It is time to take a look at withdrawal syndrome and delirium and how to reduce them in children requiring intravenous sedation and analgesia within the Paediatric Intensive Care Unit (PICU).
Isla is a 2-month-old infant in the PICU.
She has been ventilated since birth as she was found to have an antenatal defect, which required surgical repair on day three of life. She has required high levels of sedation with morphine and midazolam with intermittent paralysis over the last two months.
She has made a remarkable recovery, and the PICU team plans to extubate her this week. The team is looking at strategies to wean her sedation as she has been on it for an exceedingly long time.
Why do we use sedation and analgesia in the PICU?
The use of sedation and analgesia to provide comfort, safety, and pain treatment are central principles in the care of critically ill children. Most critically ill children are at risk of experiencing pain and discomfort while in the PICU. This may be related to patient-specific factors such as their age, ability to communicate, and underlying medical conditions, or PICU-specific factors such as the need for mechanical ventilation, invasive procedures, tolerating medical devices, sleep disruption, and reduced mobility. Providing sedation and analgesia can help achieve adequate pain relief and comfort whilst also allowing children to synchronise with a ventilator, tolerate the multiple lines and tubes often required in the PICU, and reduce the stress response.
Multiple sedation and analgesia options are available. Oral and intravenous options include alpha2-agonists, benzodiazepines, opiates, propofol, and ketamine.
Finding the right combination can be tricky not only due to the differing sizes, ages, and developmental stages of children but also due to the effect of the critical illness, which can lead to organ dysfunction and may alter the impact of the medications on the body, and the body’s ability to breakdown the drugs.
Critically ill children frequently require prolonged (>24 hours) sedation, requiring continuous use of sedative medications. Several consensus guidelines are available that can help guide the strategy for sedation and analgesia. Examples of these are linked below:
- European Society of Paediatric and Neonatal Intensive Care (ESPNIC). Clinical recommendations for pain, sedation, withdrawal, and delirium assessment in critically ill infants and children
- Pediatric Acute Lung Injury and Sepsis Investigators (PALISI). Guidelines for Paediatric Ventilator Liberation
- Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium (PANDEM).
What are the risks of under- or over-sedation?
There are risks associated with both light and deep sedation. Finding a balance between the two is essential.
Light sedation/analgesia can lead to distress, accidental line/tube removal, and long-term psychological and behavioural ramifications.
On the other hand, sedation/analgesia that is too deep can be associated with prolonged ventilation time, length of stay, extubation failure, delirium, and the development of withdrawal syndrome.
The aim is to target a minimal safe dose that achieves an appropriate level of sedation and pain relief. However, children and young people often require continuous infusions of medications (such as opioids and alpha2-agonists) to achieve this in PICU with increasing doses or cycling of agents due to the severity of illness, duration of ventilation, and tolerance.
What is delirium?
Delirium is a significant concern for critically ill children admitted to the PICU, especially for those undergoing prolonged sedation with benzodiazepines and opioids. The overall prevalence has been estimated to be around 25% (although higher rates have been reported for children younger than five).
It is a syndrome of acute-onset brain dysfunction typified by fluctuating symptoms of inattention, changes in awareness, and changes in cognition.
Based on activity levels, delirium can be categorised as hypoactive, hyperactive, or a mixture of the two. Although it is not entirely clear why this happens, it is thought that it is related to the dysregulation of multiple neurotransmitter pathways in the brain. This occurs in response to systemic illness, inflammation, and physiological stress. Guidelines recommend using validated bedside screening tools (such as SOS-PD or CAPD) at least once daily in the PICU to help identify delirium.
Multiple studies have examined the correlation between prolonged sedation and delirium in the PICU, highlighting a strong association between these two factors.
The SANDWICH trial found that children exposed to prolonged sedation and ventilation had a higher incidence of delirium, indicating the strong influence of sedation practices on delirium outcomes in critically ill patients. These findings emphasise the need for careful sedation management and monitoring to reduce the risk of this complication.
Non-pharmacological methods of reducing the risk of delirium
Non-pharmacological considerations are important in reducing the risk of delirium. It is well-recognised that the environment in the PICU can negatively affect children and their parents/caregivers, increasing the probability of delirium. Children’s circadian rhythm is often disrupted due to multiple factors such as illness, a paucity of day-night cycles due to necessary medications/interventions, and the noisy and stressful environment. Additionally, they may find themselves without their parents/caregivers by their side.
