ICU Fellowship Vivas – Peioperative deterioration, Paediatric Burns, EBM (non-inferiority trials)

FELLOWSHIP PODCAST 

Written by Dr Madhuri Anupindi

1. A 55-year-old female with no reported co-morbid conditions has been admitted unexpectedly to your tertiary intensive care unit from the operating theatre. She had an uneventful general anaesthetic for a total hip replacement. 45 minutes later, she was found unrousable by the attending nurse. An ABG showed a pH of 7.01 paCO2 110mmHg pa02 100mmHg on 15L NRBM BE +2mmol/L and lactate 1.1 mmol/L. She was urgently re-intubated and transferred to your ICU. She is haemodynamically stable. Give the most likely differential diagnoses.

Hypercapnoeac and hypoxic respiratory failure:

• Complication of anaesthetic
• New pathology
• Exacerbation of chronic disease: may not be diagnosed/self-reported

Complication of procedure

• Drug related:
  • Dose related: narcotic intra-op or recovery, inadequate reversal of paralysis
  • Drug error: accidental administration of neuromuscular blockade, atropine overdose
  • Adverse reaction: suxamethonium apnoea, transfusion related ALI, drug interaction, high spinal (may have had adjunct for analgesia but would generally also have haemodynamic instability), malignant hyperthermia (less likely)
• Negative pressure pulmonary oedema
• Fat embolism: would expect haemodynamic instability
• Aspiration event
• Pneumothorax

New pathology:

• Intra-cranial: ischaemic or haemorrhagic stroke
• Metabolic causes: hypoglycaemia
• PE
• AMI with APO

Chronic disease

• ?COPD or OSA
• Cardiac failure
• Obesity ?why needs hip replacement
• Renal or hepatic failure slowing elimination of opiates
• Hyperthyroidism – thyroid storm
• Myasthenia

 

How would you further evaluate as to the cause of her deterioration?

This would involve a targeted history, examination and relevant investigations.

History:

• Anaesthetic/recovery details:
  • vital signs/trends during the case and in recovery including neurology and respiratory function when extubated
  • medications given including amount and timing of opiate, neuromuscular blockade and reversal, blood products, neuroaxial adjuncts e.g. spinal
  • Operative details
• Background:
  • Reason for hip replacement
  • Regular medications, allergies, smoking/drug history
  • Family history of adverse reactions to anaesthetic

Examination:

• Neurology: any lateralising signs, focal deficits, pupillary size and reaction, train of four
• Cardiovascular: currently haemodynamically stable, arrhythmias including AF, tachycardia, fluid status
• Resp: O2/ventilator support requirement, auscultation -> ?wheeze, decreased air entry, creps
• Signs of chronic disease (cardiac, resp, renal, hepatic, thyroid), body habitus (?significant obesity)
• Other, Surgical site, fever (thyroid storm, MH), muscle rigidity + myoglobinuria (MH)

Investigations:

• Bedside:
  • Repeat ABG: evaluate gas exchange, metabolic parameters, BSL, electrolytes
  • ECG: tachycardia, right heart strain, AF , ischaemic changes
  • TTE if concerns re intra-op cardiac event
• Bloods:
  • UEC/LFT: organ function, FBC – Hb
  • Depending on other findings consider CK/coags (DIC + rhabdo in MH), troponin (ischaemia), TFTs (thyroid function)
• Imaging:
  • CXR: ETT position, aspiration, pneumothorax, APO, signs of chronic lung disease (e.g. hyperinflation)
  • CTB: intra-cranial pathology

 

List the potential methods of assessing for residual paralysis:

Clinical tests: all cannot reliably exclude residual paralysis

• Evaluation of breathing:
  • Recovery of spontaneous breathing: not reliable, can be present even when peripheral muscles are incompletely paralysed
  • Vital capacity > 15ml/kg – however may have normal vital capacity even with TOFR of 0.6
  • Maximal inspiratory pressure > 25 cm H20
  • Normal etco2: not reliable
• Sustained head or leg lift: ability of patient to lift head or leg up against gravity for > 5 seconds. Corresponds to TOF ratio > 0.4 – 0.7 but might be influenced by other things such as pain, medications and is not sensitive.
• Grip strength: sustained hand grip for ³ 5 seconds
• Tongue- depressor test: ability to hold an object between teeth while someone tries to remove it for ³ . Most reliable clinical test corresponding to a TOF ratio > 0.8 – 0.9.

