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September - October 2022

Includes submissions from the Perth Children's Hospital in 2022

November 2022 by Dr Heather Patterson

This educational review outlines the pathophysiology of asthma, key aspects of preoperative evaluation of children with asthma, and provides updates in asthma treatment from multinational guidelines, including recommendations for the treatment of bronchospasm under anaesthesia.

This review focuses on the ‘Th2’ or ‘atopic, aspirin exacerbated respiratory disease’ (AERD) endotype, as it is by far the most common in paediatric asthma, where sensitisation to aeroallergens results in CD4 activation and release of interleukins IL4, IL5 and IL13.

Preoperative evaluation:
Spirometry and peak expiratory flow rate (PEFR) cannot be reliably performed in children under 5 years, therefore history and examination findings may be more pragmatic in the perioperative setting.

Risk factors for perioperative respiratory adverse events (PRAEs) include age <5yrs, moderate to severe asthma, respiratory tract infection within last 4 weeks, previous exacerbations under GA, need for intubation and ventilation for an exacerbation. Anaesthetic/surgical risk factors include intubation (vs supraglottic airway or bag mask ventilation only), airway surgery, and prolonged operation. Additional components of preoperative evaluation should include frequency of symptoms, exercise limitation, frequency of short acting beta agonists or ‘reliever’ medication use, known triggers, recent exacerbations, and level of care required if hospitalised. The child should be examined for wheeze, increased work of breathing, and abnormal vital signs.

Stratification based on severity is recommended:
- Well controlled asthma (no need for reliever medication for last month, no exercise limitation, and symptom free): can proceed as a day case at a general or regional hospital
- Mild asthma (symptoms less than three times per week, and no limitation in activity): can proceed with elective cases as a day case at a general or regional hospital.
- Moderate asthma (daily or nightly symptoms, may have exercise limitation). Weighing risks vs benefits of elective surgery can be difficult. If the child is well, with a recent review by treating physician, and compliant with treatment, it is safe to proceed with elective cases.
- Severe asthma (persistent daily or nightly symptoms, requires high dose inhaled corticosteroids plus a second agent to achieve symptom control, or is uncontrolled despite therapy). Recommend review by respiratory physician to optimise control and plan for perioperative care, consider performing surgery in a centre with paediatric HDU or PICU facility.

Perioperative management recommendations:
- Ensure treatment compliance in the preceding month.
- Children on > 15mg/m2 hydrocortisone equivalent for more than 1 month, are at risk of adrenal suppression, and perioperative steroid replacement should be considered.
- Administer short acting inhaled beta agonist via spacer or nebuliser preoperatively
- Ensure adequate depth of anaesthesia before instrumenting airway or painful stimuli
- Consider sevoflurane and ketamine use to promote bronchodilation (as well as magnesium)
- Consider choice of airway & bronchospasm risk: LMA < ETT
- Minimise histamine releasing drugs (e.g., synthetic opioids over morphine)

Management of severe bronchospasm under general anaesthesia
- Pharmacological agents:
o First line: inhaled salbutamol via anaesthetic circuit
o Deepen anaesthesia and consider changing to volatile if maintaining with TIVA
o Second line: nebulised ipratropium, IV magnesium, IV salbutamol, hydrocortisone, and in extremis, IV adrenaline
o Consider commencing infusions of salbutamol, aminophylline, adrenaline or ketamine
- Ventilation strategies are listed as suggestions without an in-depth discussion of supporting literature
o Target oxygen saturation >90%, allow permissive hypercapnia with pH >7.2
o Maintain full paralysis
o Either pressure or volume control modes can be utilised- the authors recommend a mode that is most familiar to the treating clinician
o Tidal volumes of 5-7 ml/kg
o Target plateau pressure <30 cmH20, and PIP of <40 mmHg to avoid barotrauma
o Consider low PEEP of 4-5 cmH2O
o Increase expiratory time aiming I:E ratio 1:3-1:4
o Monitor for breath stacking: ensure flow reaches baseline at end expiration, and that end tidal CO2 reaches a plateau
o Refrain from manually decompressing the chest: can precipitate cardiac arrest

In summary, this review paper provides a refresher for clinicians in the risk stratification and perioperative management of children with asthma, based on international guidelines formed from available evidence and consensus expert opinion.