Guidelines have considered the potentially harmful environmental implications and universally recommend non-pharmacological treatment strategies, even if there is low-level evidence of benefit.
These recommendations include a focus on sleep hygiene, noise reduction (including earplugs and headphones), and parental/caregiver presence during their stay in the PICU. Fostering a family-friendly environment also reduces the risk of delirium and has more extensive positive implications on children’s care by promoting shared decision-making and proactive involvement in the recovery process.
What is withdrawal syndrome?
When medications used for sedation and analgesia are used in high doses or for a prolonged period, tolerance can occur.
It is thought that tolerance is due to receptors becoming desensitised to the medications. Cross tolerance can also occur, this is where tolerance to one drug occurs because of exposure to another drug for example, patients who have been on morphine often display a tolerance of other opioids. More medications are needed to achieve the same effects, and the body can become physically dependent upon the medication.
If, for example, opiates and benzodiazepines are stopped abruptly or weaned too quickly, patients can get a typical pattern of signs of symptoms representing a withdrawal syndrome. These include CNS irritability (agitation, seizures, irritability), GI disturbance (nausea, vomiting, diarrhoea), and autonomic symptoms (increased heart rate, high blood pressure, sweating and fever). The risks of withdrawal are higher in children and young people who have received a significant amount of these medications or have received them over a prolonged period, both of which can occur in the PICU setting.
It can be hard to distinguish between withdrawal from opiates versus benzodiazepines, but it is important to note differences in the management of the two.
Initial strategies include boluses of the suspected drug to alleviate immediate withdrawal. There may be clues depending on the time and dose of the medications they have been on. This also highlights the importance of close and constant review, with preventing withdrawal as a central theme.
Although tolerance, cross-tolerance, physical dependence, and withdrawal syndromes can be anticipated in patients receiving prolonged infusions of opioids and sedatives, the exact cellular mechanisms for withdrawal are poorly defined. Hence, commonly used strategies to reduce the incidence of withdrawal syndrome begin with efforts to reduce the total doses of benzodiazepines and opioids and carefully monitor for signs of withdrawal.
How can we monitor for signs of withdrawal?
Regular sedation scoring, protocolised weaning, and screening for withdrawal syndrome are important when monitoring for withdrawal.
The PANDEM guidelines recommend using the COMFORT-B Scale to assess the level of sedation. This scoring system is based on observed behaviours when sedation is briefly held and involves assessing alertness, agitation, movement, and breathing patterns.
The effectiveness and safety of this have been evaluated in the multi-centre cluster-randomised Sedation AND Weaning In CHildren (SANDWICH) trial. This trial observed that protocolised weaning resulted in a significantly reduced time to first extubation amongst children with anticipated prolonged sedation. Following this trial, more than half of the PICUs in the UK are now using this protocol for sedation and weaning.
Withdrawal can be assessed using various tools. One validated scoring system that may be used in children and young people is the Withdrawal Assessment Tool (WAT-1). The WAT-1 score is a 12-point numerical scoring system marked at 12-hour or less intervals, with a score of three or more suggesting withdrawal. This tool can be used to assess opiates and benzodiazepine withdrawal symptoms and can be applied to a wide range of paediatric age groups (2 weeks to 18 years).
The WAT-1 has been derived and validated amongst children requiring intubation, sedation, and mechanical ventilation for respiratory conditions. In theory, this might limit the applicability to children being treated for other conditions; however, the score strongly correlates with withdrawal symptoms and has proven to be a robust scoring system. It is both sensitive and specific, with good inter-rater reliability. However, it cannot differentiate between opioid and benzodiazepine withdrawal.
Some centres use the Sophia Observation Score (SOS-PD), which has also been validated to monitor delirium and withdrawal. The SOS-PD scale is designed for ease of use in a busy PICU, allowing quick assessment at the bedside. This allows early detection of delirium and withdrawal and has also shown good sensitivity, specificity, and interrater reliability.
How do we wean opiates and benzodiazepines?
There are many institution-based guidelines available. Each regime varies, incorporating adjunctive medications such as alpha2-agonists, chloral, and antihistamines. However, the general principle is to assess the risk of tolerance and physical dependence followed by a slow and gradual wean.
To prevent/ameliorate symptoms of withdrawal whilst in PICU, the team can routinely make gradual reductions of doses for patients following 5-7 days of sedation.
