Active or pulsatile hemorrhage
• Signs of limb ischemia/ compartment syndrome (the 6 Ps)
• Pulsatile or expanding hematoma

These patients require operative intervention. Imaging is not needed unless the site of bleeding is uncertain.

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Soft signs

• Proximity of injury to vascular structures
• Major single nerve deficit (e.g. sciatic, femoral, median, ulna or radial)
• Non-expanding hematoma
• Reduced pulses
• Posterior knee or anterior elbow dislocation
• Hypotension or moderate blood loss at the scene

Patients with soft signs may or may not need imaging, depending on the API (arterial pressure index)

• those with an otherwise normal physical exam and API >0.9 can be observed following appropriate wound care.
• API < 0.9 indicates possible vascular injury: requires further evaluation, preferably by computed tomography angiogram (CTA)

The incidence of arterial injuries in such patients ranges from 3% to 25%, depending on which soft sign or combination of soft signs is present.

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Arterial pressure index (API) is also known as DPI (Doppler Pressure Index) or Arterial Brachial Index or Ankle Brachial Index (ABI) – despite the last name, the same procedure can be performed for upper extremity injuries.

The procedure is performed as follows for an injured upper extremity:

• The patient is placed supine with the cuff placed on the injured upper extremity
• The ipsilateral brachial artery is detected with a Doppler device until the brachial artery is clearly heard. Alternatively the cuff can be placed on the forearm and the ulnar or radial arteries are assessed (the cuff has to be distal to the injury!).
• The cuff is pumped up 20 mmHg past the point where the Doppler sound disappears. The cuff is slowly released until the Doppler device picks up the arterial sound again (the systolic pressure)
• The pressure at which this sound occurs is recorded and the procedure is repeated for the opposite uninjured upper extremity.

IT can also be performed for an injured lower extremity:

• The patient is placed supine with the cuff placed on the injured lower extremity.
• The ipsilateral dorsalis pedis or posterior tibial artery is detected with a Doppler device until the artery is clearly heard
• The cuff is pumped up 20 mmHg past the point where the Doppler sound disappears. The cuff is slowly released until the Doppler device picks up the arterial sound again (the systolic pressure)
• The pressure at which this sound occurs is recorded and the procedure is repeated for the opposite uninjured lower extremity
• The blood pressure is also measured at the brachial artery in an uninjured upper extremity.

The API is calculated as

API = the systolic pressure of the injured extremity (ankle or forearm) divided by the brachial systolic pressure in the uninjured upper extremity

i.e.

API = Injured SBP / Uninjured brachial SBP

The magic number is 0.9

• API > 0.9 is highly unlikely to have a vascular injury and may be observed/ discharged depending on the nature of any other injuries, premorbid and social factors.
• API < 0.9 indicates possible vascular injury: requires further evaluation, preferably by computed tomography angiogram (CTA). Doppler ultrasound (50-100% sensitive, 95% specific) can be used as an alternative, and surgeons can perform intraoperative angiograms under fluoroscopy.

How good is API?

The performance characteristics of API vary between studies, but is quoted as 95% sensitive and 97% specific for arterial injury by Lynch and Johannsen (1991). In a small prospective study of knee dislocations ABI was 100% sensitive and specific (Mills et al, 2004). It is also cost effective (Levy et al, 2005).

API will miss non-obstructing vascular injuries and will give false positive results in patients with shock or significant peripheral vascular disease.  Some trauma centers use a difference in API of >=0.1 as an indication of arterial injury in elderly patients and those with known pre-existing peripheral vascular disease.

Below is a simplified approach to suspected arterial injury in trauma. Stabilise the patient first, and ensure that any fractures or dislocations are reduced.

The WEST guidelines (Feliciano et al, 2011) are much more complex and detail a number of exceptions. For instance, CTA may be performed in the presence of hard signs if there is a shot gun injury or multiple fractures to help localise the vascular injury before operating.

Interventions are discussed in Q10 below.

Patients discharged following a normal API require close outpatient follow up. This is because 1-4% of these patients, primarily those with penetrating wounds, eventually require an operation as the original undetected injury (i.e. small pseudoaneurysm) progresses rather than heals.

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Injuries to most major ‘named’ arteries requiring repair or intervention include:

• extravasation
• pulsatile hematoma
• occlusion
• pseudoaneurysm
• fistula formation

The surgeon may repair damaged vessels by:

• Direct repair — sutures, patch angioplasty, interposition graft or vein patches
• Ligation — only small, distal and redundant arteries (most are repaired)
• Damage control surgery using intravascular shunts to allow immediate restoration of distal blood flow, with later definitive repair once the patient has been resuscitated and normal physiology has resumed.

Interventional radiology measures such as embolisation are also useful in certain arterial injuries.