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A randomized, controlled study

November 2022 by Dr Neil Hauser

This small, randomized control study of 40 patients investigated the utility of erector spinae plane blocks (ESPB) in paediatric sternotomy for cardiac procedures. The primary outcome was cumulative morphine consumption in the first 24 hours post-operatively. Secondary outcomes included pain & sedation, time to extubation and ICU length of stay.
The mean age of patients presenting for cardiac surgery was 6 years (range 2 – 10 years), with procedures limited to ASD or VSD closures & aortic membrane excision. Notably the duration of surgery was significantly longer in the ESPB group, and this group also received 2 microg/kg more fentanyl than the control group despite an apparent set timing and dose protocol for the administration of Fentanyl intra-op. This was not significant, but no explanation was offered in the paper either.

Strengths and weaknesses
Strengths of the study included that there were only 2 people experienced with performing ESPB doing the blocks in a standardized manner. The assessor measuring pain scores in the first 24 hours was blinded. Blocks were performed at a standardized period in the perioperative journey (prior to surgery & after induction of anaesthesia).
Weakness of the study were the small number of patients included and no explanation as to why 2 patients were excluded. There was no assessment of dermatomes in any patient postoperatively, and despite following up patients until discharge, assessment of morphine consumption stopped at 24 hours.

As a primary outcome, the authors demonstrated a significant reduction (p=0.043) in rescue morphine (mg/kg) dosing, administered as 0.05 mg/kg boluses to a MOPS score of >4, in the first 24 hours post-operatively. The was no difference in any of the secondary outcomes listed above.

The authors acknowledge that this is a small study and suggest that further larger trials are required to determine whether the block is effective in reducing pain scores and opioid consumption post-operatively following cardiac surgery in paediatric patients. One of the arguments the authors list for performing the ESPB is as part of an ERAS program to reduce PONV because of reduced opioid consumption. There was no difference in rates of PONV between the groups, a point acknowledged by the authors, but perhaps the difference in opioid consumption, although statistically significant, fails to make a clinical difference as demonstrated by no reduction in any of the secondary clinical outcomes or PONV. The discussion also highlights that there have been both positive and negative trials previously published in the area of plane blocks performed for sternotomy procedures.

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A single center retrospective case series

November 2022 by Dr Bojana Stepanovic

- A retrospective chart review of 94 patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis between 2015 and 2020 at the American Family Children’s Hospital, University of Wisconsin, USA.
- Three patient groups:
o Group PCA received a hydromorphone PCA without methadone
o Group PCA + Methadone received pre-incisional methadone and a hydromorphone PCA
o Group Methadone received pre-incisional methadone, scheduled postoperative methadone, and no PCA
- Methadone dosing:
o Pre-incisional methadone 0.2 mg/kg (max 20 mg)
o Post-operative methadone 0.1mg/kg (max 5 mg) IV in the PACU at first request for analgesia, and methadone 0.1 mg/kg (max 5 mg) IV 6 h after the PACU dose, with backup rescue hydromorphone IV boluses available on request.
- The primary outcome was postoperative opioid use over 72hrs. Secondary outcomes included pain scores, sedation scores and length of stay.
- Intraoperatively all patients received TIVA with remifentanil or fentanyl infusion and additional opioid boluses at the anaesthetist’s discretion.
- The study period included post-operative days 0-3.

- Group Methadone used significantly less opioid than Group PCA and Group PCA + Methadone
o Mean hydromorphone equivalents in mg/kg = 0.18 vs 0.33 and 0.30 respectively
- There were no statistically significant differences between the groups for secondary outcomes.