 

Neuromuscular:

• Qualitative
  • Tactile or visual measurement of train of four and fade (using clinician’s judgement)
  • Double burst stimulation: consists of two bursts separated by 750ms with three impulses in each burst separated by 20ms à the fade detected visually by this method is often more perceptible than train of four
  • Post tetanic count: number of responses to single twitch stimulation following tetanic stimulation à more painful and generally only used in anaesthetised patients
• Quantitative: generally, quantitively analyse train of four number and ratio. They can detect residual blockade.
  • Electromyography: measures amplitude of compound muscle action potential à electrical response is proportional to the force of contraction
  • Acceleromyography: based on Newtown’s second law of motion (force = mass x acceleration) an acceleration transducer made up of a piezoelectric sensor, reflects the force of contraction à when it is displaced a current voltage is generated à generates an electrical signal à analysed and recorded in a monitor
  • Kinemyography: muscle movement distorts a sensor applied between the thumb and forefinger à measures the movement and forms an electrical signal
  • Mechanomyography: measures force of contraction, rarely used clinically à historically was gold standard but today no commercial devices available.

How does checking a train of four work?

Train of four testing is a way of monitoring the degree of neuromuscular blockade. It uses a nerve stimulator to transcutaneously apply a supra-maximal stimulus, in the form of current, to a peripheral nerve (usually the ulnar nerve) and measuring the associated muscular response. In order to minimise the resistance of the tissue, it is important to clean the skin and remove excess hair prior to applying the electrodes. Two electrodes are placed along the nerve pathway – for the ulnar nerve the negative electrode (black) is placed at the ulnar border of the wrist at the flexor crease with the positive (red) electrode) played approximately 2cm more proximal, parallel to the flexor carpi ulnaris tendon. The nerve is stimulated with four single twitches 0.5seconds apart, at a frequency of 2Hz, and the associated muscle response (twitches) noted – for the ulnar nerve the adductor pollicis (thumb adduction) is assessed. The number and amplitude of observed twitches decreases with increasing neuromuscular blockade. T4 disappears first, followed by T3, T2 then T1, with recovery occurring in reverse.

Number of observed twitches:

• Zero: 100% blockade
• One: 90% blockade
• Two: 80% blockade
• Three: 75% blockade
• Four: < 75% blockade

Amplitude: the ratio of the amplitude of the 1^st twitch (T1) to the 4^th twitch (T4) – known as the ToF ratio can also be used. When a non-depolarising neuromuscular blocking agent is given, there is a reduction in the amplitude of the responses, with T4 being affected first and T1 last. This is known as fade.

• ToF ratio > 90% now thought to be adequate for extubation
• ToF ratio > 70% previously thought to be adequate for extubation

When a depolarising neuromuscular blocker is given, the four twitches are decreased equally in size i.e. there is no fade. However, if repeated or larger doses of depolarising agents are given, a ‘phase 2’ block develops where it exhibits some features of non-depolarising agents such as fade.

 

What are the risks of residual neuromuscular block?

Studies have shown that residual neuromuscular block was an independent risk factor for anaesthesia related 24 hours post-operative morbidity and mortality. They have also shown that critical respiratory events were more common if the train of four ratio was < 0.7 in recovery, and that residual paralysis was associated with increased morbidity and mortality in the post-operative period. ^{1,2, 3}

Potential risks:

• Hypoxia
• Hypercapneoa
• Acute respiratory failure
• Airway obstruction
• Atelectasis
• Aspiration
• Difficulty swallowing
• Difficulty speaking
• Patient distress
• Increased requirement for post-operative ventilation, ICU admission, longer PACU stay
• Hypoxic brain injury
• Death

 

2. Evidence based medicine viva. What are the strengths and weaknesses of a non-inferiority trial?

Non-inferiority trials aim to show that a treatment is not worse that an active control by more than the equivalence margin. They compare a new treatment with an established standard of care. The null hypothesis is therefore that the intervention is worse than the control by greater than or equal to the non-inferiority margin.