Injuries that do not usually need immediate intervention:

• Some injuries, such as intimal defects (87-95% heal spontaneously), usually do not require intervention.
• Some arteries (profunda femoris, anterior tibial, posterior tibial, or peroneal arteries) do not require surgery but can be re-imaged at 3-5 days to check progress if occluded, or undergo embolisation if the injury involves extravasation or arteriovenous fistula.

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Amitriptyline is one of the most commonly used (and sometimes misused) tricyclic antidepressants. Amitriptyline is indicated for the treatment of major depression and as well as nocturnal enuresis (where organic pathology has been excluded). Their main therapeutic effect is thought to be due to inhibition of both noradrenaline and serotonin reuptake and is thought to lead to increased activity at their specific post-synaptic receptors. Amitriptyline is available in 10, 25 and 50mg tablets in Australia.

However, tricyclics also block inactivated fast sodium channels. Tricyclics are also similar in structure to phenothiazines and thus share many of their properties (serotonin and noradrenaline reuptake inhibition, alpha-2-adrenoreceptor blockade, muscarinic receptor blockade etc.).

These aspects of tricyclic pharmacology have significant implications with regards to their toxicology.

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Return of the ADME:

• Absorption:
  — Rapidly absorbed following oral administration. Time to peak levels is 2 hours
• Distribution:
  — Large volume of distribution (5-20L/kg).
  — Highly bound to plasma and tissue proteins
• Metabolism:
  — Undergoes hepatic metabolism by oxidation via Cytochrome p450 to active metabolites such as nortriptyline
• Excretion:
  — Mainly in the urine as metabolites. Very little is excreted unchanged

—

As mentioned earlier, amitriptyline (like other tricyclic antidepressants) have multiple potential toxicological properties due to their structure, these are:

• CNS effects
  — Delirium/confusion/agitation, sedation, seizures, coma (often precedes cardiovascular signs)
• Cardiovascular effects
  — Sinus tachycardia, hypertension, hypotension (due to alpha2-adrenoreceptor blockade), broad complex tachycardia (can develop bradycardia pre-arrest)
• Anticholinergic effects
  — Can occur at time or presentation or be delayed and prolonged
  — Agitation, restlessness, delirium, mydriasis (big pupil), dry, warm skin, tachycardia, ileus, urinary retention
• Metabolic acidosis
  (remember she was tachypnoeic at presentation… trying to compensate for this!)

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This patient has taken a life-threatening overdose and is predictably demonstrating many of the aforementioned clinical features associated with amitriptyline toxicity.

Murray et al (2011) states that ingestion of greater that 10mg/kg is thought to be considered potentially life-threatening and onset of severe toxicity often occurs within two hours of ingestion (how’s that for timing?). However the dose is less than 30 mg/kg, which is the dose expected to result in severe toxicity with pH-dependent cardiotoxicity and coma lasting >24 hours.

Nevertheless she is at significant risk of developing seizures, broad complex tachycardias, coma and ultimately cardiac arrest.

As always, co-ingestion should forever be sitting in the back of your mind as a possibility and management should be accompanied with appropriate investigations to exclude other potential toxins. Given her acute decrease in conscious state, drugs such as alcohol, opiates and other anti-depressants warrant consideration as possible co-ingestants.

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Regardless of what you would do, this is what was actually done!

In this case, the patient was fortunately in the right place (resuscitation bay) and the decision was made to promptly sedate and intubate the patient with ongoing sedation via propafol infusion. Whilst the patient was initially given boluses of sodium bicarbonate along with crystalloid, this was later changed to a sodium bicarbonate infusion (100mmol in 1L N/Saline at 250ml/hr) that was continued during the patient’s ICU admission. Serial ECGs were utilised to monitor progress, looking for resolution of the ECG changes specific to amitriptyline toxicity.

We’ll talk some more about whether this was optimal management or not below…

Learn more:

• LITFL ECG Library — Tricyclic antidepressant overdose

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Use the Resusi-RSI-DEAD approach as all good toxicologists do…

Resuscitation

• Amitriptyline and other tricyclic overdoses are potentially life-threatening and should be managed accordingly in an area that is able to provide appropriate monitoring, resuscitation and ventilatory support (given the high likelihood of intubation in significant overdoses)
• Intubation and hyperventilation (aim for pH 7.50-7.55) are mainstays of treatment for severe overdoses (where there is a decline in GCS) in addition to sodium bicarbonate (discussed below)
• Ventricular arrhythmias caused by amitriptyline toxicity are unlikely to respond to cardioversion or defibrillation
  — First line treatment is sodium bicarbonate (100mmol or 2mmol/kg) should be given IV every 1-2 minutes until rhythm and perfusion are restored
  — Second line treatment is lignocaine (1.5mg/kg) IV once pH is greater than 7.5
• Serial ECGs and blood gases are vital to proper and effective management
• Treat hypotension with volume- crystalloid, sodium bicarbonate or failing this, vasopressor (noradrenaline or adrenaline) infusions
• Treat seizures with benzodiazepines as per usual
• Don’t stop resuscitation until patient has been intubated, has received sodium bicarbonate and has been hyperventilated to achieve a pH of 7.50-7.55. Good neurological outcome following even hours of prolonged CPR and arrest is still possible.