Intravenous methadone is a unique opioid that acts at multiple receptors, including mu-opioid, kappa- opioid, N- Methyl- D- aspartate (NMDA), serotonin, and norepinephrine. The clinical duration of action is dose-dependent and is significantly extended with repeat dosing. Methadone undergoes rapid redistribution after bolus administration and so supplementation of the pre-incisional dose with subsequent doses maintains analgesic plasma levels. Dose finding studies have found similar pharmacokinetics in adolescents and adults.

There was generally standardisation of care for spinal fusion patients with a streamlined multidisciplinary care pathway developed in 2015, which limits other confounding factors in post-operative care. All patients received standardised non opioid analgesia including gabapentin, acetaminophen and non-steroidal anti-inflammatories.

In terms of safety profile, none of the patients in the methadone groups experienced QT prolongation while on telemetry for the first 24 hrs post operatively.

This is a single centre retrospective chart review, so it is prone to bias and the numbers of patients in each group is small, with unequal patient sizes, and missing pain data points in all groups.

Total opioid was calculated incorporating methadone, hydromorphone, oxycodone and morphine doses and excluded short acting opioid doses of fentanyl, remifentanil, alfentanil and sufentanil.
There was a statistically significant difference in long-acting opioid use between all groups, however there was not a clinically significant difference between the PCA group and PCA + methadone group. This review suggests that the real opioid sparing benefit was gained by the scheduled methadone group receiving multiple doses of methadone.

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Interim results of a randomized, double‐blinded, placebo‐control trial

November 2022 by Dr Falk Reinholz

Study Design
- Prospective, double-blinded, randomized, placebo-controlled trial. Single centre in USA where intrathecal morphine (ITM) is commonly utilised.
- Ondansetron 0.1mg/kg (max 16mg) or placebo given IV just prior and q6hrly for 24 hours after ITM (4-5mcg/kg) for urological or orthopaedic surgery.
- Inclusion criteria: age 3-17 years; ≤100kg weight; able to use pain assessment tool.
- Exclusion criteria: posterior spinal fusion operations; hypersensitivity or contraindications to any anti-pruritic and anti-emetic in the study protocol; regular 5-HT3 antagonist or SSRI use.
- Routine anti-emetics given: dexamethasone 0.15mg/kg (max 4mg) and diphenhydramine 0.3mg/kg (max 12.5mg).
- Postoperatively:
o Treatment of pruritus: 1st nalbuphine, 2nd diphenhydramine
o Treatment of PONV: 1st prochlorperazine, 2nd promethazine
- Power calculation suggested 56 patients in each group (total N=112) would be adequate to detect reduction in pruritus from 40% to 20%.

- Study was discontinued after interim analysis, by which time 45 patients had been recruited.
- Groups similar in age, weight, ASA, gender, surgery type. However, size of groups differed (active N=18 vs. control N=27) due to randomisation error.
- Primary outcome: efficacy of ondansetron as an anti-pruritic
o Overall, 84% incidence of pruritus, with 87% of these requiring treatment.
o No difference between groups for incidence (active 78% vs. control 89%) or treatment requirement (active 93% vs. control 83%)
- Secondary outcome: incidence of nausea
o Significant difference (p=0.008) in incidence of nausea in active group (44%) vs. control group (85%)
- Secondary outcome: adequacy of pain relief
o Similarly low mean pain scores in PACU (active 1.78 vs. control 1.96) and at 24h (2.30 vs. 2.25) with a high overall satisfaction of pain control (44/45).

This was a well-designed study, having been a prospective, double-blinded RCT that conformed to CONSORT guidelines.
It is commendable that the authors discontinued the study after their pre-planned interim analysis, citing these two reasons:
1) High overall pruritus rates with only a small difference between groups, meaning the study was very underpowered for its primary outcome.
2) The large difference in PONV rates between those receiving ondansetron and those not meant withholding ondansetron from the control group was considered unacceptable.