Strengths:

• Does not require a placebo group where this may be unethical
• Allows cheaper, more convenient or less toxic therapies to be introduced in place of older therapies
• May consider when the experimental treatment is unlikely to be superior to the established treatment or the current treatment is highly effective

Weaknesses:

• Does not prove efficacy of tested therapy – relies upon known/accepted benefit of control
• Both treatments may be similarly harmful
• Needs to be performed under similar conditions in which the active control has demonstrated benefit
• No clear consensus on what margin of non-inferiority or equivalence should be accepted
• Repeated non-inferiority trial may lead to gradual acceptance of inferior therapies
• Conditions and practice may have changed since the original placebo trial of the current standard treatment or there may never have been a placebo controlled study
• Analysis and equipoise are more complex
• In general, requires a larger sample size compared to superiority trials
• A poorly conducted study gravitates towards non-inferiority. Examples include:
  • Non adherence to allocated treatment à may dilute treatment effect in the control group or result in similar treatment effects measured in both groups
  • Non-specific end point measures
  • Inappropriate participant cohort
  • Insufficient follow up

 

What is the difference between a non-inferiority trial and an equivalence trial?

Equivalence trials aim to show that a new treatment is no better and no worse than the standard treatment by the equivalence margin. This compares to a non-inferiority trial which aims to show that it is no worse by the equivalence margin. In other words, an equivalence trial aims to show that a new treatment is not unacceptably different compared to the standard whereas a non-inferiority trial aims to show that it is not unacceptably worse.

What is an adaptive design clinical trial?

This is a clinical trial design that allows for prospectively planned modifications to one or more specified aspects of the study design after the trial’s initiation, based on accumulating data from subjects in the trial, without undermining the validity of the trial. Examples of planned modifications that could be included in an adaptive design trial include:

• Pre-specified stopping rules for efficacy or futility e.g. in group sequential designs
• Adaptations to the randomisation procedure or allocation ratio e.g. randomisation ratio is changed to favour the treatment arms with highest probability of being superior such as in adaptive randomisation trials
• Adding or abandoning treatment doses or arms e.g. in multi-arm multi-stage trials
• Adaptations to the sample size e.g. in sample size re-estimation trials
• Adaptations to the study population e.g. adaptive enrichment trial

What are the advantages and disadvantages of adaptive design trials?

Advantages:

• Generally less expensive, shorter duration and more efficient
• Fewer patients needed
• Can identify ineffective treatments or effective treatments earlier
• May assign more patients to more promising treatment arm à ethically may maximise potential benefit and minimise exposure to ineffective/harmful therapies

Disadvantages:

• More complex design and statistical analysis
• May introduce bias
• Less understood
• May increase to risk of type 1 error (rejection of a true null hypothesis)

3. You are working as a locum intensive care specialist in a regional hospital with no tertiary paediatric service. You are called as part of the trauma team to ED to assist with the management of an 8yo child with burns. The paramedics report the child was found semi-conscious and breathing in the downstairs hallway of a home on fire less than an hour ago. Describe your initial assessment and monitoring priorities for this child.

My initial assessment and monitoring priorities would involve using an EMST approach to obtain a targeted history, and perform a primary and secondary survey with specific considerations regarding potential need for early securing of the airway given higher risk of airway compromise in children, use of Broselow charts to calculate medication/equipment requirements and early liaison with a tertiary paediatric centre.