Supportive care and monitoring

• Supportive care will suffice for small ingestions so it is essential that it is done properly!
• Secure appropriate IV access
• Ensure adequate hydration with IV fluids- crystalloid will suffice with small (<10mg/kg) ingestions
• Remember FASTHUGS IN BED Please especially pressure care, bladder care and DVT prophylaxis
• Cardiac monitoring should continue until toxicity is reversed if ECG changes are present

Investigations

• The ECG is one of the most vital investigations in this scenario
  — Diagnostic features include prolongation of QRS, PR intervals, dominant R wave in aVR, and QT prolongation
  — QRS widening reflects the degree of fast sodium channel blockade
  — QRS > 100ms is predictive of seizures, QRS > 160ms is predictive of ventricular tachycardia
• Paracetamol and blood glucose levels should be performed as recommended for all intentional overdoses
• Use blood gases to monitor the adequacy of alkalinisation
• Consider possible co-ingestants

Decontamination

• Activated charcoal can be useful for large ingestions >10mg/kg but should not be given without a definitive airway (i.e. a tube) being established prior
• Charcoal not indicated for smaller ingestions as supportive care is often enough

Enhanced elimination

• Not useful

Antidotes

• Sodium Bicarbonate is a key treatment in amitriptyline and other tricyclic antidepressant toxicity.
• This is discussed in great detail in another case of amitriptyiline toxicity in Toxicology Conundrum 022.

Disposition

• As in this case, patients with severe ingestions require HDU/ICU support (or alternatively transport to a more appropriate centre if warranted) until medically stable
• Patients with non-life-threatening overdoses (<10mg/kg) can be managed in an appropriate ward setting until clinically well
• Psychiatric review is mandatory.

—

The retrospectoscope is an amazing tool but never around until after its too late… funny that.

A few thoughts:

• Following intubation and establishment of a secure airway the patient could have been administered activated charcoal. There are few downsides in this setting and the activated charcoal might decrease any ongoing drug absorption from the gut.
• Whilst an infusion of sodium bicarbonate was used due to ongoing prolongation of the patient’s QRS and for practical reasons, boluses of sodium bicarbonate are thought to be more effective as they lead to rapid shifts in concentration of free drug due to the effect on binding to plasma and tissue proteins. Also infusions may lead to renal compensation and thus reduce the effectiveness of the antidote… throwing the baby (bicarbonate) out with the bath water (well… you know).
• Hyperventilation of intubated patients is an effective means of alkalinisation and could have been used may have achieved the same aim as a sodium bicarbonate infusion

In any event, the patient went on to do well. She was extubated the following day following reversal of her ECG changes and once medically cleared was admitted to an inpatient psychiatric unit for further management.

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The key finding is:

Extensive pneumomediastinum

There is gas within the supra-aortic, sub-aortic and para-cardiac mediastinum, particularly in the posterior compartment of the mediastinum.

Other findings:

• endotracheal tube
• nasogastric tube
• bilateral lung opacities and altered lung architecture consistent with resolving ARDS

_

Possible causes include:

• Complication of tracheostomy resulting in a small tracheal tear
• Complication of mechanical ventilation due to ARDS and need for high pressures
• Esophageal rupture post NG tube placement
  — pleural effusion would be expected
• Mediastinitis
  — fluid or a collection would be expected

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There may be very few clinical findings!

If present they may include:

•  subcutaneous emphysema of the neck
• Hamman’s sign (aka Hammond’s crunch)
  — a rarely heard rasping, crunching sound synchronous with the heart beat that is best heard over the precordium in the left lateral position
  — caused by the heart beating against air-filled tissues
• hemoptysis
• partial or complete airway obstruction
• respiratory distress and/or need for increased respiratory support.

If tension pneumomediastium develops the patient will become tachycardic and hypotensive due to impaired venous return mimicking cardiac tamponade. Neck vein distention will not be seen in the presence of subcutaneous emphysema of the neck.

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Key priorities are supportive care of the patient and identification and treatment of possible tracheobronchial injury.

• ensure adequate oxygenation
• provide ventilatory support while minimising tidal volumes and airway pressures to limit exacerbation of the air leak
• fiberoptic endoscopic evaluation of the tracheobronchial tree to assess for presence, location, depth and length of tears (best performed in an operating theatre)
• tracheobronchial tears may be amenable to bypass by bronchoscopy-assisted endotracheal tube advancement, or even endobronchial intubation for tracheobronchial injury near the carina
• the indications for conservative versus surgical repair of iatrogenic tracheobronchial injury are poorly defined and remain controversial
  — surgery may be performed via thoracotomy and/or a cervical approach
  — surgery should be performed  if there is progressive pneumomediastinum, increasing subcutaneous emphysema, evidence of oesophageal injury or mediastinitis
• broad spectrum antibiotics are often used to prevent mediastinitis

Learn more:

• Esophageal rupture is considered in Pulmonary Puzzle 003.