A suggested order of weaning is benzodiazepines >> opiates >> clonidine. Each drug can be weaned by 20% of the original dose daily for 5 days and then stopped.
Below is an example of a protocol adapted from The Royal Bristol Children’s Hospital to wean IV opioids and benzodiazepines:
Each child should be assessed before weaning plan initiation and when each reduction is anticipated. A pharmacological strategy should be used alongside non-pharmacological strategies and comfort measures. The assessment should consist of two components:
1. Eliminate other conditions with similar manifestations.
Since withdrawal is diagnosed by excluding other possibilities, it is essential to investigate and discount ongoing or related symptoms. Consider the following conditions:
- Low blood sugar
- Systemic or Cerebral infections
- Reduced blood flow to the brain
- Abnormalities in metabolism
- Disorders of the blood vessels in the brain
- Psychosis/psychiatric history
2. Drug history
Before initiating the weaning process, it is essential to gather information about the child or adolescent’s previous use of opioids and/or benzodiazepines, including:
- Initial drug dosage and/or infusion rate before weaning begins.
- Duration of drug administration in days e.g. 8 days of midazolam infusion.
- Previous drug reductions expressed as a % of the highest constant dose, e.g. 20% of 300mcg/kg/hour of midazolam.
- Supplementary medications that facilitate the weaning process may also require gradual reduction (such as chloral hydrate, clonidine, and others).
This information can be used to categorise ‘at risk’ children and or young people as:
| Category 1: (Minimal Risk) | Continuous intravenous opioids or benzodiazepine therapy for < 5 days. |
| Category 2: (Moderate Risk) | Continuous intravenous opioids or benzodiazepine therapy for 5 to 14 days. |
| Category 3: (Highest Risk) | Continuous intravenous opioids or benzodiazepine therapy for > 14 days. |
Monitor for withdrawal using the WAT-1 score, Sophia score (SOS) or other scoring as per your local protocol. Remember to consult the Paediatric Pain Service or a Paediatric Pharmacist in all categories as needed.
Category 1 (Minimal Risk)
Continuous intravenous opioids or benzodiazepine therapy for <5 days.
- 4-hourly assessments using a withdrawal observation chart.
- Taper sedation and analgesic drugs as clinically indicated.
- If withdrawal symptoms are observed, cease weaning and initiate treatment if indicated by scores.
- The administration of additional rescue medication should be considered (e.g. a planned dose of opioid).
Category 2 (Moderate Risk)
For patients receiving continuous intravenous opioids or benzodiazepines for 5-14 days:
- Decrease the infusion rate of opioid and/or benzodiazepine by 20% of the baseline dose daily.
- Start clonidine at 1 microgram/kg following a 0.1 microgram/kg test dose, administering every 4 hours for up to six doses. (If no medical contraindications)
- 4-hourly assessments using a withdrawal observation chart. If withdrawal symptoms appear, slow the weaning rate to 10% daily or pause for 24 hours before reassessing and resuming.
- For moderate to severe symptoms, consider reintroducing or adding benzodiazepines, increasing opioids to the previous dose, or implementing a slower weaning process.
- Initially, wean only one medication at a time and monitor for withdrawal signs for at least 48 hours post-weaning.
Category 3 (Highest Risk)
For continuous intravenous opioids or benzodiazepine therapy for > 14 days.
- Reduce doses by approximately 10% of the initial dose 24 hourly.
- 4-hourly assessments using a withdrawal observation chart and begin treatment as indicated by the scores.
- Administer clonidine intravenously or enterally every 4 hours following a 1 microgram/kg test dose if not already prescribed.
- If withdrawal symptoms emerge, slow the weaning rate to 5% daily or pause for 24 hours, then reassess and continue at a slower pace if needed.
- For moderate to severe withdrawal symptoms, consider increasing the opioid to the previous dosage, especially if gastrointestinal symptoms are present or consider restarting or supplementing with benzodiazepine therapy.
- Once symptoms subside, wean more slowly to avoid recurrence.
- Initially, wean only one medication at a time. Seek advice from the Paediatric Pain Service as necessary.
- Reduce clonidine last and monitor for withdrawal signs for a minimum of 48 hours after weaning cessation.
What do we do if the patient is withdrawing?
The treatment of withdrawal involves giving medications that act on the same receptors; this can include doses of opiates or benzodiazepines, or alternative medicines that have similar effects (e.g. clonidine). In general, cycling between different agents can also reduce the risk of withdrawal or aid in the treatment of withdrawal symptoms.