History

• Regarding the burn
  • Exact time of the burn
  • Signs of other trauma
  • Any first aid or treatment given at the scene/en route (e.g. running child under cold water)
  • Vital signs at scene and during transfer
• Patient related: other illnesses, allergies, medications, last meal, tetanus status

Primary survey: concurrent assessment and management

• Airway/c spine
  • Evaluate for signs of airway burn/inhalational injury:
    • Stridor, facial burns, singed nasal hairs/eyebrows, significant neck burn à if these are present
    • Consider early intubation (keeping in mind potential difficulties in securing airway in children)
    • Requires repeated evaluation of airway
  • Protect C spine if associated trauma
• Breathing
  • Optimise oxygenation à apply high flow oxygen
  • Optimise monitoring: sats monitoring
  • Evaluate respiratory status:
    • RR, sats, breathing pattern, breath sounds
    • CXR
    • Injuries + chest burns – circumferential à may need escharotomy
  • Circulation
    • Optimise monitoring:
      • ECG monitor, non invasive BP
      • Insert IDC and NGT if > 10% burns
    • Obtain adequate access and bloods
      • IV/IO access x 2: take bloods including FBC, UEC, VBG (carbon monoxide/lactate/glucose), group and hold
    • Evaluate and optimise circulatory status
      • General appearance, lethargy, central cap refill, skin colour, HR, NIBP
      • If shocked: 10ml – 20ml/kg bolus IVF and evaluate for other causes of shock (e.g. secondary to trauma – bleeding, pneumothorax, cardiac contusion)
      • If ³ 10% burns: fluid resus with modified Parklands formula (3ml/kg/TBSA using Hartmanns – first half of total volume given over first 8 hours from time of injury) aiming for 1ml/kg/hr urine output.
        • This is in addition to maintenance fluid which should be glucose containing
      • Evaluate and manage burns:
        • Calculate extent of burns: weigh patient and use age appropriate Lund and Browder Chart or palmar surface method
        • Look for circumferential burns – elevate areas, escharotomies if required
        • Liaise with burns team at tertiary hospital à take photos with consent, debride clearly loose/blistered skin, apply appropriate dressings
      • Disability
        • Evaluate consciousness and neurology
          • GCS not that useful: use AVPU
          • Pupillary response
          • Focal neurology, peripheral neurovascular status if limb burns
          • Check BSL: prone to hypoglycaemia: if present give 10ml/kg of 10% dextrose
        • Optimise analgesia
          • Analgesia: paracetamol 15mg//kg, can use intranasal fentanyl 1.5microg/kg (max 100microg) or intravenous fentanyl 0.5-2microg/kg up to 50microg/bolus dose or IV morphine 0.05 -0.1mg/kg/dose
        • Exposure
          • Full exposure (including log roll to examine back) to calculate percentage and depth of burns as well as to look for other injuries à cling wrap if no definitive burns dressing available
          • Optimise temperature
            • Check temperature: children are more prone to hypothermia especially during initial resuscitation à cover as soon as possible, warm the room, warm fluids
          • ADT
        • Logistics
          • Liaise with and update family
          • Liaise with paediatric centre, burns team and retrieval re transfer

 

What are the methods of calculating the total body surface area affected by burns in this child?  

Age appropriate Lund and Browder Chart

• Most accurate method
• Charts available online

Palmar method

• Generally used for smaller burns
• Uses the size of the patient’s hand (palm and fingers) to estimate burn size à palmar surface approximately equals 1% TBSA

 

**Wallace Rule of Nines is inaccurate in children due to proportionally larger head and smaller legs à should only be used in adults. Some facilities have a specific rule of nines charts for children of varying ages **

 

What are the anatomic airway differences in children compared to adults which may make airway management more complex?

• Occiput is prominent: when lying supine the neck is flexed which is not ideal position for laryngoscopy
• Smaller mandible: mouth opening reduced
• Larger adenoids and tongue: increased risk of obstruction and more difficult to visualise structures with laryngoscope
• Softer airway structures: more prone to trauma with laryngoscopy, easier to obstruct airway with cricoid pressure
• Floppy, longer epiglottis: may need straight blade in infants, projects into airway more
• Larynx is more anterior and superior (opposite C3-4 versus C4-5 in adults): more difficult laryngoscopy
• Narrower trachea and airway: more easily obstructed by blood, secretions, oedema and external compression à even relatively little narrowing can rapidly increase airway resistance and work of breathing, cricothyroidotomy more difficult
• Shorter trachea: easier to accidentally intubate right main bronchus
• Narrowest point is the cricoid cartilage (below the vocal cords) whereas in adults it is at level of vocal cords