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True tension pneumomediastinum is rare, and requires emergency decompression by bedside mediastinotomy.

Bedside cervical mediastinotomy can be performed by making an incision in the jugular notch. If air is trapped in posterior spaces then this approach may not be effective. A subxiphoid approach can be attempted, and an approach through the esophageal hiatus via a mini-laparotomy has been described.

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It is argued that complications following PDT are rare and that new abnormalities on chest x-ray are rarely seen. However, if difficulties are encountered during the procedure, or if the patient deteriorates afterward, a chest x-ray should be performed.

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Life-threatening injuries:

• Pelvic disruption with massive hemorrhage
• Severe arterial hemorrhage
• Crush syndrome

Learn more:

• Trauma Tribulation 027 — Trauma! Pelvic Fractures I
• Trauma Tribulation 028 — Trauma! Pelvic Fractures II
• Trauma Tribulation 030 —Trauma! Extremity Arterial Hemorrhage

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Limb-threatening injuries

• Open fractures/ dislocations
• Traumatic amputation and severe vascular injuries
• Compartment syndrome
• Neurological compromise due to limb injury
• Degloving injuries

Learn more:

• Bone and Joint Bamboozler 001 — Open fractures
• Bone and Joint Bamboozler 002 — Compartment syndrome

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Crush syndrome is the complex of electrolyte disturbances, metabolic acidosis and rhabdomyolysis resulting from crush injury.

Recognition

• Suspect based on history of crush injury or entrapment
• Hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia from cellular damage
• Lactic acidosis from hypoperfusion
• Elevated creatine kinase and myoglobinuria (urinalysis positive for blood on dipstick, but no red cells seen on microscopy) due to massive muscle damage
• Acute renal failure due to rhabdomyolysis
• X-rays to assess for associated fractures
• Assess for compartment syndrome
• Assess for neurological compromise (weakness, paresthesiae, loss of sensation and neuropathic pain)
• Assess for vascular compromise (hard and soft signs of vascular injury, ankle-brachial index, CT arteriography)

Management

• resuscitation of shocked patients
• IV hydration (e.g. Hartmann’s) to target urine output of 1-2 mL/kg/h (corrects hypoperfusion, lactic acidosis, ameliorates acute renal impairment)
• Urinary alkalinisation with sodium bicarbonate is controversial, and is unproven. Proponents use this treatment based on the theory that urine pH>7.0 may limit crystalinisation of uric acid and reduce breakdown of myoglobin into nephrotoxic metabolites.
• Mannitol is also sometimes used but is unproven.
• Aggressively treat potentially life-threatening hyperkalemia (calcium gluconate, salbutamol, insulin, hemodialysis)
• Calcium administration may lead to metastatic calcification in the presence of hyperphosphatemia
• Treat associated injuries including fractures/ dislocations, wounds, neurovascular injuries and compartment syndrome
• Early analgesia, antibiotics if indicated and ADT (tetanus immunisation)

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An amputation is an injury that results in loss of the extremity distal to the wound.

Recognition

• Usually obvious!
• Check for associated neurovascular complications and crush injuries. Bleeding may be slight, thanks to arterial spasm. Severed nerves are exquisitely painful.
• Determine the time of injury. Reimplantation is less likely to be successful if warm ischemia time exceeds 6 hours (in general), but success has been achieved at up to 24+ hours.
• X-ray the amputated part and the stump to help determine the extent of injury and viability

Management

• Consult surgery (may require general surgeon, plastics and/ or orthopedics)
• Always treat an amputated part as if it may be reimplanted. It may at least be useful for achieving skin coverage of a wound.
• Handle the amputated part with care, do not debride it, irrigate with normal saline and pack loosely with sterile saline soaked gauze. Place in a water-tight plastic bag and store in an ice water slurry. Ensure ice does not directly contact the amputated part.
• Irrigate the stump with saline and control bleeding with direct pressure.
• Give AAA treatment: prophylactic IV antibiotics (e.g. cephazolin), analgesia and update ADT.

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Consult a surgeon early so that they can make the decision whether or not to reimplant. Always treat an amputated body part as if it is a candidate for reimplantation.

Reimplantation is more likely to be performed for:

• Short ischemia time (1 hour of warm ischemia equals 6 hours of cold ischemia)
• Thumb and index fingers are usually reimplanted
• Children
• Multiple amputations
• Dominant limb involved
• Patient’s occupation depends on motor skills
• Upper limb amputations are more likely to be reimplanted than lower limb amputations, as effective prostheses are more available for the latter and they are more likely to have crush injuries

A major trauma patient requiring resuscitation and emergency surgery is generally not a candidate for reimplantation.