The incidence of pruritus (84%) is considerably higher in this study than in previously published data (30-60%). It is important to consider nocebo and Hawthorne effects when monitoring for drug side effects. Additionally, these data reinforce that extrapolating drug effects and side effects from adult literature to paediatrics, although common and often necessary, has limitations.

Take Home Messages
Pruritus and nausea are common side effects of ITM use. Treatment for these side effects is rarely unsuccessful. Administering a 5-HT3 antagonist to patients having ITM lowers PONV rates dramatically.

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November 2022 by Dr Suze Bruins

An animal study (rats), investigating whether pre-treatment with dexmedetomidine (DEX) can reduce sevoflurane-induced neuronal hyperexcitation and corticosterone release at the time of exposure, as well as the long-term neurodevelopmental effects of sevoflurane (SEVO).

Rats were randomized into:
- DEX (25 mcg/kg intraperitoneal) before exposure to 2.1% SEVO for 6 hours
- Vehicle (intraperitoneal) before exposure to 2.1% SEVO for 6 hours
- DEX-only group received DEX without exposure to SEVO
- Control group received the vehicle only
Serum corticosterone levels were taken after 6 hours and the rats underwent various neurobehavioural tests over the following months. This was followed by collection of hippocampal tissue samples for in vitro studies. A subset was instrumented for EEG. Baseline recordings and recordings whilst receiving anaesthesia were made. Blood was taken on completion of the EEG recording for corticosterone levels.

Primary outcome: in vivo acute and long-term effects of SEVO and DEX.
Secondary outcome: The experimental results of the in vitro mechanistic studies.
Key findings:
DEX reduced SEVO-induced EEG-detectable epileptic seizure-like activity (hyperexcitation patterns) in neonatal rats, both in terms of frequency and duration (mean ± standard error of the mean, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < 0.001).
DEX exacerbated SEVO-increased corticosterone levels in neonatal rats at the time of exposure (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = 0.043).
DEX diminished, but did not fully prevent, SEVO-induced long-term neuroendocrine and behavioural abnormalities. It normalized DNA methylation changes in many (though not all) SEVO-affected hippocampal genes. It is not known whether these changes found in DNA methylation marks lead to transcriptional, translational, and functional abnormalities.
DEX alone, without SEVO anaesthesia, did not cause acute or long-term functional abnormalities.

Small animal study that suggests administering dexmedetomidine as an adjuvant, may improve the safety profile of sevoflurane in neonatal rats. However, dexmedetomidine only partially counteracted the sevoflurane-induced abnormalities.

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A Randomized Trial

November 2022 by Dr Liam O'Doherty

An RCT of adult patients undergoing surgery (urology, gynaecology, peripheral) with mandatory ventilation via a Proseal LMA mask randomised to PEEP 8.2 cmH2O (PEEP group) or PEEP 0 cmH2O (ZEEP group). Does this result in a higher incidence of gas leakage?

Adult ASA I/II patients were anaesthetised with Proseal LMA placed then given a mandatory ventilation protocol with no spontaneous breathing for the first 30 minutes of the case.

527 patients randomised: 174 ZEEP vs 208 PEEP
Excluded: increased risk aspiration, BMI >30, GORD, pregnancy, prone position, lateral position, laparoscopic surgery.
Intervention: 8.2 cmH2O PEEP (PEEP) or zero PEEP (ZEEP) on positive pressure ventilation.
Primary outcome: Detection of gas leakage (from ventilator, oral CO2 detection, audible leak)
Secondary outcomes: SpO2 at 25 mins; PIP, Vt, dynamic compliance and ETCO2 at 30 mins; number of desaturations occurring in the post anaesthetic care unit (PACU).