Different protocols often use different scoring systems. Using the St. Georges protocol, withdrawal could be identified when the WAT-1 score is greater than or equal to 3. Consider the following steps:
Give bolus IV dose 50-100mcg/kg of morphine
If symptoms persist, consider increasing infusion to the previous higher rate before withdrawal symptoms appeared.
If not already on it, consider clonidine enterally (up to 6 mcg/kg/dose 8 hourly) or chloral hydrate (10-50 mg/kg PRN, 6-8 hourly; administer the lowest effective dose).
Restart weaning when withdrawal symptoms have been adequately controlled for 24 hours.
When do we wean from intravenous to enteral?
Consider enteral weaning of opiates and benzodiazepines if the child is tolerating nasogastric or oral feeds and withdrawal scores are stable. Continue to wean oral medications and monitor as per the IV weaning rate category (i.e. 5-10% of original dose every 12-48hrs).
Approximate example dose conversions of morphine and benzodiazepines are given below. However, your local Paediatric pain service or Paediatric pharmacy team should verify and check the changes with you.
Morphine
IV dose of Morphine in micrograms/kg/hour X 8 = Oramorph dose 4 hourly
e.g. 10micrograms/kg/hr = 80micrograms/kg oral morphine 4 hourly dose.
To wean off IV Morphine.
1. Give 1st oral dose, wean infusion by 50% 30 minutes after dose.
2. Give 2nd oral dose and turn the infusion off 30 minutes after the dose.
Benzodiazepines
IV infusion dose of Midazolam in micrograms/kg/hour X 0.5 = Lorazepam dose 6 hourly.
e.g. 50micrograms/kg/hr = 25 micrograms/kg oral lorazepam 6 hourly (QDS)
To wean off IV Midazolam:
1. Wean infusion by 50% 30 minutes after 1st oral dose.
2. Turn the infusion off 30 minutes after 2nd oral dose.
Another example of a weaning protocol adapted from St. Georges hospital, London in pictorial format:
What is the role of Alpha2-agonists in sedation, and how to wean them?
Alpha2-agonists (such as clonidine and dexmedetomidine) have traditionally been considered opiate and benzodiazepine-sparing agents.
Alpha2-agonist sedation regimens are increasingly used in the PICU, with some guidelines suggesting that they be used as first-line agents for sedation. Several randomised controlled trials have found that sedation efficacy with an alpha2-agonist was similar to sedation with a benzodiazepine. As such, alpha2-agonists are often used in combination with opiates or benzodiazepines. However, currently, there is a lack of evidence between different agents, with further trials needed.
Currently, available withdrawal assessment tools (including WAT-1) do not include withdrawal symptoms unique to alpha2-agonist withdrawal, such as unexplained hypertension and tachycardia. This makes monitoring alpha2-agonist withdrawal tricky, and until a specific validated screening tool is developed, associated symptoms such as unexplained hypertension or tachycardia should be considered alongside WAT-1 or SOS scoring.
Withdrawal from alpha2-agonists should be treated with IV or enteral alpha2-agonist replacement.
Following your assessment, Isla is started on a sedation weaning regimen based on local guidance, reducing the morphine and midazolam by 10% alternatively every 12 hours.
She is monitored for withdrawal using the WAT-1 score.
After extubation, her IV regime is converted to oral, and she successfully steps down to the ward with a detailed weaning regime a few days later.
Take home points
Remember to cycle agents, routinely wean, and consider oral agents such as antihistamines.
Delirium is common in PICU, necessitating active screening and non-pharmacological measures for risk reduction.
Sedation and analgesia in the PICU can quickly cause tolerance and physical dependence with abrupt cessation or rapid weaning, causing withdrawal syndromes and delirium.
A protocolised weaning regimen can aid timely recognition and reduction of withdrawal syndromes.
About PICSTAR
PICSTAR is a trainee-led research network open to all doctors, nurses and allied health trainees within Paediatric Intensive Care. We are the trainee arm of the Paediatric Critical Care Society – Study Group (PCCS-SG) and work with them on research, audit and service evaluation.
If you would like to join PICSTAR and get involved in projects, have ideas you would like to propose or get advice/mentorship via PCCS-SG, don’t hesitate to contact us at picstar.network@gmail.com. See their website for more: https://pccsociety.uk/research/picstar/
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