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Recognition

• suspect nerve injury if vascular injury is present, as nerves tend to run in close proximity
• detailed motor and sensory exam distal to the injury site: e.g. loss of function, weakness, areflexia, paraesthesiae, sensory loss.
• consider coexistent vascular injury, compartment syndrome and associated fracture

Management

• consult orthopedic surgeon (or hand surgeon or plastic surgeon as appropriate)
• treat compartment syndrome if present
• reduce and splint fractures
• elevate limb to decrease edema
• rest affected limb in position of function
• most closed soft tissue injuries with neurological injury gradually resolve over 3 months
• transected nerves require operative repair, usually within 24 hours — unless minor sensory alterations only, which may be followed up at 1 week

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Degloving injuries involve separation of the skin and underlying subcutaneous connective tissue from the underlying fascia. They are usually but not always open injuries causing exposure of the underlying structures. They are associated with high morbidity.

Recognition

• usually easily identifiable by exposure of underlying fascia hat invests muscles, vessels, nerves and bone
• closed degloving injuries may not be obvious and are often missed on initial assessment – suspect based on mechanism (e.g. run over by motor vehicle, limb caught in heavy machinery) that involves shearing forces and subcutaneous swelling suggesting underlying hematoma and tissue injury
• assess distal perfusion and neurological function
• x-rays to look for fractures and foreign bodies
• ultrasound may show underlying hematoma, soft tissue disruption and foreign bodies

Management

• consult orthopedic or plastic surgeon urgently
• clean and cover wounds with saline-soaked dressings
• AAA treatment: analgesia, antibiotics, ADT if needed
• splint and elevate limb
• preserve amputated parts
• treat associated injuries and complications (e.g. fractures, dislocations, compartment syndrome, crush syndrome)
• surgical treatment aims to achieve coverage by replacing the degloved tissue or through use of flaps or skin grafts to prevent necrosis of underlying structures
• closed degloving injuries may be treated by washout and drainage of the subcutaneous tissues followed by compression bandages if the overlying tissues are viable.

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As always:

Concurrent assessment and management in an appropriately staffed and equipped trauma bay, involving activation of the trauma team and a coordinated team-based approach.

Resuscitation

• ABCDE approach with cervical spine immobilisation if indicated

Address life threats

• pelvic fracture with major hemorrhage — apply pelvic binder, hemostatic resuscitation, correct coagulopathy
• major arterial hemorrhage — direct pressure, tourniquet, elevate, hemostatic resuscitation, correct coagulopathy
• crush syndrome — fluid resuscitation to keep urine output > 1-2 mL/kg/h, treat hyperkalemia

Address limb threats

• open fractures — clean and cover wounds, reduce fracture, splint and elevate limb, antibiotics
• compartment syndrome — assess compartment pressures and neurovascular status, remove constrictions,arrange for fasciectomy
• amputation — preserve amputated part (clean, wrap in saline-soaked gauze, keep on ice), clean and cover wound, antibiotics, consider reimplantation
• vascular injury — assess for hard and soft signs, measure ABI, consider CT angiogram and surgical intervention
  (see Trauma Tribulation 030 — Trauma! Extremity Arterial Hemorrhage)
• neurological injury — assess neurovascular status, reduce fractures and relieve constrictions, consider surgical repair
• degloving injury — clean and cover wounds, antibiotics

Supportive care and monitoring

• AAA treatment: analgesia (early!), antibiotics (in severe open injuries), ADT (if tentanus immunisation is indicated)
• splint and elevate injured extremity
• FASTHUGS IN BED Please! (as needed)
• seek and treat other injuries (e.g. tendon rupture)
• seek and treat complications (e.g. compartment syndrome, neurovascular compromise)

Disposition

• urgent surgical consult for assessment, admission and operative intervention
• transfer to a specialist trauma center if appropriate

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The clinical features of hypokalaemia result from effects on multiple organ systems.

They include:

• Cardiovascular
  — ECG changes when K < 2.7mmol/L: changes include P wave prominence, T wave flattening, and U waves
  — Tachydysrhythmias
  — Hypokalaemia also potentiates digoxin toxicity
• Musculoskeletal
  — Weakness progressing to paralysis
  — Rhabdomyolysis
• Gastrointestinal
  — Ileus
• Renal
  — Nephrogenic diabetes insipidus
  — Increased ammonia production

Learn more:

• LITFL ECG Library — Hypokalemia

There are a wide variety of causes of hypokalaemia including:

• Decreased intake
• GI Losses
  — e.g. vomiting, NG losses, diarrhoea, fistula
• Renal Losses
  — e.g. drugs, aldosteronism (primary & secondary), renal tubular acidosis, diuresis
• Transcellular Shifts
  — e.g. alkalosis, hypokalaemic periodic paralysis, thyrotoxic periodic paralysis
• Congenital
  — e.g. Bartter’s Syndrome, Gitelman’s Syndrome , Liddle’s Syndrome
• Drugs
  — e.g. loop & thiazide diuretics, insulin, salbutamol, liquorice ingestion

Learn more

• LITFL Investigations — Hypokalaemia.