Incidence of gas leakage did not differ between groups: (ZEEP 13.2% vs PEEP 20.2%; P=0.07).
Incidence of severe gas leak requiring either new placement of LMA or intubation was higher in the PEEP group: (ZEEP 3.4%; PEEP 19.5%; p=0.025). This difference was primarily due to having to adjust the LMA positioning in the PEEP group.
Incidence of gas leak requiring intubation not different between the groups: (ZEEP 1.1% vs PEEP, 3.4%; p=0.190).
Mean SpO2 at 25 mins was higher in PEEP than ZEEP (ZEEP 98.0% vs PEEP 98.5%).
PIP at 30 mins was higher in PEEP than ZEEP (ZEEP 12 cmH2O vs PEEP 16 cmH2O).
Dynamic compliance at 30 mins was higher in the PEEP group (ZEEP 49 ml/mbar vs PEEP 57 ml/mbar).
No difference in duration of surgery or duration of anaesthesia.
No difference in mild or severe desaturations in the PACU.
No difference in PACU length of stay.
No aspirations in either group.

Take Home Message
The PEEP value used is higher than what would be used in usual practice with an LMA. The PEEP level was chosen “pragmatically” without any further reasoning. With this degree of PEEP, they were more likely to need to adjust the LMA due to gas leak. In usual clinical practice, with an LMA, PEEP levels would be set lower initially and if any leak occurs PEEP and PIP can be reduced.

The presence of PEEP seemed to have no clinically significant impact on any other outcomes. Aspiration is uncommon thus these numbers cannot determine if a difference is present.

This is not a paediatric study and given differences in LMA sizing and easier gastric insufflation in smaller age groups, this study cannot be generalised to all paediatric age groups, but may be applicable to older paediatric patients.

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November 2022 by Dr Sinead Farrell

This review article addresses key questions about regional anaesthesia in paediatric practice.

1. Blocks under GA or deep sedation are safe in children and should be the default.
• The benefit of an awake patient (ability to alert the practitioner to early signs of local anaesthetic toxicity or intraneural injection) is greatly outweighed by the risk of damage when the target is moving, or the patient is uncooperative.
• In 2018, a published registry of 100,000 cases confirmed the safety of this practice. They reported zero cases of permanent nerve damage, an incidence of 2.4:100,000 of temporary nerve damage and 0.76:100,000 of local anaesthetic systemic toxicity.

2. There is no evidence that regional anaesthesia increases the risk of compartment syndrome.
• Both American and European Societies for Regional Anaesthesia have found no convincing evidence that regional anaesthesia increases the risk or delays diagnosis of compartment syndrome, however debate continues among individual practitioners.
• Presence of a functional block could expedite the diagnosis of a compartment syndrome for two reasons:
i. increased vigilance regarding neurovascular observations in a patient who has had a regional block
ii. tissue ischaemia would prevent uptake of local anaesthesia and therefore the patient will experience breakthrough pain, despite the presence of the block.

3. Image-guided neuraxial/regional anaesthesia may be carefully considered in the pain management of patients with an intrathecal baclofen pump in situ.
• A reluctance in the use of regional or neuraxial anaesthesia in patients with an in-dwelling device (e.g., baclofen pump in children with cerebral palsy) can result in challenging pain control and a reliance on opiates.
• A small study of 44 patients described fluoroscopy- or ultrasound- guided epidural or lumbar plexus blocks for hip reconstruction surgery. The patients were carefully selected, and a full multidisciplinary team involved in the process, and successful analgesia was reported with no complications.

4. Regional anaesthesia catheters are safe to use in children, and ambulatory peripheral regional anaesthesia is a viable option for reducing opiate consumption and reducing length of hospital stay.
• Obvious concerns regarding dosing, as well as monitoring efficacy and toxicity in children remain a challenge.
• Reassuringly, the Pediatric Regional Anesthesia Network (PRAN) database reported zero cases of local anaesthetic systemic toxicity or permanent nerve damage from the use of peripheral catheters.

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