There are several case reports in the literature linking excessive cola consumption to severe hypokalaemia, the case series review by Tsimihodimos, et al (2009) being the largest.

All these reports involved chronic excessive consumption in the region of 2 – 9 litres per day over months to years.

The majority of cases responded well to treatment, but there have been cases of acute renal failure due to rhabdomyolysis, and deaths have been attributed to hypokalaemia secondary to cola.

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The mechanism/s of cola associated hypokalaemia as not fully understood but several mechanisms have been postulated including:

• Osmotic diuresis
  — due to large amounts of glucose in cola drinks
• Hyperinsulinaemia
  — secondary to large glucose load causing intra-cellular shift of potassium
• Osmotic diarrhoea / GI loss
  — from large unabsorbed fructose load passing through GI tract.
• Caffeine mediated
  — multifactorial involving respiratory alkalosis, intra-cellular K+ shift due to increased cAMP, increased renin release, and diuresis.

Treatment involves potassium replacement whilst ceasing excess cola consumption.

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Aside from hypokalaemia and secondary rhabdomyolysis excess, cola consumption has also been liked to other health problems, including:

• Obesity
• Dental Disease
• Increased risk of type 2 diabetes mellitus
• Non-alcoholic fatty liver disease

On a much rarer note a case report from the Journal of Toxicology linked excessive consumption of a cola containing brominated vegetable oil to systemic bromism requiring dialysis. Cola can also cause acidification of the urine, which may lead to delayed excretation of some medications (e.g. methotrexate). Whether chronic excessive cola consumption is linked to any form of cancer is uncertain. Finally, cola was also implicated in a out-break of epidemic illness in Belgium in 1999, later attributed to mass sociogenic illness following a food contamination scare.

Alprazolam is a short-acting benzodiazepine.

Like other benzodiazepines, alprazolam binds to a specific site on the GABA-A receptor (gamma-amino-butyric acid) increasing the frequency of chloride channel opening. This is the basis for its anxiolysis, sedation, hypnosis, skeletal muscle relaxation, amnesia and anti-convulsant effects.

Alprazolam is typically used for the treatment of anxiety disorders including panic disorder, social anxiety disorder and generalised anxiety disorder. Alprazolam is available in Australia as a standard-release preparation ranging from 250micrograms to 2mg in dosage.

Alprazolam is considered to be more toxic in overdose than other benzodiazepines.

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ADME again:

• Absorption
  — Rapid oral absorption ranging from 80 to virtually 100% complete. Peak levels in 1-2 hours.
  Distribution
  — Total body water (volume of distribution 0.8 to 1.3L/kg)
  — Highly protein-bound as observed with other benzodiazepines
• Metabolism
  — Metabolised into active alpha-hydroxy metabolites (less active than alprazolam itself) by hepatic microsomal oxidation.
• Excretion
  — Elimination half-life of 12 to 15 hours and clearance of 0.7 to 1.5ml/min/kg (reduced in the elderly and cirrhosis).
  — Metabolites excreted via urine.

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Alprazolam, in particular, is associated with a greater degree of CNS depression compared with other benzodiazepines and there is increased need for intubation and ventilation.

Alprazolam overdose causes drowsiness, ataxia, and slurred speech 1-2 hours after ingestion (as reflected by the time to reach peak plasma levels). Conscious state can steadily decrease put the patient at risk of airway obstruction, hypoxia and aspiration. In very large ingestions, overdoses can produce cardiovascular compromise with bradycardia and hypotension in addition to hypothermia and rarely coma.

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This patient has had a large alprazolam overdose with a predictable decrease on his level of consciousness.

As observed in most benzodiazepine overdoses, cardiovascular compromise is absent. Most benzodiazepine overdoses can be managed with supportive therapy — usually an overnight stay in an appropriate ward with psychiatric review once conscious state has improved.

This being said, despite the history of isolated alprazolam overdose, it is important to always consider the possibility of co-ingestion. This can have significant consequence both with regards to diagnosis and to appropriate toxicological management (such as consideration of the use of the benzodiazepine antagonist, flumazenil). Agents of note to consider are other CNS depressants such as alcohol, opiates and anti-depressants.

The use of flumazenil and whether it is appropriate to use in this scenario will be discussed later in the article.

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As always with a tox case, we use the Resus-RSI-DEAD approach…

Supportive care is sufficient for most benzodiazepine overdoses in the absence of cardiovascular compromise, provided adequate toxicological work-up has been completed.

Resuscitation

• Patients should be managed in an appropriate environment with consideration to airway management in the event of obstruction secondary to decreased conscious state.
• Intensive resuscitation should be considered in the instance of very large ingestions of alprazolam alone or mixed polypharmacy overdose with significant compromise.
• Seek and treat potential life threats such as hypoxia due to respiratory depression, airway obstruction and/ or aspiration

Supportive care and monitoring

• Secure appropriate IV access
• Consider re-warming of patients in the event of hypothermia
• Remember FASTHUGS IN BED Please: especially pressure cares, bladder cares and DVT prophylaxis as required

Investigations

• Screening paracetamol level, blood glucose levels and 12-lead ECG
• Further investigations if complications, comorbidities or coingestions suspected

Decontamination

• As symptoms typically begin 1-2 hours after ingestion, there is no benefit in decontamination and administration of activated charcoal may lead to life-threatening aspiration in the sedated patient

Enhanced elimination

• Not clinically useful

Antidotes

• Flumazenil, a competitive benzodiazepine antagonist, can be considered in some instances of benzodiazepine overdose. This will be discussed in greater detail below.

Disposition

• Patients presenting with isolated alprazolam overdose without cardiovascular compromise should be managed as inpatients until clinically well (alert and able to eat, drink and ambulate safely).
• An observation ward environment with appropriately trained nursing staff is usually adequate and no intensive monitoring is required.
• Profound coma, cardiovascular compromise or ECG changes may suggest a co-ingestant and may contra-indicate ward management.
• Patients requiring intubation or flumazenil infusion require admission and management in an HDU/ICU environment until medically stable.

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Flumazenil is a competitive benzodiazepine antagonist that is structurally similar to midazolam, and binds to the benzodiazepine receptor sites on the GABA-A receptor.

Binding inhibits benzodiazepine activity and reverses their effects on the CNS. Flumazenil is given intravenously (0.1-0.2mg IV) and doses repeated every minute until reversal of benzodiazepine effects achieved. Infusions can also be used but are rarely required.

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Indications for flumazenil administration

• Benzodiazepine overdose
  — Accidental paediatric ingestion with compromised airway and breathing
  — Deliberate self-poisoning with compromised airway and breathing where equiptment/skills for intubation and/or ventilation not available
• Confirming the diagnosis of benzodiazepine overdose
• Reversal of benzodiazepine conscious sedation (iatrogenic overdose)

Contraindications

• Known seizure disorder
• Known or suspected co-ingestions of drugs with pro-convulstant properties
• Known benzodiazepine dependence
• QRS prolongation of ECG (i.e. suggestion of TCA co-ingestion)

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There are three important considerations with regards to the use of flumazenil that can present challenges to the emergency physician.

• re-sedation is common after flumazenil administration and repeated doses or even an infusion may be required until the patient’s clinical state improves.
• flumazenil can precipitate withdrawal in patients with dependence on benzodiazepines (e.g. agitation, tachycardia and seizures)
• flumacan also cause seizures in patients with an underlying predisposition (e.g. pro-convulsant medication, epilepsy).

Recommended management of these symptoms is titrated doses of benzodiazepines but the use of the initial toxin to treat the side-effects of the antidote is a highly undesirable situation! Benzodiazepines will not be as effective in treating seizures secondary to flumazenil administration given the existing antagonism at the benzodiazepine receptors. Other agents (e.g. barbiturates, propofol) may be needed to control seizures and the patietn may require intubation and ventilation.

In this case, the patient was assessed in a hospital with sufficient resources to intubate and ventilate if airway and breathing became compromised. This patient was regularly using alprazolam for the past year thus dependence is likely. It is also worth noting that none of the indications for the administration of flumazenil were present. The risk-benefit balance does not favour the use of flumazenil in this setting.

Fortunately, the patient suffered no ill effects but no further flumazenil doses were administered after consultation with a toxicologist.  The patient was discharged the following day following psychiatric review.

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Lithium is a small monovalent cation. It is primarily used as lithium carbonate in the treatment for bipolar affective disorder but its actual mechanism of action is not clearly understood. It is thought to modulate intracellular second messengers (such as inositol triphosphate) as well as affect neurotransmitter production and release.

Lithium carbonate is available as a standard release (250mg) or a slow-release (450mg) presentation.

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Remember ADME:

• Absorption
  — With standard release preparations, absorption is virtually complete within 6-8 hours with peak plasma levels occurring within 4 hours.
  — Slow release preparations reach peak levels up to 12 hours
• Distribution
  — Total body water (Vd=0.7-0.9L/g) with slow entry into tissue compartments including the central nervous system.
  — No plasma protein binding.
• Metabolism
  — None
• Excretion
  — Almost entirely renally excreted (some sequestration in bone).
  — Excretion is dependent on creatinine clearance (about 20% equals lithium clearance) so is reduced in states such as hypovolemia, renal impairment and hyponatremia.
  — Elimination half-life is 24 hours

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These do:

• Drugs
  — e.g. NSAIDs, ACE inhibitors, SSRIs, thiazide diuretics, topiramate
• Dehydration
• Hyponatremia
• Hyperthyroidism
• Renal impairment (acute or chronic)

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Yes, it is relevant.

Lithium toxicity can present as two distinct entities, either:

• an acute poisoning (almost always a deliberate ingestion), or
• a chronic poisoning (usually where lithium excretion is altered by extraneous factors such as dehydration or renal impairment)

The context in which the patient presents determines how useful a lithium level is. In this case, the patient has acute lithium toxicity.

In acute ingestions, the plasma level allows confirmation of ingestion and allows monitoring of ongoing lithium excretion (important especially with regards to neurotoxicity caused by lithium), the latter also assisting in determining disposition.

In chronic poisoning, lithium levels help confirm the diagnosis but do not correlate well with the severity of toxicity (they do not reflect levels in tissue compartments well, most importantly in the central nervous system). As in acute poisoning, levels can also be used for monitoring in those receiving treatment.

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Acute lithium toxicity mainly affects the GI tract as lithium (like other metal salts) is a direct irritant. It causes nausea, vomiting, abdominal pain and diarrhoea.

25 grams is the magic number for risk assessment

• Ingestions of less than 25 g are usually benign, causing the aforementioned symptoms.
• Ingestions greater than 25 g produce more severe GI symptoms but in rare cases can lead to the neurotoxicity seen in chronic lithium toxicity if clearance of lithium is impaired. Reduced ability to excrete lithium promotes entry of lithium into the central nervous system and can lead to subsequent neurotoxicity.

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This patient has taken a large amount of lithium (much greater than 25 g) and has the classic GI symptoms of acute lithium ingestion. Of note, he has mild renal impairment, which, if it should worsen, could lead to neurotoxicity without appropriate supportive treatment.

The danger for this patient lies in the timing of treatment —  lithium clearance can become further impaired from the hypovolemia secondary to GI losses and consequently the risk of lithium neurotoxicity increases.

The patient’s alteration in heart rate may be related to lithium as it settled following treatment, but as he was not haemodynamically compromised it was of little further clinical relevance.

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As lithium excretion is ultimately dependent on renal function, supportive therapy is paramount in both acute and chronic toxicity.

Resuscitation

• Patients should be managed in an appropriately equipped and staffed resuscitation area until potentially toxic coingestants are excluded.
• There are no immediate life threats in this patient.

Supportive care and monitoring

• Correction of water deficits and ongoing hydration with intravenous fluid to prevent renal impairment (e.g. normal saline). Monitor urine output, >1 ml/kg/hr is recommended
• Correction of sodium deficits is also important as this too can affect lithium clearance
• Avoidance and cessation of any drugs that impair lithium clearance
• Remember FASTHUGS IN BED Please as required

Investigations

• Screening paracetamol level, blood glucose and 12-lead ECG
• Lithium level
• Urea, electrolytes and creatine

Decontamination

• Whole bowel irrigation has been advocated for overdose with sustained-release preparations, however there is no proven benefit compared to supportive therapy alone.
• As with other metals, activated charcoal does not adsorb lithium effectively and is not recommended.

Antidotes

• There are no antidotes for either acute or chronic lithium toxicity

Enhanced Elimination

• As lithium is not protein bound and has a small volume of distribution, it is potentially amenable to haemodialysis.
• In acute toxicity, haemodialysis is reserved for patients with established renal failure and those presenting with features of neurotoxicity.
• There is no lithium level cut-off for hemodialysis in acute lithium toxicity, unlike chronic lithium toxicity where hemodialysis is usually advised if serum lithium levels are >2.5mmol/L.

Disposition

• Patients with renal impairment or signs of neurotoxicity should be managed in an HDU/ICU environment until medically stable.
• Acutely poisoned patients without these concerning features can be admitted for observation and supportive care until resolution of GI symptoms, and may need ongoing monitoring of renal function and lithium levels (until <2.5 mmol/L and falling).

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Not so fast! We’re going to break with LITFL case-based Q&A tradition and give you some time to mull this one over…

Feel free to leave a comment if you think you know the answer or you have something worthy of discussion. We’ll put you out of your misery sooner or later…

Addendum 15 May 2012

The question was:

“Did you thoroughly mix the bag of fluid after adding the KCl?”

KCl at 20 mmol/ 10 mL is considerably more dense than normal saline. Unless thouroughly mixed the KCl solution will simply sit at the bottom of the bag… The patient will thus receive a dose of highly concentrated, and potentially lethal, KCl.